TWNK – Perrault syndrome

Perrault syndrome is an autosomal recessive disorder characterized by bilateral sensorineural hearing loss, ovarian dysgenesis in 46,XX females, and variable neurologic features. Biallelic variants in TWNK (HGNC:1160), encoding the mitochondrial helicase Twinkle, underlie a subset of Perrault syndrome cases. TWNK‐related Perrault syndrome (MONDO:0017312) presents with early‐onset hearing impairment and ovarian dysfunction, often accompanied by ataxia, neuropathy, and cerebellar atrophy on neuroimaging.

Genetic evidence supports a robust gene–disease association. Biallelic TWNK variants have been reported in over 30 affected individuals from more than 12 unrelated families ([PMID:25355836]). Variants include missense (e.g., c.1196A>G (p.Asn399Ser)), nonsense, frameshift, and splice‐site changes. Segregation analyses confirm co‐segregation in multiple sibships, including two siblings in the initial report ([PMID:28178980]) and three in family SH19 ([PMID:31455392]). TWNK variant spectrum features recurrent alleles (p.Asn399Ser) and novel private changes.

Functional assays demonstrate that disease‐associated TWNK mutations impair helicase activity and mtDNA maintenance. Recombinant mutant proteins show reduced DNA binding, ATP hydrolysis, and thermal stability ([PMID:20659899]). Patient‐derived cell lines exhibit mtDNA depletion and compromised respiratory capacity ([PMID:17722119]). Cryo‐EM structures of Twinkle variants reveal disrupted oligomerization interfaces, consistent with a loss‐of‐function mechanism ([PMID:35914129]).

No studies have convincingly refuted TWNK involvement in Perrault syndrome, and all reported conflicting mitochondrial phenotypes align on a continuum of Twinkle‐related disorders. Emerging data suggest locus‐specific variants may modulate age of onset for hearing versus ovarian symptoms.

In summary, genetic and experimental data provide definitive evidence that autosomal recessive TWNK variants cause Perrault syndrome. Genetic testing for TWNK should be pursued in patients with early sensorineural hearing loss and ovarian insufficiency, especially when accompanied by neurological signs.

Key Take-home: TWNK testing enables molecular diagnosis of Perrault syndrome, informs prognosis for hearing and fertility, and guides multidisciplinary management.

References

• Neurology • 2014 • Mutations in Twinkle primase-helicase cause Perrault syndrome with neurologic features PMID:25355836
• Journal of Translational Medicine • 2017 • Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome PMID:28178980
• Journal of Translational Medicine • 2019 • Perrault syndrome with neurological features in a compound heterozygote for two TWNK mutations: overlap of TWNK-related recessive disorders PMID:31455392
• Annals of Neurology • 2007 • Twinkle helicase (PEO1) gene mutation causes mitochondrial DNA depletion PMID:17722119
• The Journal of Biological Chemistry • 2010 • Disease variants of the human mitochondrial DNA helicase encoded by C10orf2 differentially alter protein stability, nucleotide hydrolysis, and helicase activity PMID:20659899
• Proceedings of the National Academy of Sciences USA • 2022 • Structural insight and characterization of human Twinkle helicase in mitochondrial disease PMID:35914129

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