Methylmalonic Aciduria And Homocystinuria, Cblc Type

A number sign (#) is used with this entry because of evidence that combined methylmalonic aciduria and homocystinuria type cblC (MAHCC) is caused by homozygous or compound heterozygous mutation in the MMACHC gene (609831) on chromosome 1p34.

There is also evidence that MAHCC is caused by digenic mutations: one caused by a coding MAHCC mutation, and the other, a secondary epimutation, triggered by a mutation in the PRDX1 gene (176763).

Description

Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC, cblD (277410), cblF (277380), and cblJ (614857).

Isolated methylmalonic acidurias have also been classified by complementation groups: MMA 'mut' (251000) is caused by mutation in the MUT gene on chromosome 6p21; MMA cblA (251100) is caused by mutation in the MMAA gene (607481) on 4q31; and MMA cblB (251110) is caused by mutation in the MMAB gene (607568) on 12q24.

Methylmalonic aciduria and homocystinuria, cblC type, is the most common inborn error of vitamin B12 (cobalamin) metabolism, with about 250 known cases (Lerner-Ellis et al., 2006). Affected individuals may have developmental, hematologic, neurologic, metabolic, ophthalmologic, and dermatologic clinical findings. Although considered a disease of infancy or childhood, some individuals develop symptoms in adulthood (Rosenblatt et al., 1997).

Heterogeneity

Mahoney et al. (1975) identified 4 forms of methylmalonic aciduria as defined by ability to synthesize the coenzyme AdoCbl: patients with deficiency of the mutase apoenzyme retained the ability to synthesize both AdoCbl and MeCbl ('mut'); a second group had a deficiency in synthesis of both AdoCbl and MeCbl ('cblC'); and 2 others had isolated AdoCbl deficiency ('cblA' and 'cblB'). The authors concluded that the defect in cblC was proximal to the separation of the pathways for AdoCbl and MeCbl synthesis.

Gravel et al. (1975) confirmed the genetic heterogeneity of mut, cblA, cblB, and cblC. In vitro complementation studies measuring C14 incorporation into propionate showed that each of the mutants failed to incorporate C14 alone, whereas heterokaryons produced by fusing members of each of the 4 mutant classes with any other class produced results comparable to controls.

Clinical Features

Mudd et al. (1969) reported an infant with homocysteinemia, methylmalonic aciduria, cystathioninemia, and a decrease in blood methionine. He died at 7.5 weeks of age. In vitro analysis identified a defect in the 2 reactions in which vitamin B12 derivatives function as coenzymes: methionine formation from 5-methylfolate-H(4) (MTR) and homocysteine, and isomerization of methylmalonyl-CoA to succinyl-CoA (MUT). Since vitamin B12 was present in normal concentrations in the liver, Mudd et al. (1969) concluded that the gene-determined defect involved the conversion of B12 to the active coenzymes. McCully (1969) studied the same patient as that reported by Mudd et al. (1970) and noted arterial changes and atherosclerosis on pathologic examination.

The patient described by Dillon et al. (1974) differed from the others in that in addition to severe mental retardation and megaloblastosis, clinical and pathologic changes typical of subacute degeneration of the spinal cord were present. Baumgartner et al. (1979) reported a male infant who died at 4 months of age after 2 episodes of acute heart failure. He had hemolytic and megaloblastic anemia, hematuria, proteinuria, and mild uremia. Plasma and urine levels of methionine were low, whereas levels of cystathionine were increased. Vitamin B12 deficiency, malabsorption, and transport defect were excluded by normal serum cobalamin and transcobalamins. Autopsy showed severe vascular lesions with changes of thrombotic thrombocytopenia in the kidney, suggesting the hemolytic-uremic syndrome. Elevated plasma homocysteine was presumed to be responsible for the vascular lesions. Analysis of postmortem liver showed deficiency of both cobalamin-dependent enzymes.

