[Analysis of clinical characteristics of children with combined malonic and methylmalonic aciduria].

Objective: To investigate the clinical characteristics, genetic variants and outcomes of children with combined malonic and methylmalonic aciduria (CMAMMA) caused by ACSF3 gene variant. Methods: This was a retrospective case series. Clinical manifestations, biochemical findings, genetic sequencing and outcomes were collected from 7 infants with CMAMMA who were evaluated at the Department of Pediatric Endocrinology and Genetic Metabolism, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine between December 2021 and November 2025. Blood acylcarnitine profiles were analyzed by tandem mass spectrometry, urinary organic acids by gas chromatography-mass spectrometry and causative variants by Sanger or next generation sequencing. Results: The cohort included 6 males and 1 female, with an age at onset of 1.0 (0.4, 8.0) years and 6 patients did not experienced acute metabolic decompensation during the neonatal or infantile period. Five patients had varying degrees of developmental delay, including 1 patient with seizures and 1 patient with hypotonia. Biochemical analysis revealed elevated urinary methylmalonic acid level in all patients, and 5 patients also had elevated urinary malonic acid levels. Plasma propionylcarnitine (C3) and homocysteine levels were within normal ranges in all patients, while a mildly increased C3/acetylcarnitine (C2) ratio was observed in 1 patient. Five patients were unresponsive to vitamin B12 therapy. Genetic analysis identified 11 ACSF3 gene variants, including 2 novel variants, c.785C>T (p.A262V) and c.889T>A (p.Y297N). Follow-up assessments showed 5 patients exhibited severe or borderline developmental delay, 1 patient developed normally and 1 patient died. Conclusions: CMAMMA caused by ACSF3 variants is characterized by marked phenotypic heterogeneity and a subset of patients experience unfavorable outcomes. The predominant biochemical finding is elevated urinary methylmalonic acid, with or without concurrent elevation of malonic acid, while blood acylcarnitine profiles were often within the normal range.