Chapter 138. Disorders of Sulfur-Containing Amino Acid Metabolism

Sulfur-containing amino acids have various roles: They mediate the transfer of methyl groups for virtually all transmethylation reactions; they provide reactive thiol groups that are needed for detoxification of endogenous and exogenous substances; they help maintain the intracellular redox potential; and they are a source of sulphate. Thirteen disorders of sulphur amino acid metabolism have been consistently described, 11 of them potentially leading to disease.

Severe hyperhomocysteinemia, defined as plasma total homocysteine (tHcy) concentrations above 100 μmol/L, is generally caused by single-enzyme deficiencies of homocysteine metabolism. When concentrations of free homocysteine exceed the plasma protein binding capacity, the disulfide homocystine forms nonenzymatically and is excreted in urine, hence causing homocystinuria. The term homocystinuria is sometimes used to indicate the most common form of the disease, which is caused by defective activity of the enzyme cystathionine β-synthase (CBS).1 Homocystinuria, however, results from a defect in CBS and from defects in the folate- and cobalamin-dependent remethylation cycle (see Chapter 147). Severe deficiency of cobalamin or folate can also cause homocystinuria and should always be ruled out.

Homocystinuria should not be confused with mild (tHcy 15 to 30 μmol/l) or moderate (tHcy 30 to 100 μmol/l) hyperhomocysteinemia, which is much more common and is usually caused by nutritional deficiency of folates or cobalamin. It can also occur secondary to systemic or liver and kidney disease, or from medication, often in combination with homozygosity for a common polymorphism in the enzyme.

Clinical Presentation

Classical homocystinuria presents as multisystemic disease with a dysplasia of connective tissue, with a predisposition to arterial and venous thromboembolism, and with mental retardation. Clinical variability is wide,2but presentation is usually in the first decade with the exception of embolism, which occurs later. Homocystinuria is one of the few disorders of amino acid metabolism in which clinical manifestations tend to be progressive in adulthood, because many clinical manifestations result from arteriosclerosis and thrombotic complications.

The most characteristic feature of this disorder is subluxation of the ocular lens, which occurs in almost all untreated individuals until adulthood. Most patients have osteoporosis and skeletal abnormalities similar to those seen in Marfan syndrome, such as tall stature, scoliosis, genu valgum, pes cavus, arachnodactyly, and pectus carinatum or excavatum.3 In homocystinuria, however, the joints tend to be limited in mobility rather than hypermobile. Mental retardation is common, although it is often mild, and many individuals have psychiatric disturbances.4

Metabolic Derangement, Pathophysiology

The disturbance in metabolism resulting in homocystinuria is shown in Figure 138-1. CBS initiates the first step of homocysteine elimination. As a consequence of CBS deficiency, homocysteine, SAH, SAM, and methionine accumulate when methionine intake exceeds the residual transsulfuration and total remethylation activity. Moreover, high SAH inhibits many transmethylases, which increases accumulation of SAM and methionine. Increased homocysteine facilitates remethylation, which leads to further accumulation of methionine. The intermediate metabolites cystathionine and cysteine are decreased. The pathophysiology of CBS deficiency is not yet completely understood, but accumulation of homocysteine plays a major role in the development of vascular damage and thromboembolic complications. Classic tests of clotting function are normal, but elevated homocysteine causes increased platelet adhesiveness, damage to endothelial cells, and proliferation of smooth muscle and fibrous tissue within the vessel wall. Defective cross-linking of collagen fibrils contributes to the connective tissue dysplasia, and structural alterations of fibrillin structures in zonular fibres are causing lens dislocation.5

Genetics

CBS deficiency (OMIM No. 236200) is an autosomal recessive trait. The CBS gene has been mapped to chromosome 21q22.3, and more than 100 different mutations have been identified, most of them being private.6,7 However, two mutations, I278T and G307S, account for 25% to 50% of all affected alleles, depending on the population. A few other mutations, including I278T, are usually associated with pyridoxine responsiveness. Antenatal diagnosis has been performed by assaying CBS activity in cultured amniocytes or cultured chorionic villi. Mutational analysis can be used for prenatal diagnosis once the mutation of the index case is known. The real incidence of CBS deficiency is not known but may vary between 1:20,000 and 1:200,000.8

