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Natural disease course and genotype-phenotype correlations in Complex I deficiency caused by nuclear gene defects: what we learned from 130 cases

Lookup NU author(s): Dr Victoria Nesbitt



Mitochondrial complex I is the largest multi-protein enzyme complex of the oxidative phosphorylation system. Seven subunits of this complex are encoded by the mitochondrial and the remainder by the nuclear genome. We review the natural disease course and signs and symptoms of 130 patients (four new cases and 126 from literature) with mutations in nuclear genes encoding structural complex I proteins or those involved in its assembly. Complex I deficiency caused by a nuclear gene defect is usually a non-dysmorphic syndrome, characterized by severe multi-system organ involvement and a poor prognosis. Age at presentation may vary, but is generally within the first year of life. The most prevalent symptoms include hypotonia, nystagmus, respiratory abnormalities, pyramidal signs, dystonia, psychomotor retardation or regression, failure to thrive, and feeding problems. Characteristic symptoms include brainstem involvement, optic atrophy and Leigh syndrome on MRI, either or not in combination with internal organ involvement and lactic acidemia. Virtually all children ultimately develop Leigh syndrome or leukoencephalopathy. Twenty-five percent of the patients died before the age of six months, more than half before the age of two and 75 % before the age of ten years. Some patients showed recovery of certain skills or are still alive in their thirties . No clinical, biochemical, or genetic parameters indicating longer survival were found. No clear genotype-phenotype correlations were observed, however defects in some genes seem to be associated with a better or poorer prognosis, cardiomyopathy, Leigh syndrome or brainstem lesions.

Publication metadata

Author(s): Koene S, Rodenburg RJ, van der Knaap MS, Willemsen MAAP, Sperl W, Laugel V, Ostergaard E, Tarnopolsky M, Martin MA, Nesbitt V, Fletcher J, Edvardson S, Procaccio V, Slama A, van den Heuvel LPWJ, Smeitink JAM

Publication type: Review

Publication status: Published

Journal: Journal of Inherited Metabolic Disease

Year: 2012

Volume: 35

Issue: 5

Pages: 737-747

Print publication date: 30/05/2012

ISSN (print): 0141-8955

ISSN (electronic): 1573-2665

Publisher: SPRINGER


DOI: 10.1007/s10545-012-9492-z