Abstract
ObjectiveThe importance of late-onset cobalamin C (cblC) disorder is underestimated in adults. Improved awareness on its clinical and neuroimaging features helps timely diagnosis and appropriate treatment.MethodsTotally 16 late-onset cblC cases were diagnosed based on clinical, biochemical findings and MMAHC gene mutation analysis. Clinical presentations, neuroimaging features and mutational spectrum were reviewed.ResultsThe case series included 10 males and 6 females, with average age of 22 (range 13–40) years. All the 16 patients displayed bilateral pyramidal tract signs, and most of the cases (13) had cognitive impairment. Other symptoms included psychiatric symptoms (6), epilepsy (6), peripheral nerve damage (5), ocular symptoms (4) and lower-limb thrombosis (1). The neuroimaging findings were dominated by cerebral atrophy (11/16), followed by white matter lesions (4), cerebellar lesions/atrophy (2) and spinal cord lesions (1). There were also 2 patients with normal imaging. All the MMACHC mutations were compound heterozygous, of which the most and second frequent was c.482G > A (p.R161Q; 15/16 case; allele frequency: 46.88%) and c.609G > A(p.W203X; 6/16 case; allele frequency: 18.75%). In addition, patients carrying frameshift mutations (deletion/duplication) presented more frequently with psychiatric symptoms (57.1%) and optic nerve damages (42.9%) than those carrying point mutations (22.2 and 11.1%, respectively). In contrast, peripheral nerve (44.4%) and white matter lesions (33.3%) were more frequently identified in point mutation- carriers. However, the differences did not achieve statistical significance (all p > 0.05).ConclusionCompared to the early-onset form, late-onset cblC displayed some clinical, neuroimaging and mutational profiles, which warrants particular attention in adult neurologic practice. These findings not only broaden our insights into the genotypes and phenotypes of the disease, but highlight the importance of early diagnosis and initiation of appropriate treatments.
Highlights
Methylmalonic academia (MMA) with homocysteinemia, cobalamin-C type, is the most common subtype of defective intracellular cobalamin metabolism [1, 2]. cblC disease results from mutations in the MMACHC gene, which result in impaired conversion of dietary vitamin B12 or cobalamin (Cbl) to its two metabolically active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl)
After re-evaluation and diagnostic confirmation by two senior neurologists and a geneticist, all cases were treated with parenteral hydroxocobalamin combined with oral betaine, folate and carnitine for 3–4 weeks
By treating with parenteral hydroxocobalamin combined with oral betaine, folate and carnitine for 3–4 weeks, the majority of patients showed marked decrease of the urine MMA and plasma homocysteine levels, as well as different extent of symptomatic improvement
Summary
Methylmalonic academia (MMA) with homocysteinemia, cobalamin-C (cblC) type, is the most common subtype of defective intracellular cobalamin (vitamin B12) metabolism [1, 2]. cblC disease results from mutations in the MMACHC gene, which result in impaired conversion of dietary vitamin B12 or cobalamin (Cbl) to its two metabolically active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). CblC disease results from mutations in the MMACHC gene, which result in impaired conversion of dietary vitamin B12 or cobalamin (Cbl) to its two metabolically active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). Wang et al Orphanet Journal of Rare Diseases (2019) 14:109 early-onset form, the late-onset cblC is less common and has less severe presentations and more favorable outcomes if treated promptly [1, 2]. More and more late-onset cases have been diagnosed and the incidence of late-onset appears to be higher than the previous estimate. 16 Chinese cases with late-onset cobalamin C disorder were diagnosed and confirmed by mutation analysis of the MMACHC gene (NM_015506.2). We aim to characterize the clinical and neuroimaging profiles, as well as the mutational spectrum and genotype-phenotype correlation of the late-onset cblC cases
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