Late-onset cblC deficiency around puberty: a retrospective study of the clinical characteristics, diagnosis, and treatment

Abstract

Background cblC deficiency is the most common type of methylmalonic aciduria in China. Late-onset patients present with various non-specific symptoms and are usually misdiagnosed. The purpose of this study is to investigate the clinical features of patients with late-onset cblC deficiency and explore diagnosis and management strategies around puberty. Results This study included 56 patients (35 males and 21 females) with late-onset cblC deficiency who were admitted to our clinic between 2002 and September 2021. The diagnosis was confirmed by metabolic and genetic tests. The clinical and biochemical features, disease triggers, outcome, and associated genetic variants were examined. The onset age ranged from 10 to 20 years (median age, 12 years). Fifteen patients (26.8%) presented with symptoms after infection or sports training. Further, 46 patients (82.1%) had neuropsychiatric diseases; 11 patients (19.6%), cardiovascular diseases; and 6 patients (10.7%), pulmonary hypertension. Renal damage was observed in 6 cases (10.7%). Genetic analysis revealed 21 variants of the MMACHC gene in the 56 patients. The top five common variants detected in 112 alleles were c.482G > A (36.6%), c.609G > A (16.1%), c.658_660delAAG (9.8%), c.80A > G (8.0%), and c.567dupT (6.3%). Thirty-nine patients carried the c.482G > A variant. Among 13 patients who exhibited spastic paraplegia as the main manifestation, 11 patients carried c.482G > A variants. Six patients who presented with psychotic disorders and spastic paraplegia had compound heterozygotic c.482G > A and other variants. All the patients showed improvement after metabolic treatment with cobalamin, l-carnitine, and betaine, and 30 school-aged patients returned to school. Two female patients got married and had healthy babies. Conclusions Patients with late-onset cblC deficiency present with a wide variety of neuropsychiatric symptoms and other presentations, including multiple organ damage. As a result, cb1C deficiency can easily be misdiagnosed as other conditions. Metabolic and genetic studies are important for accurate diagnosis, and metabolic treatment with cobalamin, l-carnitine, and betaine appears to be beneficial.

Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry

“…The MMA concentration was identified by MS-MS using specific cutoff values for propionylcarnitine (C3) and its ratio with acetylcarnitine (C2). This patient (P5) with cblC-MMA was missed because her C3 level and C3/C2 were normal but with compound heterozygous for two missense variants (c.482G>A/c.565C>T) of the MMACHC gene; the variant c.482G>A is associated with milder disease [ 24 ] and late onset [ 25 ]. Therefore, these two missing patients were very difficult to avoid by MS/MS.…”

“…The variant c.80A>G is reported to be associated with late-onset diffuse lung disease (DLD) [ 26 ] and prominent renal complications, and the most frequent renal pathological manifestation is thrombotic microangiopathy [ 27 ]. The variant c.80A>G should be considered to indicate disease of the cardiovascular system [ 25 ]. Analysis of the composition of the MMACHC gene variants in the healthy population ( Supplemental Figure S2 ) revealed the four most common variants to be c.609G>A, c.658_660delAAG, c.482G>A, and c.80A>G, which is basically consistent with reported data for Chinese patients.…”

Clinical and electroencephalogram characteristics of methylmalonic acidemia with neurological injury

“…Later onset patients or adults may show cognitive abnormalities such as progressive encephalopathy, movement disorders, speech disorders, learning di culties, psychoneurotic symptoms, dementia, and executive dysfunction. It can also manifest as spinal cord degeneration and spinal cord thrombosis (5,6). It can also impact the optic nerve (7), resulting in impaired vision.…”

“…According to the age of onset, cb1C can be divided into early-onset (onset within 1 year) and late-onset (after 4 years), with different clinical manifestations according to the type and location of gene mutation (9). Early onset was associated with a higher mortality risk (5). Common MRI signs include myelination dysplasia, brain atrophy, lateral ventricle dilatation, and bilateral pallidum symmetry signal abnormalities (10).…”

Follow-up study of neuropsychological scores of infant patients with cobalamin C defects and influencing factors of cerebral magnetic resonance imaging characteristics

“…In mainland China, cblC defects are the main type of combined methylmalonic aciduria (MMA) and homocystinuria ( Cui et al, 2018 ). Studies have found that the prevalence of cb1C deficiency in Shandong province of China was 1/3,920 from 2011 to 2014 ( Han et al, 2016 ), however, the nationwide prevalence of cblC deficiency is unclear ( Chen et al, 2022 ). In the case of combined defects (cblC, cblD, and cblF), both MMA and homocysteine accumulate, and these defects are vital characteristics of patients with MMA.…”