Cystathioninuria

A number sign (#) is used with this entry because cystathioninuria is caused by homozygous or compound heterozygous mutation in the gene encoding cystathionine gamma-lyase (CTH; 607657) on chromosome 1p31.

Description

Cystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).

Biochemical Features

During a survey by paper chromatography of amino acids in the urine of patients in an institution for mental defectives, Harris et al. (1959) discovered a case with abnormal excretion of cystathionine. An inborn error involving the cleavage of cystathionine to give cysteine and homoserine was suggested. The subject was a severely retarded female, aged 64 years at the time of study. However, the metabolic disorder may have been fortuitously associated with mental retardation. Another case was studied at The New York Hospital. Other clinical manifestations have been clubfoot, developmental defects about the ears, convulsions, and thrombocytopenia. Urinary lithiasis also occurs.

Mongeau et al. (1967) described the case of a 2-year-old boy with normal mentality, thrombocytopenia, and urinary calculi. The relation of the latter two features to the metabolic defect was problematic. Both parents (who were apparently unrelated) showed cystathioninuria after methionine loading test. With administration of pyridoxine, cystathioninuria was diminished in the proband.

Schneiderman (1967) studied 2 mentally retarded brothers who excreted large amounts of cystathionine after methionine ingestion. The mother and another brother excreted lesser but abnormal amounts after methionine loading. The father was not tested.

Perry et al. (1968) discovered cystathioninuria in a brother and sister when the brother's urine was by chance subjected to 2-dimensional paper chromatography for amino acids. Both children were normal. The parents excreted cystathionine only after methionine loading. The authors suggested that mental defect and other disorders reported in association with cystathioninuria may have been coincidental. Whelan and Scriver (1968) also found cystathioninuria as an apparently benign inborn error.

Observations of cystinuria in connection with neuroblastoma (Klein et al., 1987) may derive from a secondary effect of the tumor process. Among cases of primary cystathioninuria, there are biochemical differences, such as variable response to methionine loading and/or B-vitamin treatment, suggesting the possibility of molecular genetic heterogeneity (Pascal et al., 1978; Tada et al., 1968).

Espinos et al. (2010) reported 3 unrelated Spanish girls with cystathioninuria. They were investigated because of neurologic problems, and the relationship between the cystathioninuria and clinical abnormalities may have been due to ascertainment bias. Two girls had mental retardation, 1 with seizures, and 1 had normal intelligence but showed tremor. All had increased urinary cystathionine at the time of the study. Two had mildly increased plasma homocysteine. Oral pyridoxine treatment normalized the biochemical parameters, but resulted in only partial clinical improvement in the 2 mildly affected individuals. None of the patients had sibs, and all parents were unaffected.

Pathogenesis

Frimpter (1965) showed that the defect involves cystathionase that does not properly bind its coenzyme, pyridoxal phosphate. In vitro studies suggested that high pyridoxine would be therapeutically beneficial.

Population Genetics

Screening surveys of neonatal urine samples have estimated the prevalence of cystathioninuria at 1 per 14,000 live births (Wong et al., 1979), with somewhat lower incidence in other reports (Wilcken et al., 1980; Lemieux et al., 1988).

Molecular Genetics

From genomic DNA, Wang and Hegele (2003) sequenced the CTH gene in 4 unrelated probands with cystathioninuria. They found 2 nonsense and 2 missense mutations (607657.0001-607657.0004). All affected subjects were either homozygotes or compound heterozygotes.

Tadiboyina et al. (2005) reported 3 patients from 2 apparently unrelated Old Colony Mennonite families, each of whom had the hepatocerebral form of mitochondrial DNA depletion syndrome (251800) together with cystathioninuria. All 3 children were homozygous for a missense mutation (601465.0007) in the DGUOK gene, for which the parents were heterozygous, but no mutations were identified in the CTH gene in any subject. Tadiboyina et al. (2005) suggested that the hepatocerebral form of mtDNA depletion syndrome might be associated with secondary cystathioninuria.

Espinos et al. (2010) identified a homozygous mutation in the CTH gene (T67I; 607657.0003) in 3 unrelated Spanish girls with cystathioninuria. Haplotype analysis of these 3 patients and of 2 Czech patients with the mutation suggested a founder effect, and the mutation was estimated to be 7,336 years (262 generations) old. The event may have occurred during the spread of the European population in the Neolithic era. Espinos et al. (2010) noted that T67I, which is the most common change in the CTH gene and has been observed in heterozygous state in 1.5% of controls in the Czech population, has been considered a polymorphism (rs28941785).

Animal Model

Ishii et al. (2010) found that Cth-null mice mice developed normally and did not show hypertension. Both male and female mutant mice showed hypercystathioninemia and hyperhomocysteinemia, but not hypermethioninemia. Ishii et al. (2010) also found that Cth-null mice developed acute skeletal muscle atrophy and myopathy resulting in severe paralysis and death when fed a low cysteine diet. Both Cth-null mice and hepatocytes derived from these mice showed increased vulnerability to oxidative injury. Glutathione levels were reduced in liver and skeletal muscle. The findings indicated that cysteine is an essential amino acid in Cth-null mice. Ishii et al. (2010) postulated that the severe myopathy in Cth-null mice may be present in unknown cases of human CTH deficiency, and noted that these patients may have hyperhomocysteinemia, which may be an independent risk factor for disease.