neuromuscular human diseases have been associated with
mitochondrial DNA (mtDNA) variations, causing defects of
oxidative phosphorylation. These dysfunctions affect
preferentially tissues with high energy demands and give arise
to several degenerative disorders such as optic neuropathy,
cerebellar ataxia, movement disorders, dementia, muscle
weakness and deafness. The extremely heterogeneous clinical
phenotype is due to the involved tissue, to specific mtDNA
mutations and their heteroplasmic level, but also to nuclear
DNA alterations, environmental and epigenetic factors. In this
study we investigated a child affected by a complex
neurological disease whose clinical features were suggestive
of a mitochondrial involvement.
Methods: mtDNA from proband, her healthy relatives
(grandmother, mother and two sisters) and 80 controls were
collected and studied by sequencing. The enzymatic activity of
specific respiratory chain complex was tested on lymphocytes
by spectrophotometric assay. Bioinformatic analysis was
performed to predict the pathogenicity of the detected variants.
Results: In all subjects we detected 11 known polymorphisms,
whereas 1 novel heteroplasmic variant in complex I
[ND5:12514G>A (E60K)] was present only in the proband and
in her grandmother and absent in controls. The bioinformatics
predicted the novel variant to be deleterious. Further,
spectrophotometric assay of complex I activity was lower both
in the proband and in her relatives than in the controls.
Conclusions: We report a novel mtDNA variant detected in a
patient affected by a complex neurological disease. The
reduction of complex I respiratory chain activity associated to
this variant suggests it could exert a pathogenic role in the
disease