Homozygous c.482G>A and compound heterozygotes for c.394C>T mutations are also associated with late-onset disease. The most prevalent mutation in late-onset cases (> 1 year of age) is the homozygous c.394C>T mutation (present in about 20% of all disease alleles), most commonly seen in patients from Indian, Pakistani and Middle Eastern descent, but also detected in Portugal and Italy. Homozygous c.271dupA is most commonly identified in patients of European descent, is almost universally associated with early-onset disease (T mutation, present in about 5% to 9% of disease alleles, associated with French Canadian, Acadian or Cajun descent, is also associated to early-onset disease when in homozygosity and when in compound heterozygosity with c.271dupA. More than 80 MMACHC gene mutations have been described, the most frequent being the c.271dupA mutation, identified in approximately 40-61% of disease alleles. Ĭommon mutations and genotype-phenotype correlations An epigenetic cause of cblC disease has recently been described, named epi-cblC, in which a PDRX1 mutation resulting in a MMACHC epimutation causes promoter hypermethylation and thus silences a wild-type MMACHC allele, which causes disease in a patient carrying a single mutant MMACHC allele. In absence of normal MMACHC function, intracellular trafficking of cbl is compromised, resulting in increased levels of methylmalonic acid (MMA) and homocysteine (Hcy), as well as decreased production of methionine (Met). MMACHC is also thought to closely interact with the MMADHC protein in this pathway. The MMACHC protein is able to bind to cbl-R cargo as it exits the lysosomal compartment and to release R groups by reductive decyanation (in case of cyanocobalamin) and dealkylation (in the case of methylcobalamin and adenosylcobalamin) in the cytosol, resulting in a common cbl intermediate, allowing it to be further processed towards the two final reactions mediated by methymalonyl-CoA-mutase (mitochondrial route) and methionine synthase (cytosolic route) to synthesize the two active cofactors, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). The MMACHC gene is responsible for coding the MMACHC protein, which is directly involved in the early cobalamin processing pathway via both cytosol and mitochondrial routes. ĬblC disease is an autosomal recessive disorder caused by mutations in the MMACHC gene (OMIM *609831) on chromosome 1p34.2. Some series have shown a predominance of male patients. Newborn screening (NBS) studies revealed an incidence of 1:100,000 in New York State, 1:121,000 in the state of New Jersey, 1:67,000 in California and 1:46,000 in Hispanic populations, 1:85,000 in Portugal, 1:3,920 in Shandong, China, confirming that cblC deficiency is panethnic and the most common inborn error of intracellular cobalamin metabolism, comprising around 80% of such cases. CblC is responsible for a wide range of systemic manifestations and severe ophthalmological features, usually presenting as an infantile-onset macular and retinal degeneration, leading to extreme visual acuity loss early in life. 9 Follow-up and surveillance strategiesĬobalamin C (cblC) deficiency (OMIM #277400, Methylmalonic aciduria and homocystinuria, cblC type) is the most common inborn error of intracellular vitamin B12 metabolism, belonging to the cobalamin(cbl)-related methylation disorders group, along with cblD, cblE, cblF, cblG, cblJ, cblX and MTHFR deficiency.5.3.2 Optical coherence tomography (OCT).2.2 Common mutations and genotype-phenotype correlations.
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