Somatic Variants in PDHA1 Expand the Phenotypic Spectrum

Authors

• Jessica Priestley, Corewell Health West
• Jessica Park, Michigan State University College of Human Medicine Medical Student
• Elizabeth VanSickle, Corewell Health West
• Jeremy Prokop, Corewell Health West

Document Type

Conference Proceeding

Publication Date

5-2026

Publication Title

Molecular Genetics and Metabolism

Abstract

Background: Pyruvate dehydrogenase complex deficiency (PDCD), a rare mitochondrial disorder, impairs carbohydrate metabolism and energy production, predominantly affecting the central nervous system. Most cases stem from germline variants in PDHA1, but somatic mosaicism has been identified in a handful of patients, typically male and presenting with severe neonatal phenotypes.

Methods: A retrospective chart review was performed to summarize the course of a late-diagnosed adult male with mosaic PDHA1-related PDCD, expanding the known phenotypic spectrum and highlighting challenges in diagnosing attenuated forms. The proband's variant was modeled by conservation across species and known human pathogenic variants using publicly available tools. A comprehensive review was performed to compare and contrast his case to others in the published literature.

Results: At 17 years of age, our proband exhibited congenital microcephaly, structural brain abnormalities, optic nerve atrophy, global developmental delay, dystonia, and neuromuscular scoliosis. Clinical exome sequencing from peripheral blood specimen identified a de novo PDHA1 likely pathogenic variant (c.572 T N A, p.(L191Q)) present in 43% (10/23) of sequencing reads. This patient's phenotype overlaps with previously reported cases of mosaic PDHA1 variants yet demonstrates relative clinical stability and functional engagement. This case illustrates the variable expressivity and diagnostic complexity of mosaic PDCD.

Conclusions: From these data, we conclude that somatic mosaicism for PDHA1 pathogenic variants may present with milder and atypical phenotypes, leading to underdiagnosis, especially in adult populations. This report underscores the value of vigilance in unexplained neurologic syndromes and contributes to a growing body of literature on the clinical spectrum of PDCD.

Volume

148

Issue

1

First Page

110063

Last Page

110063

Recommended Citation

Priestley J, Park J, Vansickle E, Prokop J. Somatic variants in PDHA1 expand the phenotypic spectrum. Mol Genet Metab. 2026;148(1):110063. doi: 10.1016/j.ymgme.2026.110063.

Comments

Annual Meeting of the Society for Inherited Metabolic Disorders (SIMD), May 17-20, 2026, Rio Grand, PR

DOI

10.1016/j.ymgme.2026.110063

ISSN

1096-7192