AUTHOR=Almudhry Montaha , Saini Arushi Gahlot , Al-Omari Mohammed A. , Sharma Yashu , Nouri Maryam Nabavi , Rupar C. Anthony , Prasad Chitra , Yu Andrea C. , Attri Savita Verma , Prasad Asuri Narayan 

TITLE=Methylmalonic aciduria as a biochemical marker for mitochondrial DNA depletion syndrome in patients with developmental delay and movement disorders: a case series

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1265115

DOI=10.3389/fneur.2023.1265115

ISSN=1664-2295

ABSTRACT=Background: Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from reduction in mtDNA content in the cells, tissues and organ systems leading to symptoms related to energy deficits. Deficiency in the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile.Methods: This cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the SUCLG1 and SUCLA2 genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations and outcome were gathered through chart reviews.Results: All subjects presented early in infancy with neurological manifestations including movement disorder, psychomotor regression, developmental delay, hearing loss, and behavioral issues or a combination thereof. Elevated methylmalonic acid metabolites abnormal acylcarnitine profile and lactic acidemia were noted in the biochemical profile in each of the patients, in (n=5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four, and compound heterozygosity in one subject.MDDS associated with SUCLG1 and SUCLA2 genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC and C5-OH acylcarnitine. Conducting metabolic work up including MMA and acylcarnitine profile in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management.