Over 800 human diseases that are due to inborn errors of metabolism (IEM) are now recognized, and this number is constantly increasing. However, the incidence of inborn errors may well be underestimated because diagnostic errors are frequent. Despite the relative abundance of new case reports, there is considerable evidence, including that based on the recent introduction of next-generation sequencing, that many of these disorders remain undetected or misdiagnosed. More than 300 “new” disorders have been described in the past 5 years, 85% of which present with predominantly neurologic manifestations. Several factors conspire to make the clinical diagnosis of IEM difficult.
IEM are individually rare but collectively numerous. The application of tandem mass spectrometry (tandem MS) to newborn screening and prenatal diagnostic testing has enabled presymptomatic diagnosis for some IEMs. However, for many IEM disorders, neonatal screening tests are either too slow, too expensive, or too unreliable; consequently, a simple method of clinical screening is mandatory before initiating sophisticated biochemical investigations. The clinical diagnosis of IEM relies upon a limited number of principles:
Consider IEM in parallel with other more common conditions; for example, sepsis or anoxic-ischemic encephalopathy in neonates, and intoxication, encephalitis, and brain tumors in older patients.
Be aware of symptoms that persist and remain unexplained after the initial treatment and the usual investigations have been performed.
Collect blood and urine samples at the right time in relation to an acute illness.
Suspect that any neonatal death may be due to an IEM, particularly deaths that are attributed to sepsis.
Carefully review all autopsy findings.
Do not confuse a symptom (eg, peripheral neuropathy, retinitis pigmentosa, cardiomyopathy) or a syndrome (eg, Reye syndrome, Leigh syndrome, sudden infant death) with etiology.
Remember that an IEM can present at any age, from fetal life to old age.
Know that although most genetic metabolic errors are hereditary and transmitted as recessive disorders, the majority of individual cases appear sporadically.
Initially consider inborn errors that are amenable to treatment (mainly those that cause intoxication). Do not miss a treatable disorder.
In acute emergency situations, undertake first those few investigations that are able to diagnose treatable IEM: First take care of the patient (emergency treatment) and then the family (genetic counseling).
In this section, inborn errors amenable to treatment are printed in bold. Additional information and diagnostic checklists are available online.
The vast majority of IEMs involve abnormalities in enzymes and transport proteins. However, all the metabolic disorders can be divided into the following 2 large clinical categories.
This category includes disorders that either involve only 1 functional system (eg, the endocrine system, immune system, coagulation factors, or lipoproteins) or affect only 1 organ or anatomic system (eg, the intestine, renal tubules, erythrocytes, or connective tissue). Presenting symptoms are uniform (eg, a bleeding tendency in coagulation factor defects or hemolytic anemia in defects of glycolysis), and the correct diagnosis is usually easy to establish even when the basic biochemical lesion gives rise to systemic consequences. These disorders are usually well known and identified by organ-specific specialists (eg, cardiologists, endocrinologists, immunologists, hematologists).
This category includes diseases in which the basic biochemical lesion either affects 1 metabolic pathway common to a large number of cells or organs (eg, storage diseases due to lysosomal disorders, energy deficiency in mitochondrial disorders) or is restricted to 1 organ but gives rise to humoral and systemic consequences (eg, hyperammonemia in urea cycle defects, hypoglycemia in hepatic glycogenosis). The diseases in this category have a great diversity of presenting symptoms. The specific disorders mentioned are discussed later in this section.
From a pathophysiologic perspective, metabolic disorders from category 2 can be divided into 3 diagnostically useful groups.
Group 1: Disorders That Cause Intoxication
This group includes inborn errors of intermediary metabolism (IEIM) that lead to acute or progressive intoxication from the accumulation of toxic compounds proximal to the metabolic block. In this group are inborn errors of amino acid catabolism (eg, phenylketonuria, maple syrup urine disease, homocystinuria, tyrosinemia), most organic acidurias (eg, methylmalonic, propionic, isovaleric), congenital urea cycle defects, sugar intolerances (eg, galactosemia, hereditary fructose intolerance), and metal intoxication (eg, Wilson, Menkes, hemochromatosis, porphyrias). All the conditions in this group share clinical similarities: They do not interfere with embryonic and fetal development, and they present with a symptom-free interval and clinical signs of “intoxication” that may be acute (eg, vomiting, coma, liver failure, thromboembolic complications) or chronic (eg, failure to thrive, developmental delay, ectopia lentis, cardiomyopathy, epilepsy).
Conditions that can provoke acute metabolic attacks include catabolism, fever, intercurrent illness, and ingestion of specific foods. Clinical expression is often both late in onset and intermittent. The diagnosis is straightforward and most commonly relies on plasma and urine amino acid, organic acid, or acylcarnitine chromatography. Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extracorporeal procedures, or “cleansing” drugs (eg, carnitine, sodium benzoate, penicillamine).
Although the pathophysiology is somewhat different, the inborn errors of neurotransmitter synthesis and catabolism (monoamines, γ-aminobutyric acid [GABA], and glycine) and the inborn errors of amino acid synthesis (serine, glutamine, proline/ornithine, and asparagine) can also be included in this group because they share many characteristics: They are IEIMs; their diagnosis relies on plasma, urine, and cerebrospinal fluid (CSF) investigations (eg, amino acid, organic acid analyses); and some are amenable to treatment even when the disorder is present in utero—for example, 3-phosphoglycerate dehydrogenase deficiency.
Group 2: Disorders Involving Energy Metabolism
These consist of IEMs with symptoms due, at least in part, to a deficiency in energy production or utilization within the liver, myocardium, muscle, brain, or other tissues. This group can be divided into mitochondrial and cytoplasmic energy defects. Mitochondrial defects are the most severe and are generally untreatable. They include the congenital lactic acidemias (eg, defects of the pyruvate transporter, pyruvate carboxylase, pyruvate dehydrogenase, and the Krebs cycle), mitochondrial respiratory chain disorders, and fatty acid oxidation (FAO) and ketone body defects. Only the latter are partly treatable. Cytoplasmic energy defects are generally less severe. They include disorders of glycolysis, glycogen metabolism and gluconeogenesis, hyperinsulinism, and glucose transporter defects (all treatable disorders); the more recently described disorders of creatine metabolism (partly treatable); and the new inborn errors of the pentose phosphate pathways (untreatable). Common symptoms in this group include hypoglycemia, lactic acidemia, hepatomegaly, acute recurrent crises, severe generalized hypotonia, myopathy, cardiomyopathy, failure to thrive, cardiac failure, circulatory collapse, sudden unexpected death in infancy, and brain involvement. Some of the mitochondrial disorders and pentose phosphate pathway defects can interfere with embryonic and fetal development and can cause dysmorphism, dysplasia, and malformations. Diagnosis is difficult and relies on function tests, enzymatic analyses requiring biopsies or cell culture, and molecular analyses.
Group 3: Disorders Involving Complex Molecules
This group involves cellular organelles (lysosomes, peroxisomes, endoplasmic reticulum, Golgi apparatus, mitochondria, and intracellular trafficking) and includes diseases that disturb the synthesis, remodeling, recycling, trafficking, and catabolism of complex molecules. Symptoms are most often permanent, progressive, independent of intercurrent events (even if an acute crisis may have occurred in the course of a disorder), and unrelated to food intake. All lysosomal storage disorders (LSDs), peroxisomal disorders (PBDs), disorders of intracellular trafficking and processing (eg, α1-antitrypsin), and congenital disorders of glycosylation (CDG) belong to this group. Besides these well-known disorders, a novel and rapidly expanding group of IEMs involving the synthesis, remodeling, and recycling of complex lipids and fatty acids has recently been described. This biochemical group encompasses metabolic defects of phospholipids, triglycerides, sphingolipids, isoprenoids, cholesterol, ubiquinone, dolichol, plasmalogens, and non–mitochondrial complex long-chain fatty acid metabolism (very-long-chain fatty acids [VLCFA], fatty alcohol, branched chain fatty acids, eicosanoids derived from arachidonic acid, prostaglandins, and leukotrienes).
Almost none of these are treatable acutely; however, enzyme replacement therapy is now available for several lysosomal disorders. Intracellular localization of all these disorders is presented in Figure 129-1.
Cartoon showing intracellular localization of inborn errors of metabolism.
The newly described metabolic disorders affecting cytoplasmic and mitochondrial tRNA synthetases, autophagy, and other factors related to cytoplasmic protein synthesis, transporters, channels, and enzymes implicated in the logistics and regulation of the cell challenge our current classification based on organelles and form a bridge between “classic” metabolic diseases with metabolic markers and those caused by structural proteins mutations without such markers and that are most often diagnosed by molecular techniques.
Although most of these disorders are inherited as autosomal recessive conditions, a significant minority are transmitted as X-linked recessive disorders and a few as dominant diseases. Many cases appear to be sporadic given the small size of sibships in developed countries. Consanguinity is rare, and thus many affected patients are compound heterozygotes. In these cases, the phenotype is generally driven by the less severe mutation. Mutations in the mitochondrial genome, which is maternally inherited, make up a rapidly growing subgroup of IEMs; these disorders exhibit unique genetic and clinical characteristics. Compared to many other genetic diseases in which the gene product is unknown or not fully recognized, almost all IEMs were primarily identified because of a suggestive biochemical profile and confirmed by an enzymatic defect. These biochemical methods remain the basis of diagnostic procedures and assessment of management, although a growing number of IEMs are henceforth identified by molecular techniques (gene panels and next-generation sequencing). Antenatal diagnosis is available for most of these conditions.
A few metabolic disorders are recognized by newborn screening of the general population (eg, phenylketonuria) or through at-risk families. Apart from these, there are 5 groups of clinical circumstances in which a metabolic disorder is possible:
Acute or chronic neonatal period (birth to 1 month)
Later-onset acute and recurrent attacks of symptoms such as coma, ataxia, vomiting, and acidosis (crisis)
Chronic and progressive generalized symptoms that can be mainly gastrointestinal (eg, chronic vomiting), failure to thrive, hypotonia, recurrent infections, or muscular or neurologic symptoms (eg, myopathy, developmental delay, neurologic deterioration, epilepsy)
Specific and irreversible presentations that can involve any organ or system (eg, heart, liver, intestine, kidney, lungs, endocrine, immune and hematologic systems, bone, collagen, skin); many IEMs can present with specific isolated symptoms, such as cardiomyopathy, hepatomegaly, lens dislocation, renal tubulopathy, hyperkeratotic plaques, and so on
These can be classified in 3 major clinical categories:
True malformations such as skeletal malformations, congenital heart disease, visceral aplasias, and neural tube defects
Dysplasias (eg, cortical heterotopias, cortical cysts, posterior fossa abnormalities, polycystic kidneys, liver cysts)
Functional signs such as intrauterine growth retardation, hydrops fetalis, hepatosplenomegaly, microcephaly, coarse facies, or facial dysmorphism
According to this classification, true irreversible malformations are only observed in O-glycosylation disorders, primary or secondary to manganese transporter SLC39A8 mutations (Chapter 164), in cholesterol synthesis defects (Chapter 159), in amino acid synthesis disorders such with glutamine and asparagine synthetase deficiency (lissencephaly) (Chapter 140), and rarely in severe energetic defects such as glutaric aciduria type II (Chapter 145), some respiratory chain disorders, and the mitochondrial thiamine pyrophosphate carrier defect (SLC25A19) responsible for the Amish lethal microcephaly (Chapter 144). Notably, the congenital microcephaly observed in serine synthesis defects is partly reversible upon early treatment with serine in its mild form, but not in the severe Neu-Laxova presentation (Chapter 135). Lysosomal, peroxisomal, and N-glycosylation defects are responsible for dysplasia and functional abnormalities that are variably reversible. The vast majority of “true intoxication” disorders (amino acid and organic acid catabolism disorders) do not interfere with the embryo-fetal development and do not give rise to dysmorphism and antenatal symptoms (although some severe organic acidurias may present with subtle congenital signs).
Neonatal and Early Infancy Period
Acute Encephalopathy and Metabolic Crash
The neonate has a limited repertoire of responses to severe illness. IEMs may present with nonspecific symptoms such as respiratory distress, hypotonia, a poor sucking reflex, vomiting, lethargy, or seizures—problems that can easily be attributed to sepsis or some other common cause. Prior death of a sibling from a similar IEM may have been attributed to sepsis, cardiac failure, or intraventricular hemorrhage.
Group 1 disorders are illustrated by an infant born full term who, after a normal pregnancy and delivery and an initial symptom-free period, relentlessly deteriorates for no apparent reason and does not respond to symptomatic therapy. The interval between birth and clinical symptoms may range from hours to weeks. Investigations that are routinely performed in sick neonates include a chest x-ray, CSF examination, bacteriologic studies, and cerebral ultrasound examination, and all yield normal results. This unexpected and “mysterious” deterioration after a normal initial period is the most important indication for this group of IEMs. Careful reevaluation of the child’s condition is then warranted.
In group 2 disorders (energy deficiencies), the clinical presentation is often less striking and displays variable severity. A clinical algorithm for screening for treatable IEMs in neonates is presented in Figure 129-2.
The “sick” neonate: An algorithm for screening for treatable inborn errors of metabolism (IEMs). 3PGD, 3-phosphoglycerate dehydrogenase; CDG, congenital disorders of glycosylation; FAO, fatty acid oxidation disorders; HFI, hereditary fructose intolerance; IVA, isovaleric acidemia; LCHAD, 3-hydroxy long-chain acyl-CoA dehydrogenase; MCD, multiple carboxylase deficiency; MMA, methylmalonic aciduria; MSUD, maple syrup urine disease; PA, propionic acidemia; PHHI, primary hyperinsulinemic hypoglycemia of infancy; PKU, phenylketonuria; PNPO, pyridox(am)ine-5′-phosphate oxidase; TYR-1, tyrosinemia type 1; UCD, urea cycle defects.
Neurologic Deterioration (Coma, Lethargy)
This is the most frequent presenting sign in “intoxication” disorders. Typically, the first reported sign is poor sucking and feeding, after which the child sinks into an unexplained coma despite supportive measures. At a more advanced state, neurovegetative problems with respiratory abnormalities, hiccups, apnea, bradycardia, and hypothermia can appear. In the comatose state, characteristic changes in muscle tone and involuntary movements appear. Generalized hypertonic episodes with opisthotonus, boxing, or pedaling movements and slow limb elevations are observed in maple syrup urine disease (MSUD). As most nonmetabolic causes of coma are associated with hypotonia, the presence of “normal” peripheral muscle tone in a comatose child reflects a relative hypertonia. In organic acidurias, axial hypotonia and limb hypertonia with fast, large-amplitude tremors and myoclonic jerks (often mistaken for convulsions) are typical. An abnormal urine and body odor is present in some diseases in which volatile metabolites accumulate; for example, a maple syrup odor in MSUD and a sweaty-feet odor in isovaleric acidemia (IVA) and glutaric acidemia type II.
