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=14

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=<sec id="sec1"><title>Background</title><p>Mitochondrial DNA (mtDNA) depletion syndromes (MDDS) are genetically and clinically variable disorders resulting from a reduction in mtDNA content in the cells, tissues, and organ systems, leading to symptoms related to energy deficits. Deficiency of the mitochondrial succinyl-CoA ligase/synthetase enzyme secondary to pathogenic variations in the <italic>SUCLG1</italic> and <italic>SUCLA2</italic> genes is a subtype of MDDS that presents with neurological manifestations and a specific biochemical profile.</p></sec><sec id="sec2"><title>Methods</title><p>This cross-sectional series describes five patients with MDDS secondary to pathogenic variations in the <italic>SUCLG1</italic> and <italic>SUCLA2</italic> genes from two tertiary care centers in Canada and India. Clinical data concerning the course, investigations, and outcome were gathered through chart reviews.</p></sec><sec id="sec3"><title>Results</title><p>All subjects presented in early infancy with neurological manifestations, including movement disorder, psychomotor regression, developmental delay, hearing loss, behavioral issues, or a combination thereof. Elevated methylmalonic acid metabolites, an abnormal acylcarnitine profile, and lactic acidemia were noted in the biochemical profile of each patient (<italic>n</italic> = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject.</p></sec><sec id="sec4"><title>Conclusion</title><p>MDDS associated with <italic>SUCLG1</italic> and <italic>SUCLA2</italic> genes can be detected biochemically by the presence of methylmalonic aciduria besides the elevation of lactate, C3, C4DC, and C5-OH acylcarnitine. Conducting metabolic workups including MMA and acylcarnitine profiles in patients with heterogeneity of clinical symptoms associated with the presence of this biochemical marker may potentially reduce the time to diagnosis and management.</p></sec>