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Early-Onset Cataracts, Spastic Paraparesis, and Ataxia Caused by a Novel Mitochondrial tRNA(Glu) (MT-TE) Gene Mutation Causing Severe Complex I Deficiency: A Clinical, Molecular, and Neuropathologic Study

Lookup NU author(s): Dr Nichola Lax, Dr Charlotte Alston, Dr Tuomo Polvikoski, Dr Evelyn Jaros, Dr John Yarham, Emeritus Professor Doug Turnbull, Professor Robert Taylor


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Mitochondrial respiratory chain disease is associated with a spectrum of clinical presentations and considerable genetic heterogeneity. Here we report molecular genetic and neuropathologic findings from an adult with an unusual manifestation of mitochondrial DNA disease. Clinical features included early-onset cataracts, ataxia, and progressive paraparesis, with sequencing revealing the presence of a novel de novo m. 14685G>A mitochondrial tRNAGlu (MT-TE) gene mutation. Muscle biopsy showed that 13% and 34% of muscle fibers lacked cytochrome c oxidase activity and complex I subunit expression, respectively. Biochemical studies confirmed a marked decrease in complex I activity. Neuropathologic investigation revealed a large cystic lesion affecting the left putamen, caudate nucleus, and internal capsule, with evidence of marked microvacuolation, neuron loss, perivascular lacunae, and blood vessel mineralization. The internal capsule showed focal axonal loss, whereas brainstem and spinal cord showed descending anterograde degeneration in medullary pyramids and corticospinal tracts. In agreement with muscle biopsy findings, reduced complex I immunoreactivity was detected in the remaining neuronal populations, particularly in the basal ganglia and cerebellum, correlating with the neurologic dysfunction exhibited by the patient. This study emphasizes the importance of molecular genetic and postmortem neuropathologic analyses for furthering our understanding of underlying mechanisms of mitochondrial disorders.

Publication metadata

Author(s): Lax NZ, Gnanapavan S, Dowson SJ, Alston CL, He LP, Polvikoski TM, Jaros E, O'Donovan DG, Yarham JW, Turnbull DM, Dean AF, Taylor RW

Publication type: Article

Publication status: Published

Journal: Journal of Neuropathology and Experimental Neurology

Year: 2013

Volume: 72

Issue: 2

Pages: 164-175

Print publication date: 01/02/2013

ISSN (print): 0022-3069

ISSN (electronic): 1554-6578

Publisher: Lippincott Williams & Wilkins


DOI: 10.1097/NEN.0b013e31828129c5


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Funder referenceFunder name
UK NHS Specialist Commissioners
UK NIHR Biomedical Research Centre for Ageing and Age-related Disease
906919Wellcome Trust Centre for Mitochondrial Research
G0700718MRC as part of the cross-council Lifelong Health and Wellbeing Initiative