In energy deficiencies, the clinical presentation is less obvious and displays a more variable severity. In many conditions, there is no symptom-free interval. The most frequent findings are a severe generalized hypotonia, rapidly progressive neurologic deterioration, and possible dysmorphism or malformations. In contrast to the intoxication group, lethargy and coma are rarely initial signs. Lactic acidemia with or without metabolic acidosis is frequent. Cardiac and hepatic involvement are also commonly associated with energy deficiencies.
In the neonatal period, only a few lysosomal storage disorders present with neurologic deterioration. By contrast, many peroxisomal biogenesis defects present at birth with dysmorphism and severe neurologic dysfunction. Severe forms of CDG involving N- and O-glycosylation, glycosylphosphatidylinositol anchor, and dolichol phosphate biosynthesis may also present with acute congenital neurologic dysfunction, although they more often present with hypotonia, seizures, dysmorphism, malformations, and diverse visceral involvement.
Always consider the possibility of an IEM in a neonate with unexplained and refractory epilepsy. Neonatal metabolic seizures are often a mixture of partial, erratic myoclonus of the face and extremities, or tonic seizures. Classically the term early myoclonic encephalopathy (EME) has been used if myoclonic seizures dominate the clinical pattern. The electroencephalogram (EEG) often shows a burst-suppression pattern; however, myoclonic jerks may occur without EEG abnormalities.
Five treatable disorders can present in the neonatal period predominantly with intractable seizures: pyridoxine-responsive seizures, folinic acid–responsive epilepsy (both allelic to antiquitin deficiency), pyridox(am)ine-5′-phosphate oxidase deficiency, 3-phosphoglycerate dehydrogenase deficiency responsive to serine supplementation, and persistent hyperinsulinemic hypoglycemia. Also, biotin-responsive holocarboxylase synthetase deficiency may rarely present predominantly with neonatal seizures. GLUT1 deficiency (brain glucose transporter), which is responsive to a hyperketotic diet, and biotin-responsive biotinidase deficiency can also present in the first months of life as epileptic encephalopathy.
Many other untreatable inherited disorders can present in the neonatal period with severe epilepsy: nonketotic hyperglycinemia, D-glyceric aciduria, and mitochondrial glutamate transporter defect (all 3 presenting with myoclonic epilepsy and a burst-suppression EEG pattern), peroxisomal biogenesis defects, respiratory chain disorders, sulfite oxidase deficiency, and Menkes disease. In all these conditions, epilepsy is severe; has an early onset; and can present with spasms, myoclonus, and partial or generalized tonic-clonic crises.
Severe hypotonia is a common symptom in sick neonates. It is more generally observed in nonmetabolic severe fetal neuromuscular disorders (Chapter 560). Only a few IEMs present with isolated hypotonia in the neonatal period, and very few are treatable. The most severe metabolic hypotonias are observed in hereditary lactic acidemia, respiratory chain disorders, urea cycle defects, nonketotic hyperglycinemia (NKH), sulphite oxidase deficiency, peroxisomal disorders, Lowe syndrome, and trifunctional enzyme deficiency. Severe forms of Pompe disease (α-glucosidase deficiency) can initially mimic respiratory chain disorders or trifunctional enzyme deficiency when generalized hypotonia is associated with cardiomyopathy. However, Pompe disease does not strictly start in the neonatal period. Prader-Willi syndrome, one of the most frequent causes of isolated neonatal hypotonia at birth, can mimic hypotonia-cystinuria syndrome. Severe global hypotonia and hypomotility mimicking neuromuscular diseases can appear in some treatable IEMs such as biogenic amine defects, primary carnitine deficiency (not strictly in the neonatal period), fatty acid oxidation (FAO) defects (Chapter 145), genetic defects of riboflavin transport, and primary coenzyme Q10 defects (Chapter 153). A pyridostigmine-responsive congenital myasthenic syndrome can be a presenting sign in ALG2, ALG14, DPAGT1, GFPT1, and GMPPB CDGs (Chapter 158).
These 3 neurologic presentations are summarized in Table 129-1.
TABLE 129-1NEUROLOGIC PRESENTATIONS IN NEONATES AND IN EARLY INFANCY ||Download (.pdf) TABLE 129-1NEUROLOGIC PRESENTATIONS IN NEONATES AND IN EARLY INFANCY
|Predominant Clinical Symptom ||Main Clinical Signs ||Biological Signs ||Best Diagnoses (Disorder/Enzyme Deficiency) |
|Neurologic deterioration: mostly metabolic and treatable || |
Lethargy, coma, hiccups
Poor sucking, hypothermia
Bone marrow suppression
Characteristic changes of AAC or OAC
MMA, PA, IVA (odor)
Urea cycle defects
GA type II (odor)
|Seizures: sometimes metabolic, sometimes treatable || |
Typical OAC profile
| ||None || |
Pyridoxine responsive, folinic acid responsive
| || ||Hypocalcemia with hypomagnesemia ||Congenital magnesium malabsorption |
| || ||Severe hypoglycemia ||PHHI |
| || |
|Low serine (plasma/CSF) ||3-PGD |
| || |
Low HVA, 5-HIAA in CSF, vanillactic acid (urine)
PNPO (pyridoxamine phosphate responsive)
| || |
vlcfa, phytanic, plasmalogen
Sterols in plasma
|Severe hypotonia: rarely metabolic, many not treatable ||Isolated ||None ||Prader-Willi syndrome |
| ||Massive cystinuria ||Hypotonia cystinuria syndrome |
VLCFA, phytanic, plasmalogen
Sterols in plasma
Polymalformation syndromes with muscular dystrophy (Walker-Warburg syndrome, with muscle, eye, brain, and other anomalies)
| || |
|Lowe syndrome |
| || |
|Respiratory chain |
| ||Cardiomyopathy ||Vacuolated lymphocytes ||Pompe disease |
| ||Abnormal movements (dystonia-parkinsonism, oculogyric crises), feeding difficulties, temperature instability || |
Biogenic amines/pterines, glycine
|Neurotransmitter disorders |
| ||Pyridostigmine-responsive congenital myasthenic syndrome || |
Serum transferrin IEF type 1 pattern in some
|ALG2, ALG14, DPAGT1, GFPT1, and GMPPB CDGs |
| ||Macroglossia ||Lactic acidemia ||Respiratory chain |
| ||Hepatopathy ||Acylcarnitine || |
Trifunctional enzyme (FAO)
| || ||COQ10 fibroblasts, muscle ||Primary COQ10 defects |
Hepatic and Gastrointestinal Presentation
Seven main clinical groups of hepatic symptoms can be identified:
Hepatomegaly with hypoglycemia and seizures without liver failure suggest glycogenosis type I or III (typically massive hepatomegaly), gluconeogenesis defects, or severe hyperinsulinism (with moderate hepatomegaly).
Liver failure (jaundice, coagulopathy, hepatocellular necrosis with elevated serum transaminases, and hypoglycemia with ascites and edema) suggests fructosemia due to hereditary fructose intolerance (now rare because infant formulas are fructose free); galactosemia; tyrosinemia type I (after 3 weeks); neonatal hemochromatosis; respiratory chain disorders (and notably mitochondrial DNA depletion syndromes); and transaldolase deficiency, a disorder of the pentose phosphate pathway that can present with hydrops fetalis. Severe fetal growth retardation, lactic acidosis, failure to thrive, hyperaminoaciduria, very high serum ferritin concentrations, hemosiderosis of the liver, and early death suggest GRACILE syndrome (Finnish lethal neonatal metabolic syndrome). Investigating patients with severe hepatic failure is difficult, with many pitfalls. At an advanced state, nonspecific abnormalities secondary to liver damage can be present. Mellituria (galactosuria, glycosuria, fructosuria), hyperammonemia, lactic acidemia, hypoglycemia after a short fast, hypertyrosinemia (> 200 μmol/L), and hypermethioninemia (sometimes > 500 μmol/L) are encountered in all cases of advanced hepatocellular disease.
The recently described mutations in IARS and LARS (coding for cytoplasmic isoleucyl- and leucyl-tRNA synthetases, respectively) present with hypoalbuminemia, recurrent acute infantile liver failure (RALF), anemia, seizures, and encephalopathic crisis. Recently, NBAS (neuroblastoma amplified sequence; involved in Golgi vesicular transport) mutations were also identified as a new cause of fever-dependent episodes of RALF with onset in infancy.
Cholestatic jaundice with failure to thrive is a predominant finding in α1-antitrypsin deficiency, Byler disease, inborn errors of bile acid metabolism, peroxisomal disorders, Niemann-Pick type C disease, CDG syndromes, citrin deficiency, and hepatocerebral syndrome due to mitochondrial DNA depletion. Long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency can present early in infancy as cholestatic jaundice, liver failure, and hepatic fibrosis. Cerebrotendinous xanthomatosis, citrin deficiency, arginase deficiency, and Niemann-Pick C can present as a transient asymptomatic jaundice before neurologic signs appear later in life. Two new complex lipid synthesis disorders, the MEGDHEL syndrome (SERAC mutations) that can mimic Niemann-Pick type C disease with a positive filipin test and the spastic paraparesis type 5 due to oxysterol 7-hydroxylase deficiency, may also present with such a transient cholestatic liver disease.
Liver steatosis: Hepatic presentations of FAO disorders and urea cycle disorders (UCDs) consist of acute steatosis or Reye syndrome–like with normal bilirubin rather than true liver failure. LCHAD deficiency is an exception that may present early in infancy (but not strictly in the neonatal period) as cholestatic jaundice, liver failure, and hepatic fibrosis (Chapter 145). Chanarin-Dorfman syndrome (ABHD5 mutations) presents early in infancy with liver steatosis, cataracts, deafness, congenital ichthyosis, and myopathy while the newly described cytoplasmic glycerol-3-phosphate dehydrogenase 1 deficiency displays an asymptomatic early infantile hepatomegaly and steatosis with transient hypertriglyceridemia.
Hepatosplenomegaly (HSM) with other signs of storage disorders (coarse facies, macroglossia, hydrops fetalis, ascites, edema, dysostosis multiplex, vacuolated lymphocytes) is observed in lysosomal diseases. HSM with inflammatory syndrome, including hematologic or immunologic features, may be observed in lysinuric protein intolerance (macrophage-activating syndrome), mevalonic aciduria and leukopenia (inflammatory syndrome and recurrent severe anemia), and transaldolase deficiency (hydrops fetalis with severe anemia).
Congenital diarrheal disorders (CDDs) may be caused by mutations in genes related to disaccharidase deficiency or an ion or nutrient transport defect like SLC26A3 mutations causing congenital secretory chloride diarrhea, pancreatic insufficiency, lipid trafficking, or PMI-CDG(Ib) and ALG8-CDG(Ih). A disorder presenting with CDD linked to DGAT1 mutations involved in triglyceride synthesis has recently been described. Affected neonates present with vomiting, colicky pain, nonbloody, watery diarrhea, protein-losing enteropathy, hypoalbuminemia, and hyperlipidemia.
Some metabolic disorders can present predominantly with cardiac disease. Heart failure and a dilated or hypertrophic cardiomyopathy, most often associated with hypotonia, muscle weakness, and failure to thrive, suggest FAO disorders, respiratory chain disorders, or Pompe disease. Carnitine-uptake defect (systemic carnitine defect) responds dramatically to carnitine administration. Some respiratory chain disorders are tissue specific and expressed only in the myocardium. CDG syndrome (PMM-CDG) can sometimes present in infancy with cardiac failure due to pericardial effusion, cardiac tamponade, and cardiomyopathy. Dolichol kinase 1 deficiency (DOLK-CDG) may present with progressive dilated cardiomyopathy resulting in death within 1 year. Other clinical manifestations include microcephaly; “parchment-like” ichthyosis with loss of hair, eyebrows, and eyelashes; intractable seizures; severe hypotonia with elevated creatine kinase (CK); and severe liver dysfunction (Chapter 158). Many defects of long-chain FAO can present with cardiomyopathy, arrhythmias, or conduction defects (atrioventricular block, bundle branch block, ventricular tachycardia), which may lead to cardiac arrest.
Initial Approach to the Investigation
If clinical assessment suggests an IEM, general supportive measures and laboratory investigations should be undertaken concurrently (Table 129-2). Abnormal urine odor can be diagnostic.
TABLE 129-2PROTOCOL FOR EMERGENCY INVESTIGATIONS (NEONATAL AND LATE-ONSET SITUATIONS) ||Download (.pdf) TABLE 129-2PROTOCOL FOR EMERGENCY INVESTIGATIONS (NEONATAL AND LATE-ONSET SITUATIONS)
| ||Immediate Investigations ||Storage of Samples |
|Urine || |
Smell (special odor)
Look (special color)
Acetone (Acetest, Ames)
Reducing substances (Clinitest, Ames)
pH (pHstix Merck)
Electrolytes (Na, K), urea, creatinine
Urine collection: collect fresh sample and put it in the refrigerator
Freezing: freeze samples collected before and after treatment at –20°C, and collect an aliquot 24 h after treatment
Metabolic investigation: OAC, AAC, orotic acid, porphyrins
|Blood || |
Blood cell count
Electrolytes (search for anion gap)
Blood gases (pH, Pco2, HCO3, H, Po2)
Transaminases (and other liver tests)
Creatine kinase (CK)
Free fatty acids
Plasma (5 mL) heparinized at –20°C
Blood on filter paper: 2 spots (as “Guthrie” test)
Whole blood (10–15 mL) collected on EDTA and frozen (for molecular biology studies)
Major metabolic investigations: Total homocysteine, AAC, acylcarnitine (tandem MS), OAC, porphyrins, neurotransmitters
|Miscellaneous || |
Cardiac ultrasound, ECG
Cerebral ultrasound, EEG
Skin biopsy (fibroblast culture)
CSF (1 mL), frozen (neurotransmitters, AA)
Postmortem: liver, muscle biopsies
Ketonuria (2–3+) in a newborn is always abnormal and is an important sign of a metabolic disease. Hypocalcemia and elevated or reduced blood glucose concentrations are frequently present in metabolic diseases. The physician should be wary of attributing marked neurologic dysfunction purely to these findings.
