Clinical phenotypes and genetic mutation analysis of 45 neonatal-onset methylmalonic acidemia

Background Methylmalonic acidemia (MMA), the most prevalent organic acidemia in China, is an autosomal recessive disorder. Neonatal-onset MMA often presents with non-specific manifestation, often causing diagnostic delays. Methods A retrospective analysis was conducted on the clinical data, laboratory findings, and genetic information of 45 neonatal-onset MMA patients admitted to the Children's Hospital Affiliated to Shandong University from October 2016 to June 2024. Results 1) Classification: 32 combined MMA, 13 isolated MMA. Median onset: 11 days. Common manifestations: feeding difficulties (60.0%), failure to thrive (57.8%), jaundice (46.7%), respiratory distress (40.0%), impaired consciousness (28.9%). Key labs: hyperammonemia (40.0%), macrocytic anemia (33.3%), granulocytopenia (31.1%). Hydrocephalus occurred in 3/31, abnormal EEGs in 15/19. Elevated C3, C3/C0, methylmalonic acid, and methylcitric acid were diagnostic. 2) Combined MMA had significantly lower methionine, blood ammonia, and C3/C0 vs. isolated MMA. Isolated MMA showed lower leukocyte counts ( p < 0.05). 3) Whole-exome sequencing: 31/32 (96.8%) had MMACHC mutations; c.609G>A recurrent (12/31). One had ABCD4 mutation. Isolated MMA: All 13 had MMUT mutations; c.729_730insTT common (46.2%). Missense mutations predominated. Conclusion Neonatal-onset MMA presents with non-specific clinical phenotypes. Therefore, unexplained feeding difficulties, neutropenia, hyperammonemia, or seizures warrant prompt homocysteine, tandem MS, and urinary organic acid screening. Isolated MMA shows earlier free carnitine decline and higher ammonia. MMACHC c.609G>A and MMUT c.729_730insTT are recurrent in combined and isolated subtypes, respectively.