Brandstetter et al. (1990) reported a 16-week-old infant with cblC who died from cor pulmonale due to thromboemboli in the pulmonary circulation. They suggested that the pathogenesis was the same as that of thromboembolic disease in homocystinuria due to cystathionine beta-synthase deficiency (236200). Brandstetter et al. (1990) emphasized the frequent finding of pigmentary retinopathy and abnormality in the macular area of the ocular fundus. Russo et al. (1992) described 3 infants with cblC disease characterized by metabolic acidosis, methylmalonic aciduria, and homocystinuria. In the first weeks of life, all showed failure to thrive, hypotonia, and lethargy associated with pancytopenia and hepatic dysfunction, which progressed to severe respiratory insufficiency and renal failure consistent with hemolytic-uremic syndrome. The infants died at 40, 45, and 75 days of age. Postmortem findings were dominated by thrombotic microangiopathy of the kidneys and lungs, diffuse hepatic steatosis, and megaloblastic changes in the bone marrow. Severe gastritis with striking cystic dysplastic mucosal changes and total absence of parietal and chief cells was found in all 3 patients, with the rest of the gastrointestinal tract being essentially normal.

Rosenblatt et al. (1997) reviewed 50 cblC patients who could be classified into 2 broad phenotypes: 44 had early onset and 6 had later onset. The 44 patients presented in the first year of life with feeding difficulties, hypotonia, developmental delay, seizures, pigmentary retinopathy, and anemia. About one-fourth of the patients died, and those who survived had neurologic impairment.

Cerone et al. (1999) described mild facial anomalies in combined methylmalonic aciduria and homocystinuria of the cblC form. Features included a long face, high forehead, large, floppy, and low-set ears, and flat philtrum. The morphologic characteristics became more evident after 3 years of age, and were noted separately by physicians of 2 different departments. A female patient showed high forehead and low-set ears when first observed at the age of 2 months.

Andersson et al. (1999) described the clinical and biochemical features of 8 cblC patients who were treated for an average of 5.7 years. Treatment consisted of daily oral carnitine and intramuscular hydroxocobalamin. The patients had congenital malformations including microcephaly at birth (2 of 8), congenital heart disease (2 of 8), dysmorphic facial features (1 of 8), and thyroglossal duct cyst (1 of 8). Postnatal hydrocephalus (2 of 8) and hip dislocation caused by ligament laxity (1 of 8) were also noted. One patient had profound visual impairment before 6 months of age secondary to cblC retinopathy, and 2 patients had abnormal retinal pigmentation with normal visual function. All patients presented with poor growth, feeding problems, and/or seizures.

Van Hove et al. (2002) described a 12-year-old boy and his 4-year-old sister who presented with proteinuria, hematuria, hypertension, and chronic hemolytic anemia. Renal biopsy showed a chronic thrombotic microangiopathic nephropathy. Hyperhomocysteinemia and mild methylmalonic aciduria were also found. Fibroblast studies were compatible with a mild cblC complementation group. The children had no neurologic symptoms and minimal pigmentary retinal abnormalities. Both children and their father carried a balanced reciprocal translocation, t(8;19)(q23.2;q13.3). Treatment with higher than usual doses of parenteral hydroxycobalamin and oral betaine stopped the thrombotic microangiopathy.

Schimel and Mets (2006) reported the ocular findings in 3 patients with cblC disease. All 3 presented with macular pigmentary changes and showed attenuation of electroretinographic (ERG) responses. Based on the findings in these patients and a literature review, Schimel and Mets (2006) concluded that cblC disease results in progressive retinal degeneration beginning in the first few months of life and progressing rapidly over the first few years of life.

Komhoff et al. (2013) studied 4 patients with combined pulmonary arterial hypertension and renal thrombotic microangiopathy, who were identified from the Dutch national referral center for pediatric pulmonary hypertension. A fifth patient with this combination was contacted to collect clinical data. All 5 had cobalamin C (cblC) deficiency, diagnosed postmortem in 2 patients. Onset of disease ranged from 1.5 to 14 years of age. The 2 youngest patients presented with concomitant pulmonary and renal disease; in the older patients, pulmonary arterial hypertension was preceded by renal thrombotic microangiopathy from age 2.5 to 7 years. Three patients presenting at 3 years of age or younger died of right ventricular failure secondary to progressive pulmonary arterial hypertension. Three patients were treated with hydroxocobalamin; 1 died 2 weeks after diagnosis, 1 exhibited progressive pulmonary vasculopathy, and 1 patient was in stable condition at the time of the study. cblC deficiency was diagnosed biochemically 2 days to 18 years after initial presentation. Komhoff et al. (2013) identified cblC deficiency as the cause of the rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy in these patients. The authors proposed that early recognition of cblC deficiency and vigorous treatment with hydroxocobalamin may ameliorate the devastating course of this condition.