The metabolic acidosis of organic acidurias is usually accompanied by an elevated anion gap. Urine pH should be below 5; otherwise, renal acidosis is a possibility. A normal blood pH does not exclude a moderate lactic acidemia, which is significant in the absence of infection or tissue hypoxia. Blood ammonia and lactic acid concentrations should be determined systematically in at-risk newborns. Hyperammonemia with ketoacidosis suggests an underlying organic acidemia. However, isolated hyperammonemia can occur in organic acidemias, and an elevated ammonia level alone can induce respiratory alkalosis. Moderately elevated lactate concentrations (3–6 mmol/L) are often observed in organic acidemias and in the hyperammonemias; levels > 10 mmol/L are frequent in hypoxia. With hypoxic lactic acidosis, the lactate-to-pyruvate ratio is > 20, and ketosis is absent. Propionic, methylmalonic, and isovaleric acidemias frequently present with granulocytopenia and thrombocytopenia, which may be mistaken for sepsis. Transaldolase deficiency and early-onset forms of mevalonate kinase deficiency present with severe recurrent hemolytic anemia. Adequate amounts of plasma, urine, blood on filter paper, and CSF should always be stored, because they may later be important in establishing a diagnosis. Using these precious samples should be carefully planned after advice from specialists in IEM.
After obtaining clinical and laboratory data, a process that should be completed within 2 to 4 hours, specific therapeutic recommendations can be made; this avoids long delays associated with waiting for the results of sophisticated diagnostic investigations. On the basis of this evaluation, most patients can be classified into 1 of 5 types (Table 129-3; see also earlier section on hepatic and gastrointestinal presentations). Some significant symptoms (eg, metabolic acidosis and especially ketosis) can be moderate and transient, largely depending on the symptomatic therapy. Conversely, at an advanced state, many nonspecific abnormalities (eg, respiratory acidosis, severe lactic acidemia, secondary hyperammonemia) can disturb the original metabolic profile. This applies particularly to IEM with a rapid fatal course, such as urea cycle disorders, in which the initial characteristic presentation of hyperammonemia with respiratory alkalosis shifts rapidly to a rather nonspecific picture of acidosis and lactic acidemia as respiratory effort is lost due to encephalopathy.
TABLE 129-3CLASSIFICATION OF INBORN ERRORS REVEALED IN THE NEONATAL PERIOD AND EARLY IN INFANCY WITH NEUROLOGIC DETERIORATION ||Download (.pdf) TABLE 129-3CLASSIFICATION OF INBORN ERRORS REVEALED IN THE NEONATAL PERIOD AND EARLY IN INFANCY WITH NEUROLOGIC DETERIORATION
|Types ||Clinical Type ||Acidosis/Ketosis ||Other Signs ||Most Usual Diagnosis (Disorder/Enzyme Deficiency) ||Elective Methods of Investigation |
|I || |
Neurological deterioration, “intoxication” type
Abnormal slow movements (boxing)
NH3 N or ↑ ±
Lactate N or ↑
Glucose N, Calcium N
|MSUD (special odor) || |
Amino acid chromatography (plasma, urine)
Blood spot for tandem MS-MS
|II || |
Fast large tremors
NH3 ↑ +/++
Lactate N or ↑ ± leukopenia, thrombopenia
Glucose N or ↑ +
Calcium N or ↓ +
Organic acidurias (MMA, PA, IVA, MCD)
OAC by GLCMS (urine, plasma)
Carnitine esters by tandem MS (urine, plasma)
Blood spot for tandem MS
| || |
“energy deficiency” type,
with liver or cardiac symptoms
NH3 ↑ ±/++
Lactate ↑ ±/++
Glucose ↓ +/++
|Fatty acid oxidation (FAO), ketogenesis defects (GA II, CPT II, CAT, VLCAD, MCKAT, HMGCoA lyase) || |
Tolerance test, fasting test, fatty acid oxidation studies on lymphocytes or fibroblasts
|III || |
“energy deficiency” type
sometimes well tolerated
NH3 N or ↑ ±
Blood count: anemia or N
Glucose N or ↓ ±
|Congenital lactic acidoses (pyruvate carrier, PC, PDH, Krebs cycle, RCD MCD) || |
Plasma redox states ratios (L:P, 3 OHB: AA)
OAC (urine), AAC (plasma)
Enzyme, molecular assays
|IV (a) || |
Neurological deterioration, “intoxication” type
Moderate hepatocellular disturbances
Hypotonia, seizures, coma
Acidosis 0 (alkalosis)
NH3 ↑ +/+++
Lactate N or ↑ +
Urea cycle defects
FAO defects (GAII, CPTII, VLCAD, LCHAD, CAT)
PA, MMA, IVA (with leukothrombopenia)
AAC, OAC (plasma, urine)
Carnitine esters by tandem MS (urine, plasma)
Orotic acid (urine)
Liver or intestine enzyme studies (CPS, OTC)
|(b) || |
No major metabolic disturbance
Lactate N or ↑ +
Blood count N
NKH, SO plus XO
B6-dependency/PNPO and neurotransmitter defects
AAC (plasma, CSF)
AAC (plasma, CSF)
OAC, neurotransmitters (plasma, urine, CSF)
VLCFA, phytanic acid in plasma
Acylcarnitine profile, OAC
Glycosylated transferrin (plasma)
Lactate and molecular studies
|V (a) || |
Recurrent hypoglycemia with hepatomegaly
No liver failure
Lactate ↑ +/++
NH3 ↑ +/0
Glycogenosis type I (acidosis, acetest ±)
Glycogenosis type III (acetest ++)
Fructose Bi Pase
FAO defects (acetest –)
PHHI (acetest –) intractable hypoglycemia
Fasting test, loading test
DNA analyses, enzyme studies
Lactic acidosis and ketosis
Organic acids, acylcarnitine
Insulin plasma levels
|(b) || |
NH3 N or ↑ +
Glucose N or ↓ ++
Tyrosinemia type I (tubulopathy)
TALDO (with anemia)
RCD (mito DNA depletion)
DNA analyses, enzyme studies
Organic acids (succinyl acetone)
Polyols (tandem MS)
Lactate, molecular studies
|(c) || |
+ Failure to thrive
+ Chronic diarrhea
Bile acid defects
Cholesterol metabolism and CTX
Citrin and Arginase deficiency
Bile acids (plasma, urine, bile)
VLCFA, phytanic, and bile acids
Plasma sterols, Filipin test
Filipin test, molecular studies
OAC, acylcarnitine profile
AAC (citrulline can be normal)
|(d) || |
“Storage” signs (coarse facies, ascites, hydrops fetalis, macroglossia, bone changes, cherry-red spot, vacuolated lymphocytes)
+ Failure to thrive
+ Chronic diarrhea
+ Hemolytic anemia
Lactate N or ↑
Hepatic signs +/++
Congenital erythropoietic porphyria
ISSD (sialidosis type II)
Niemann-Pick type A
TALDO (with anemia)
Oligosaccharides, sialic acid
Enzyme, molecular studies
Polyols (tandem MS)
We have found that more than 80% of newborns with IEM have MSUD (maple syrup urine disease), organic acidurias, urea cycle defects, nonketotic hyperglycinemia, mitochondrial respiratory chain disorders, or fatty acid oxidation disorders.
Immediate therapy of acute encephalopathy due to any of the likely IEMs involves measures to decrease the production of offending metabolites and to increase their excretion. Treatment should include the following:
Ensure adequate cardiorespiratory function to allow removal of any accumulating metabolites. Adequate hydration is essential to maintain good urine output, because many of the offending diffusible metabolites are freely filtered at the glomerulus.
Reverse the catabolic state and reduce exposure to the offending nutrients. Neonates with severe ketoacidosis present with intracellular dehydration that is often underestimated. In this situation, aggressive rehydration with hypotonic fluids and alkalization may cause or exacerbate preexisting cerebral edema. Therefore, rehydration should be planned over a 48-hour period, with an infusion of less than 150 mL/kg/24 hours that contains an average concentration of 75 to 150 mmol/L of Na+ (4.5–9 g/L of NaCl), 30 to 40 mmol/L of K+ (2–3 g/L of KCl), and 5% glucose. Acidosis can be partially corrected with intravenous bicarbonate, especially if it does not improve with the first measures applied for toxin removal. However, aggressive therapy with repeated boluses of intravenous bicarbonate may induce hypernatremia, cerebral edema, and even cerebral hemorrhage. In mildly affected patients, hydration can be performed using a standard 5% to 10% glucose solution containing 75 mmol/L of Na+ (4.5 g/L of NaCl) and 20 mmol/L of K+ (1.5 g/L of KCl). High-calorie, protein-free nutrition should be started in parallel, using carbohydrates and lipids to provide 100 kcal/kg/d. Initially, for the 24- to 36-hour period needed to test gastric tolerance, parenteral and enteral nutrition are used together.
After these measures have been instituted, and even before a precise biochemical diagnosis has been made, begin hemodialysis or hemofiltration to remove the offending small molecule as quickly as possible if the patient is comatose or semicomatose.
Provide therapy specific to the disease; for example:
Whatever the disease, nutrition is extremely important, and both the method of administration and the composition of feeds must be rapidly determined. Briefly, 4 types of diet can be considered: normal, low-protein, carbohydrate-restricted, and high-glucose, with or without lipid restriction.
Cofactor administration, which will sometimes improve the function of a genetically defective enzyme (eg, vitamin B6 in recurrent intractable seizures, B12 in some cases of methylmalonic aciduria because B12 is a cofactor for methylmalonyl-CoA mutase).
Metabolic manipulation and cleansing drugs such as administering sodium benzoate and phenylacetate in hyperammonemias or carnitine in organic acidurias to divert a toxic substrate to a benign excretable form.
Later Onset, Acute, and Recurrent Attacks (Late Infancy and Beyond)
In about 50% of the patients with IEM, onset of symptoms is delayed. The symptom-free period is often longer than 1 year and may extend into late childhood, adolescence, or even adulthood. Each attack can follow a rapid course ending either in spontaneous improvement, permanent disability, or unexplained death despite supportive measures. Between attacks, the patient may appear normal. Onset of acute disease may occur without overt cause but may be precipitated by an intercurrent event related to excessive protein intake, prolonged fasting, prolonged exercise, infection, or any condition that enhances protein catabolism. Recurrent crisis in a context of chronic encephalopathy or neurologic deterioration is an important sign of an IEM.
Coma, Strokes, and Attacks of Vomiting with Lethargy
Acute encephalopathy is a common problem in children and adults with IEM. All types of coma may be indicative of an IEM, including those presenting with focal neurologic signs (Table 129-4). Age at onset, accompanying clinical signs (eg, hepatic, gastrointestinal, neurologic, psychiatric), mode of evolution (improvement, sequelae, death), and routine laboratory data do not allow an IEM to be ruled out a priori. Two categories can be distinguished:
Metabolic coma without focal neurologic signs. The main varieties of metabolic coma may be observed in these late-onset, acute diseases, such as predominant metabolic acidosis, predominant hyperammonemia, predominant hypoglycemia, or combinations of these 3 abnormalities. A rather confusing finding in some organic acidurias and ketolytic defects is ketoacidosis with hyperglycemia and glycosuria that mimics diabetic coma. The diagnostic approach to these metabolic derangements is discussed below. Many late-onset ornithine transcarbamylase patients are first diagnosed as viral encephalitis and treated with acyclovir (Zovirax). Our aphorism to our residents was “Write on the Zovirax box: Did you measure ammonia?”
Neurologic coma with focal signs, seizures, severe intracranial hypertension, strokes, or stroke-like episodes. Although most recurrent metabolic comas are not accompanied by neurologic signs other than encephalopathy, some patients with organic acidemias and urea cycle defects present with focal neurologic signs or cerebral edema. These patients can be mistakenly diagnosed as having a cerebrovascular accident or cerebral tumor. In these disorders, stopping the protein intake, infusing large amounts of glucose, and giving “cleansing drugs” (eg, carnitine, sodium benzoate) can be lifesaving. Biotin-responsive basal ganglia disease is a treatable condition that presents in childhood with a subacute encephalopathic picture of undefined origin, including confusion, vomiting, and a vague history of febrile illness. Pyruvate dehydrogenase (PDH) and biotinidase deficiency are other treatable causes that may present in a similar manner. Arterial tortuosity syndrome (GLUT10 mutations) characterized by generalized tortuosity and elongation of all major arteries may result in acute infarction due to ischemic strokes or an increased risk of thrombosis.
