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

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

doi:10.3389/fneur.2023.1265115

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

Front Neurol. 2023 Nov 24:14:1265115. doi: 10.3389/fneur.2023.1265115. eCollection 2023.

Authors

Montaha Almudhry^#^{1

2}, Arushi Gahlot Saini^#³, Mohammed A Al-Omari^{4

5}, Yashu Sharma³, Maryam Nabavi Nouri^{1

6

7}, C Anthony Rupar^{1

6

8}, Chitra Prasad^{1

6

9}, Andrea C Yu¹⁰, Savita Verma Attri³, Asuri Narayan Prasad^{1

6

7}

Affiliations

¹ London Health Sciences Centre, London, ON, Canada.
² Department of Neuroscience, King Fahad Specialist Hospital, Dammam, Saudi Arabia.
³ Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
⁴ Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
⁵ King Fahad Hospital of the University, Al-Khobar, Saudi Arabia.
⁶ Department of Pediatrics, University of Western Ontario, London, ON, Canada.
⁷ Department of Clinical Neurological Science, Western University, London, ON, Canada.
⁸ Department of Biochemistry, University of Western Ontario, London, ON, Canada.
⁹ Department of Pediatrics, Medical Genetics Program of Southwestern Ontario, London, ON, Canada.
¹⁰ Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

^# Contributed equally.

Abstract

Background: 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 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 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 (n = 5/5, 100%). Molecular genetic testing disclosed the presence of pathogenic homozygous mutations in four subjects and compound heterozygosity in one subject.

Conclusion: 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 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.

Keywords: SUCLA2; SUCLG1; dystonia; methylmalonic acid; mitochondrial DNA depletion syndrome; mitochondrial disorder; movement disorder.

Grants and funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article. Three patients have been evaluated in the project funded under the “Core Research Grant” scheme of DST-SERB (CRG/2020/005877), India, given to one of the co-authors (AS).