Ahrens-Nicklas et al. (2017) completed a retrospective analysis of 12 patients with cblC referred for abnormal newborn screening results and followed at the Children's Hospital of Pennsylvania between 1999 and 2015. Of the patients, 87.5% had intellectual disability and 75% had retinopathy; 16.7% had 1 episode of mild acidosis. However, no patients manifested major metabolic decompensation. Developmental outcomes correlated more closely with initial metabolic abnormalities than with long-term metabolic control. Increased intake of medical foods resulted in better control but also perturbations in the ratios of essential amino acids and lower z-scores for head circumference. Ahrens-Nicklas et al. (2017) found no relationship between diet and cognitive outcomes.

Late-Onset cblC Disease

Goodman et al. (1970) reported 2 brothers with a milder, possibly allelic form of the disorder. The elder, a 14-year-old Mexican American, was first admitted to the hospital in an acute psychotic episode. He had an IQ of about 50, a somewhat marfanoid habitus, and mild abnormalities on neurologic examination. Ectopia lentis and chest deformity were lacking. The parents were first cousins once removed.

Shinnar and Singer (1984) described a clinically atypical patient with the cblC defect. An adolescent girl had been a straight-A student and in excellent health until age 12. Over the period of a year, her grades deteriorated markedly and her work became equivalent to that of a first-grader. She developed apathy, unsteady gait, and impaired speech. Examination showed broad-based gait, impaired vibration and position sense, and extensor Babinski response. IQ was 40 to 50. Hemoglobin was 12.6 gm%, mean corpuscular volume 96, serum B12 level normal, and red cell folate level 88 ng per ml red cells (mildly decreased). Blood showed elevated homocysteine and only a trace of methionine. The urine contained large amounts of homocysteine and methylmalonic acid. On parenteral hydroxycobalamin (1,000 micrograms per day), the patient improved markedly. A 12-year-old sister and an 8-week-old brother were found to have the same cblC defect, confirmed by fibroblast studies.

Rosenblatt et al. (1997) found that 6 of 50 cblC patients had later onset, after age 4 years. These patients presented with acute neurologic dysfunction, including cognitive decline, confusion, psychosis, dementia, and extrapyramidal signs. Later-onset patients had better survival, better response to treatment, and less neurologic sequelae compared to the early-onset patients.

Bodamer et al. (2001) reported what they believed to be the first case of adult-onset cblC. The patient was a 20-year-old man who presented with slowly progressive leg weakness, loss of bowel and bladder function, episodes of forgetfulness, slurred speech, and deep venous thromboses. He later became unresponsive and required mechanical ventilation. A diagnosis of cobalamin defect was suggested after he was determined to have elevated plasma homocysteine and methylmalonic aciduria. Treatment with hydroxycobalamin and carnitine proved effective. The authors suggested that the patient may have had a mild mutation resulting in significant residual enzyme activity.

Ben-Omran et al. (2007) reported 2 unrelated patients with late-onset cblC disease. The first patient was a 14-year old girl, born of first-cousin Pakistani parents, who developed progressive neurologic decline, including dementia, depression, ataxia, lethargy, incontinence, and seizures over a period of 2 years. After visits to several physicians without a correct diagnosis, analysis of plasma and urine showed increased homocysteine and methylmalonate consistent with a defect in cobalamin synthesis. Appropriate treatment resulted in clinical improvement with residual mild gait ataxia. The second patient was a 10-year-old girl of Bengali descent who presented with acute dementia, anorexia, extreme weight loss, and 'catatonic psychotic behavior.' She had a mild learning disability with an IQ of 72 and seizures. Brain MRI performed at ages 4 and 10 years showed progressive volume loss. Laboratory analysis detected cblC disease, and appropriate treatment resulted in clinical improvement. Both patients were found to be homozygous for the R132X mutation in the MMACHC gene (609831.0003). Ben-Omran et al. (2007) noted the diagnostic difficulty in late-onset cblC disease and emphasized the utility of plasma and urine analysis, as patients may have normal red blood cell indices.

