Long-term prognosis of 35 patients with methionine adenosyltransferase deficiency based on newborn screening in China

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.

Keywords: MAT1A; S-adenosylmethionine; hypermethioninemia; long-term prognosis; methionine adenosyltransferase deficiency (MATD); neurological deficits.

FIGURE 1

Methionine values based on newborn screening and follow-up among 35 patients and 31 carriers. (A) Initial Met values by newborn screening distributed in carriers (black) and patients (red). Significant difference was found in the mean initial Met values between carriers (73 μmol/L) and patients (145 μmol/L). F12 + M10 = 12 females and 10 males. 4 asymptomatic patients (AD-P11; AR-P17, P33, P34) had initial Met <82.7 μmol/L. (B) Mean plasma Met during follow-up in patients (AD, AR) and carriers. Asymptomatic patients P1, P33 and P34 had a mean Met below 82.7 μmol/L. (C) Fluctuated plasma Met values (including minimum, maximum and mean value of Met) during follow-up among each 35 individuals. *, p < .05; **, p < .01; ***, p < .001.

FIGURE 2

White matter lesions and development status in patient 16 and patient 27. (A) Brain MRI scanning before and after liver transplantation in patient 16 at different time points. 7Y9M = patient at 7 years-9 months old. Patient 16 harbored a heterozygosis c.695 C>T/p. P232L. White matter lesions was reversed after liver transplantation. (B) Significant decrease of Met levels after transplantation in patient 16, from 844.1 μmol/L (before) to 96.9 µmol/L (after). mMet1:844.1 = mean Met value before transplantation was 844.1 μmol/L; mMet2:96.9 = mean Met value after transplantation was 96.9 μmol/L (C) Brain MRI scanning of patient 27 at the age of 4 years 11 m with anomalies in white matter. The plasma Met concentration was maintained at 839.1 μmol/L left panel display his development status measured by ASQ (Ages-Stages Questionnaire). P27 had a normal development after SAMe supplementation. *, p < .05; **, p < .01; ***, p < .001.

FIGURE 3

Summary of 38 variants of MAT1A identified in MATD patients and carriers. (A) Distribution of 38 variants in the MAT1A gene and protein among MATD patients and carriers. Black, 24 novel variants found in this study; grey, reported variants in MATD elsewhere. (B) Conservation analysis of 24 novel variants in different species, excluding the splicing c.292 + 5G>A.

FIGURE 4

Distribution of mean plasma Met values in the first 4 months of life in patients (red) and carriers (black). Ten patients with interventions deviated from the other 25 cases with a mean Met >500 μmol/L. Black arrows indicate patients (P16 and P27) with white matter lesions.