Recently several mutations have been identified in nuclear genes that predispose to autosomal dominant or recessive progressive external ophthalmoplegia (PEO) with multiple deletions of mitochondrial DNA (mtDNA). In autosomal dominant PEO (adPEO, MIM# 157640), mutations were reported in the genes ANT1 (MIM# 103220; encoding the heart-muscle isoform of the adenine nucleotide translocator) [Kaukonen et al., 2000], C10orf2 (MIM# 606075; encoding the novel mitochondrial protein Twinkle) [Spelbrink et al., 2001], and POLG (MIM# 174763; encoding the catalytic subunit of the mitochondrial DNA polymerase gamma) [Van Goethem et al., 2001]. In recessive PEO, mutations have been identified in POLG [Van Goethem et al., 2001, 2003;Lamantea et al., 2002] and in ECGF1 (MIM# 131222; encoding thymidine phosphorylase) [Nishino et al., 1999. ECGF1 mutations specifically caused mitochondrial neurogastrointestinal encephalomyopathy (MNGIE, MIM# 603041), a subgroup of arPEO that is characterized by leukodystrophy [Nishino et al., 2000;Vissing et al., 2002].
We here report a novel C10orf2 mutation co-occurring with a previously reported recessive POLG mutation in a sporadic PEO patient with multiple mtDNA deletions. Direct sequencing of all coding exons demonstrated a heterozygous mutation in POLG (c.2542G4A), corresponding with the G848S substitution [Lamantea et al., 2002], and a novel heterozygous mutation in C10orf2 (c.1031G4A), predicting a R334Q substitution in Twinkle. Both mutations were absent in 180 Belgian control chromosomes. Neither were mutations found in ANT1. The corresponding residue of Twinkle R334 in phage T7 gp4 is located in the primase domain, and the residue is conserved in mouse and Drosophila.
Clinical onset in the patient was at 52 years with blepharoptosis, depression, and levodopa responsive Parkinson disease. Later she suffered from severe dysphagia leading to cachexia and necessitating enteric feeding. On examination, she had dysarthria, mild ophthalmoparesis, generalized myopathy, and extrapyramidal signs. Nerve conduction studies were normal