Clinical and genetic characteristics of late-onset cobalamin C deficiency: A multicenter study in northern China

Late-onset cobalamin C (cblC) deficiency, an inherited metabolic disorder, is often misdiagnosed due to its heterogeneous clinical presentation. This study aims to characterize the clinical and genetic spectrum of late-onset cblC deficiency in a large northern Chinese cohort and proposes a novel clinical classification based on initial symptoms. A retrospective, multicenter study of 156 patients diagnosed between October 2012 and December 2023 was conducted. Clinical, biochemical, neuroimaging, and genetic data were analyzed. Patients were classified into six subtypes based on predominant initial symptoms, and genotype-phenotype correlations were explored. The cohort (95 males, 61 females) had a median onset age of 16 years (range: 2-65). Common symptoms included spastic paralysis (41.0%), mental and behavioral abnormalities (36.5%), and renal damage (28.8%). Genetic analysis identified 52 <i>MMACHC</i> variants, with c.482G>A (34.3%) and c.609G>A (17.6%) being most frequent. Elevated total homocysteine (tHcy) levels correlated with mental and behavioral abnormalities, renal damage, and anemia (<i>p</i> < 0.05). The proposed clinical classification identified six subtypes, with encephalopathy-dominant and encephalomyelopathy-dominant types being most prevalent. This study highlights the clinical heterogeneity of late-onset cblC deficiency and introduces a novel symptom-based classification system to aid diagnosis and management. Elevated tHcy levels and specific <i>MMACHC</i> variants are key biomarkers for disease severity. These findings underscore the importance of early intervention to improve outcomes.