Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants

Area of Science:

• Genetics
• Mitochondrial Biology
• Neurology

Background:

• Leigh syndrome (LS) is a severe genetic disorder characterized by defective mitochondrial bioenergetics, leading to neurological symptoms and often early mortality.
• LS is genetically heterogeneous, with mutations in mitochondrial DNA (mtDNA), particularly in the MT-ATP6 gene (e.g., m.8993T>G, m.8993T>C), linked to impaired ATP synthesis.
• These specific mtDNA variants affect a conserved amino acid in ATP synthase subunit 6, disrupting the F0 domain and mitochondrial energy production.

Purpose of the Study:

• To investigate the genetic and bioenergetic profiles of patients suspected of Leigh syndrome.
• To characterize the clinical and genetic findings in five cases with the m.8993T>G mtDNA variant and one family with a combination of m.8993T>C and m.1555A>G variants.
• To highlight the diagnostic challenges and the importance of comprehensive analysis in LS.

Main Methods:

• Received and analyzed 48 samples from LS-suspected patients.
• Performed bioenergetic assessments, including mitochondrial respiratory chain (MRC) complex activity and ubiquinone content.
• Conducted genetic analyses, such as mtDNA copy number determination, sequencing, and PCR-RFLP.

Main Results:

• Identified six cases with pathogenic mtDNA variants at nucleotide 8993 associated with LS.
• Five cases harbored the m.8993T>G variant, with varying heteroplasmy levels and associated MRC complex deficiencies.
• One family presented a combination of homoplasmic m.1555A>G and heteroplasmic m.8993T>C variants, with the proband showing Complex V deficiency.

Conclusions:

• Pathogenic variants in the mtDNA 8993 nucleotide are associated with LS and impaired mitochondrial respiratory chain complex V activity.
• LS exhibits significant clinical variability and genetic heterogeneity, with some patients lacking classic pathogenic variants and others being asymptomatic carriers.
• Comprehensive characterization using classical methods and multi-tissue analysis remains crucial for diagnosing LS patients and identifying carriers.