Diagnostic Tests, Differential Diagnoses

Newborn screening for CBS deficiency has been traditionally done using methionine in dried blood spots.9 This method is not sensitive enough to detect milder, pyridoxine-responsive cases. Screening using tHcy is more sensitive but has a high rate of false positives. Its usefulness in populations with a higher incidence of homocystinuria has recently been demonstrated in the state of Qatar.10 Selective screening for CBS deficiency beyond the newborn age can be done reliably by measuring tHcy in blood. Once hyperhomocysteinemia has been identified, usually in the range of 80 to 300 μmol/L, plasma amino acid chromatography can be used to search for hypermethioninemia and low cystine, cystathionine, and serine concentrations. Defects of folate- and cobalamin-dependent remethylation can be differentiated by a low or normal plasma methionine concentration and increased cystathionine. Increased urinary methylmalonic acid excretion and megaloblastic anemia suggest either concomitant cobalamin deficiency or a defect in cobalamin transport or metabolism. Severe folate or cobalamin deficiency should be ruled out by measuring serum vitamin concentrations (see Table 138-1 and Chapter 147). The diagnosis can be confirmed by measuring enzyme activity in fibroblasts or in phytohemagglutinin-stimulated lymphocytes.

Treatment, Prognosis, and Long-Term Outcome

Approximately half of all CBS-deficient individuals respond with clear biochemical improvement to supplementation with large doses of pyridoxine.11 Responsiveness is determined by the properties of the mutant apoenzyme and should be tested in every patient by administration of pyridoxine for at least a week (500 mg daily in children and 1000 mg per day in adults). Medical treatment aims to control the biochemical abnormalities to prevent complications or halt the progression of symptoms. Early treatment and maintenance of tHcy below 50 μmol/L prevents the patient’s exposure to excessive concentrations of free homocysteine and appears to be associated with a near-normal risk for thromboembolic events, improvement in behavior and IQ, and avoidance of lens dislocation.1 Those who do not respond sufficiently to pyridoxine supplementation need to be treated with a diet low in methionine and supplemented with L-cystine. In addition, the methyl donor betaine should be added to enhance remethylation. Individuals who do not restrict their methionine intake may develop extreme hypermethioninemia with betaine and are at risk for brain edema if methionine exceeds 1000 μmol/L.12 Cobalamin and folate supplementation is advisable to avoid deficiencies. The usefulness of platelet aggregation inhibitors such as acetylsalicylate or dipyridamole has not been demonstrated, but these may have a role in preventing recurrent thromboembolic events. Ascorbic acid has improved endothelial dysfunction in some patients13 and should be considered. Pregnancies of women with CBS deficiency resulted in an increased incidence of thromboembolic events in mothers but no adverse outcome in their children.14

Clinical Presentation

Like individuals with CBS deficiency, those with 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency are at risk for arteriosclerosis and thromboembolism. They have, however, fewer skeletal symptoms, and lens dislocation is not observed.15 Most suffer from gait disturbance, a dysmyelinating encephalopathy, seizures, and mental retardation. Psychiatric disturbances are very common. The phenotype of severe MTHFR deficiency ranges from early neonatal death to nearly asymptomatic adults and is dependent on genetic and environmental modifiers.

Metabolic Derangement, Pathophysiology

MTHFR provides 5-methylfolate for the remethylation of homocysteine, a reaction that is catalyzed by the enzyme methionine synthase and requires cobalamin. MTHFR diverts one-carbon units from nucleotide synthesis to remethylation. Lacking MTHFR causes homocysteine accumulation in many extrahepatic tissues, including the brain. Alternative hepatic remethylation using betaine is enhanced, leading to betaine depletion. Transsulfuration is enhanced and cystathionine accumulates. Methionine and SAM are decreased. The latter may be responsible for the dysmyelination, resembling the one seen in cobalamin deficiency.

Genetics

MTHFR deficiency (OMIM no. 236250) is an autosomal recessive trait caused by biallelic pathogenic mutations in the MTHFR gene on chromosome 1p36.3. More than 30 mostly private mutations have been identified.16 Antenatal diagnosis has been successfully made by enzymatic testing in fetal tissue or by molecular testing. The common polymorphism c.677C>T does confer a thermolabile variant, and homozygotes have a decreased MTHFR activity when their folate status is poor. They may have mild hyperhomocysteinemia but no clinical symptoms. The c.677C>T polymorphism has gained much interest as a possible risk factor for cardiovascular disease and possibly for other multifactorial conditions in the general population.

Diagnostic Tests, Differential Diagnoses

Severe MTHFR deficiency can be suspected in the presence of moderate or severe hyperhomocysteinemia in combination with low-normal methionine and increased cystathionine in the absence of methylmalonic aciduria, megaloblastic anemia, and folate and cobalamin deficiency. The diagnosis must be confirmed with direct enzyme assay in fibroblasts. Molecular testing is available.

