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J Med Genet 2004;41:293-295 doi:10.1136/jmg.2003.015289
  • Letters to JMG

Mitochondrial DNA haplogroups influence the Friedreich’s ataxia phenotype

  1. M Giacchetti1,
  2. A Monticelli1,2,
  3. I De Biase1,
  4. L Pianese1,3,
  5. M Turano1,3,
  6. A Filla4,
  7. G De Michele4,
  8. S Cocozza1
  1. 1Dipartimento di Biologia e Patologia Cellulare e Molecolare “L Califano” Università “Federico II”, Via S Pansini, 5, 80131 Napoli, Italy
  2. 2IEOS CNR
  3. 3BioGeM Consortium
  4. 4Dipartimento di Scienze Neurologiche, Università Federico II, Via S Pansini, 5, 80131 Napoli, Italy
  1. Correspondence to:
 Prof S Cocozza
 Dipartimento di Biologia e Patologia Cellulare e Molecolare “L. Califano” Università “Federico II”, Via S Pansini, 5, 80131 Napoli, Italy; cocozzaunina.it
  • Received 10 October 2003
  • Accepted 22 December 2003

Friedreich’s ataxia, an autosomal recessive neurodegenerative disorder, is the most common hereditary ataxia among white people.1 The disease is characterised by gait and limb ataxia, dysarthria, absent tendon reflexes, Babinski’s sign, impairment of position and vibratory senses, scoliosis, and pes cavus.2 Cardiac manifestations are prominent in some cases.3 Diabetes mellitus or carbohydrate intolerance is frequently described.1 The age of onset is variable. The disease usually comes at puberty but several cases have become symptomatic after 40 years.4 The molecular defect that occurs in Friedreich’s ataxia is the trinucleotide GAA expansion in the first intron of the X25 gene. This gene encodes for a 210 aa mitochondrial protein called frataxin.5 Levels of frataxin mRNA and protein are severely reduced as a result of this expansion.5 Although the exact physiological function of frataxin is not known, its involvement in iron–sulphur (Fe–S) cluster biogenesis6 has been suggested.

The Friedreich’s ataxia phenotype shows a variable expression with respect to the age of onset and the presence of some signs or symptoms. Disease duration has been proposed to influence dysarthria, decreased vibration sense, optic atrophy, and diabetes.7 Some Friedreich’s ataxia phenotype features are strongly correlated with GAA expansion size. An inverse relationship has been demonstrated between GAA repeat size and the age of onset.7,8 Friedreich’s ataxia with retained reflexes or absence of cardiomyopathy was associated with shorter expansions. In a previous report, we demonstrated that GAA size accounts for about 70% of the onset age variance,8 with sibling age of onset independently accounting for an additional 13%.9 Then we suggested that siblings shared genetic or environmental factors that, in addition to the GAA size, influence the age of onset. Modifier genes are defined on the basis of their ability to modulate the …

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