TWNK – Hepatocerebral Mitochondrial DNA Depletion Syndrome

TWNK encodes the mitochondrial DNA helicase Twinkle, essential for mtDNA replication and maintenance. Biallelic pathogenic variants in TWNK cause autosomal recessive mitochondrial DNA depletion syndrome type 7 (hepatocerebral form), manifesting as infantile-onset spinocerebellar ataxia (IOSCA) with progressive neurodegeneration and multi‐system involvement.

Autosomal recessive inheritance is supported by multiple consanguineous and non‐consanguineous families. Eight probands ([PMID:16135556]) from five unrelated pedigrees present with normal early development followed by ataxia, sensory neuropathy, hearing loss, seizures, ophthalmoplegia, and myopathy. Segregation in two sibships confirms co‐segregation of homozygous or compound heterozygous TWNK variants with disease ([PMID:22353293]).

The variant spectrum includes missense changes (e.g., c.1387C>T (p.Arg463Trp)), splice‐site alleles, and rare founder mutations. Recurrent Finnish founder alleles (p.Tyr508Cys) and private family‐specific missense or splice mutations have been described across ethnicities. Hypomorphic and loss‐of‐function alleles both contribute to disease severity.

Functional studies demonstrate that IOSCA‐associated TWNK variants impair helicase activity, nucleotide hydrolysis, and DNA binding, leading to mtDNA replication stalling and depletion in patient tissues and model systems. In vitro assays of 20 mutant enzymes reveal partial defects consistent with delayed disease onset ([PMID:20659899]).

No conflicting evidence has been reported for AR TWNK‐associated IOSCA, and no alternative gene-disease assignments have been proposed.

In summary, robust genetic and experimental data firmly establish biallelic TWNK mutations as the cause of hepatocerebral mtDNA depletion syndrome type 7. TWNK sequencing should be integrated into diagnostic panels for early‐onset ataxia and suspected mitochondrial DNA depletion.

Key Take-home: Biallelic TWNK variants reliably predict autosomal recessive hepatocerebral mtDNA depletion syndrome, guiding genetic diagnosis and management.

References

• Human Molecular Genetics • 2005 • Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. PMID:16135556
• Case Reports in Pediatrics • 2012 • Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia. PMID:22928142
• Pediatric Neurology • 2012 • Identification of a novel Twinkle mutation in a family with infantile onset spinocerebellar ataxia by whole exome sequencing. PMID:22353293
• Neurogenetics • 2014 • Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy. PMID:24816431
• 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

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