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Organic Amino Acidurias
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A number of disorders involving amino acid metabolism result in similar symptoms and can be identified via urinary organic acid analysis. A number of different disorders exist and are similar though not directly related. The most important consideration is to recognize the general classification of the disorder by its symptom complex. The urinary organic acid panel can be obtained to identify the exact metabolic defect.12
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All the organic acidurias are inherited in an autosomal recessive fashion and begin during infancy. A number of characteristics are common to the organic acidurias including vomiting, anorexia, lethargy, ketoacidosis, dehydration, hyperammonemia, neutropenia, and failure to thrive.13,14 Several neurological manifestations also arise, including seizures, hypomyelination, mental retardation, and coma. Without treatment, these are potentially life-threatening disorders.
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Hyperammonemia and hyperglycinemia are common amongst the amino acudurias. Urine and serum organic acid panels can be used to identify the specific disorder.15
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Specific Organic Acidurias
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Proprionic acidemia is associated with hypotonia, infantile spasms, hypsarrhythmia, and myoclonus in addition to the signs and symptoms common to all the organic acidurias. Treatment includes a diet low in valine, isoleucine, methionine, and threonine. Carnitine supplementation is also necessary.16,17
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Methylmalonic aciduria typically becomes symptomatic in the first week of life with vomiting, hypotonia, and metabolic acidosis. This may be followed by spascticity, dystonia, strokes, chorea, and developmental delay. The principle treatment is supplemental vitamin B12. If the patient does not respond to Vitamin B12, then a low-protein diet with supplemental L-carnitine may be required.16,17
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Patients with isovaleric aciduria typically have a strong odor of urine and stale perspiration. Pancytopenia may also complicate the clinical course. Oral glycine supplements are the primary treatment.
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Just as in the organic aminoacidurias, the family of glutaric acidurias is composed of several unrelated diseases.
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Glutaric Aciduria Type I
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Biochemistry and Clinical Characteristics
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Glutaric aciduria type I (Box 23-4) is an autosomal recessive disorder that begins in infancy. The condition presents with a variety of manifestations. Some patients present with an early neurodegenerative disorder with hypotonia, chorea, and seizures. Others have relatively normal early development until the deterioration is suddenly triggered. Macrocephaly is present in 70% and developmental delay is common.16,17
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Evaluation and Pathology
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The evaluation of glutaric aciduria type I reveals abnormal urine and serum organic acids. Enzyme assays are also helpful in the diagnosis. Neuroimaging reveals cortical atrophy, gliosis in the caudate and putamen, and atrophy of the caudate.
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Treatment consists of a low-protein diet, carnitine supplements, and riboflavin supplements. The diet should, however, be high in calories and low in lysine and tryptophan.
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Glutaric Aciduria Type II
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Biochemistry and Clinical Characteristics
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Glutaric aciduria type II (Box 23-5) is also an autosomal recessive (AR) disorder that has several different courses depending on the subtype. There are three subtypes: neonatal with congenital abnormalities, neonatal without congenital abnormalities, and late-onset form. Neonatal glutaric aciduria type II presents with severe metabolic acidosis, cardiomyopathy, and hypoglycemia. The physical features associated with glutaric aciduria type II include macrocephaly, high forehead, flat nasal bridge, and malformed ears.
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Evaluation and Pathology
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The evaluation of glutaric aciduria type II reveals abnormal urine and serum organic acids. Enzyme assays are also helpful in the diagnosis. Neuroimaging reveals agenesis of the cerebellar vermis and hypoplasia of the temporal lobes.
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Treatment consists of a high-carbohydrate, low-fat, low-protein diet. Carnitine supplements and riboflavin supplements may be of benefit.
