A clinical and gene analysis of late-onset combined methylmalonic aciduria and homocystinuria, cblC type, in China

Abstract

Background

Combined methylmalonic aciduria and homocystinuria, cblC type (cblC disease), is the most common inborn disorder of cobalamin metabolism. This disorder is caused by MMACHC gene mutations, and it is usually diagnosed in the early neonatal period. Late-onset cblC is rare and difficult to recognize due to a wide diversity of symptoms.

Methods

Three cases with late-onset combined methylmalonic aciduria and homocystinuria, cblC type, are reported; patients' clinical presentation, imaging and MMACHC gene mutations were analyzed.

Results

The age of onset in the three patients was 22 years, 40 years and 7 years of age. Two of the patients had MMACHC gene mutations heterozygous for c.609G>A and c.482G>A (case 1 and case 3). The other patient (case 2) presented with gene mutations heterozygous for c.609G>A and c.1A>G. The three patients presented with a heterogeneous clinical picture, including cognitive impairment, epilepsy, ataxia, pyramidal and peripheral nerve symptoms. Cerebral atrophy and bilateral hyperintensity in the deep white matter were visible in MRI scans of the patients' brains; those were significant findings in the three patients with late-onset cblC disease. In contrast with previous reports, bilateral cerebellar cortex abnormalities were also found in one patient (case 2).

Conclusion

Although its occurrence is rare, late-onset combined methylmalonic aciduria and homocystinuria, cblC type, should be considered in making a differential diagnosis in patients who present with neurological symptoms that are not consistent with common neurological diseases, especially when cognition, the pyramidal tract and peripheral nerves are involved.

Introduction

Combined methylmalonic aciduria and homocystinuria, cobalamin (cbl) C type (cblC disease), is an inborn error of intracellular cobalamin metabolism resulting from impaired conversion of dietary cobalamin to its two metabolically active forms, methylcobalamin (MeCbl) and adenosylcobalamin (AdoCbl). AdoCbl and MeCbl are cofactors for the methylmalonyl-CoA mutase and methionine synthase respectively. The decreased activity of these enzymes (mutase and synthase) cause an elevation of methylmalonic acid (MMA) and homocysteine [1]. For most cblC patients, systemic, hematological, and neurological abnormalities are present within the first year of life; these abnormalities usually include feeding difficulties, hypotonia, developmental delay, seizure, pigmentary retinopathy, and anemia [2]. Late-onset cblC disease is considered rare and has not been comprehensively characterized. Among the various clinical manifestations of late-onset cblC disease, neurological symptoms are frequently evident [3], [4]. It has been reported that in some patients with late-onset cblC disease only neurological manifestations were evident [3], [4], [5]. However, because of the difficulty in recognizing symptoms of the late-onset inborn metabolic disorder as cblC disease, and because these patients may have an otherwise normal medical history, the disease could be easily misdiagnosed. To help identify patients with late-onset cblC disease, we describe the clinical presentation and imaging of three patients with late-onset combined methylmalonic aciduria and homocystinuria, cblC type, whose diagnoses were confirmed by genetic analysis.