TABLE 129-4DIAGNOSTIC APPROACH TO RECURRENT ATTACKS OF COMA AND VOMITING WITH LETHARGY ||Download (.pdf) TABLE 129-4DIAGNOSTIC APPROACH TO RECURRENT ATTACKS OF COMA AND VOMITING WITH LETHARGY
|Clinical Presentation ||Laboratory Studies ||Other Features ||Most Frequent Diagnosis (Disorder/Enzyme Deficiency) ||Differential Diagnosis |
|Metabolic coma (without focal neurological signs) || |
(pH < 7.20, CO3H < 10 mmol, pCO2 < 25 mm)
+/–Hyperammonemia (NH3 > 100 μmol/L)
Organic acidurias, MSUD
MCD, PC, RCD
Ketolysis defects, MCT1
| || || |
PDH, Ketogenesis defects
FAO, FDP, EPEMA
| || |
Hyperammonemia (NH3 > 100 μmol/L)
Respiratory alkalosis (pH > 7.45, pCO2 < 25)
Urea cycle defects
Triple H, LPI
| || |
| ||Hypoglycemia (< 2 mmol/L) ||Acidosis + || |
MSUD (ketosis +)
FAO (ketosis –)
Drugs and toxin
| ||Lactic acidemia (> 4 mmol/L) || |
PC, MCD, Krebs cycle
PDH (without ketosis)
| || || |
Gluconeogenesis defects (ketosis variable)
FAO (moderate lactic acidemia, no ketosis)
|Neurological coma (with focal signs, seizures, or intracranial hypertension) ||Biological signs are very variable, can be absent or moderate; see above “Metabolic coma” ||Cerebral edema ||MSUD, OTC || |
|Hemiplegia (hemianopsia) ||MSUD, OTC, MMA, PA, PGK ||Moyamoya syndrome |
|Extrapyramidal signs || |
MMA, GA I, Wilson disease
|Vascular hemiplegia |
| || ||Basal ganglia necrosis || |
BGBRD (caudate and putamen necrosis)
Infectious acute necrotizing encephalitis
| || ||Stroke and stroke like || |
UCD, MMA, PA, IVA
Respiratory chain (MELAS)
Thiamine–responsive megaloblastic anemia
Fabry (rarely presenting sign)
Maltase acid (rare)
| ||Abnormal coagulation ||Thromboembolic accidents ||Homocystinurias (all kinds) || |
| ||Hemolytic anemia || ||CDG, PGK || |
|Hepatic coma (hepatomegaly cytolysis or liver failure) || |
Slight elevation of transaminases
|Steatosis and fibrosis ||FAO, UCD || |
|Reye syndrome ||Lactic acidemia ||Liver failure ||Respiratory chain defects || |
| ||Hemolytic jaundice ||Cirrhosis || |
Manganese transporter deficiency
| ||Hypoglycemia ||Exudative enteropathy ||Hepatic fibrosis with enteropathy (CDG Ib) || |
All severe forms of homocystinuria (total homocysteine > 100 μM/L) can cause an acute cerebrovascular accident from early childhood to adulthood. These forms include cystathionine-β-synthase deficiency (usually B6-responsive in late-onset presentations), severe methylenetetrahydrofolate reductase (MTHFR) defects (folate responsive), and cobalamin defects CblC and CblD (hydroxycobalamin responsive). Patients with methylmalonic acidemia (MMA) may, after first presenting with metabolic decompensation, have acute extrapyramidal and corticospinal tract involvement caused by destruction of the globus pallidus bilaterally. Glutaric acidemia (GA) type I frequently presents with an encephalopathic episode, mimicking encephalitis. Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is another important diagnostic consideration in such late-onset and recurrent comas. Early episodic central nervous system problems, possibly associated with liver insufficiency or cardiac failure, have been the initial findings in some cases of congenital disorders of glycosylation (CDG) syndrome. Wilson disease can rarely present with an acute episode of encephalopathy with extrapyramidal signs. Monocarboxylate transporter type 1 deficiency (MCT1) has been reported as a cause of recurrent episodes of severe ketoacidosis often associated with cycling vomiting but without reduced consciousness. Riboflavin transporter defects can present as brainstem encephalitis since the symptoms can be triggered by viral infections followed by progressive weakness and cranial nerve involvement, including bulbar palsy. Depending on the underlying genetic defect, treatment with riboflavin reverts the clinical picture. Mutations in TANGO2 (transport and Golgi organization 2) causing infancy-onset recurrent metabolic crises with encephalocardiomyopathy have been recently described.
In summary, all these disorders should be considered in the differential diagnosis of strokes or stroke-like episodes. Vaguely defined or undocumented diagnoses such as encephalitis, basilar migraine, intoxication, poisoning, or cerebral thrombophlebitis should therefore be questioned, particularly when even moderate ketoacidosis, lactic acidemia, or hyperammonemia is present. In fact, these apparent initial acute manifestations are frequently preceded by other premonitory symptoms, such as acute ataxia, persistent anorexia, chronic vomiting, failure to thrive, hypotonia, and progressive developmental delay—all symptoms that are often observed with urea cycle disorders (eg, ornithine transcarbamylase deficiency [OTC] and argininosuccinic aciduria), mitochondrial respiratory chain defects, late MSUD, and organic acidurias. Late-onset forms of PDH deficiency can present in childhood with recurrent attacks of ataxia, sometimes described by the patient as recurrent episodes of pain or muscular weakness (due to dystonia or to peripheral neuropathy). Hartnup disease is a classical but rare cause of acute recurrent ataxias.
When coma is associated with hepatic dysfunction, Reye syndrome secondary to disorders of fatty acid oxidation or the urea cycle should be considered. Hepatic coma with liver failure and lactic acidemia can be the presenting sign of respiratory chain disorders and is a fairly common presentation of late-onset OTC. Hepatic coma with cirrhosis, chronic hepatic dysfunction, hemolytic jaundice, and various neurologic signs (psychiatric, extrapyramidal) is a classic but underdiagnosed manifestation of Wilson disease. A similar clinical scenario can be found at advanced stages of manganese transporter deficiency characterized by dystonia/parkinsonism, hypermanganesemia, polycythemia, and chronic liver disease.
Acute Psychiatric Symptoms
Late-onset forms of congenital hyperammonemia, mainly partial OTC deficiency, can present late in childhood or in adolescence with psychiatric symptoms. Because hyperammonemia and liver dysfunction can be mild even at the time of acute attacks, these intermittent late-onset forms of urea cycle disorders can easily be misdiagnosed as hysteria, schizophrenia, or alcohol or drug intoxication. Acute intermittent porphyria and hereditary coproporphyria present classically with recurrent attacks of vomiting, abdominal pain, neuropathy, and psychiatric symptoms. Patients with homocysteine remethylation defects may present with schizophrenia-like episodes that are responsive to folate. In view of these possible diagnoses, it is justified to systematically measure ammonia, porphyrins, and plasma homocysteine in every patient presenting with unexplained acute psychiatric symptoms.
Reye Syndrome and Sudden Infant Death Syndrome (SIDS)
Within the past decade, an increasing number of IEMs have been described that produce episodes fulfilling the criteria originally used to define Reye syndrome. There is now considerable evidence that many of the disorders (mostly fatty acid oxidation and urea cycle defects) responsible for Reye syndrome were misdiagnosed in the past because of inadequate investigations for IEM. Another important reason for this underestimation is that blood and urine specimens for metabolic investigations must be collected at an appropriate time in relation to the illness, because most conditions affecting the mitochondrial pathway and urea cycle and fatty acid oxidation (FAO) disorders may produce only intermittent abnormalities. In addition, a normal or nonspecific urinary organic acid and acylcarnitine pattern, even at the time of an acute attack, does not exclude an inherited FAO disorder. However, true SIDS due to an IEM is a rare event despite the large number of publications on the topic and despite the fact that at least > 30 metabolic defects are possible causes. This assertion is not true in the first week of life, in which SIDS may be due to a fatty acid oxidation disorder, and investigations for these disorders is mandatory. The recently described IARS and LARS (coding for isoleucine and leucine tRNA synthetases, respectively) and NBAS mutations (the latter triggered by fever) presenting with recurrent episodes of acute liver failure may have been mistaken for Reye syndrome.
Exercise Intolerance and Recurrent Myoglobinuria
Many IEMs may present with exercise intolerance and recurrent myoglobinuria syndrome (myalgias, cramping, and/or limb weakness associated with elevated serum levels of creatine phosphokinase [CK is usually > 100 times upper limit of normal], recurrent pigmenturia, and sometimes acute renal failure). In the last instance, or when the patient is in a comatose state, clinical muscular symptoms can be missed. An important rule is to check serum CK and for myoglobinuria in such conditions. The disorders of muscle energy metabolism present in 2 ways.
First, in the glycogenosis disorders, exercising muscle is most vulnerable during the initial stages of exercise and during intense exercise. A “second-wind” phenomenon sometimes develops. Clinically, the glycogenosis disorders are mostly observed in late childhood, adolescence, or adulthood. The CK level remains elevated in most patients. The most frequent and typical disorder in this group is McArdle disease due to myophosphorylase deficiency (Chapter 149).
Second, in the FAO disorders, attacks of myoglobinuria occur typically after mild to moderate prolonged exercise and are particularly likely when patients are additionally stressed by fasting, cold, or infection. This group is largely dominated by muscle carnitine palmitoyltransferase (CPT) II, very-long-chain acyl-CoA dehydrogenase, LCHAD, and trifunctional protein (TFP) deficiencies, which may occur in childhood, in adolescence, or later (Chapter 145).
Mutations in TANGO2 encoding transport and Golgi organization 2 homolog have been recently described in infants and children with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias mimicking an FAO defect. Mutations in RYR1 encoding the ryanodine receptor present with muscle rigidity and rhabdomyolysis when affected individuals are exposed to general anesthesia from infancy (recessive mutations) to adulthood (dominant mutations).
Lpin1 mutations have recently been found in 60% of a series of patients presenting with unexplained recurrent myoglobinuria triggered by fever after exclusion of a primary FAO disorder. This suggests that lpin1 deficiency should be regarded as a major cause of severe myoglobinuria in infants and toddlers in an inflammatory context.
Adenylate deaminase deficiency has been suspected to cause exercise intolerance and cramps in a few patients, but the relationship between clinical symptoms and the enzyme defect is uncertain. Respiratory chain disorders (RCDs) can present with recurrent muscle pain and myoglobinuria from the neonatal period to adolescence. RCD should be suspected when lactic acidemia is accompanied by an elevated lactate-to-pyruvate ratio, either permanently or after meals. Sometimes the lactate abnormality will be found only after an exercise test. In RCD, muscle symptoms are often associated with cardiomyopathy or diverse neurologic signs (encephalomyopathy).
Initial Approach to and Protocol for Investigation of Acute Late-Onset Encephalopathy
As with the approach to acute neonatal distress, the initial approach to these disorders is based on the appropriate use of a few screening tests. As with neonates, the laboratory data listed in Table 129-2 must be collected simultaneously during the acute attack and before and after treatment.
Metabolic Acidosis and Ketosis
Metabolic acidosis can be observed in a large variety of acquired conditions, including infections, severe catabolic states, tissue anoxia, severe dehydration, and intoxication, all of which should be ruled out. However, these can also trigger acute decompensation of an unrecognized IEM. Metabolic acidosis resulting from IEM may develop as result of accumulation of an anion (lactate, ketone bodies, organic acid, or a combination of both) or loss of bicarbonate, which is usually due to renal tubular dysfunction. In metabolic acidosis resulting from a fixed anion, the plasma chloride concentration is normal, and the anion gap, a reflection of the concentration of unmeasured anions, is increased. In patients with metabolic acidosis caused by loss of bicarbonate, the plasma chloride is elevated, and the anion gap (the difference between the plasma sodium and the sum of the chloride and bicarbonate) is generally normal (ie, 10–15 mmol/L). In metabolic acidosis with a high anion gap, the presence or absence of ketonuria is the major clinical clue to the diagnosis.
When metabolic acidosis is not associated with ketosis, pyruvate dehydrogenase (PDH) deficiency, FAO disorders, and some disorders of gluconeogenesis should be considered, particularly when there is moderate to severe lactic acidemia. All these disorders except PDH deficiency have concomitant fasting hypoglycemia. When metabolic acidosis occurs with a “normal” anion gap and without lactic acidemia or hypoglycemia, the most frequent cause is renal tubular acidosis (RTA), but pyroglutamic aciduria can be mistaken for RTA type II.
A number of IEMs cause metabolic acidosis with an associated ketosis. They can be classified according to blood glucose concentration—high, normal, or low (Fig. 129-3). With hyperglycemia, the first diagnosis is diabetic ketoacidosis. However, organic acidurias such as propionic, methylmalonic, or isovaleric acidemia and ketolytic defects can also be associated with hyperglycemia and glycosuria, mimicking diabetes. Monocarboxylic transporter-1 (MCT1; encoded by SLC16A1), involved in lactate, pyruvate, and ketone transport, and TANGO II (involved in transport and Golgi organization) are 2 newly described disorders presenting as recurrent crisis of ketoacidosis with variable levels of glucose, lactate, and ammonia.
Metabolic acidosis and ketotic states. E3, lipoamide oxidoreductase; FBP, fructose bisphosphatase; G6P, glucose-6-phosphatase; GS, glycogen synthetase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; IVA, isovaleric acidemia; KGDH, α-ketoglutarate dehydrogenase; MCAD, medium-chain acyl-CoA dehydrogenase; MCD, multiple carboxylase deficiency; MCT, monocarboxylate transporter; MMA, methylmalonic aciduria; MSUD, maple syrup urine disease; OATD, oxoacid CoA transferase; PA, propionic acidemia; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase; SCAD, short-chain acyl-CoA dehydrogenase; SCHAD, hydroxy short-chain acyl-CoA dehydrogenase; TANGO II, transport and Golgi organization 2. Bold type indicates treatable disorders.
With hypoglycemia, the gluconeogenesis defects are most probable (glucose-6 phosphatase: glycogenosis type I and fructose-1,6-biphosphatase deficiency), all with hepatomegaly and lactic acidemia. Rarely, respiratory chain defects can also mimic this presentation. When there is no significant hepatomegaly, late-onset forms of MSUD and organic acidurias should be considered. A classic differential diagnosis is adrenal insufficiency, which can cause a ketoacidotic attack with hypoglycemia.
If the glucose level is normal, congenital lactic acidosis must be considered in addition to the disorders discussed above. According to this schematic approach to inherited ketoacidotic states, a simplistic diagnosis of fasting ketoacidosis or ketotic hypoglycemia should be questioned when there is a concomitant severe metabolic acidosis.
While ketonuria should always be considered abnormal in neonates, it is a physiologic result of catabolism in late infancy, childhood, and even adolescence. However, as a general rule, hyperketosis that produces metabolic acidosis is not physiologic. Ketosis that is not associated with acidosis, lactic acidemia, or hypoglycemia is likely to be a normal physiologic reflection of the nutritional state (fasting, catabolism, vomiting, or medium-chain triglyceride-enriched or other ketogenic diets). Of interest are ketolytic defects (succinyl-CoA transferase and 3-ketothiolase deficiencies) that can present with permanent moderate ketonuria occurring mainly after eating at the end of the day.
Significant fasting ketonuria without acidosis is often observed in glycogenosis type III in childhood (with marked hepatomegaly) and in the rare glycogen synthase defect in infancy (with normal liver size). In both disorders, there is fasting hypoglycemia and postprandial lactic acidemia and hyperglycemia (Fig. 129-4).
Clinical approach to inborn errors in hypoglycemias. CK, creatine kinase; FAO, fatty acid oxidation disorders; FBP, fructose-1,6-biphosphatase; Gal, galactosemia; Gly Synth, glycogen synthetase; GSD, glycogenosis; HFI, hereditary fructose intolerance; MCAD/SCAD, medium-/short-chain acyl-CoA dehydrogenase; PC, pyruvate carboxylase; PHI, persistent hyperinsulinism.
Ketosis without acidosis is observed in ketotic hypoglycemias of childhood (a frequent condition) and is associated with hypoglycemias due to adrenal insufficiency. Absence of ketonuria in hypoglycemic states, as well as in fasting and catabolic circumstances, is an important observation, suggesting an inherited disorder of fatty acid oxidation or ketogenesis disorder. It can also be observed in hyperinsulinemic states at any age and in growth hormone deficiency in infancy.
