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Hereditary and Metabolic Diseases of the Central Nervous System in Adults
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
MT-ATP6 is the only gene associated with NARP. Not all clinical cases have a detectable deletion. Clinical findings include: Proximal muscle weakness.Sensory neuropathy.Ataxia.Retinal pigmentary degeneration.
Mitochondrial Pathologies and Their Neuromuscular Manifestations
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Carlos Ortez, Andrés Nascimento
NARP syndrome is due to the transversion m.8993T>G and, less commonly, to the transition m.8993T>C in the MT-ATP6 gene, encoding subunit 6 of ATP synthase115. The T8993C mutation is generally considered to be less severe than the T8993G mutation. The clinical presentation of patients with heteroplasmic NARP mutations is dominated by proximal neurogenic muscle weakness with sensory neuropathy, ataxia due to cerebellar atrophy, epilepsy, learning difficulties and pigmentary retinopathy. Associated myopathy is rare and muscle biopsy is usually normal. Electromyography (EMG) and nerve conduction studies may demonstrate peripheral neuropathy (which may be a sensory or sensori-motor axonal polyneuropathy)116,117. Onset of symptoms is often in early childhood; individuals can be relatively stable for many years, but may suffer episodic deterioration. When the heteroplasmy level is higher than 80% patients frequently have a more early and severe impairment which is presented as Leigh syndrome. CMT2 related to MT-ATP6 mutation.
Functional imaging of mitochondria in genetically confirmed retinal dystrophies using flavoprotein fluorescence
Published in Ophthalmic Genetics, 2022
Matthew W. Russell, Justin C. Muste, Kanika Seth, Madhukar Kumar, Collin A. Rich, Rishi P. Singh, Elias I. Traboulsi
Because patients with MT-ATP6 mutations have errors in ATP synthase resulting in dysfunctional mitochondria, this subset of patients had potential to serve as a positive control for detection of mitochondrial dysfunction with increased metrics of FPF intensity (20,21). This hypothesis proved to be correct at the eyes studied with MT-ATP6 had significantly increased FPF intensity. The MELAS cohort examined was also hypothesized to be a potential positive control for FPF imaging. Interestingly, no significant differences were seen between patients with MELAS and age-matched control patients. Multiple reasons may explain this finding. Only 6 eyes from patients with MELAS were included in this study, and these eyes were only found to have mottling noted on fundus exam and color fundus photography. As mottling noted in these patients is often reflective of abnormal pigment deposition, there is reason to believe a pigmentary change alone may not be representative of retinal stress and mitochondrial dysfunction (22). Because of this, it is possible these patients did not have severe dysfunction and ocular pathology to be detected by FPF imaging. Because patients with MELAS have mutations in tRNA and are non-protein encoding, it is plausible that these patients will not have decreases in cellular respiration and increases in ROS necessary to elicit an FPF signal (23). Conversely, MT-ATP6 mutations directly impact mitochondrial cellular respiration by affecting ATP synthase, making increased FPF more plausible in theory. Longitudinal imaging and expansion of these cohorts may further reveal how trends in FPF values correspond to long term visual function.
Leber’s Hereditary Optic Neuropathy with visual recovery caused by two rare mutations
Published in Ophthalmic Genetics, 2021
Eli Kisilevsky, Edward A. Margolin
In-silico prediction of this mutation is classified as “deleterious” in Sorting Intolerant From Tolerant (SIFT) program and “probably damaging” in PolyPhen-2. MT-ATP6 gene encodes a transmembrane protein that is a pore subunit of ATP synthase (complex V) in the oxidative phosphorylation pathway. Mutations in MT-ATP6 are inherited via maternal transmission and most commonly cause Leigh syndrome, Neuropathy, Ataxia and Retinitis Pigmentosa syndrome or complex V deficiency (3). These syndromes typically present at a young age, producing severe systemic phenotype including encephalopathy, seizures, and premature death.
Improving genetic diagnostics of skeletal muscle channelopathies
Published in Expert Review of Molecular Diagnostics, 2020
Vinojini Vivekanandam, Roope Männikkö, Emma Matthews, Michael G. Hanna
MT-ATP6 and MT-ATP8 are mitochondrial DNA genes, in which mutations cause classical mitochondrial phenotypes such as Leigh syndrome. Auré et al. report patients in six independent families with periodic paralysis, negative for known genes causing periodic paralysis, in whom they identified pathogenic MT-ATP6/8 mutations [79]. Attacks were often triggered by cold, exercise, prolonged sitting, or rest after exercise. Development of a motor neuropathy was seen in these patients.