Genetic variation and clinical phenotype analysis of hypermethioninemia caused by MAT1A gene mutation: Case report.

Abstract

Rationale: The high clinical heterogeneity of hypermethioninemia caused by MAT1A gene defects has resulted in a paucity of studies examining the association between clinical phenotypes, biochemical characteristics, and gene mutations in this patient group. Furthermore, the indications for therapeutic interventions in patients remain unclear. The objective of this study is to provide a foundation for clinical diagnosis, genetic counseling, and follow-up management of hypermethioninemia caused by MAT1A gene defects.

Patient concerns: A retrospective analysis of children with hypermethioninemia at Jinan Maternal and Child Health Hospital from January 2016 to December 2023 was performed using tandem mass spectrometry (MS/MS). The screened and diagnosed children were tested for gene mutations using second-generation sequencing technology and confirmed using Sanger sequencing.

Diagnoses: Newborn MS/MS screening for diseases demonstrated an elevated methionine level, which was outside the reference range. Upon recalling the newborns, the methionine levels remained elevated, necessitating further refinement of genetic testing. Ultimately, genetic testing confirmed hypermethioninemia, which was attributed to a mutation in the MAT1A gene.

Interventions: The intervention for the patients in this study took the following forms: regular follow-up without treatment (n = 3), intake of methionine-free milk powder without any medication (n = 4), intake of methionine-free milk powder with some medication, and eventually liver transplantation (n = 1).

Outcomes: A total of 14 mutation types were detected, including 3 compound heterozygous mutation types (c.926G > T, c.37_38delCT, and c.316G > A) that have not been previously reported. One patient had monoheterozygous mutations, including the novel mutation c.550-1G > A. Eight cases were monitored over time, 7 of which demonstrated typical growth and development. One infant with growth retardation was fed a special formula lacking methionine. The patient underwent liver transplantation. Subsequent follow-up examinations showed methionine and homocysteine levels within normal limits and no further neurological manifestations.

Lessons: Compound heterozygous mutations c.874C > T and c.896G > A may result in higher levels of methionine, affecting the central nervous system. For newborns with initial methionine levels of >500 µmol/L, treatment with a low-Met diet is recommended. Liver transplantation may be beneficial for children with severe hypermethioninemia, particularly in preventing central nervous system damage.