A rare mutation c.1663G\u2009>\u2009A (p.A555T) in the MMUT gene associated with mild clinical and biochemical phenotypes of methylmalonic acidemia in 30 Chinese patients

Lili Liang,Shengnan Wu,Yongxing Chen,Haiyan Wei,Hui Zou,Tingting Niu,Xuefan Gu,Hejing Hu ,Jie Feng ,Chenghui Yang ,Xigui Chen,Zhuwen Gong,Deyun Lu,Peng Xu,Wenjuan Qiu,Wenjun Ji,Ruixue Shuai,Yongguo Yu,Jun Ye,Xia Zhan,Yue Yu,Huiwen Zhang,Linghua Shen,Lianshu Han

doi:10.1186/s13023-020-01632-0

Abstract

BackgroundMethylmalonic acidemia is an inherited organic acid metabolic disease. It involves multiple physiological systems and has variable manifestations. The primary causative gene MMUT carries wide range of mutations, and one of them, c.1663G > A (p.A555T), is considered to be a rare type, which is seen more frequently in Asian than other populations. So far, little is known about the clinical features of patients carrying this mutation. In the present study, we aimed to define the clinical and biochemical features of the patients with this genotype.MethodsAmong 328 mut type methylmalonic acidemia patients from multiple hospitals in China, we collected 30 compound heterozygous patients sharing the mutation c.1663G > A (p.A555T) in the MMUT gene. Their clinical characteristics and biochemical index were described in detail and compared with methylmalonic acidemia patients without this variant.ResultsMost of these patients were diagnosed via newborn screening (26/30), treated in a timely manner, and kept healthy (24/30). Disease onset occurred in 7 patients. Developmental delay or intellectual impairment occurred in 4 patients. 100% of these patients (29/29) were responsive to Vitamin B12 administration. The blood propionylcarnitine, blood propionylcarnitine/acetylcarnitine ratio, urinary methylmalonic acid, urinary methylcitric acid before and after treatment in c.1663G > A (p.A555T) carrying patients were much lower than those in non-c.1663G > A (p.A555T) carrying patients.ConclusionCompared to patients with other mutations in the MMUT gene, patients with the c.1663G > A (p.A555T) mutation showed later onset, milder clinical phenotype, lighter biochemical abnormalities, better vitamin B12 responsiveness, lower morbidity, easier metabolic control, and thereby better prognosis. Newborn screening project plays an important role in early diagnosis, treatment, and prognosis of these patients.

Highlights

Methylmalonic acidemia (MMA) is a series of rare inherited organic acid metabolic disorders
We examined 30 isolated MMA patients carrying this mutation from multiple hospitals during the last 15 years
26 cases were diagnosed by using a positive newborn screening, 2 patients were diagnosed because of onset of the disease (P18, P30), and 2 cases (P9, P13) were diagnosed because of sibling MMA diagnosis (P8, P12)

Summary

Introduction

Methylmalonic acidemia (MMA) is a series of rare inherited organic acid metabolic disorders. The accumulation of methylmalonic acid and abnormal metabolites causes various clinical symptoms [2]. Implementation of newborn screening in various countries has allowed for the estimation of birth prevalence of MMA and its isolated form. The advancing use of MS/MS in newborn screening and identification of clinically suspected cases beneficially serve for proper and timely diagnosis of MMA. Methylmalonic acidemia is an inherited organic acid metabolic disease. It involves multiple physiological systems and has variable manifestations. The primary causative gene MMUT carries wide range of mutations, and one of them, c.1663G > A (p.A555T), is considered to be a rare type, which is seen more frequently in Asian than other populations. Little is known about the clinical features of patients carrying this mutation. We aimed to define the clinical and biochemical features of the patients with this genotype

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Results

Discussion

Conclusion