Methylmalonic Aciduria And Homocystinuria, Cblj Type


A number sign (#) is used with this entry because of evidence that methylmalonic aciduria and homocystinuria of the cblJ type (MAHCJ) is caused by compound heterozygous mutation in the ABCD4 gene (603214) on chromosome 14q24.


Combined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, 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). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; 277380) (summary by Coelho et al., 2012).

Clinical Features

Coelho et al. (2012) reported 2 unrelated patients with methylmalonic aciduria and homocystinuria. Both patients showed abnormalities soon after birth. One patient, of North American origin, had respiratory distress, hypotonia, lethargy, poor feeding, periodic breathing, and episodes of posturing in the neonatal period. There was evidence of bone marrow suppression requiring red blood cell and platelet transfusion. The second child, of European origin, had increased temperature and tachypnea at birth. The patient had feeding difficulties, poor growth, hypotonia, and developmental delay. Some dysmorphic features were also present, including hypertelorism, micrognathia, widely spaced nipples, bell-shaped thorax, horizontal ribs, and short extremities. He also had some cardiac abnormalities, including atrial septal defect, coarctation of the aorta, enlarged right ventricle, and pulmonary hypertension. The patient had an episode of neutropenia later in childhood. Studies of cultured fibroblasts in both patients showed increased cobalamin uptake, but poor cobalamin utility, as manifest by virtually absent synthesis of AdoCbl and MeCbl and decreased function of MUT and MTR. There was cellular accumulation of free cbl, similar to that observed in cblF (277380). Somatic cell complementation studies showed that both patients had the same genetic defect; mutations in the LMBRD1 gene (612625) were not found.


The transmission pattern of methylmalonic aciduria and homocystinuria of the cblJ type reported by Coelho et al. (2012) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 unrelated children with methylmalonic aciduria and homocystinuria type cblJ, Coelho et al. (2012) identified 4 different mutations in the ABCD4 gene (603214.0001-603214.0004) in compound heterozygous state. The mutations, which were found using microcell-mediated chromosome transfer and exome sequencing, resulted in a loss of function. Biochemical studies confirmed a defect in cobalamin metabolism and were similar to abnormalities observed in patients with cblF (277380). Patient cell lines showed no rescue of the defect when transfected with LMBRD1, suggesting that these 2 genes function in the same pathway. Studies suggested that ABCD4 is involved in the lysosomal release of cbl into the cytoplasm.