Clinical and Molecular Spectrum of Patients with Methylmalonic Acidemia

Neerja Gupta; Mounika Endrakanti; Meenakshi Bhat; Nivedita Rao; Ravneet Kaur; Madhulika Kabra

doi:10.1007/s12098-023-04651-4

Clinical and Molecular Spectrum of Patients with Methylmalonic Acidemia

Indian J Pediatr. 2023 Jul 8. doi: 10.1007/s12098-023-04651-4. Online ahead of print.

Authors

Neerja Gupta¹, Mounika Endrakanti², Meenakshi Bhat³, Nivedita Rao³, Ravneet Kaur², Madhulika Kabra²

Affiliations

¹ Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India. neerja17@gmail.com.
² Division of Genetics, Department of Pediatrics, All India Institute of Medical Sciences, Room 840, 8th floor, Mother and Child Block, Ansari Nagar, New Delhi, 110029, India.
³ Centre for Human Genetics, Bangalore, Karnataka, 560100, India.

PMID: 37420116
DOI: 10.1007/s12098-023-04651-4

Abstract

Objectives: To study the clinical and molecular spectrum of Methylmalonic acidemia (MMA).

Methods: In this retrospective study, the records of 30 MMA patients were evaluated for their phenotype, biochemical abnormalities, genotype, and outcomes.

Results: Thirty patients with MMA (age range 0-21 y) from 27 unrelated families were enrolled. Family history and consanguinity were noted in 10/27 (37%) and 11/27 (41%) families respectively. Acute metabolic decompensation was more common (57%) than chronic presentation. Biochemical work-up was suggestive of isolated MMA (n = 18) and MMA with homocystinuria (n = 9) respectively. Molecular testing in 24 families showed 21 pathogenic or likely pathogenic variants with MMA cblC as the commonest molecular subtype (n = 8). B12 responsiveness, an important determinant of long-term outcome, was observed in eight patients [MMAA (n = 3) and MMACHC (n = 5)]. Mortality was 30% (n = 9/30) with a high proportion of early-onset severe disease and fatal outcome in isolated MMA mut⁰ (4/4) and MMA cblB (3/3), as compared to MMA cblA (1/5) and MMA cblC (1/10).

Conclusions: This study cohort had MMA cblC subtype as the most common type of MMA followed by the MMA mutase defect. Outcomes in MMA are influenced by the type of molecular defect, age, and severity of presentation. Early detection and management is likely to result in better outcomes.

Keywords: Homocystinuria; MMACHC; Methylmalonic acidemia; Methylmalonyl-CoA mutase enzyme; Newborn screening; Next generation sequencing.