Treatment, Prognosis, Andlong-Term Outcome

There is no dietary treatment for MTHFR deficiency, but methionine supplementation can be beneficial.17 For alternative remethylation, an increased supply of betaine can partly compensate for the lack of folate- and cobalamin-dependent remethylation.18 Betaine supplementation is highly effective in preventing disease-associated symptoms when started early in newborns19 and in an animal model of this disease.20 Late-diagnosed patients show an improvement of myelination and neuropsychiatric symptoms on treatment with betaine, but their prognosis is generally poor.

Clinical Presentation

Individuals with MTR or MTRR deficiency share clinical similarities to those with MTHFR deficiency. The have a dysmyelinating encephalopathy that morphologically resembles subacute combined degeneration of the cord found in cobalamin deficiency, and they are often mentally retarded. However, they have two distinct features: (1) early presenting retinopathy and nystagmus and (2) mild macrocytic anemia with megaloblastic changes on bone marrow examination. Failure to thrive has also been observed.21,22

Metabolic Derangement, Pathophysiology

The methylcobalamin cofactor of methionine synthase needs to be reduced by methionine synthase reductase. The metabolic derangement in MTR(R) deficiency is similar to that found in MTHFR deficiency, with the important difference being that it leads to a trapping of one-carbon units as 5-methylfolate. It thus causes a lack of substrate for nucleotide synthesis, which is probably responsible for its additional symptoms. At least three other defects in metabolism or transport of cobalamin (Cbl C, D, F) cause a combined deficiency of both adenosyl- and methylcobalamin and lead to functional methionine synthase deficiency with associated methylmalonic acidemia (see Chapter 147).

Genetics

MTR deficiency (OMIM no. 250940, formerly known as CblG disease) and MTRR deficiency (OMIM no. 602568, formerly known as CblE disease) are autosomal recessive traits caused by two pathogenic mutations in the genes for either MTR (1q43) or MTRR (5p15.3-15.2). Over 20 different mutations have been identified in the MTR gene23-25 and more than 13 in the MTRR gene.26,27 Antenatal diagnosis is possible by enzymatic or mutational testing.

Diagnostic Tests, Differential Diagnoses

The diagnosis of MTR or MTRR deficiency must be confirmed using cultured fibroblasts. A decreased remethylation of homocysteine to methionine can be found by using labeled methylfolate as a substrate and complementation analysis, or mutation testing can be used to differentiate both disorders. The combined cobalamin defects associated with functional MTR deficiency can be differentiated by measuring methylmalonic acid in urine and cobalamin in plasma (see Table 138-1).

Treatment, Prognosis, Long-Term Outcome

Both these disorders are treated with pharmacological doses of parenteral hydroxy- or methylcobalamin. In addition, betaine supplementation promotes alternative remethylation of homocysteine, and L-methionine supplements have been used in acute treatment.28 The metabolic derangement is not completely corrected with this treatment, and individuals who are treated late usually have significant developmental delay and cognitive impairment.29

Clinical Presentation

Cystathioninuria was first reported in two adults with mental deficiency. Subsequently, however, cystathioninuria has been found in numerous individuals who have no clinical signs and is currently considered a benign variant.

Metabolic Derangement, Pathophysiology

A deficiency of the pyridoxal phosphate–dependent enzyme cystathionine -lyase leads to accumulation of cystathionine, which is found in increased amounts in plasma and especially in urine.

Genetics

Cystathionine γ-lyase deficiency (OMIM no. 219500) is inherited as an autosomal recessive trait. An incidence of up to 1:14,000 has been reported. The CTH gene is located on chromosome 1p31.1, and several mutations have been described.30

Diagnostic Tests, Differential Diagnoses

High urinary excretion of cystathionine in the absence of other biochemical abnormalities suggest this disorder. Secondary cystathioninuria due to pyridoxine deficiency, remethylation defects, or systemic disease is known.

Treatment, Prognosis, Long-Term Outcome

Pyridoxine supplementation does improve the biochemical abnormality but is probably not necessary. Pregnancies in women with cystathionase deficiency had a normal outcome.31

The terminal step in the oxidative degradation of cysteine and methionine, the conversion of sulfite to sulfate, is catalyzed by the molybdenum-containing enzyme sulfite oxidase. Sulfite oxidase deficiency can be caused by a defect in the gene for the apoenzyme itself or by defects in the synthesis of the molybdenum cofactor required for its function.

