MT-ND5 Mutation Exhibits Highly Variable Neurological Manifestations at Low Mutant Load

Area of Science:

• Genetics
• Neurology
• Mitochondrial Biology

Background:

• The m.13094T>C mutation in the MT-ND5 gene has been associated with Leigh Syndrome (LS).
• Mitochondrial DNA (mtDNA) mutations can cause a spectrum of neurological disorders with variable clinical presentations.

Purpose of the Study:

• To investigate the clinical spectrum, inheritance patterns, and pathological features associated with the m.13094T>C MT-ND5 gene mutation.
• To evaluate the diagnostic utility of whole mtDNA genome sequencing for suspected mitochondrial diseases.

Main Methods:

• Retrospective international cohort study.
• Clinical data collection and analysis of 20 affected individuals and 4 asymptomatic carriers.
• Mitochondrial respiratory chain activity analysis in muscle biopsies.
• Neuropathological examination of brain tissue.

Main Results:

• Identified 20 affected individuals across 13 families, with presentations including LS, MELAS, Leber hereditary optic neuropathy, and overlapping syndromes.
• Observed marked variability in tissue segregation and phenotypic expression, even at low blood mutant loads.
• Neuropathology revealed capillary proliferation, microvacuolation, and neuronal loss in the brainstem and cerebellum, without basal ganglia involvement.

Conclusions:

• The m.13094T>C MT-ND5 mutation is associated with a wide range of neurological phenotypes beyond Leigh Syndrome.
• Whole mtDNA genome sequencing is crucial for diagnosing mitochondrial diseases with complex neurological manifestations.
• Understanding tissue segregation and phenotypic variability is key for accurate diagnosis and genetic counseling.