The diagnostic approach to hypoglycemia is based on 4 major clinical criteria: (1) characteristic timing of hypoglycemia (unpredictable, only postprandial, or after exposure, and only after fasting), (2) liver size, (3) association with lactic acidemia (after eating or in fasting state), and (4) association with hyperketosis or hypoketosis (see Fig. 129-4). Other clinical findings of interest are hepatic failure; vascular hypotension; dehydration; short stature; neonatal body size (head circumference, weight, and height); and evidence of encephalopathy, myopathy, or cardiomyopathy.
Erratic and postprandial hypoglycemias are observed in hyperinsulinism and in Munchausen syndrome by proxy. Most patients with hepatic failure display short-term postprandial hypoglycemia.
Fasting hypoglycemias can be classified into 2 groups based on the liver size:
Fasting hypoglycemia with permanent hepatomegaly. Hypoglycemia associated with permanent hepatomegaly is usually due to an IEM. When hepatomegaly is the most prominent feature without liver insufficiency, gluconeogenesis defects with fasting lactic acidosis (glucose-6-phosphatase deficiency: glycogenosis type I, fructose-1,6-bisphosphatase deficiency) and glycogenolysis defects with postprandial lactic acidemia (glycogenosis types III, VI, and IX) are the most likely diagnoses. FAO defects and respiratory chain disorders can also present with hepatomegaly at the time of acute fasting hypoglycemia mimicking gluconeogenesis enzyme defects. CDG syndrome type Ib (phosphomannose isomerase deficiency) with hepatic fibrosis and exudative enteropathy can cause hypoglycemia early in infancy.
Fasting hypoglycemia without permanent hepatomegaly. It is important to assess the presence of metabolic acidosis and ketosis when the patient is hypoglycemic. Absence of or only mild ketonuria in concomitant fasting hypoglycemia (or in catabolic context) is almost diagnostic of a fatty acid oxidation disorder (FAO). Adrenal insufficiency should also be considered, especially when vascular hypotension, dehydration, and hyponatremia are present. Severe hypoglycemia with metabolic acidosis and absence of ketosis, in the context of Reye syndrome, suggests HMG-CoA lyase deficiency, HMG-CoA synthetase deficiency, or FAO disorders. Fasting hypoglycemia with ketosis occurring mainly in the morning and in the absence of metabolic acidosis suggests recurrent functional ketotic hypoglycemia, which presents mostly in late infancy or childhood in those who were small for gestational age or those with macrocephaly. Patients with all types of adrenal insufficiency (peripheral or central) and glycogen synthetase deficiency can share this presentation, as can the rare patients with distal blocks of FAO and ketolysis defects.
In summary, fasting hypoglycemia with at least 1 of the 3 following features is a priori due to an IEM: (1) permanent hepatomegaly, (2) metabolic acidosis, and (3) absence of ketonuria concomitant with hypoglycemia. Hypoketotic hypoglycemias encompass several groups of disorders, including hyperinsulinemic states, growth hormone deficiency, inborn errors of FAO, and ketogenesis defects (see the previous “Ketosis” section).
Many IEMs can give rise to hyperammonemia. In the context of acute neonatal encephalopathy, severe hyperammonemia (> 500 μmol/L) is generally caused either by a UCD (with respiratory alkalosis, no ketosis, and no bone marrow suppression) or an organic acidemia (OA; propionic acidemia [PA], MMA, IVA with metabolic acidosis, ketosis, and leukothrombocytopenia) (Chapter 132). Plasma glutamine is generally elevated in UCD (> 1000 μmol/L) and LPI, whereas it is close to normal or low (< 500 μmoles/l) in OAs. Plasma citrulline levels further allow the distinction between mitochondrial and cytoplasmic UCDs (Chapter 141). Severe neonatal forms of ornithine aminotransferase defect may mimic ornithine transcarbamylase deficiency, before ornithine elevation occurs. Hyperammonemia with hyperornithinemia and homocitrullinuria is diagnostic for the mitochondrial ornithine transporter defect (HHH syndrome) (Chapter 141).
Neonatal hyperammonemia associated with lactic acidosis (> 6 mmol/L) and hyperketosis suggests pyruvate carboxylase (with low glutamine and high citrulline) (Chapter 154), multiple carboxylase or carbonic anhydrase VA deficiencies both with characteristic organic acid profile.
In a context of severe hypoketotic hypoglycemia, hyperammonemia (in general NH3 < 250 μmol/L) suggests a hyperinsulinism/hyperammonemia syndrome linked to activating mutations in the glutamate dehydrogenase gene or a fatty oxidation defect with cardiac involvement (Chapter 145). Transient hyperammonemia with hypoglycemia may also be observed in premature babies with respiratory distress syndrome. A low plasma lysine level with low ornithine and arginine in the face of a high urinary excretion of these dibasic amino acids is diagnostic for lysinuric protein intolerance (Chapter 139). Mild elevations of NH3 (< 150 μmol/L) may also be a concomitant finding in MSUD, PDH deficiency, and patients treated with sodium valproate (the latter with hyperglycinemia).
Lactate and pyruvate are normal metabolites. Their plasma levels reflect the equilibrium between their cytoplasmic production from glycolysis and their mitochondrial consumption by different tissues. Lactic acidemia (> 2.5 mmol/L) can be due to an elevation of pyruvate (> 0.30 mmol/L), the NADH/NAD ratio (> 20), or H+ (severe acidosis: pH < 7:20), or all of these.
Blood lactate accumulates due to elevation of the NADH/NAD ratio in circulatory collapse, in hypoxia, and in other conditions involving failure of cellular respiration and all severe acidotic states. These conditions must be excluded before an inborn error of lactate-pyruvate oxidation is sought. Persistent lactic acidemias can also result from many acquired conditions, such as diarrhea, persistent infections (mainly of the urinary tract), hyperventilation, and hepatic failure. Ketosis is absent in most lactic acidemias secondary to tissue hypoxia, while it is a nearly constant finding in most IEMs (except in PDH deficiency, GSD type I, and FAO disorders). On the other hand, the level of lactate is not discriminating; some acquired disorders are associated with very high levels, whereas lactate is only moderately raised in some inborn errors of lactate-pyruvate metabolism. Nutritional state also influences the levels of lactate and pyruvate.
Four types of IEM can be considered: The cytoplasmic defects present in a context of hypoglycemia with hepatomegaly: disorders of liver glycogen metabolism and liver gluconeogenesis. The mitochondrial defects present in a context of neurologic deterioration: lactate-pyruvate oxidation defects (mitochondrial pyruvate transporter [MPC], PDH, pyruvate carboxylase [PC], and Krebs cycle defects) and deficient activity in 1 of the components of the respiratory chain (Chapter 153).
The diagnosis of lactic acidemia is further based on 2 metabolic criteria:
Time of occurrence of lactic acidemia relative to feeding: in glycogenosis (GSD) type 1a (glucose-6-phosphatase deficiency) and in gluconeogenesis defect (fructose bisphosphatase), lactic acidemia reaches its maximum level (up to 15 mmol/L) when the patient is fasting, acidotic, and hypoglycemic. By contrast, in GSD types III and VI and in glycogen synthetase deficiency, lactic acidemia is observed only in the postprandial period in patients on a carbohydrate-rich diet. Here, lactic acidemia never exceeds 6 mmol/L, and therefore, there is no acidosis (bicarbonate > 18 mmol/L). In PC deficiency severe lactic acidemia (> 7 mmol/L) is present in both the fed and the fasted states but tends to decrease in the postprandial period. In disorders of MPC, PDH, α-ketoglutarate dehydrogenase, and respiratory chain function, maximum lactate levels are observed in the fed state (although all lactic acidemias exceeding 7 mmol/L appear more or less persistent). In these disorders, there is a real risk of missing a moderate (although significant) lactic acidemia if the level is checked only before breakfast after an overnight fast (as is usual for laboratory investigations).
Determination of lactate-to-pyruvate (L/P) and ketone body ratios before and after meals. These ratios are useful only in “mitochondrial” lactic acidemias in a neurologic context. They indirectly reflect cytoplasmic (L/P) and mitochondrial (3OHB/AA) redox potential states. They must be measured in carefully collected blood samples.
When pyruvic acidemia (> 0.3 mmol/L) is associated with a normal or low L/P ratio (< 12) without hyperketonemia, PDH deficiency or MPC is highly probable, regardless of the lactate level.
When the L/P ratio is very high (> 30) and is associated with a paradoxical postprandial hyperketonemia and with a normal or low 3OHB/AA ratio (< 1.5), a diagnosis of PC deficiency is virtually certain. In severe PC deficiency, there is also a very characteristic AA profile with hyperammonemia, high citrulline, and low glutamine.
When both L/P and 3OHB/AA ratios are elevated and associated with a significant postprandial hyperketonemia, RCD should be suspected.
All other situations, especially when the L/P ratio is high without hyperketonemia, are compatible with RCD, but acquired anoxic conditions should also be ruled out (see above).
Chronic and Progressive General Symptoms
Many late-onset acute presentations of IEM are actually preceded by premonitory symptoms that may have been ignored or misinterpreted. These symptoms fall schematically into 3 categories: gastrointestinal, muscular, or neurologic.
Gastrointestinal Involvement, Failure to Thrive, Anemia, and Recurrent Infections
Gastrointestinal (GI) nonspecific findings (anorexia, failure to thrive, chronic vomiting) and osteoporosis occur in a wide variety of IEMs. Unfortunately, their cause often remains unrecognized, thus delaying the diagnosis. Persistent anorexia, feeding difficulties, chronic vomiting, failure to thrive, frequent infections, osteopenia, generalized hypotonia in association with chronic diarrhea, anemia, and bone marrow suppression are frequent presenting symptoms and signs in IEM. They are easily misdiagnosed as cow’s milk protein intolerance; celiac disease; chronic ear, nose, and throat infections; late-onset chronic pyloric stenosis; and so on. Congenital immunodeficiencies (CIDs) are also frequently considered, although only a few CIDs present early in infancy with this clinical picture. Faced with these presentations with no definitive diagnosis despite extensive gastroenterological, hematologic, and immunologic investigation, it is mandatory to seriously consider conditions such as organic aciduria-methylmalonic aciduria (MMA), propionic acidemia (PA), isovaleric acidemia (IVA), urea cycle defects, lysinuric protein intolerance, and respiratory chain defects. Appropriate studies should be carried out (Table 129-5).
TABLE 129-5DIAGNOSTIC APPROACH TO INBORN ERRORS OF METABOLISM WITH CHRONIC DIARRHEA, POOR FEEDING, VOMITING, AND FAILURE TO THRIVE ||Download (.pdf) TABLE 129-5DIAGNOSTIC APPROACH TO INBORN ERRORS OF METABOLISM WITH CHRONIC DIARRHEA, POOR FEEDING, VOMITING, AND FAILURE TO THRIVE
|Leading Symptoms ||Other Signs ||Age of Onset ||Diagnosis (Disorder/Enzyme Deficiency) |
Severe watery diarrhea
|Congenital to infancy ||Congenital chloride diarrhea |
Attacks of dehydration
| || |
| ||Acidic diarrhea, reducing substances in stools ||Neonatal ||Glucose-galactose malabsorption |
|Lactase deficiency |
| ||Acidic diarrhea, reducing substances in stools after weaning ||Neonatal to infancy ||Sucrase isomaltase |
| ||Skin lesions, alopecia ||Neonatal or postweaning ||Acrodermatitis enteropathica |
|Protein-losing enteropathy || |
Nonbloody, watery diarrhea
Cholangitis crisis +/ hypoglycemia
PMI-CDG (Ib), ALG8- CDG (Ih), ALG6-CDG (Ic)
| ||Hypoglycemia ||Infancy ||PMM-CDG (1a) |
Fat-soluble vitamin malabsorption
|Neonatal to infancy || |
Bile acid synthesis defects
Ichthyosis, keratodermia, deafness, mental retardation
| || |
| || || |
|Hepatomegaly, hypotonia, retinitis pigmentosa, deafness ||Infancy || |
| ||Abdominal distension, ataxia, acanthocytosis, peripheral neuropathy, retinitis pigmentosa ||Infancy ||Abetalipo I and II (no acanthocytes, no neurologic sign in type II) |
| ||Pancreatic insufficiency, neutropenia, pancytopenia ||Early in infancy || |
|Severe failure to thrive, anorexia, poor feeding, with predominant hepatosplenomegaly ||Severe hypoglycemia, inflammatory bowel disease, neutropenia ||Neonatal to early infancy ||Glycogenosis type Ib (no splenomegaly) |
|Hypotonia, vacuolated lymphocytes, adrenal gland calcifications ||Neonatal ||Wolman |
|Recurrent infections, inflammatory bowel disease ||Infancy ||X-linked chronic granulomatosis |
| ||Megaloblastic anemia, neuropathy, homocystinuria, MMA ||1–5 years ||Intrinsic factor |
| ||Leukoneutropenia, osteopenia, hyperammonemia, interstitial pneumonia, ||Infancy ||Lysinuric protein intolerance |
| ||Recurrent fever, inflammatory bowel syndrome, hyper-IgD, recurrent hemolytic anemia ||Infancy ||Mevalonate kinase |
|Severe failure to thrive, anorexia, poor feeding, with megaloblastic anemia ||Oral lesion, neuropathy, infections, pancytopenia, homocystinuria, MMA ||1–2 years ||TCII |
| ||Intrinsic factor |
|Stomatitis, peripheral neuropathy, infections, intracranial calcifications ||Infancy ||Congenital folate malabsorption |
| ||Severe pancytopenia, abnormal marrow precursors, lactic acidosis ||Neonatal ||Pearson syndrome |
|Severe failure to thrive, anorexia, poor feeding, no hepatosplenomegaly, no megaloblastic anemia ||Severe hypoproteinemia, putrefaction diarrhea ||Infancy ||Enterokinase |
|Diarrhea after weaning, cutaneous lesion (periorificial), low plasma zinc ||Infancy ||Acrodermatitis enteropathica |
|Ketoacidotic attacks, vomiting ||Infancy ||Organic acidurias (MMA, PA), mito. DNA deletions |
| ||Intestinal pseudo-obstruction with peripheral neuropathy ||Childhood to adulthood ||MNGIE syndrome |
| ||Vomiting, lethargy, hypotonia, hyperammonemia ||Infancy ||Urea cycle defects (mainly OTC) |
| ||Frequent infections, lymphopenia ||Infancy ||Adenosine deaminase |
| ||Developmental delay, relapsing petechiae, orthostatic acrocyanosis ||Infancy ||EPEMA syndrome |
| ||Skin laxity, pili torti, hypothermia, hypotonia, seizures, facial dysmorphism ||Infancy ||Menkes disease |
Many IEMs present with severe hypotonia, muscular weakness, and poor muscle mass. These include most of the late-onset forms of urea cycle defects and many organic acidurias. Severe neonatal generalized hypotonia and progressive myopathy, with or without an associated nonobstructive idiopathic cardiomyopathy, can be the presenting features of mitochondrial respiratory chain disorders and other congenital lactic acidemias, FAO defects, peroxisomal disorders, muscular glycogenolysis defects, Pompe disease, some other lysosomal disorders, and complex lipids synthesis/remodeling defects.