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Biochemistry and Clinical Characteristics
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Phenylketonuria (PKU) is an autosomal recessive disorder (Table 23-2, Box 23-6) that results in decreased phenylalanine hydroxylase (conversion of phenylalanine to tyrosine). Patients born with phenylketonuria appear normal at birth, but symptoms begin shortly after birth and after exposure to phenylalanine.18,19 Vomiting is one of the first symptoms. By several months of age, the patients have developmental delay, with seizures in the more severely affected. In untreated patients, a variety of physical signs are noted, including fair skin, blue eyes, blonde hair, hyperreflexia, hyperkinetic activity, photosensitivity, eczema-like rash, and a musty body odor. Malignant PKU, the stiff baby variant, results from dihydropterin reductase (biopterin) deficiency.
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Evaluation and Pathology
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The phenylalanine screen is positive if phenylalanine level is more than 20 mg/dL. The level should be checked at birth and at 2 weeks of age. If phenylalanine levels are high, a biopterin screen should be obtained. Tyrosine levels are low.
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In the untreated, the EEG often reveals paroxysmal activity and hysarrhythmia. The EEG may be normal in the treated patients. Imaging findings remain abnormal even when treated. The MRI reveals atrophy and increased T-2 signal intensity in the posterior deep white matter. There is also decreased metabolism in the caudate and putamen.20
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Treatment consists of a low-phenylalanine diet for PKU. Infants with malignant PKU require treatment with supplemental biopterin. Even with treatment, malignant PKU has a poor prognosis.21-23
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Nonketotic Hyperglycinemia
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Biochemistry and Clinical Characteristics
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The nonketotic hyperglycinemias (Box 23-7) are a relatively common group of disorders with widely variable genetics, phenotypes, and severities.24 There are five reported forms of the disease, with four arising during infancy or childhood. The neonatal form is the most common. This form consists of initial hypotonia progressing to hypertonia. Seizures are a common complication. The condition typically progresses to coma, respiratory arrest, and death. Survivors have severe developmental delay and mental retardation.24,25
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A rare, transient form appears to occur in some patients who are heterozygous for the disease. These patients have a brief, self-limited syndrome that is clinically similar to the more common neonatal form. The late infantile form typically arises toward the end of the first year, with cognitive decline, decerebrate posturing, and extrapyramidal findings. The juvenile form is associated with mild mental retardation and language dysfunction.
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Evaluation and Pathology
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Nonketotic hyperglycinemia is rarely identified on newborn screening.26 Laboratory evaluation requires spinal fluid evaluation. Elevation of the CSF glycine/serum glycine ratio (ratio > 0.10) is diagnostic. The EEG can reveal burst suppression, hypsarrhythmia, or focal epileptiform discharges. Neuroimaging reveals atrophy and hypomyelination.27
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The principle treatment is supportive care and treatment of the seizures with antiepileptic medication.
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Biochemistry and Clinical Characteristics
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The disorders of the urea cycle all result in hyperammonemia and therefore have similar symptom complexes (Table 23-3).28-30 Symptoms usually arise during the neonatal period. These conditions should always be considered when an infant's ammonia level is elevated. Carbamoyl phosphate synthetase deficiency is the most severe of the urea cycle defects. When the enzyme is completely absent, it is usually fatal. Partial absence or dysfunction of the enzyme results in variable degrees of severity. The clinical presentation includes coma, seizures, hypotonia, respiratory arrest, occasional intracranial hemorrhages, vomiting, and death without treatment. Some patients, especially with milder forms of the disease, may be normal with early treatment.
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Evaluation and Pathology
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Disorders of the urea cycle are usually associated with dramatic elevations of serum ammonia, often more than 500 mg/dL.31 Increased glutamine levels are found on serum amino acid testing. Hepatic function studies typically reveal elevated AST and ALT levels. Neuroimaging studies reveal cerebral edema with occasional intracranial hemorrhage. A number of findings are common on microscopic pathologic evaluation including cerebral edema, Alzheimer type II cells, decreased myelination, and neuronal loss. Alzheimer type II cells are not common in carbamoyl phosphate synthetase deficiency, most likely because it is often rapidly fatal.