Clinical Presentation

The classical presentation is that of a severe neonatal epileptic encephalopathy, muscular hypo- or hypertonia, progressive microcephaly, and developmental arrest. Early death is frequent. Lens dislocation is an early finding.32 A milder presentation has been described with mental retardation and regression and slowly progressive dystonic and choreoathetotic movement disorder.33,34

Metabolic Derangement, Pathophysiology

Sulfite oxidase functions in the last step of oxidative degradation of the sulfur-containing amino acid cysteine. Deficiency results in increased amounts of the toxic compound sulfite, together with its endogenous detoxification products thiosulfate and S-sulfocysteine in the urine.35

Genetics

Sulfite oxidase deficiency (OMIM no. 272300) is an autosomal recessive trait. The SUOX gene is located on chromosome 12q13.2, and more than 20 mutations have been reported.34,36

Diagnostic Tests, Differential Diagnoses

Increased urinary sulfite can be detected in fresh urine using commercial strip tests normally utilized for wine making. Mild cases may not excrete increased amounts of sulfite. Sulfocysteine can be detected by amino acid chromatography, which usually shows low cystine concentrations as well. Thiosulfate measurement requires a specific chromatographic technique. Normal uric acid and normal urinary xanthine concentration excludes a combined defect, molybdenum cofactor deficiency. Sulfite oxidase deficiency can be confirmed in cultured fibroblasts or liver tissue.

Treatment, Prognosis, Andlong-Term Outcome

Treatment is purely to ease symptoms and so far has not altered the early lethal course.

Clinical Presentation

The clinical picture is similar to isolated sulfite oxidase deficiency. In addition, kidney stones may develop.

Metabolic Derangement, Pathophysiology

The molybdenum cofactor is required for three enzymes: aldehyde oxidase, xanthine dehydrogenase, and sulfite oxidase. The brain pathology is believed to result from defective sulfite oxidase activity. Xanthinuria may lead to xanthine stones.37

Genetics

Molybdenum cofactor deficiency (OMIM no. 252150) may result from defects in three different genes: (1) MOCS1 (6p21.3), which encodes two enzymes for the synthesis of the precursor; (2) MOCS2 (5q11), which encodes molybdopterin synthase that converts the precursor into the organic moiety of molybdenum cofactor; and (3) GEPH (14q24), which encodes the gephyrin gene. Gephyrin catalyzes the insertion of molybdenum into molybdopterin. More than 20 mutations in MOCS1 and MOCS2 and a deletion in GEPH have been identified in affected individuals.38,39

Diagnostic Tests, Differential Diagnoses

In addition to the typical finding of sulfite oxidase deficiency, very low uric acid levels in blood and urine are a clue to this condition. In molybdenum cofactor deficiency, the urinary excretion of hypoxanthine and xanthine is highly elevated. Molybdenum cofactor deficiency can be confirmed in cultured fibroblasts or liver tissue or with mutational testing.

Treatment, Prognosis, Long-Term Outcome

All therapeutic attempts made so far failed to alter the course of this disease in humans. Precursor replacement and gene-transfer mediated expression of a mocs1 minigene were successfully used in a lethal MOCS1-deficient animal model.40 GEPH-deficient individuals may benefit from molybdate supplementation.

Clinical Presentation

In the few affected individuals identified so far, abnormal findings included a history of neonatal cholestasis, retarded psychomotor development, failure to thrive, muscular hypotonia with myopathy and cardiomyopathy, and poor synthetic liver function with mild hepatitis on biopsy. Brain white matter atrophy and delayed myelination were found, and CK and transaminases were elevated.41

Metabolic Derangement, Pathophysiology

Plasma S-adenosyl-L-homocysteine (SAH) is grossly elevated, but tHcy (total plasma homocysteine) is only slightly increased. An accumulation of SAM (S-adenosyl methionine) and methionine occurs from the inhibitory regulatory function of SAH on many transmethylases. Plasma tyrosine is not increased. A deregulation of biological methylation is believed to be the main pathogenic factor.

Genetics

SAH hydrolase deficiency (OMIM no. 180960) is an autosomal recessive trait. The AHCY gene is located on chromosome 20cen-q13.1, and several mutations have been identified. Antenatal diagnosis has not been reported but should be possible from chorionic villi or mutational testing.

