MT-ATP8 – Mitochondrial Disease

MT-ATP8 encodes subunit 8 of the mitochondrial ATP synthase (complex V) and has been implicated in diverse multisystem mitochondrial disorders. Three unrelated patients harboring homoplasmic MT-ATP8 variants have been reported: m.8529G>A (p.Trp55Ter) in a 16-year-old with cardiomyopathy and neuropathy (PMID:17954552), m.8393C>T in a 65-year-old with valproate-induced encephalopathy (PMID:30214424), and m.8403T>C in episodic paralysis responding to acetazolamide (PMID:24153443). Clinical features include developmental delay, hypotonia, failure to thrive, ptosis, encephalopathy, cardiomyopathy and peripheral neuropathy.

Functional studies in patient fibroblasts and transmitochondrial cybrid models demonstrate severely reduced complex V assembly and ATPase activity, accumulation of subcomplexes and threshold-dependent defects in oxidative phosphorylation (PMID:17954552; PMID:16217706). The mechanism is consistent with loss of function of subunit 8 leading to impaired ATP synthesis.

No clear Mendelian segregation has been observed due to maternal inheritance and homoplasmy, and variant recurrence is limited. There is no strong contradictory evidence disputing MT-ATP8’s role in mitochondrial disease.

Overall, the clinical and experimental data support a Limited clinical validity classification for MT-ATP8 in mitochondrial disease. Additional case reports, systematic segregation data and broader population studies would strengthen the association.

Key take-home: Rare homoplasmic MT-ATP8 loss-of-function variants cause mitochondrial disease via complex V deficiency, warranting inclusion in diagnostic mtDNA testing panels.

References

• Journal of Medical Genetics • 2008 • A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy PMID:17954552
• Frontiers in Neurology • 2018 • Reversible Valproate-Induced Subacute Encephalopathy Associated With a MT-ATP8 Variant in the Mitochondrial Genome PMID:30214424
• Neurology • 2013 • Episodic weakness due to mitochondrial DNA MT-ATP6/8 mutations PMID:24153443
• Neuropediatrics • 2005 • Two new mutations in the MTATP6 gene associated with Leigh syndrome PMID:16217706

Evidence Based Scoring (AI generated)