Late-onset cblC defect: clinical, biochemical and molecular analysis

Abstract

Background cblC defect is the most common type of methylmalonic acidemia in China. Patients with late-onset form (>1 year) are often misdiagnosed due to heterogeneous symptoms. This study aimed to describe clinical characteristics and evaluate long-term outcomes of Chinese patients with late-onset cblC defect. Methods A total of 85 patients with late-onset cblC defect were enrolled. Clinical data, including manifestations, metabolites, molecular diagnosis, treatment and outcome, were summarized and analyzed. Logistic regression was used to analyze the factors influencing the prognosis of patients. Results The median age at disease onset and median time delay from initial symptoms to diagnosis were about 8.6 years old (ranging from 2 to 32.8 years old) and 2 months (ranging from few days to 20 years), respectively. Patients with late-onset cblC defect presented neuropsychiatric symptoms (68.2%), renal involvement (20.0%), cardiovascular disease (8.2%) and metabolic crises (3.5%) as first symptoms, which seemed to be age-associated. Disease progressed in most patients. Overall, cognitive decline is the most frequent symptom. The level of propionylcarnitine, propionylcarnitine / acetylcarnitine ratio, methylmalonic acid, methylcitric acid and homocysteine, were decreased remarkably after treatment( (P<0.001). 24 different mutations of MMACHC were identified in 78 patients, of which two were novel. The c.482G >A was the most frequent mutated alleles in this cohort (25%). Except 16 patients were completely recovered, the remaining patients still left with various severities of sequel in a long-term follow-up. The available data of 76 cases were analyzed by logistic regression, and the results showed that the time from onset of symptoms to diagnosis was significantly associated with the prognosis of patients (P < 0.05). Conclusions The diagnosis of late-onset cblC defect is often delayed due to poor awareness of its various and nonspecific symptoms, thus leading to a significant disability. It should be considered in patients with unexplained neuropsychiatric, renal and cardiovascular diseases or even multiple organ damage. Early diagnosis and prompt initiation of therapy are essential for the improvement of prognosis.