Neurologic symptoms are frequent and encompass progressive psychomotor retardation, seizures, several neurologic abnormalities in both the central and peripheral system, sensorineural defects, and psychiatric symptoms.
However, some aminoacidopathies and urine organic acidopathies that were identified in children with intellectual disabilities in the late 1970s, when urine and plasma amino acid chromatography was first systematically measured, are now recognized to be of similar frequency in unaffected populations, such that their causative relationship with intellectual disability is uncertain. These include histidinemia, hyperlysinemia, some types of hyperprolinemia, α-amino-adipic aciduria, saccharopinuria, and acetyl amino aciduria due to amino acylase I deficiency, adenylosuccinase deficiency, dihydropyrimidine dehydrogenase deficiency, 4-hydroxybutyric aciduria, D-2-hydroxyglutaric aciduria, and late-onset NKH. Several other inborn errors are now known to rarely, if ever, cause true developmental arrest. Rather, repeated episodes of subacute metabolic crises result in progressive developmental delay. In the 21st century, many new disorders involving the nervous system were revealed by a genome-wide next-generation sequencing (NGS) approach, in patients in whom clinical suspicion of an IEM was low prior to the genetic testing. This is mostly true for the mitochondrial disorders (> 300 new defects), the congenital disorders of glycosylation (> 100 new defects), and the new category of complex lipid and fatty acid synthesis and remodeling defects (> 60 new disorders).
A highly simplified general approach to identification of IEMs associated with chronic encephalopathy is shown in Figure 129-5.
An approach to the identification of inborn errors of metabolism causing chronic encephalopathy. CblC, cobalamin C disease; CNS, central nervous system; CRSM, cherry-red spot myoclonus; GLD, globoid cell leukodystrophy; IRS, infantile Refsum syndrome; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome; MLD, metachromatic leukodystrophy; MPS, mucopolysaccharide storage disorder; MSD, multiple sulfatase deficiency; NALD, neonatal adrenoleukodystrophy; NCL, neuronal ceroid lipofuscinosis; NPD, Niemann-Pick disease; PNS, peripheral nervous system; RES, reticuloendothelial system; XLALD, X-linked adrenoleukodystrophy.
Neurologic signs of IEM can be classified according to age at presentation, the presence or absence of associated extraneurologic signs, and the neurologic presentation itself. IEMs with neurologic signs presenting in the neonate (birth to 1 month) and those presenting intermittently as acute attacks of coma, lethargy, ataxia, or acute psychiatric symptoms were discussed earlier (see Tables 129-1, 129-3, and 129-4).
Disorders Associated with Extraneurologic Symptoms
Visceral signs appear in lysosomal disorders. Cardiomyopathy (associated with early neurologic dysfunction, failure to thrive, and hypotonia), sometimes responsible for cardiac failure, is suggestive of respiratory chain disorders, D-2-hydroxyglutaric aciduria (with atrioventricular block), or CDG syndrome. Abnormal hair and cutaneous signs appear in Menkes disease, Sjögren-Larsson syndrome, biotinidase deficiency, and respiratory chain disorders. Peculiar fat pads on the buttocks, thick and sticky skin, and inverted nipples are highly suggestive of CDG syndrome. Generalized cyanosis unresponsive to oxygen, suggesting methemoglobinemia and associated with severe hypertonicity, indicates cytochrome-b5-reductase deficiency. Orthostatic acrocyanosis, relapsing petechiae, pyramidal signs, intellectual disability, and recurrent attacks of lactic acidosis suggest ethylmalonic encephalopathy (EPEMA syndrome). The presence of megaloblastic anemia suggests an inborn error of folate and cobalamin (Cbl) metabolism. Ocular abnormalities, such as cherry-red spot, optic atrophy, nystagmus, abnormal eye movements, and retinitis pigmentosa, can be extremely helpful diagnostic signs.
Disorders with Specific or Suggestive Neurologic Signs
Predominant extrapyramidal symptoms are associated with inborn errors of biopterin and aromatic amino acid metabolism, pyridox(am)ine-5′-phosphate oxidase deficiency, Lesch-Nyhan syndrome, cytochrome-b5-reductase deficiency, Crigler-Najjar syndrome, the early-onset form of glutaric acidemia (GA) type I, and cerebral creatine deficiency. (Table 129-6) Dystonia can also be observed as a subtle but presenting sign in X-linked Pelizaeus-Merzbacher syndrome. It can be also associated with psychomotor retardation, spastic paraplegia, and ataxia in cerebral folate deficiency syndrome. Epileptic encephalopathy, neurologic regression, ocular symptoms, and recurrent attacks of neurologic crises are also useful symptoms that lead one to suspect the diagnosis.
TABLE 129-6PROGRESSIVE NEUROLOGIC AND MENTAL DETERIORATION WITH SUGGESTIVE NEUROLOGIC SIGNS (1–12 MONTHS) ||Download (.pdf) TABLE 129-6PROGRESSIVE NEUROLOGIC AND MENTAL DETERIORATION WITH SUGGESTIVE NEUROLOGIC SIGNS (1–12 MONTHS)
|Leading Symptoms ||Other Signs ||Diagnosis (Disorder/Enzyme Deficiency) |
|With Suggestive Neurologic Signs |
|Extrapyramidal signs ||Major parkinsonism ||Inborn errors of biopterin metabolism |
| ||Abnormal neurotransmitters ||Aromatic amino acid decarboxylase |
| || ||Tyrosine hydroxylase, PNPO |
| ||Choreoathetosis, self-mutilation ||Lesch-Nyhan (X-linked) hyperuricemia |
| ||Bilateral athetosis, hypertonicity ||Cytochrome b5 reductase |
| ||Dystonia, stridor ||Pelizaeus-Merzbacher (X-linked) |
| ||Kernicterus syndrome ||Crigler-Najjar |
| ||Acute-onset, pseudoencephalitis ||Glutaric aciduria type I |
| ||Low cerebral creatine ||Creatine deficiency (GAMT) |
| ||Spastic paraplegia, ataxia, epilepsy ||Cerebral folate deficiency |
| ||Leigh syndrome ||PDH, RCD |
|Painful pyramidal hypertonia ||Opisthotonos ||Krabbe, Gaucher III, Niemann-Pick type C |
|Early epilepsy ||Spasticity ||NKH, SO, untreated MSUD and OA |
|Infantile spasm || ||MCD, Menkes |
|Macrocephaly, startle response to sound ||Cherry-red spot, myoclonic jerks ||Tay-Sachs, Sandhoff, Canavan, Alexander
Vacuolating leukoencephalopathy |
|Ocular symptoms ||Optic atrophy, incessant crying ||Krabbe (infantile) |
| ||Dystonia, choreoathetosis ||GA I, L-2-hydroxyglutaric aciduria |
| ||Progressive irritability ||Respiratory chain, peroxisomal defects |
|Recurrent attacks of neurological crises ||Failure to thrive, hyperventilation attacks ||Leigh syndrome (pc, pdh, respiratory chain, MAMEL syndrome) |
| ||Stroke-like episodes ||Urea cycle defects, MSUD, OA, GA I |
| || ||CDG syndrome, respiratory chain |
| ||Thromboembolic accidents ||Homocystinurias, CDG syndrome |
|Without Suggestive Neurologic Signs |
|Evidence of developmental arrest ||Infantile spasms, hypsarrhythmia, autistic features ||Untreated PKU, biopterin defects Peroxisomal defects, Rett syndrome |
|Nonspecific symptoms ||Frequent autistic feature ||Hyperammonemia (late-onset subacute) |
|Apparently nonprogressive disorder ||Poor feeding, failure to thrive ||4-OH-butyric, L2-OH-, D2-OH-glutaric acidurias |
| ||Hypotonia, seizures ||Mevalonic aciduria |
| ||With diverse neurologic findings simulating cerebral palsy ||Adenylosuccinase, pyrimidine defects |
| ||3-Methylglutaconic, fumarase |
| ||Other OA, creatine deficiency |
| ||3-PGD, 3-phosphoserine phosphatase |
| ||Homocystinurias, Salla disease |
| ||Neurotransmitter defects, |
| ||Cerebral folate deficiency |
| ||Angelman, GLUT-1 |
Macrocephaly with a startle response to sound, incessant crying, and irritability occur in Tay-Sachs, Sandhoff, Canavan, and Alexander diseases, vacuolating leukoencephalopathy, and hydroxyglutaric aciduria and respiratory chain disorders (RCD) due to complex I deficiency in which hypertrophic cardiomyopathy may also be observed.
Recurrent attacks of neurologic crisis associated with progressive neurologic and mental deterioration suggest Leigh syndrome, which is really a clinical phenotype of a number of mitochondrial disorders. Recurrent stroke-like episodes, often associated with anorexia, failure to thrive, and hypotonia, can be presenting symptoms in urea cycle defects (mostly ornithine transcarbamylase [OTC] deficiency), late-onset MSUD, organic acidurias, GA type I, CDG syndrome, and RCD. Thromboembolic events later in life can be the presenting sign of classical homocystinuria, CDG syndrome, and Fabry disease.
Disorders with Nonspecific Developmental Delay
Many IEMs present with nonspecific early progressive developmental delay, poor feeding, hypotonia, some degree of ataxia, frequent autistic features, and seizures. They can masquerade as cerebral palsy by presenting as a permanent impairment of movement or posture. Consequently, it is mandatory to systematically screen such children for the following IEMs, which are at least partly treatable: late-onset subacute forms of hyperammonemia (usually OTC deficiency in girls) and inborn errors of neurotransmitter synthesis, especially dopa-responsive dystonia due to cyclohydrolase deficiency, tyrosine hydroxylase deficiency, and aromatic-L-amino-acid-decarboxylase deficiency. Recurrent seizures that are unresponsive to anticonvulsants are the presenting symptom of the blood-brain barrier glucose-transporter (GLUT-1) defect. The treatable cerebral folate deficiency syndrome (improved by folinic acid) should also be subject to systematic screening.
Late Infancy to Early Childhood (1–5 Years)
In this age group, establishing a diagnosis becomes easier. Seven general categories that encompass almost all pediatric neurology can be defined according to the accompanying signs and leading symptom: (1) with prominent extraneurologic symptoms, (2) spastic or flaccid paraplegia, (3) unsteady gait including ataxia and dyspraxia or myoclonia, (4) epilepsy, (5) arrest of development or regression, (6) dystonia/abnormal movements, and (7) behavioral disturbances.
Progressive paraplegia and spasticity are presenting signs in many IEMs. A growing number of so-called hereditary spastic paraplegias (SPG) linked to mutations of genes implicated in phospholipid synthesis and remodeling have very recently been elucidated. Of the potentially treatable disorders, a rapidly progressive flaccid paraparesis resembling subacute degeneration of the cord can be the presenting sign of inherited cobalamin-synthesis defects. Spastic paraparesis is an almost constant finding in HHH syndrome and can be the leading symptom in dopaminergic synthesis defects and biotinidase deficiency. Arginase deficiency is a rare disorder that presents early in infancy to childhood (2 months to 5 years) with progressive spastic diplegia, scissoring or tiptoe gait, and developmental arrest.
Unsteady gait and uncoordinated movements (when standing, walking, sitting, reaching for objects, speaking, and swallowing) may be due to cerebellar ataxia, dyspraxia, or myoclonia. Several groups of disorders must be considered. A careful investigation of organic acid and amino acid metabolism is always mandatory, especially during episodes of metabolic stress. Disorders with disturbances of OA and AA and/or other metabolic biomarkers are numerous, and some are potentially treatable, including PDH, creatine deficiency due to guanidinoacetate-methyltransferase deficiency, PA, MMA, GLUT1, LCHAD, and vitamin E–responsive ataxias.
Predominant epilepsy and myoclonus with progressive deterioration are frequent presenting signs in many untreatable IEMs (eg, ceroid lipofuscinosis and sphingolipidosis and the emerging group of GPI-anchor biosynthesis defects). Some of the most representative treatable IEMs leading to refractory seizures as a major symptom without clear neurologic deterioration are creatine defects, GLUT1 deficiency, and late-onset pyridoxine-dependent epilepsy.
Only a few disorders present between 1 and 5 years of age with an isolated developmental arrest or regression of cognitive and perceptual abilities without other significant neurologic or extraneurologic signs. Sanfilippo disease is one, although regression of high-level achievements, loss of speech, and agitation usually begin after 5 years of age. Although nonmetabolic, Rett syndrome is another such disease; it should be considered when a girl, without a family history, presents between 1 and 2 years of age with autistic behavior, developmental regression, typical stereotyped hand movements, and acquired microcephaly.
Extrapyramidal symptoms observed in IEM include dystonia, parkinsonism, chorea, and tremor; however, dystonia is predominant in this age category (from 1–5 years of life) and until late infancy. Although usually associated with other neurologic symptoms, some IEMs can initially present as an isolated dystonia, eg, neurotransmitter defects (in particular Segawa disease, pantothenate kinase–associated neurodegeneration [PKAN], Leigh syndrome, Lesch-Nyhan disease, PDH deficiency, and homocystinurias). However, in general, in intermediary and energy metabolism defects, dystonia tends to be abrupt, develops rapidly, and is generalized and postural from the very first stages of the disease. Some illustrative examples are GA1, PDH deficiency, thiamine transporter 2 deficiency due to SLC19A3 mutations (biotin-thiamine basal ganglia responsive disorder), and homocystinurias. GLUT1 deficiency can cause paroxysmal exercise-induced dyskinesia and other paroxysmal complex movement disorders. Most IEMs with extrapyramidal symptoms exhibit abnormal brain magnetic resonance imaging patterns; however, brain image is usually normal in neurotransmitter defects, GLUT1 deficiency, and genetic primary dystonias.
Marked hyperactivity and agitation are very common in Sanfilippo disease (even before regression), whereas autistic behavior may be striking in creatine transporter defect, succinate semialdehyde dehydrogenase, untreated phenylketonuria (PKU), mild forms of Smith-Lemli-Opitz, and a rare disease recently described due to inactivating mutations in BCKDK (branched chain ketoacid dehydrogenase kinase) that is associated with low plasma branched chain amino acids. This disorder should be potentially treatable by branched chain amino acid supplementation.
