Homocystinuria-Megaloblastic Anemia, Cblg Complementation Type

A number sign (#) is used with this entry because homocystinuria-megaloblastic anemia, cblG complementation type, is caused by homozygous or compound heterozygous mutation in the MTR gene (156570) on chromosome 1q43.

Description

Homocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase. Clinical features are somewhat variable, but include delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE (236270) and CblG (Watkins and Rosenblatt, 1988). Most patients present in early infancy, but some patients with CblG have shown later onset (Outteryck et al., 2012). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (summary by Leclerc et al., 1996).

CblE is caused by mutation in the MTRR gene (602568).

Watkins and Rosenblatt (1989) commented on the clinical and biochemical heterogeneity in patients with cblE and cblG.

Clinical Features

Thomas et al. (1985) and Rosenblatt et al. (1987) reported a boy with methylcobalamin deficiency who presented at age 6 weeks with lethargy, staring spells and vomiting after varicella infection. He was hypotonic and unresponsive to stimuli and required intubation and ventilation. Findings included homocystinuria, hypomethioninemia, megaloblastic anemia, and normal serum folate and B12 levels. No methylmalonic aciduria was detected. Skin fibroblasts could not grow when methionine was replaced by homocysteine in the medium. Clinical response to vitamin B12 (hydroxocobalamin) was dramatic, with disappearance of homocystine and rise in blood methionine. Although the patient was originally thought to have CblE, methionine synthetase activity was decreased in patient fibroblasts when the assay was performed under both optimal and suboptimal reducing conditions, consistent with CblG.

Gulati et al. (1996) analyzed cell lines derived from 2 cblG patients: 1 patient had onset in the first 4 months of life of severe neurologic dysfunction and homocystinuria, but no megaloblastic anemia, whereas the other patient had mental retardation, macrocytic anemia, and homocystinuria.

Leclerc et al. (1996) studied cell lines from 2 Caucasian boys with methylcobalamin deficiency. One presented at age 3 months with failure to thrive, severe eczema, megaloblastic anemia, methylmalonic aciduria, homocystinuria, and methylmalonic aciduria; the other presented at age 4 years with developmental delay, tremors, gait instability, megaloblastic anemia, and homocystinuria.

Kvittingen et al. (1997) reported a child with methionine synthase deficiency who presented with neonatal homocystinuria, hypomethioninemia, and severe neurologic symptoms, including developmental delay and seizures. Over an 8-year period both off and on treatment, the patient did not develop megaloblastic anemia. The activity of methionine synthase in fibroblasts was severely deficient, and formation of methylcobalamin from labeled cyanocobalamin was very low. Complementation studies indicated a cblG defect. In addition, the patient was homozygous for the 677C-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene (607093.0003). Kvittingen et al. (1997) hypothesized that the MTHFR polymorphism protected the patient against anemia, and speculated that homozygosity for the MTHFR 677C-T mutation may cause the dissociation between hematologic and neurologic disease seen in some patients with vitamin B12 deficiency.

Wilson et al. (1998) reported a brother and sister what they termed the 'cblG variant form' of methionine synthase deficiency, defined as no detectable methionine synthase activity and lack of binding of the cobalamin cofactor to the enzyme. The boy developed generalized seizures at 3 days of age, became progressively hypotonic, and developed respiratory failure at 10 weeks of age. An initial diagnosis of methylenetetrahydrofolate reductase (MTHFR) deficiency (236250) was made on the basis of elevated plasma and urine homocysteine but low plasma methionine without macrocytic anemia. With treatment based on that diagnosis, he was well enough to be weaned from the respirator by 14 weeks of age. At 2 years of age, he had severe psychomotor retardation and microcephaly. A definitive diagnosis of methionine synthase deficiency was made by means of complementation analysis of cultured fibroblasts, which placed him in the cblG complementation group. He was subsequently treated with vitamin B12, betaine, and aspirin, and, at age 8 years, methionine was added. He required femoral osteotomies and bilateral adductor- and heel-cord release for neuromuscular hip dislocations and contractures. At age 10 years, he had short stature, microcephaly, rotary nystagmus, thin fingers, and spasticity. He smiled but was not able to sit or speak. The younger sister was found to have elevated plasma homocysteine and low methionine at 6 days of age. She also was presumed to have MTHFR deficiency and was started on therapy for that, but medications were discontinued by her mother after a few days because the child appeared to be doing well. At 3 months of age, she had seizures and respiratory distress, and medication was restarted. By 18 months of age, she was microcephalic and severely developmentally delayed. The diagnosis of cblG was established at 2 years of age, and she was treated in the same manner as her brother. At 9 years, she had short stature, microcephaly, rotary nystagmus, and pes planus. She was able to walk, responded to simple commands, and could speak a few words. Wilson et al. (1998) reported another boy with the so-called cblG variant. He presented with short stature, failure to thrive, progressive weakness, hypotonia, ocular nystagmus, jaundice, feeding difficulties, and diarrhea at 7 to 10 weeks of age (Wildin and Scott, 1992). He had severe megaloblastic anemia and neutropenia, homocysteinemia, hypomethioninemia, and formiminoglutamic aciduria without methylmalonic aciduria, which led to the diagnosis of a defect in methionine synthesis. Treatment resulted in improved metabolite levels, improvement of tone, and reduction of nystagmus, but poor growth, developmental delay, feeding difficulties requiring a gastrostomy, persistent anemia, and immunologic deficits were present at age 4 years. All 3 of these patients were found to have biallelic null mutations in the MTR gene (156570.0004-156570.0007), resulting in absence of the protein.