Diagnostic Tests, Differential Diagnoses

Hypermethioninemia and hypertransaminasemia are unspecific signs of liver dysfunction and are also found in metabolic disorders such as galactosemia, hereditary hepatorenal tyrosinemia, and CBS deficiency. Amino acid analysis can confirm isolated hypermethioninemia, which is found only in methionine adenosyltransferase deficiency or in glycine-N-methyltransferase deficiency. The measurement of tHcy, SAH, and SAM allows for further differentiation. The diagnosis can then be confirmed by measuring SAH hydrolase activity in red blood cells, cultured fibroblasts, or liver tissue.

Treatment, Prognosis, Long-Term Outcome

Treatment with methionine restriction and supplementation with creatine and phosphatidylcholine improved muscle strength and mental responsiveness. The long-term outcome is not known.

Clinical Presentation

Over 50 individuals have been reported with confirmed methionine adenosyltransferase (MAT) deficiency. Most have some residual enzyme activity and no clinical abnormalities; however, neurological abnormalities and demyelination have been reported in rare cases with almost complete loss of enzyme activity.42-44

Metabolic Derangement, Pathophysiology

Methionine needs to be activated by MAT to become the methyl donor SAM. Deficiency of the hepatic MAT isoforms (MAT I/III) results in isolated hypermethioninemia and mild hyperhomocysteinemia.45 SAM concentrations in plasma are low-normal due to the presence of a second isoform, MAT II, in nonhepatic tissues. The insufficiency of transferable methyl groups impairs transmethylation and may be responsible for demyelination in severe cases. Methionine accumulation promotes the transamination of methionine to 4-methylthio-3-oxobutyrate and dimethyl sulfide. The latter causes a distinct rotten-egg odor of the breath.

Genetics

MAT deficiency (OMIM no. 250850) is caused by mutations in the MAT1A gene, which is located at chromosome 10q22 and is inherited in an autosomal recessive manner. It has been hypothesized that a dominant negative effect of a heterozygous mutation on oligomerization of the enzyme may explain the dominant inheritance that was observed in one family. More than 17 mutations within the MAT1A gene have been described.43

Diagnostic Tests, Differential Diagnoses

Persistent isolated hypermethioninemia with low-normal SAM makes this diagnosis very likely. Premature babies with a high consumption of methionine and a developmentally low activity of MAT, CBS, or cystathionase, or term babies with neonatal hepatitis may have transient isolated hypermethioninemia. The diagnosis can be confirmed by enzyme assay in a liver biopsy or by mutational testing.

Treatment, Prognosis, Long-Term Outcome

SAM supplementation is biochemically effective for individuals who have severe MAT deficiency or who are symptomatic with neurological symptoms or demyelination. Long-term outcome is generally good. Affected women have reproduced without complications.46

The synthesis and recycling of the sulfur-containing tripeptide glutathione involves a series of six enzymatic reactions termed the γ-glutamyl cycle. Glutathione has different important biological functions (eg, transporting amino acids, detoxifying free radicals and drugs, reducing reactions, and synthesizing other biomolecules). Deficiencies in four of the enzymes of the gamma-glutamyl cycle are associated with disease (see Table 138-2), two of which manifest with hemolytic anemia. The most frequently recognized and most severe disease is glutathione-synthetase deficiency.47

Clinical Presentation

Two clinically distinct forms of glutathione synthetase deficiency (GSSD) are known: a rare mild erythrocytic form that manifests as mild hemolytic anemia and that can be associated with splenomegaly,48 and a more frequent generalized form that is associated with a variable degree of early neonatal metabolic acidosis, jaundice, and hemolytic anemia. The condition stabilizes beyond the neonatal period but catabolic crises, triggered by infection and inadequate fluid and energy intake, can lead to life-threatening episodes of metabolic acidosis and electrolyte disturbance. Chronic progressive CNS damage with mental retardation, ataxia, spasticity, and seizures are frequently observed. Some patients have increased susceptibility to bacterial infections due to a compromised granulocyte function.49

Metabolic Derangement, Pathophysiology

GSS catalyzes the second step in glutathione synthesis from γ-glutamylcysteine and glycine. GSSD leads to glutathione deficiency and, due to the lacking negative feedback of glutathione on the preceding enzyme, γ -glutamylcysteine synthetase, leads to an overproduction of γ-glutamylcysteine, which is converted to 5-oxoproline (pyroglutamic acid). Excessive 5-oxoproline cannot be readily metabolized, and its accumulation leads to metabolic acidosis.