Late Childhood to Adolescence (5–15 Years)
Some conditions affect primarily cognitive function, whereas others present with more extensive neurologic involvement with normal or subnormal intellectual functioning
There are 6 clinical categories :
With predominant extrapyramidal signs (parkinsonian syndrome, dystonia, choreoathetosis). In fact, almost all neurometabolic disorders can cause dystonia at some stage, which is frequently a combined dystonia (with associated symptoms). At this period of life, IEMs that produce dystonia as a major sign include disorders that have been also included from 1 to 5 years of age; however, Wilson disease, Segawa disease (dominant GTPCH), GLUT1 deficiency, and neurodegeneration with brain iron accumulation (NBIA) syndrome are among the most relevant at this period of life. Some IEMs can also initially present as pure dystonias such as PKAN deficiency, PDH, Lesch-Nyhan syndrome, and juvenile metachromatic leukodystrophy. Although more common in older age groups, lysosomal disorders can also begin in childhood with parkinsonism as the leading sign. Special consideration should be given to ceroid lipofuscinosis (CNL), GM1 gangliosidosis, and Niemann-Pick disease type C.
Severe neurologic and mental deterioration and diffuse central nervous system involvement. Patients have in common severe neurologic dysfunction with pyramidal signs, incoordination, seizures, visual failure, impaired school performance, and dementia. In association with splenomegaly or hepatomegaly, these signs suggest Niemann-Pick disease type C or Gaucher disease type III. When visceral signs are absent, they may indicate juvenile metachromatic leukodystrophy, X-linked adrenoleukodystrophy, Krabbe disease, juvenile GM1 and GM2 gangliosidoses, or mitochondrial disorders. Peroxisomal biogenesis defects can also present in the second decade of life with peripheral neuropathy initially mimicking Charcot-Marie-Tooth type II disease.
Polymyoclonus and epilepsy. These are often present in the juvenile form of ceroid lipofuscinosis, Lafora disease after puberty, and some sphingolipidoses and respiratory chain disorders.
Predominant cerebellar ataxia. This can be the presenting feature of peroxisomal disorders, CDG syndrome, Refsum disease (these 3 can also manifest peripheral neuropathy and retinitis pigmentosa), Lafora disease, cerebrotendinous xanthomatosis (CTX), late-onset forms of sphingolipidoses, and RCD. Some forms of coenzyme Q10 (CoQ10) synthesis defects can respond to idebenone supplementation. Other forms of treatable ataxia are GLUT1 deficiency, vitamin E–responsive ataxias, and Hartnup disease.
Predominant polyneuropathy. Porphyrias and tyrosinemia type I can present with an acute attack of polyneuropathy that mimics Guillain-Barré syndrome. Many other disorders can present with late-onset progressive polyneuropathy that can mimic hereditary ataxia, such as Charcot-Marie-Tooth disease, lysosomal and peroxisomal diseases, energy metabolism defects (PDH, LCHAD), abetalipoproteinemia, and CDG syndrome.
Behavioral disturbances. Behavioral disturbances (personality and character changes), loss of speech, scholastic failure, mental regression, dementia, psychosis, and schizophrenia-like syndrome may be presenting signs of treatable IEMs. OTC deficiency can present with episodes of abnormal behavior and character change until hyperammonemia and coma reveal the true situation. Homocystinuria due to MTHFR deficiency has presented as isolated schizophrenia. Searching for these treatable disorders is mandatory, including also CTX and Wilson disease.
Recommended Laboratory Tests in Neurologic Syndromes
Patients are motivated by the hope of a potentially effective treatment, understanding about the prognosis, and availability of genetic counseling.
IEMs are attractive diagnoses because (1) in many cases, simple blood and urine tests (many of them available in an emergency) can be diagnostic; (2) knowing the biochemistry can (theoretically) point toward a treatment; (3) for some diagnoses, treatment is indeed available; and (4) if recognized early during a pregnancy, antenatal testing is possible for at-risk families.
In this context, beware of the following attitudes: (1) ignorant or slow (“Oh, metabolic disease are too rare; I didn’t see any in my practice!”), with the risk of missing an opportunity to make a diagnosis and start a life-saving therapy; (2) too naïve (lack of familiarity with metabolic disease) with the risk of ordering tests for the wrong situations; and (3) too systematic (the overly detailed approach: “Too much thought, not enough thinking”) with the risk of ordering inappropriate tests. All 3 attitudes have a high cost-benefit ratio.
Metabolic testing is mandatory in 3 situations: (1) in urgent situations: rule out treatable disorders: test, treat, then think! (see Table 129-2); (2) the unexpected pregnancy (in families at risk): test according to the proband’s phenotype; rush in case prenatal diagnosis is important and available; and (3) symptoms are persistent, progressive, and unexplained: think (and get help from specialized centers) and then test; use diagnostic algorithms for help and prioritize treatable disorders. Avoid ordering long lists of tests for potential possibilities. Otherwise, monitor and reevaluate.
Nonmetabolic differential diagnoses are numerous: Nutritional phenocopies, toxic ingestions, infections, endocrinopathies, many unexplained or vaguely defined neurologic and psychiatric conditions, and Munchausen or Munchausen-by-proxy are the most frequent.
Table 129-7 lists a tentative metabolic approach to neurologic syndromes focusing on treatable IEMs.
TABLE 129-7RECOMMENDED LABORATORY TESTS IN NEUROLOGIC SYNDROMES FOCUSED ON TREATABLE INBORN ERRORS OF METABOLISM ||Download (.pdf) TABLE 129-7RECOMMENDED LABORATORY TESTS IN NEUROLOGIC SYNDROMES FOCUSED ON TREATABLE INBORN ERRORS OF METABOLISM
|Predominant Neurologic Syndrome ||Laboratory Tests (Rational Approach Based on Associated Clinical Signs and Treatable Disorders) ||Treatable Disorders |
|Isolated developmental delay/intellectual disability (ID) || |
Basic laboratory testsa: blood glucose, acid-base status, blood counts, liver function, creatine kinase, uric acid, thyroid function, alkaline phosphatase
Plasma: lactate, ammonium, amino acids, total homocysteine, folate, biotinidase activity
Urine: creatine metabolites, organic acids (including 4-hydroxybutyric acid), amino acids, glycosaminoglycans (GAGs), purines, pyrimidines
Consider maternal phenylalanine
|Phenylketonuria (PKU), homocystinurias, urea cycle defects, amino acid synthesis defects, thyroid defects, biotinidase deficiency, Hartnup disease |
|With dysmorphic features || |
Consider also plasma sterols, peroxisomal studies (very-long-chain fatty acids, phytanic acid, plasmalogens), transferrin isoelectric focusing for glycosylation studies (CDG), mucopolysaccharides and oligosaccharides in urine
For the study of ID +/– dysmorphic features, genetic tests (cytogenetic studies, microarrays, NGS, and targeted DNA studies have the highest diagnostic yield)
|Smith-Lemli-Opitz (SLO) syndrome, peroxisomal diseases (only partially by some supplements) Mucopolysaccharidosis |
|Behavioral and psychiatric manifestations including autistic signs || |
Basic laboratory testsa
Plasma: ammonium, amino acids, total homocysteine, folate, sterols (including oxysterols), copper, ceruloplasmin
Urine: GAGs, organic acids (4-hydroxybutyric acid), amino acids, purines, creatine, creatinine, and guanidinoacetate
Depending on additional clinical signs and brain MRI pattern: peroxisomal studies, lysosomal studies
|PKU, urea cycle disorders, homocystinurias, folate metabolism defects, Wilson disease, BCKDH kinase deficiency, CTD, mild forms of SLO, Niemann-Pick disease type C, X-ALD (at some stages), Hartnup disease |
|Epilepsy || |
Basic laboratory testsa adding calcium, magnesium
Plasma: lactate, ammonium, amino acids, total homocysteine, folate, biotinidase activity, copper and ceruloplasmin, VLCFA
Urine: organic acids, creatine, creatinine and guanidinoacetate, sulphite test, purines and pyrimidines, pipecolic acid, and 5-AASA
CSF: glucose, lactate, amino acids, 5-methyltetrahydrofolate (5-MTHF), pterines, biogenic amines, GABA
Consider lysosomal studies and targeted tests if PME
Consider genetic tests for GPI-anchor biosynthesis pathway defects and other defects of complex lipid synthesis (FA2H, ELOVL4, GM3 synthase)
|GLUT-1, homocystinurias, IEM of folate metabolism, organic acidurias, biotinidase deficiency, creatine synthesis defects, serine biosynthesis defects, Menkes disease (only partially treatable), late-onset forms of pyridoxine-dependent epilepsy, pterin defects (DHPR), AADC deficiency, MoCo deficiency (cyclic pyranopterin monophosphate: treatment recently introduced) |
|Ataxia || |
Basic laboratory testsa adding albumin, cholesterol, triglycerides, and α-fetoprotein
Plasma: lactate, pyruvate, ammonium, amino acids, biotinidase activity, vitamin E, sterols (including oxysterols), ceruloplasmin, peroxisomal studies (including phytanic acid), coenzyme Q10, transferrin electrophoresis
Urine: organic acids (including 4-hydroxybutyric and mevalonic acids), amino acids, purines
CSF: glucose, lactate, pyruvate
Consider lysosomal/mitochondrial/NBIA studies depending on the clinical and brain MRI signs
Consider lipidome studies (plasma, CSF)
Consider genetic panels of inherited ataxias and other NGS techniques
|PDH deficiency (thiamine-responsive; ketogenic diet), biotinidase deficiency, GLUT-1, abetalipoproteinemia, CTX, Refsum disease, coenzyme Q10 deficiencies, Hartnup disease, Niemann-Pick disease type C |
|Dystonia-parkinsonism || |
Basic laboratory testsa
Plasma: lactate, pyruvate, ammonium, amino acids, biotinidase activity, sterols (including oxysterols), copper, ceruloplasmin, uric acid, manganese
Urine: organic acids, uric acid, creatine, creatinine and guanidinoacetate, purines, GAGs, oligosaccharides
CSF: glucose, lactate, pyruvate, amino acids, 5-methyltetrahydrofolate, pterines, biogenic amines, GABA
Consider lysosomal/mitochondrial/NBIA studies depending on the clinical and brain MRI signs
Consider genetic panels of inherited dystonias, parkinsonism, and other NGS techniques
|Neurotransmitter defects, GLUT-1 deficiency, thiamine transport defects (TBBGDs), PDH defects, organic acidurias, homocystinurias, IEM of folate metabolism, defects of creatine biosynthesis, Wilson disease, biotinidase deficiency, Niemann-Pick disease type C, CTX, manganese defects |
|Chorea || |
Basic laboratory testsa
Plasma: lactate, pyruvate, ammonium, amino acids, total homocystinuria, folate, biotinidase activity, sterols (including oxysterols), copper, ceruloplasmin, uric acid, galactose 1 P, transferrin electrophoresis
Urine: organic acids, uric acid, creatine, creatinine and guanidinoacetate, purines, galactitol, sulphite test
CSF: glucose, lactate, pyruvate, amino acids, 5-methyltetrahydrofolate, pterines, biogenic amines, GABA
Consider NCL studies and GPI-anchor synthesis defect genetic tests
Consider genetic panels of inherited choreas and other NGS techniques
|Glutaric aciduria I and other classic organic acidurias (MMA, PA), GAMT, GLUT-1, homocystinurias, pterin and neurotransmitter defects, Niemann-Pick disease type C, Wilson disease, galactosemia, cerebral folate deficiency due to FOLR mutations, MoCo deficiency, NKH |
|Spasticity || |
Basic laboratory testsa
Plasma: lactate, pyruvate, ammonium, amino acids, total homocystinuria, folate, biotinidase activity, vitamin E, triglycerides, cholesterol, sterols, peroxisomal studies
Urine: organic acids, amino acids, GAGs, oligosaccharides, sialic acid
CSF: biogenic amines, pterines, and 5-MTHF
Consider lysosomal/mitochondrial/NBIA studies depending on clinical and MRI findings
Consider genes related to HSP and plasma, CSF lipidome
HHH, arginase deficiency,
ornithine aminotransferase deficiency, homocysteine remethylation defects, biotinidase deficiency, cerebral folate deficiencies, dopamine synthesis defects (atypical TH), CTX, vitamin E deficiency
|Peripheral neuropathy || |
Basic laboratory testsa
Plasma: lactate, pyruvate, ammonium, amino acids, folate, vitamin E, triglycerides, cholesterol, acylcarnitines, sterols, peroxisomal studies, transferrin electrophoresis
Urine: amino acids, GAGs, oligosaccharides, thymidine, porphyrins
Consider lysosomal/mitochondrial/NBIA studies depending on clinical and MRI findings
|Refsum disease, X-ALD (treatable at some stages), homocysteine remethylation defects, CTX, abetalipoproteinemia, LCHAD, trifunctional protein, PDH, vitamin E malabsorption, ornithine aminotransferase, serine deficiency |
Storage Syndrome and Conditions with Dysmorphic Physical Findings
A diagnostically challenging group of IEMs are those associated with somatic dysmorphism. These disorders present a challenge because (1) they are rare; (2) they often involve the metabolism of large, water-insoluble metabolites that are technically difficult to isolate and analyze; (3) the defect is often in a relatively inaccessible subcellular organelle (eg, peroxisomes, mitochondria, lysosomes, Golgi, endoplasmic reticulum); (4) the techniques required to demonstrate the presence of the specific biochemical abnormality are difficult to master and often still at an experimental/research step (metabolomics, lipidomics); (5) the basic defect often impairs the synthesis or remodeling of some compound so that substrate accumulation does not occur and therefore cannot help in making a diagnosis; and (6) there are few screening tests that are useful for ruling out entire classes of disorders, such as amino acid analysis for aminoacidopathies. Although the dysmorphism associated with IEM may be severe, with some prominent exceptions, it generally involves disturbances of shape (distortions) rather than fusion or cellular migration defect (disruptions) or abnormalities of number, such as polydactyly (true malformations). The dysmorphism tends to become more pronounced with age, and histologic and ultrastructural abnormalities obtained by tissue biopsy are often prominent.
Symptoms Specific to an Organ or System
IEM can involve any organ or system, in any scenario, at any age. Some of these phenotypes are rare and very distinctive (eg, lens dislocation and thromboembolic accidents in homocystinuria or palmoplantar hyperkeratosis with keratitis in tyrosinemia type II), whereas others are common and rather nonspecific (eg, hepatomegaly, seizures, intellectual disability).
