Finding twinkle in the eyes of a 71‐year‐old lady: A case report and review of the genotypic and phenotypic spectrum of TWINKLE‐related dominant disease

Abstract

Progressive external ophthalmoplegia (PEO) can be caused by a disorder characterized by multiple mitochondrial DNA (mtDNA) deletions due to mutations in the TWINKLE gene, encoding a mtDNA helicase. We describe a 71-year-old woman who had developed PEO at age 55 years. She had cataracts, diabetes, paresthesias, cognitive defects, memory problems, hearing loss, and sensory ataxia. She had muscle weakness with ragged red fibers on biopsy. MRI showed static white matter changes. A c.908G>A substitution (p.R303Q) in the TWINKLE gene was identified. Multiple mtDNA deletions were detected in muscle but not blood by a PCR-based method, but not by Southern blot analysis. MtDNA copy number was maintained in blood and muscle. A systematic literature search was used to identify the genotypic and phenotypic spectrum of dominant TWINKLE-related disease. Patients were adults with PEO and symptoms including myopathy, neuropathy, dysarthria or dysphagia, sensory ataxia, and parkinsonism. Diabetes, cataract, memory loss, hearing loss, and cardiac problems were infrequent. All reported mutations clustered between amino acids 303 and 508 with no mutations at the N-terminal half of the gene. The TWINKLE gene should be analyzed in adults with PEO even in the absence of mtDNA deletions in muscle on Southern blot analysis, and of a family history for PEO. The pathogenic mutations identified 5' beyond the linker region suggest a functional role for this part of the protein despite the absence of a primase function in humans. In our patient, the pathogenesis involved multiple mtDNA deletions without reduction in mtDNA copy number.

Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells

“…To explore the hypothesis that Parkin can selectively target mitochondria with deleterious mtDNA mutations, we examined Parkin translocation to mitochondria in cells transiently expressing a catalytically inactive form of the mitochondrial DNA helicase, Twinkle. Mutations in Twinkle, which disrupt mtDNA replication and lead to multiple mtDNA deletions, can cause dominant progressive external opthalmoplegia (20), parkinsonism (21), and other symptoms (22). In addition, overexpression of catalytically inactive Twinkle mutants (such as Twinkle G575D) in cell culture leads to acute loss of mtDNA and mitochondrial dysfunction (23).…”

Comprehensive next-generation sequence analyses of the entire mitochondrial genome reveal new insights into the molecular diagnosis of mitochondrial DNA disorders

“…mtDNA multiple deletions are associated with aging and oxidative damage, or more importantly, secondary to primary mutations in nuclear genes responsible for mtDNA biosynthesis and integrity maintenance, such as POLG, TWINKLE, and OPA1. 16,39,40 Fifteen DNA samples from muscle showing mtDNA multiple deletions on MPS-based analysis were subjected to sequence analysis of a panel of nuclear genes responsible for the maintenance of mtDNA integrity. POLG mutations were identified in three patients and RRM2B and OPA1 mutations in one patient each (unpublished data).…”

Mitochondrial DNA maintenance: an appraisal

“…These TWINKLE mutations are associated with neuromuscular disorders [271]. The majority of patients with PEO harbor heterozygous TWINKLE mutations with autosomal dominant inheritance when one mutant allele is sufficient to develop the disease in adulthood [272]. Rare homozygous patients manifest more severe phenotypes and develop the disease earlier than their heterozygous relatives [69, [273][274][275].…”