Tsai et al. (2007) described a 36-year-old woman with a spinal cord infarct who was subsequently diagnosed with methylmalonic aciduria and homocystinuria, cblC type. Her past medical history was significant for joint hypermobility, arthritis, bilateral cataracts, unilateral hearing loss, chronic anemia, and frequent urinary tract infections secondary to a urogenital fistula. She reported emotional difficulties beginning in her teens and was diagnosed with depression and psychosis requiring hospitalization in her thirties. One to 2 years prior to the spinal cord infarct, the patient experienced increasing muscular weakness, leg paresthesias, and difficulty walking. The woman sought help in the emergency department for her weakness and parasthesia but was misdiagnosed with malingering because of her psychiatric history. One week later, she experienced lower extremity hemiplegia, and bladder incontinence and diagnosed with a spinal cord infarct. Laboratory evaluation revealed elevated homocysteine and methylmalonic acid consistent with cblC disease. Molecular analysis of the MMACHC gene revealed the 271dupA (609831.0001) and R161Q (609831.0005) mutations. Tsai et al. (2007) recommended that all patients with psychiatric disease complicated by dementia and myelopathy be screened with plasma amino acids and urine organic acids allowing cblC disease to be preliminarily diagnosed or effectively excluded.

Mapping

Atkinson et al. (2002) mapped the locus for cobalamin C deficiency to chromosome 1q by linkage analysis. Lerner-Ellis et al. (2006) refined the assignment using homozygosity mapping and haplotype analyses and identified the MMACHC gene on 1p34.1 as the site of disease-causing mutations.

Molecular Genetics

Lerner-Ellis et al. (2006) refined the chromosomal map interval containing the mutation for methylmalonic aciduria and homocystinuria, cblC type, to a region of the short arm of chromosome 1 containing the MMACHC gene. In 204 individuals, 42 different mutations were identified, many consistent with a loss of function of the protein product. One mutation, 271dupA (609831.0001), accounted for 40% of all disease alleles. Transduction of wildtype MMACHC into immortalized cblC fibroblast cell lines corrected the cellular phenotype.

Among 79 unrelated Chinese patients with combined methylmalonic aciduria and homocystinuria, cblC type, Liu et al. (2010) identified 24 different mutations in the MMACHC gene, including 7 novel mutations. All patients had 2 mutations, except for 3 patients in whom only 1 mutation was identified. The 2 most common alleles were W203X (609831.0006) and 658delAAG (609831.0007), which accounted for 48.1% and 13.9% of mutant alleles, respectively. Haplotype analysis indicated a different founder effect for each mutation, but the major mutation profile did not differ between patients from northern and southern China.

In 3 affected members of unrelated families with autosomal recessive cblC vitamin B12 deficiency, Gueant et al. (2018) identified compound heterozygous mutations in the MMACHC gene: a different coding mutation on 1 allele in all 3 (609831.0011-609831.0013), combined with the same 'secondary epimutation' on the other allele. The epimutation, 32 hypermethylated CpG sites detected by bisulfite sequencing, was a consequence of a heterozygous mutation in the adjacent, reverse-oriented, PRDX1 gene: c.515-1G-T (176763.0001) or c.515-2A-T (176763.0002). The PRDX1 mutations were also found in unaffected relatives who carried the secondary epimutation. In all instances, the PRDX1 mutations affected a canonical splice acceptor site of intron 5 and caused skipping of exon 6 and the polyA termination signal of PRDX1. The resulting read-through transcript extended through the adjacent MMACHC locus in the antisense orientation. The authors proposed that the antisense transcript leads to the formation of triplexes in the promoter of MMACHC and generates CpG methylation resulting in reduced expression of the normal message. This was confirmed experimentally by growing fibroblasts from an affected proband in 5-azacytidine, which reduced promoter methylation, and by silencing PRDX1 with an siRNA, both of which increased expression of MMACHC.

