| Abstract |
Mutations in the 'MMACHC' gene cause 'cblC', the most common inborn error
of cobalamin metabolism, with approximately 400 known cases. It results in
the inability to convert vitamin B12 (cobalamin) into its two active
coenzyme forms, methylcobalamin and adenosylcobalamin, required by
methionine synthase and methylmalonyl-CoA mutase respectively. It can be
characterized according to age of onset, with early onset patients
presenting within the first year of life with a number of pathologies and
later onset patients presenting after the age of four with predominantly
neurological symptoms. Individuals with the c.394C>T (p.R132X) as well as
a number of missense mutations generally have later onset of disease
whereas patients with the c.331C>T (p.R111X) and c.271dupA (p.R91KfsX14)
mutations usually present in infancy. Expression experiments measuring
allele-specific transcripts and quantitative real-time RT-PCR measuring
overall 'MMACHC' transcript amount revealed increased transcription from
alleles bearing late onset related mutations when compared to early onset
mutation-bearing alleles. Understanding the mechanisms underlying early
and late onset of disease may improve treatment and prognosis for 'cblC'
patients.
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