Genetics

Glutathione synthetase deficiency (OMIM no. 266130) is an autosomal recessive trait. The GSS gene is located on chromosome 20q11.3, and more than 30 mutations were identified in over 40 patients. There was no clear genotype-phenotype correlation.50 Antenatal diagnosis has been successfully performed by measuring 5-oxoproline in amniotic fluid.

Diagnostic Tests, Differential Diagnoses

Urine organic acid analysis can readily detect 5-oxoproline in newborns with metabolic acidosis without ketosis, hypoglycemia, or hyperlactic acidemia. The diagnosis can be confirmed by assay of enzyme activity in blood cells or cultured fibroblasts. Oxoprolinuria secondary to severe depression of glutathione levels has been described in various other conditions such as intoxication with acetaminophen, primary or secondary hyperhomocysteinemia, or in patients with a decompensated urea cycle defect.47

Treatment, Prognosis, Long-Term Outcome

Therapy aims at repleting intracellular glutathione levels and antioxidant activity. Early supplementation of vitamins C and E may be beneficial.51 Secondary glutathione depletion due to treatment with drugs that need glutathione for detoxification must be avoided. These are the same known to induce hemolysis in the much more common glucose-6-phosphate dehydrogenase deficiency.

Clinical Presentation

Gamma-glutamylcysteine synthetase deficiency (GCS-D) has been found in a small number of individuals with hemolytic anemia. It is not clear whether additional symptoms, such as peripheral neuropathy, myopathy, cerebellar involvement, and hyperaminoaciduria, that were found in a subset of patients are part of this disorder.52

Metabolic Derangement, Pathophysiology

GCS catalyzes the first and rate-limiting step in glutathione synthesis—converting glutamate and cysteine to γ-glutamylcysteine. Intracellular glutathione and gamma-glutamylcysteine concentrations are low.

Genetics

Gamma-glutamylcysteine synthetase deficiency (OMIM no. 230450) is an autosomal recessive trait. Mutations in the GCLC gene on chromosome 6p12 coding for the catalytic unit were identified.53 A modifier subunit is coded by the gamma-GCLM gene on chromosome 1p22.1.54

Diagnostic Tests, Differential Diagnoses

Glutathione and gamma-glutamylcysteine concentrations in erythrocytes, cultured lymphoblasts, or fibroblasts are low. The diagnosis can be confirmed by enzyme activity assay in erythrocytes to distinguish from glutathione synthetase deficiency.

Treatment, Prognosis, Long-Term Outcome

There is no known therapy established. Medication leading to glutathione depletion such as those precipitating hemolysis in glucose-6-phosphate dehydrogenase deficiency should be avoided.

Clinical Presentation

This extremely rare disorder is associated with mental retardation and seizures in a subset of individuals, but the causal relationship has not been established.55,56

Metabolic Derangement, Pathophysiology

Gamma-glutamyl transpeptidase (GGT) cleaves glutathione and catalyzes the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors. The enzyme is located on the outer surface of the cell membrane, where it is widely involved in absorption and secretion, especially of amino acids. Affected individuals have increased plasma glutathione concentrations and grossly increased glutathione excretion in urine.57

Genetics

GGT deficiency (OMIM no. 231950) is an autosomal recessive trait. At least four different GGT genes are located on chromosome 22q11.1-q11.2, and pseudogenes have been described.

Diagnostic Tests, Differential Diagnoses

Glutathione excretion can be detected by amino acid analysis in urine. Enzyme activity measurements in leukocytes or cultured fibroblasts is possible.

Treatment, Prognosis, Long-Term Outcome

There is no specific treatment known.

Clinical Presentation

There is no consistent clinical picture of this very rare disorder.

Metabolic Derangement, Pathophysiology

The enzyme 5-oxoprolinase cleaves oxoproline to yield glutamate. This is the last step of the glutathione cycle. The accumulating oxoproline is excreted in urine and is not sufficient to cause metabolic acidosis such as in glutathione synthetase deficiency.47,58

Genetics

The genetic basis for 5-oxoprolinase deficiency (OMIM no. 260005), an inherited autosomal recessive trait, has not been thoroughly studied yet.

Diagnostic Tests, Differential Diagnoses

Gas chromatographic analysis can measure 5-oxoproline excretion in urine. The diagnosis can be confirmed and distinguished from glutathione synthetase deficiency or secondary oxoprolinuria by enzyme activity assay in leukocytes or cultured fibroblasts.

Treatment, Prognosis, Long-Term Outcome

There is no specific treatment available.