Human Genetics

, Volume 106, Issue 1, pp 86–92 | Cite as

Genotype and phenotype analysis of Friedreich's ataxia compound heterozygous patients

  • M. De Castro
  • J. García-Planells
  • E. Monrós
  • J. Cañizares
  • R. Vázquez-Manrique
  • J.J. Vílchez
  • M. Urtasun
  • M. Lucas
  • G. Navarro
  • G. Izquierdo
  • M.D. Moltó
  • F. Palau
Original Investigation

Abstract.

Friedreich's ataxia is caused by mutations in the FRDA gene that encodes frataxin, a nuclear-encoded mitochondrial protein. Most patients are homozygous for the expansion of a GAA triplet repeat within the FRDA gene, but a few patients show compound heterozygosity for a point mutation and the GAA-repeat expansion. We analyzed DNA samples from a cohort of 241 patients with autosomal recessive or isolated spinocerebellar ataxia for the GAA triplet expansion. Patients heterozygous for the GAA expansion were screened for point mutations within the FRDA coding region. Molecular analyses included the single-strand conformation polymorphism analysis, direct sequencing, and linkage analysis with FRDA locus flanking markers. Seven compound heterozygous patients were identified. In four patients, a point mutation that predicts a truncated frataxin was detected. Three of them associated classic early-onset Friedreich's ataxia with an expanded GAA allele greater than 800 repeats. The other patient associated late-onset disease at the age of 29 years with a 350-GAA repeat expansion. In two patients manifesting the classical phenotype, no changes were observed by single-strand conformation polymorphism (SSCP) analysis. Linkage analysis in a family with two children affected by an ataxic syndrome, one of them showing heterozygosity for the GAA expansion, confirmed no linkage to the FRDA locus. Most point mutations in compound heterozygous Friedreich's ataxia patients are null mutations. In the present patients, clinical phenotype seems to be related to the GAA repeat number in the expanded allele. Complete molecular definition in these patients is required for clinical diagnosis and genetic counseling.

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Copyright information

© Springer-Verlag 1999

Authors and Affiliations

  • M. De Castro
    • 1
  • J. García-Planells
    • 1
  • E. Monrós
    • 2
  • J. Cañizares
    • 3
  • R. Vázquez-Manrique
    • 1
  • J.J. Vílchez
    • 4
  • M. Urtasun
    • 5
  • M. Lucas
    • 6
  • G. Navarro
    • 7
  • G. Izquierdo
    • 7
  • M.D. Moltó
    • 3
  • F. Palau
    • 1
  1. 1.Unitat de Genètica, Hospital Universitari La Fe, Av. Campanar 21, E-46009 Valencia, Spain
  2. 2.Secció de Genètica, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain
  3. 3.Departament de Genètica, Facultat de Biologia, Universitat de València, Valencia, Spain
  4. 4.Departament de Neurologia, Hospital Universitari La Fe, Av. Campanar 21, E-46009 Valencia, Spain
  5. 5.Departamento de Neurología, Hospital Nuestra Señora de Aranzazu, San Sebastián, Spain
  6. 6.Departamento de Bioquímica Médica y Biología Molecular, Hospital Universitario Virgen Macarena, Seville, Spain
  7. 7.Departamento de Neurología, Hospital Universitario Virgen Macarena, Seville, Spain

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