Title:Diversities in Leigh Syndrome Associated with MT-ATP6 Gene Variants
Volume: 24
Issue: 16
Author(s): Sara Martins, Maria João Santos, Marta Simões, Sandra Jacinto, Cristina Martins Halpern, Juliette Dupont, Luísa Diogo and Manuela Grazina*
Affiliation:
- University of Coimbra CNC - Center for Neuroscience and Cell Biology, FMUC – Faculty of Medicine; CIBB - Center for Innovative Biomedicine and Biotechnology Coimbra Portugal
Keywords:
Leigh syndrome, mitochondrial cytopathies, disease heterogeneity, methodology, mtDNA, pathogenic sequence variants
Abstract: Introduction: Leigh syndrome (LS) is clinically and genetically heterogeneous and
presents defective mitochondrial bioenergetics. Patients present neurological symptoms and
imagiological features that may result in early death [1]. The LS has been associated with mitochondrial
DNA (mtDNA) variants, e.g., m.8993T>G (L156R) and m.8993T>C (L156P), in the
MT-ATP6 gene. They lead to the substitution of a highly conserved amino acid in subunit 6 of
ATP synthase, affecting the F0 domain and ATP synthesis [1-3]. We present five cases with
m.8993T>G and a family harbouring m.8993T>C+m.1555A>G (proband and four relatives).
Methods: Our laboratory received 48 samples from LS-suspected patients. The samples (various
tissues) were assessed for bioenergetics (activity of mitochondrial respiratory chain (MRC)
complexes, ubiquinone content) and genetic analyses (mtDNA copy number, Sequencing and
PCR-RFLP) by established protocols.
Results/Case Report: Bioenergetics were assessed in 5 patients (various tissues) with varying
levels of MRC/ATP synthase impairment. Six cases had a mtDNA pathogenic variant in the
8993 nucleotide associated with LS. Five cases presented the m.8993T>G variant, one of which
(P5) possibly de novo. This variant was homoplasmy (P1-3) or very high heteroplasmy (P4/5,
90-95%). Of the four patients with bioenergetics assessment, three (P1/3/4) had deficiencies of
MRC complexes, and P5 had small deficits. The other case (familial, proband and 4 relatives)
presented a combination of m.1555A>G (homoplasmy) and m.8993T>C (heteroplasmy) variants.
The proband presents m.8993T>C in 95% heteroplasmy and 85-35% in three relatives. All
have m.1555A>G in homoplasmy, including the fourth relative without m.8993T>C. A deficiency
(31%) was found in complex V activity in muscle for proband.
Conclusion: We present a case series of patients harbouring pathogenic variants in the 8993
nucleotide of mtDNA, which have been associated with LS and impairment of MRC's complex
V. These cases highlight the variability in clinical symptoms and their severity, as well as genetic
heterogeneity within LS. Many patients will not present a classic pathogenic variant and there
are many cases of asymptomatic relatives (carriers). It is important to get a broader view of the
cases - classical methods and multiple tissue analysis are still valuable tools for the comprehensive
characterization of patients.
