Novel Deletion Mutation Identified in a Patient with Late-Onset Combined Methylmalonic Acidemia and Homocystinuria, cblC Type

Abstract

Combined methylmalonic aciduria and homocystinuria, cblC type (MMACHC), is the most common inborn error of cellular vitamin B 12 metabolism and is caused by mutations in the MMACHC gene. This metabolic disease results in impaired intracellular synthesis of adenosylcobalamin and methylcobalamin, coenzymes for the methylmalonyl-CoA mutase and methionine synthase enzymes, respectively. The inability to produce normal levels of these two coenzymes leads to increased concentrations of methylmalonic acid and homocysteine in plasma and urine, together with normal or decreased concentration of methionine in plasma. Here, we report a novel homozygous deletion mutation (NM_015506.2:c.392_394del) resulting in an in-frame deletion of amino acid Gln131 and late-onset disease in a 23-year-old male. The patient presented with sensory and motoric disabilities, urine and fecal incontinence, and light cognitive impairment. There was an excessive urinary excretion of methylmalonic acid and greatly elevated plasma homocysteine. The clinical symptoms and the laboratory abnormalities responded partly to treatment with hydroxycobalamin, folinic acid, methionine, and betaine. Studies on patient fibroblasts together with spectroscopic activity assays on recombinant MMACHC protein reveal that Gln131 is crucial in order to maintain enzyme activity. Furthermore, structural analyses show that Gln131 is one of only two residues making hydrogen bonds to the tail of cobalamin. Circular dichroism spectroscopy indicates that the 3D structure of the deletion mutant is folded but perturbed compared to the wild-type protein.

Guidelines for diagnosis and management of the cobalamin‐related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency

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Adult-onset CblC deficiency: a challenging diagnosis involving different adult clinical specialists

“…Among these, two cases (Patient 29 and 30) were asymptomatic and the disease onset corresponded to the age at which the typical biochemical abnormalities of the disease were first noticed. One clinically asymptomatic female (Patient 29) was identified thanks to her child’s newborn screening showing low carnitine [ 13 ]. One apparently clinically asymptomatic male (Patient 30) patient was identified after diagnosis of his symptomatic sibling [ 14 ].…”

Diagnosis of cobalamin C deficiency with renal abnormality from onset in a Chinese child by next generation sequencing: A case report

“…CblC is the most common congenital disorder of intracellular cobalamin metabolism and is characterized by combined MMA and homocystinuria ( 4 ). It is clinically divided into two main forms according to the age of onset ( 5 , 6 ).…”

“…Since the discovery of the DNA double helix structure and the development of DNA sequencing methods, including Sanger sequencing, the area of genome sequencing has advanced with regard to research applications and clinical diagnostics. The advent of next generation sequencing (NGS) has revolutionized the field of genomic medicine and enabled efficient and accurate analysis of associated genes in hereditary diseases, including renal pathologies and neuromuscular disorders ( 2 – 4 , 6 , 7 ). Using a small amount of DNA from patients, multigene mutational profiling may be conducted with bioinformatics tools, which is now widely used in the identification of causative genes and undiagnosed early-onset disorders ( 8 , 9 ).…”