Labrune et al. (1999) described a girl, born of first-cousin parents, who presented at the age of 18 months with megaloblastic anemia. One month later, she developed pulmonary hypertension and renal failure, leading after renal biopsy to the diagnosis of hemolytic uremic syndrome. Investigations showed reduced methionine synthase activity under standard reducing conditions, compatible with cblG complementation group. At age 13 years, this girl required hemodialysis after acute rejection of a renal transplant.

Clinical Variability

Carmel et al. (1988) described the cblG mutation in a 21-year-old white woman who had been misdiagnosed as having multiple sclerosis. Her manifestations closely resembled subacute combined degeneration. Mild macrocytic anemia was present. Throughout childhood she had been awkward and had poor coordination. Urinary homocystine excretion was elevated, plasma methionine was decreased, and urinary cystathionine excretion was normal. No methylmalonic acid was detected in the urine. This constellation of findings suggested either the cblE or cblG mutation. Complementation analysis showed complementation with fibroblasts from 2 patients with the cblE mutation, but not with cells from 2 patients with the cblG mutation, indicating that the patient's defect corresponded to the latter mutation. Methionine synthase activity in fibroblast extracts was subnormal.

Outteryck et al. (2012) reported a young woman who presented at age 23 years with pain in the lower limbs. She had macrocytosis without anemia. Over the following 6 years, she developed progressive paraparesis and cognitive dysfunction. Brain and spinal cord MRI showed moderate cerebral atrophy with periventricular leukoencephalopathy and mild thinning of the cervical spinal cord; she also had optic neuropathy. Biochemical studies showed hyperhomocysteinemia, homocystinuria, hypomethioninemia, and absence of methylmalonic aciduria. Studies of cultured fibroblasts showed a defect in homocysteine remethylation, and complementation studies confirmed a cblG defect. Treatment with hydroxycobalamin and oral betaine resulted in rapid biochemical and slower clinical improvement. Outteryck et al. (2012) noted the unusual presentation of the disorder in this patient.

Biochemical Features

Patients with cblG have reduced methionine synthase activity even under standard assay conditions. Hall et al. (1989) presented evidence suggesting a defect in S-adenosyl methionine binding in cblG cells.

Clinical Management

Rosenblatt and Cooper (1990) commented that, whereas therapy with OH-Cbl has been effective in many cblE patients, a few of the cblG patients have been more difficult to treat and have required additional treatment with folates and betaine.

Inheritance

The transmission pattern of methionine synthase deficiency in the family reported by Wilson et al. (1998) was consistent with autosomal recessive inheritance.

Molecular Genetics

Gulati et al. (1996) analyzed the molecular basis for methionine synthase deficiency in cell lines derived from 2 cblG patients. The 79/76 cell line had low levels of methionine synthase activity and a diminished level of methionine synthase mRNA. In the WG1892 cell line, they detected compound heterozygous mutations in the MTR gene (156570.0001 and 156570.0002).

Leclerc et al. (1996) cloned the gene for methionine synthase and demonstrated mutations in this gene in 2 cblG cell lines which had deficient methionine synthase enzyme activity (see 156570.0003).

In 2 sibs with severe cblG, Wilson et al. (1998) identified compound heterozygosity for 2 null mutations in the MTR gene (156570.0004 and 156570.0005). Another patient with a severe form of the disorder was compound heterozygous for 2 null mutations in the MTR gene (156570.0006 and 156570.0007).

In a panel of 21 patients with methylcobalamin deficiency G (cblG) disorder, Watkins et al. (2002) identified 13 novel mutations. These included 5 deletions and 2 nonsense mutations that resulted in synthesis of truncated proteins that lacked portions critical for enzyme function. In addition, a previously described missense mutation, P1173L (156570.0001), was detected in 16 patients in an expanded panel of 24 patients with cblG. Analysis of haplotypes constructed using sequence polymorphisms identified within the MTR gene demonstrated that this mutation, a C-to-T transition in a CpG island, has occurred on at least 2 separate genetic backgrounds.

History

A possible case of deficiency of methionine synthase was reported by Arakawa et al. (1967), but the evidence was at best equivocal (Mudd, 1977). The patient was a 6-month-old girl with mental retardation, megaloblastic anemia, and high folate activity in the serum and red cells. Assays of liver showed the specific activity of N-5-methyltetrahydrofolate-homocysteine methyltransferase, measured in the presence of cyanocobalamin, to be 32 to 45% of that in control liver. The patient was not homocystinuric.