Variable phenotypes and outcomes associated with the MMACHC c.482G>A mutation:follow-up in a large CblC disease cohort

Background The aim of this study was to characterize the variable phenotypes and outcomes associated with the methylmalonic aciduria and homocystinuria type C protein gene(MMACHC)c.482G>A mutation in 195 Chinese cases with CblC disease.Methods We carried out a national,retrospective multicenter study of 195 Chinese patients with CblC disease attributable to the MMACHC c.482G>A variant either in a homozygous or compound heterozygous state.The control group consisted of 200 patients diagnosed with CblC disease who did not possess the c.482G>A mutation.Clinical features,including disease onset,symptoms,biochemical metabolites,gene mutation,and follow-up outcomes were reviewed and analyzed in detail.The median follow-up period spanned 3 years and 8 months,with a range of 1 year and 2 months to 12 years and 10 months.Results Among 195 patients carrying the c.482G>A variant,125(64.1%)cases were diagnosed by newborn screening(NBS),60(30.8%)cases were detected due to disease onset,and 10(5.1%)cases were identified from sibling diagnoses.One hundred and seventeen(93.6%)individuals who were diagnosed by NBS,and nine patients who came from sibling diagnoses remained asymptomatic in this study.From 69 symptomatic patients of the c.482G>A group,more patients presented with later onset,and the top six common clinical symptoms at disease onset were developmental delay(59.4%),lower limb weakness and poor exercise tolerance(50.7%),cognitive decline(37.7%),gait instability and abnormal posture(36.2%),seizures(26.1%),and psychiatric and behavioral disturbances(24.6%).In the 159 symptomatic patients lacking c.482G>A variants,the most frequently observed clinical manifestations at disease onset included developmental delay(81.8%),lethargy and feeding difficulty(62.9%),lower limb weakness and poor exercise tolerance(54.7%),prolonged neonatal jaundice(51.6%),vomiting(47.2%),and seizures(32.7%).Before treatment,the levels of blood propionylcarnitine,propionylcarnitine/acetylcarnitine ratio,and homocysteine in the c.482G>A group were significantly lower(P<0.05)than those in the non-c.482G>A group,while the concentration of urinary methylmalonic acid was slightly lower(P>0.05).The degree of decline in the above metabolites after treatment in different groups significantly differed in both plasma total homocysteine values and urinary methylmalonic acid levels(P<0.05).In patients carrying the c.482G>A variant compared with the non-c.428G>A group,there were markedly lower rates of mortality(0.5%vs.2.0%)and developmental delay(20.5%vs.65.5%).When compared with individuals diagnosed due to disease onset,those identified through NBS in either group exhibited a reduced proportion of disease onset(6.7%vs.100%in the c.482G>A group,54.4%vs.100%in the non-c.482G>A group),lower mortality(0.0%vs.1.7%in the c.482G>A group,0.0%vs.3.6%in the non-c.482G>A group),and had a higher percentage of patients exhibiting normal psychomotor and language development(99.3%vs.33.3%in the c.482G>A group,58.9%vs.10.9%in the non-c.482G>A group).Conclusions The c.482G>A variant in MMACHC is associated with late-onset and milder phenotypes of CblC disease.Patients with this mutation tend to have a relatively better response to hydroxocobalamin,better metabolic control,and more favorable neurological outcomes.NBS and other appropriate pre-symptomatic treatments seem to be helpful in early diagnosis,resulting in favorable clinical outcomes.