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Treatment consists primarily of hemodialysis to decrease ammonia and dietary restriction of nitrogen (low-protein diet). Valproate should be avoided for seizures since this drug increases ammonia production.32
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Renal Amino Acid Transport
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Biochemistry and Clinical Characteristics
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Hartnup disease (Box 23-8) is a familial disorder of renal amino acid transport caused by defective Na-dependent neutral amino acid transport in the small intestine and renal tubules, leading to increased fecal and urinary amino acid excretion.33 The symptoms begin during infancy. The clinical presentation is highly variable, with failure to thrive, a photosensitive scaly rash, intermittent ataxia, personality changes, nystagmus, and a tremor.34 The symptoms tend to improve with age; in some cases there is slow progression.
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Evaluation and Pathology
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Intermittent cerebral symptoms should suggest the diagnosis. Laboratory studies may reveal low serum tryptophan on neutral amino acid screening.
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Treatment includes a high-protein diet with nicotinic acid supplements (niacin). Tryptophan ethylester can also be of benefit. There is, however, a general improvement with increasing age.
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Lowe Syndrome (Oculocerebrorenal Syndrome)
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Lowe syndrome (Box 23-9), a disorder of renal amino acid transport, is thought to be caused by a membrane transport defect. It is transmitted in an X-linked recessive pattern.35 The symptoms typically begin during the neonatal period. The clinical presentation includes mental retardation and developmental delay, glaucoma, cataracts, myopathy, and pendular nystagmus.36 In addition, punctate cortical lens opacities may be the only sign in heterozygote female carriers. Death usually occurs secondary to renal failure. Pathology reveals loss of both central and peripheral myelinated fibers.
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Maple Syrup Urine Disease
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Biochemistry and Clinical Characteristics
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Maple syrup urine disease (Box 23-10) is a disorder of branched- chain amino acid metabolism secondary to a defect of alpha-ketoacid dehydrogenase deficiency resulting in abnormal oxidative decarboxylation.37 It is inherited in an autosomal recessive pattern. The symptoms typically begin during the neonatal period. The clinical presentation includes hypertonia, opisthotonos, fluctuating ophthalmoplegia that correlates with serum leucine levels, clonus, generalized seizures, and developmental delay.38 The patient eventually becomes flaccid and areflexic. Coma ensues without treatment. Conversely, the prognosis is good and the patient may have a normal IQ if treatment is instituted within 5 days.
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Evaluation and Pathology
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Laboratory evaluation reveals elevated branched-chain amino acids (leucine, isoleucine, and valine) on serum amino acid screening. Approximately 50% of patients develop severe hypoglycemia. The urine has a characteristic odor and tests positive for 2,4-dinitrophenylhydrazine (DNPH).39 Imaging during the acute phase reveals cerebral edema greatest in cerebellar deep white matter and brainstem. Pathologic specimens reveal white matter cystic degeneration and gliosis.
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Treatment consists of thiamine supplementation and dietary restriction of branched-chain amino acids.40
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Biochemistry and Clinical Characteristics
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Homocystinuria (Box 23-11) is a genetic disorder of homocysteine metabolism with AR inheritance (chromosome 21). Cystathionine beta synthase deficiency results in accumulation of homocysteine and methionine.41 There is also impaired methylation of homocysteine to methionine from enzyme deficiency or cofactor B12 deficiency. The onset and severity of symptoms are variable. The clinical presentation includes marfanoid habitus and codfish vertebra (biconcave). Ocular anomalies include ectopia lentis (lens displaced downward) in 90% of patients, myopia, glaucoma, and optic atrophy. Central nervous system complications include mental retardation, seizures, behavioral disorders, and stroke (beginning at age 5 to 9 months).42
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Evaluation and Pathology
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Laboratory evaluation reveals increased homocysteine on serum and urine amino acids, and a positive methionine challenge test. Pathologic evaluation reveals intimal thickening and fibrosis of blood vessels leading to arterial and venous thrombosis.
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Treatment consists of dietary restriction of methionine, pyridoxine supplements, vitamin B12 supplements, and cysteine supplements.