TWNK – Autosomal Dominant Progressive External Ophthalmoplegia

Autosomal dominant progressive external ophthalmoplegia (adPEO) is a mitochondrial disorder characterized by bilateral ptosis, progressive external ophthalmoplegia, and multiple mitochondrial DNA deletions in skeletal muscle fibers. Heterozygous mutations in TWNK, encoding the mitochondrial DNA helicase Twinkle, were first described in a family with a c.956A>C (p.Lys319Thr) change causing sparse COX‐deficient fibers and mtDNA deletions ([PMID:12921794]).

The inheritance mode is autosomal dominant, with over 28 unrelated probands across 11 pedigrees reported ([PMID:12163192]) and segregation of pathogenic TWNK alleles in 19 additional affected relatives ([PMID:19428252]).

The variant spectrum is dominated by missense changes clustering in the N-terminal primase and flexible linker domains of Twinkle. A prototypic allele is c.956A>C (p.Lys319Thr), which co-segregates with multiple mtDNA deletions and the PEO phenotype in muscle biopsy ([PMID:12921794]).

Clinically, TWNK‐related adPEO presents in the 3rd–6th decades with ptosis, ophthalmoplegia, limb weakness, dysphagia, and occasional cardiomyopathy. Phenotypic expressivity varies intrafamilially and between populations ([PMID:24018892], [PMID:24091712]).

Functional assays show that adPEO-associated TWNK variants impair ATPase and helicase activities, reduce DNA binding affinity, and stall mtDNA replication, resulting in replication intermediate accumulation and mtDNA depletion in cell models and in the Deletor mouse ([PMID:18971204], [PMID:20659899]).

Some TWNK missense alleles retain partial helicase function under optimized biochemical conditions, highlighting challenges in genotype–phenotype correlation and variant interpretation ([PMID:20659899]).

Together, robust genetic, segregation, and functional data support a Strong ClinGen gene–disease association for TWNK in adPEO via a dominant-negative mechanism. TWNK testing is recommended for patients with adult-onset PEO to guide diagnosis and genetic counseling.

References

• Neuromuscular disorders • 2003 • A novel Twinkle gene mutation in autosomal dominant progressive external ophthalmoplegia. PMID:12921794
• Journal of the neurological sciences • 2002 • Clinical and molecular features of adPEO due to mutations in the Twinkle gene. PMID:12163192
• Neuromuscular disorders • 2009 • Molecular analysis in a family presenting with a mild form of late-onset autosomal dominant chronic progressive external ophthalmoplegia. PMID:19428252
• JAMA neurology • 2013 • Longitudinal clinical follow-up of a large family with the R357P Twinkle mutation. PMID:24018892
• Neurological sciences • 2014 • Twinkle mutations in two Chinese families with autosomal dominant progressive external ophthalmoplegia. PMID:24091712
• Human molecular genetics • 2009 • Twinkle mutations associated with autosomal dominant progressive external ophthalmoplegia lead to impaired helicase function and in vivo mtDNA replication stalling. PMID:18971204
• 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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