Genotype/Phenotype Correlations

Morel et al. (2006) reported genotype-phenotype correlations in 37 patients from published case reports, representing most of the landmark descriptions of cobalamin C deficiency. Twenty-five of 37 had early-onset disease, presenting in the first 6 months of life; 17 of these 25 were found to be either homozygous for the 271dupA mutation (609831.0001) (n = 9) or for the 331C-T (R111X; 609831.0004) mutation (n = 3) or compound heterozygous for these 2 mutations (n = 5). Nine of 12 late-onset cases presented with acute neurologic symptoms: 4 of 9 were homozygous for the 347T-C mutation (L116P; 609831.0002), 2 of 9 were compound heterozygous for the 271dupA and 394C-T (R132X; 609831.0003) mutations, and 3 of 9 for the 271dupA mutation and a missense mutation. The 394C-T mutation is common in the Asiatic-Indian/Pakistani/Middle Eastern populations.

Among 118 patients with cblC, Lerner-Ellis et al. (2009) identified 34 different MMACHC mutations, including 11 novel mutations. The 271dupA mutation was the most common, accounting for 42% of pathogenic alleles, followed by the R132X (20%) and R111X (5%) mutations. Six variants defined specific haplotypes that varied with ethnicity. Genotype/phenotype correlations were apparent. Individuals with the R132X and R161Q (609831.0005) mutations tended to present with late-onset disease, whereas patients with the R111X and 271dupA mutations tended to present in infancy. Functional expression analysis on cblC fibroblasts showed that the early-onset 271dupA mutation was consistently underexpressed compared to control alleles and the late-onset R132X and R161Q mutations. The early-onset R111X mutation was also underexpressed when compared to control alleles and the R132X mutation. Quantitative RT-PCR studies showed that the late-onset R132X mutation had significantly higher levels of transcript compared to cell lines homozygous for the early-onset mutations.

In 4 patients with a rare combination of pulmonary arterial hypertension and renal thrombotic microangiopathy caused by cblC deficiency, Komhoff et al. (2013) detected 1 of 2 basepair substitutions (G-to-A or G-to-T) at nucleotide 276 of the MMACHC gene (609831.0008, 609831.0009). These mutations were not found in approximately 500 patients with cblC deficiency and other phenotypes, or in 200 control individuals. Komhoff et al. (2013) concluded that these mutations hold specific vascular pathogenicity in addition to compromising enzyme function. These patients were additionally heterozygous for various frameshift mutations on the other MMACHC allele.

Clinical Management

Bartholomew et al. (1988) reported variable results with vitamin B12 therapy.

Enns et al. (1999) reported a 4-year-old Hispanic girl with cblC methylmalonic acidemia who had undergone intramuscular hydroxocobalamin therapy starting at 3 weeks of age. Despite treatment, she showed progressive neurologic deterioration and worsening head MRI changes.

Andersson et al. (1999) reported successful treatment of 8 patients with cblC. All patients had dramatic reduction of plasma free homocystine and urine methylmalonic acid excretion after initiation of treatment with carnitine, intramuscular hydroxocobalamin and, in 2 cases, oral betaine. Growth was significantly improved in most cases after the initiation of therapy, and microcephaly resolved in 1 patient. All patients were developmentally delayed regardless of the age at which treatment began, although 2 patients had relatively mild developmental delay.

Pathogenesis

Mellman et al. (1979) found that cells from a cblC patient were unable to associate newly taken up (57)Co-cobalamin with the methyltransferase, whereas hybrids of mouse cells and cblC cells showed human (57)Co-cobalamin-methyltransferase whenever human chromosome 1 was present (Mellman et al., 1979). The authors concluded that the cblC mutation did not affect the methyltransferase apoprotein, but rather a metabolic step that converts cobalamin to the coenzyme capable of attaching to the enzyme.