Methylmalonic Aciduria And Homocystinuria, Cblf Type

A number sign (#) is used with this entry because of evidence that methylmalonic aciduria and homocystinuria of the cblF type (MAHCF) is caused by homozygous or compound heterozygous mutation in the LMBRD1 gene (612625) on chromosome 6q13.

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 (MAHCC; 277400), cblD (MAHCD; 277410), cblF, and cblJ (MAHCJ; 614857).

Clinical Features

Rosenblatt et al. (1985, 1986) reported an infant girl with developmental delay, stomatitis, glossitis, seizures, and minimal methylmalonic aciduria responsive to vitamin B12. There was no megaloblastic anemia or homocystinuria. Like control cells, the patient's fibroblasts accumulated the transcobalamin II-B12 complex within lysosomes and released B12 from the binding protein. However, the patient's cells were defective in the release of cobalamin from the lysosome into the cytoplasm. The cells also showed indirect evidence of methylmalonyl-CoA mutase and methionine synthase activity, as well as inability to synthesize AdoCbl and MeCbl. No abnormality of lysosomal structure was detected by electron microscopy. After incubation in labeled vitamin B12, accumulation was found in lysosomes (Vassiliadis et al., 1991). Like Salla disease (604369) and cystinosis (219800), this disorder appeared to result from impeded egress (efflux) from lysosomes. Rosenblatt et al. (1986) suggested that the disorder be called cblF, cobalamin F disease. In vitro studies showed that the patient's fibroblasts complemented the other known groups of methylmalonic aciduria (Watkins and Rosenblatt, 1986).

Shih et al. (1987, 1989) reported a female infant with failure to thrive, developmental delay, minor facial anomalies, stomatitis, skin rashes, macrocytosis, homocystinuria, and methylmalonic acidemia. In vitro studies showed decreased synthesis of AdoCbl and MeCbl, and accumulation of unmetabolized free cobalamin. Treatment with hydroxocobalamin resulted in clinical and biochemical improvement, but sudden death occurred at 5 months of age.

MacDonald et al. (1992) reported 2 unrelated males with cblF. The older patient had recurrent stomatitis during infancy, juvenile rheumatoid arthritis at age 4 years, and a reticulate pigmented skin abnormality at age 10.

Rutsch et al. (2009) reported 12 unrelated patients with cblF. Frequent clinical findings included being small for gestational age, poor feeding, failure to thrive, developmental delay and persistent stomatitis. Two individuals had minor facial abnormalities, including pegged teeth and bifid incisors, and 4 had congenital heart defects. Other common features included macrocytic anemia, neutropenia, thrombocytopenia, and pancytopenia. Affected individuals were identified by elevated homocysteine and methylmalonic acid concentrations in blood or urine samples, although 3 patients were identified by increased propionylcarnitine concentrations detected by newborn screening. The diagnosis of the cblF defect was established by complementation analysis on fibroblasts.

Clinical Management

Alfadhel et al. (2011) reported an 18-year follow-up of a girl with cblF disease, confirmed by genetic analysis, who started treatment with intramuscular hydroxycobalamin (vitamin B12) beginning at age 6 months. She presented at that time with failure to thrive, delayed development, recurrent infections, skin rash, megaloblastic anemia, borderline neutropenia, and impaired T-cell response. Laboratory studies showed decreased serum B12, increased plasma homocysteine, methylmalonic aciduria, and decreased AdoCbl and MeCbl. Treatment resulted in normalization of hematologic and immunologic parameters and growth parameters. She showed progress in psychomotor development, with speech acquisition, but remained mildly intellectually disabled. Physical examination at age 18 years showed no abnormalities of the major organ systems, although she had delayed cognitive skills. Alfadhel et al. (2011) noted that cblF disease is a treatable condition and that the disorder should be suspected in patients with failure to thrive, developmental delay, recurrent infections, and megaloblastic anemia.

Mapping

By linkage analysis of several families with cblF, Rutsch et al. (2009) identified a locus on chromosome 6q12-q13 (maximum lod score of 4.7).

Molecular Genetics

In 12 unrelated patients with MAHCF, Rutsch et al. (2009) identified 5 different homozygous or compound heterozygous mutations in the LMBRD1 gene (612625.0001-612625.0003). A 1-bp deletion (612625.0001) was present in 18 of the 24 disease chromosomes, consistent with a common founder of European ancestry. All mutations were truncating, but the phenotype was variable, ranging from developmental delay to asymptomatic long-term survival; thus there were no genotype/phenotype correlations.