Background Multiple deletions of mitochondrial DNA (mtDNA) arising from nuclear gene defects underlie a spectrum of disorders ranging from the severe Alpers syndrome to mild cases of progressive external ophthalmoplegia. Cognitive impairment is an unusual presenting feature.
Case History The patient presented aged 50 with an 18 month history of memory problems and poor concentration. He developed slowly progressive unsteadiness and involuntary jerky movements of his limbs. He had lost 8 kg over 3 years. Examination revealed myoclonus of his arms; mild cerebellar signs; bilateral upgoing plantars and a mild distal sensory neuropathy. There was no ptosis, but he had restriction of upgaze. Neuropsychological testing revealed moderate cognitive impairment. Muscle histology revealed a high proportion of cyclooxygenase (COX)-negative fibres; he had a reduction in complex II/III activity. PCR analysis demonstrated multiple mtDNA deletions. Sequencing of POLG1, POLG2, SLC25A4 and a targeted screen of PEO1 did not identify any mutations. A screen for MNGIE was negative.
Conclusion This patient has a mitochondrial disorder with a prominent cognitive presentation. Despite the presence of multiple deletions of his mtDNA, a screen of several nuclear genes was negative, suggesting his disorder is driven by an as yet unidentified nuclear gene involved in mtDNA maintenance.