How Does Laboratory Investigation Help?
The definitive diagnosis of IEM is based on a wide range of biochemical studies, many of which are not readily available in community hospitals or in routine diagnostic laboratories. In recent years, biochemical testing has been supplemented by molecular genetic studies, including gene panels and NGS of exomes and genomes. Although molecular testing has undeniably enhanced the investigation of these disorders, the biochemical phenotype remains central to identifying the primary metabolic defect and confirming the pathogenicity of DNA variants. The pattern and extent of tissue involvement often provide important clues to the underlying nature of the condition. Imaging studies, electrophysiologic testing (eg, nerve conduction velocities, brainstem auditory-evoked responses, EEG, electromyography), and histopathologic, histochemical, and ultrastructural studies on biopsied tissue are all useful. Analysis of various metabolic intermediates—such as amino acids, organic acids, acylcarnitines, free fatty acid profile including VLCFA, sterols, neurotransmitters, creatine, purines and pyrimidines, and isoelectrofocusing of serum sialotransferrin—in plasma, urine, and CSF may also provide critical leads to a diagnosis. At this stage of investigation, it is often helpful to consider whether the condition is more likely to be an inborn error of small-molecule metabolism, such as an aminoacidopathy or organic acidopathy, or an organelle disease. This distinction is useful, because the investigation of each group differs, especially with respect to the analysis of metabolic intermediates. In small-molecule diseases, analysis of water-soluble metabolites, such as amino acids and organic acids, is helpful. It is also technically easier than analyzing the high-molecular-weight, often water-insoluble metabolites that accumulate in organelle diseases, such as the lysosomal storage disorders. With amino acid and organic acid defects, a single laboratory test often covers a wide range of diseases and has some of the characteristics of metabolic screening. Recent (and accelerating) progress in metabolomics and lipidomics (still not readily available in current practice) will allow the identification in the near future of many more metabolic signatures, including those of organelle diseases in which secondary accumulation of other high-molecular-weight compounds is common and diagnostically confusing. The diagnostic value of analyzing metabolic intermediates is greatly enhanced in children with small-molecule diseases (intoxication and energy disorders) by provocative physiologic testing such as carefully monitored prolonged fasting. However, this type of investigation is inherently dangerous, and it should only be undertaken under carefully monitored circumstances in a hospital. Ultimately, identifying the biochemical phenotype in children with IEM requires specific analysis of the activity of the mutant gene product, the catalytic protein such as the enzyme or transporter involved. This is particularly true of the organelle diseases in which clinical overlap often creates diagnostic confusion. For example, type 1 Gaucher disease is easily confused clinically with type B Niemann-Pick disease. Confident differentiation requires measurement of the relevant lysosomal enzyme activities in an appropriate tissue, such as leukocytes or cultured skin fibroblasts.
As with all genetic diseases, the highest level of definition of IEM is demonstration of disease-causing mutations in the relevant genes. However, because locus and allelic heterogeneity is often enormous, mutation analysis has been only rarely useful as a first line of investigation. However, mutation analysis does provide powerful confirmation of defects identified on the basis of biochemical data, and the more recent ability to perform whole-exome analysis in an ever shorter time frame (days to weeks) has the potential to have a major impact on patient diagnosis and management. After a mutation is identified as causing disease within a family, testing for the molecular defect provides a relatively simple and reliable method for carrier detection and prenatal diagnosis.
Robert Guthrie pioneered newborn screening in the early 1960s when he developed a test for phenylketonuria (PKU) using a novel bacterial-inhibition assay. Guthrie was also responsible for introducing the use of a dried blood sample on filter paper (the “Guthrie test”). This was followed by further bacterial-inhibition assays to detect other aminoacidopathies (eg, maple syrup urine disease, homocystinuria, urea cycle disorders), but initially, only screening for PKU was widely adopted. In 1975, Jean Dussault described screening for congenital hypothyroidism, and since then, other disorders covered in screening programs have included congenital adrenal hyperplasia, the galactosemias, cystic fibrosis, biotinidase deficiency, glucose-6-phosphate dehydrogenase deficiency, aminoacidopathies, fatty acid oxidation disorders, various lysosomal storage disorders, and most recently peroxisomal disorders. The application of tandem mass spectrometry to newborn screening was first described in 1990, allowing for the quantitation of certain amino acids. Further technical advances led to the use of acylcarnitines as a means for detecting certain organic acidurias and fatty acid oxidation disorders. This new technology has greatly improved both newborn screening and the diagnosis of many IEM.
Aims and Criteria of Newborn Screening
The initial aim of newborn screening was to identify infants who had serious but treatable disorders so as to facilitate interventions to prevent or ameliorate the clinical consequences of the disease. In recent years, with the advent of tandem mass spectrometry—which can detect many disorders at one time, providing the ability for early detection of currently untreatable disorders (see below)—there has been discussion about how screening might benefit families, rather than just individual neonates. The World Health Organization has published guidelines, as has the United States. In the United States, national guidelines, termed Recommended Uniform Screening Panel (RUSP), are established by Secretary’s Advisory Committee on Heritable Disorders in Newborns and Children (SACHDNC) in conjunction with the Department of Health and Human Services. Recommended testing can be divided into “core” and “secondary” conditions, with the latter being disorders identified unintentionally in the course of screening for core disorders. Core disorders are defined as fulfilling the following criteria: there is a specific and sensitive test available, the health outcomes of the condition are well understood, there is an available and effective treatment, and identification of the condition could affect the future reproductive decisions of the family. In reality, the criteria can be reduced to 2 main considerations that would justify screening for any specific disorder: (1) There should be a benefit from neonatal detection, and (2) the overall benefit should be reasonably balanced by the costs of all kinds—the financial costs and the cost of harm, if any, to individuals by early detection of the disorder or by false assignment of a positive or negative result. It is important to remember that newborn screening covers the whole process, from sampling to the appropriate referral of an affected baby for the start of treatment and assessment of overall outcome. Currently, the RUSP is limited to 34 recommended core conditions and 24 secondary conditions. However, individual states define which conditions will be subject to newborn screening, and although the majority of conditions are included in all state programs, there are differences in implementing newer tests such as X-linked adrenoleukodystrophy and various lysosomal storage disorders such as Pompe, Fabry, and Krabbe disease. This in part reflects the advocacy system used by states in defining their screened conditions, where motivated lay groups may influence legislative mandates and competing financial needs and priorities may affect implementation. Online information on each state’s program is available (http://genes-r-us.uthscsa.edu/resources/newborn/newborn_menu.htm).
Cutoff Values for Screening Labs
Determining the cutoff point for each analyte is always a compromise between the aim for perfect sensitivity (detecting all the cases) and keeping the false-negative rate as low as possible. It is important for the laboratory to establish age-dependent cutoff values, as these can vary greatly. Physicians must bear in mind that no screening test is perfect, although some may be close. If clinical presentation suggests a disorder that is included in newborn screening, a diagnostic test should be done, even if the screening test was negative.
Classification of IEM Detected by Newborn Screening
Newborn screening has opened new perspectives in preventive medicine. Disorders of amino acid, organic acid, and fatty acid metabolism are now often detected in the newborn screening laboratory, rather than by the clinical metabolic service. Early detection provides 4 possibilities.
The disorder may present in the first days of life, before any newborn screening result is likely. Disorders in this category include neonatal presentations of urea cycle defects; organic acidemias such as methylmalonic acidemia; classic galactosemia; and, less commonly, almost any of the fatty acid oxidation defects. Detection by newborn screening is unlikely to directly benefit most cases in this category. However, it seems appropriate to include these early presenting disorders in the screening suite, as some may have delayed diagnosis or onset of symptoms. On occasion, a diagnosis may never be made, with the baby having been thought to have died from sepsis.
The disorder may be later presenting, and an effective treatment can beneficially alter the natural history. Cases in this category include the less severe urea cycle disorders; most aminoacidopathies, such as maple syrup urine disease (MSUD); tyrosinemias; homocystinuria; phenylketonuria (PKU); some organic acidemias; and most fatty acid oxidation disorders. The recent possibility to screen for most of the lysosomal disorders from a blood spot now raises the question of whether to extend the newborn screening to those disorders in which a preventive therapeutic effectiveness has been shown, and screening these disorders is being implemented or subjected to pilot studies. This possibility raises many practical, organizational, financial, and ethical questions.
The disorder may be benign, or largely so, and most cases will have no benefit from early diagnosis. It is hard to know yet which cases will fit into this category, but newborn screening, if carefully and sensitively conducted, provides an excellent opportunity for elucidating the natural history of disorders that might fall into this category. Such conditions include 3-methylcrotonyl CoA carboxylase and 2-methylbutyryl CoA dehydrogenase deficiency. Mild forms of several disorders will readily be detected by newborn screening but will not need treatment.
The disorder may be severe and progressive, starting late in life and not being treatable, like many sphingolipidoses. With a few exceptions, these defects are not screened despite the benefits of genetic counseling for at-risk parents.
Screening for Individual Inborn Errors of Metabolism
Well over 50 IEMs can now be detected by newborn screening, with varying degrees of certainty. Only the most frequent IEIM are cited below.
Screening for phenylketonuria (PKU) has been implemented in most developed countries since the late 1960s. The initial test first reported in 1963 was the “Guthrie test,” a bacterial-inhibition assay. Alternative methods that were subsequently developed include fluorimetry and colorimetry. More recently, PKU screening has been done by tandem mass spectrometry (MS), where this is available. Screening in the United States may take place after 24 hours, but elsewhere, testing after at least 48 hours is more typical. Patients under good control of phenylalanine levels by 3 to 4 weeks along with maintenance of good average control have good neuropsychological outcomes. There are still minor deficits, in particular in those with poor dietary compliance, and maternal PKU remains a persistent problem.
Galactose-1-phosphate uridyl transferase (GALT) deficiency, galactokinase deficiency, and galactose epimerase deficiency can all be detected by newborn screening. Methods used in screening include measuring metabolites, galactose, and galactose-1-phosphate, or measuring enzyme activity directly. Enzyme screening for GALT deficiency is the most common approach, but the use of galactose has the advantage of identifying other defects of the Leloir pathway. Moderate metabolite elevations and severely reduced but not absent GALT activity are seen in compound heterozygosity for a severe mutation in the transferase GALT gene and a common “Duarte” mutation. The differentiation is important, as a Duarte/galactosemia compound heterozygotes need no treatment. Despite early identification and treatment, the long-term outcome for severe GALT deficiency (“classic galactosemia”) is not good, with at least half of affected children having early intellectual problems and long-term educational and health complications. There is no evidence that presymptomatic treatment alters outcome, although death may be avoided in neonates who are prone to sepsis. The poor outcomes seen in treated patients reflects the biological complexity of galactose and glycoprotein metabolism, and as a result, not all developed countries screen for the galactosemias.
Disorders of the Urea Cycle
Citrullinemia and argininosuccinic aciduria, either severe or delayed onset, can be diagnosed with high sensitivity by measuring citrulline, although the test will also detect mild, asymptomatic citrullinemia. N-Acetylglutamate synthetase, carbamyl phosphate synthetase, and ornithine transcarbamylase deficiencies cannot be so easily detected due to the fundamental problem of using low concentrations of metabolites to identify disorders. Low citrulline is an indicator of a proximal urea cycle disorder, but a low cut-off for citrulline overlaps with the lower end of normal ranges, especially when citrulline may be low in sick neonates in general. In addition, patients may be well into the disease course before screening results are available.
Problems in the identification of the tyrosinemias reflect the limitations of particular analytes. In tyrosinemia type 1 (fumarylacetoacetate hydrolase deficiency), the blood tyrosine level in newborns is often initially not high, and there is considerable overlap with transient tyrosinemia seen in a significant fraction of newborn. Hence this disorder is usually not detectable by tandem MS without an unacceptable false-positive rate when using tyrosine as the primary analyte. However, combining tyrosine with the disease-specific analyte succinylacetone markedly improves the positive predictive value. Tyrosinemia type 2 is readily detectable but lacks the attendant second metabolite and thus may be missed. Classical MSUD can readily be detected, but milder variant forms may be missed. A result indicating classic MSUD needs to be handled as an emergency since outcomes depend heavily on the early institution of appropriate therapy. Cystathionine β-synthase deficiency (homocystinuria) is currently detected by an elevated methionine level, but there may be a delay in the rise in methionine. Direct detection of homocysteine is a better analyte for identifying both homocystinuria and cobalamin disorders but is not currently achievable due to the fact that the majority of homocysteine is protein bound.
Organic acids that form acylcarnitines can be detected by tandem MS, and a number of organic acid disorders have been so detected. The classic organic acid disorders, methylmalonic (MMA), propionic (PA), and isovaleric acidemias, can readily be detected, although the baby may be symptomatic before newborn screening results are available. An elevation of propionyl carnitine (C3) may indicate PA, MMA, vitamin B12 deficiency secondary to maternal deficiency, or a defect in the formation of adenosylcobalamin such as cobalamin C, D, or F defects. Newborn screening has uncovered an unexpected frequency of cases of 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency, previously thought to be rare. This disorder is 1 of several that appear to be benign in most instances. Biotinidase deficiency can be detected by a specific enzyme assay on dried blood spots that is more sensitive than tandem MS testing, whereas holocarboxylase synthetase deficiency, previously thought to be a more severe early-onset disorder, can be detected based on elevated C3 and C5-OH, and this has led to the recognition of milder and intermittent forms of the disorder. Disorders that do not accumulate acylcarnitines such as the hydroxyglutaric acidurias cannot currently be detected by tandem MS testing.
Fatty Acid Oxidation (FAO) Disorders
Disorders of carnitine uptake, the carnitine cycle, and mitochondrial β-oxidation can be detected by tandem MS testing of acylcarnitine. For several disorders, newborn screening programs have detected more cases than have historically presented clinically. While some of these subjects might never have experienced episodes of decompensation, it is currently not possible to distinguish who is most at risk; by definition, all have a functional defect in oxidation rates. This is especially true of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most frequently occurring FAO disorder, in which the detection rate improved considerably with the inclusion into newborn screening programs, and importantly, the death rate and long-term complications dropped precipitously.
Other disorders often tested for in various combinations in newborn screening programs, but of more importance for general pediatricians or those with other specialties, are congenital hypothyroidism, cystic fibrosis, congenital adrenal hyperplasia (CAH), glucose-6-phosphate dehydrogenase deficiency, hemoglobinopathies, and immunodeficiencies. Newborn screening for critical heart lesions using pulse oximetry and screening for congenital hearing loss are also being broadly adopted.
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