Late-onset cox deficiency with variable clinical expression in a family: mtdna or ndna defect?

C. Casali, F. M. Santorelli, M. Ella, G. Azan, R. Carrozzo, V. S. Toll, M. Spadaro, C. Morocutti

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Human disorders due to defects of the mitochondrial respiratory chain have been the subject of intense investigation in the past years. In particular, those associated with COX deficiency are regarded as clinically and genetically heterogeneous. Alterations in the nuclear DNA have been hypothesized in the fatal and benign infantile COX-deficient myopathies of infancy, as well as in Leigh syndrome (IS), while mutations in the mitochondrial genome (mtDNA) have been associated with diverse mitochondrial encephalomyopathies. A 23-year-old girl, born to nonconsanguinous parents, developed progressive ataxia at age 10. Retinitis pigmentosa was diagnosed at age 12 years. She is now developing behavioural problems. Brain MRI showed bilateral symmetrical abnormalities in the globus pallidus. Although not evident at neurological examination, myopathy was demonstrated by electromyography. Muscle biopsy showed no ragged-red fibers (RRF) but numerous (30%) COX negative fibers. Biochemical analysis of respiratory chain enzyme activities in muscle evidenced a marked reduction of COX activity (less than 20% of controls). The 26-year-old sister is mentally retarded and has bilateral ptosis; the mother is also mildly mentally retarded; the maternal grandmother died because of cardiomyopathy. Extensive mtDNA analysis was performed. Southern blot was normal. Direct sequencing of the mtDNA genes for ATP 8 and 6, COX I, II, III, and the 22 tRNAs discosed only a G9777A mutation (Gly190Ser) in the COX III gene. This novel mutation, located at the beginning of an a-helix transmembrane region of the protein, was homoplasmic in both the proband and her maternal relatives. Since the Gly190Ser mutation is poorly conserved during evolution, its pathogenic role seems unlikely. On the other hand, multisystem clinical presentation associated with defects of nuclearencoded COX subunits, such as in LS, are transmitted by an autosomal recessive trait and onset is rarely In adolescence. On the basis of current criteria for pathogenicity, it is difficult to attribute cases like this to nuclear or mitochondrial DNA defects, which in turn has important consequences for genetic counseling.

Original languageEnglish
Pages (from-to)110
Number of pages1
JournalItalian Journal of Neurological Sciences
Issue number4
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)


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