PDF(Pubmed)
Abstract：
Methionine adenosyltransferase deficiency (MATD) is a rare metabolic disorder caused by mono- or biallelic MAT1A mutations that are not yet well understood. Of the 4,065,644 neonates screened between November 2010 and December 2021, 35 individuals have been diagnosed with an estimated incidence of 1: 116,161 by a cutoff value of methionine 82.7 μmol/L and follow-up over 11 years. MATD patients with autosomal recessive (AR) type had higher clinical and genetic heterogeneity than those with autosomal dominant (AD) type. Fifteen unrelated AD patients harbored one well-known dominant variant, c.791 G>A or c.776 C>T, and were clinically unaffected with a mean plasma methionine (Met) value <300 μmol/L. Twenty AR cases have unique genotypes and presented a wide range of clinical abnormalities from asymptomatic to white matter lesions. Of them, 10 AR patients displayed severe manifestations, such as verbal difficulty, motor delay, development delay, and white matter lesions, with mean Met >500 μmol/L and thereby were treated with a methionine-restricted diet alone or in combination with betaine, folate, or vitamin B6, and were healthy finally. Neurological abnormalities were evidenced in two patients (P16 and P27) with Met values >800 μmol/L by MRI scan. Neurological abnormalities were reversed here by liver transplantation or by the determination of S-adenosylmethionine supplementation. Additionally, 38 variants of MAT1A were distributed within patients and carriers, of which 24 were novel and mostly predicted to be damaged. Our findings with an extensive clinical and genetic dataset provided new insights into its diagnosis and treatment and will be helpful for its optimal management in the future.
摘要：
甲硫氨酸腺苷转移酶缺乏症（MATD）是一种罕见的代谢紊乱，由单或双等位基因MAT1A突变引起，目前尚不清楚。在2010年11月至2021年12月期间筛查的4,065,644名新生儿中，有35人被甲硫氨酸82.7μmol/L的临界值诊断为1：116,161，并随访了11年。常染色体隐性（AR）型MATD患者的临床和遗传异质性高于常染色体显性（AD）型。15名无关的AD患者有一个众所周知的显性变异，c.791G>A或c.776C>T，并且在临床上不受平均血浆蛋氨酸（Met）值<300μmol/L的影响。20例AR病例具有独特的基因型，并表现出从无症状到白质病变的广泛临床异常。其中,10例AR患者表现为严重表现，如言语困难，电机延迟,发展滞后,和白质病变，平均Met>500μmol/L，因此单独使用甲硫氨酸限制饮食或与甜菜碱联合治疗，叶酸,或维生素B6，最后是健康的。通过MRI扫描，在Met值>800μmol/L的两名患者（P16和P27）中发现了神经系统异常。通过肝移植或通过测定补充S-腺苷甲硫氨酸可以逆转神经系统异常。此外,38种MAT1A变体分布在患者和携带者体内，其中24个是新颖的，大部分预计会损坏。我们的发现具有广泛的临床和遗传数据集，为其诊断和治疗提供了新的见解，并将有助于其未来的优化管理。
