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Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia.
Mov Disord. 2001 Nov; 16(6):1153-8.MD

Abstract

Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing.

Authors+Show Affiliations

Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi 39216, USA. omcdaniel@surgery.umsmed.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

11748752

Citation

McDaniel, D O., et al. "Sequence Variation in GAA Repeat Expansions May Cause Differential Phenotype Display in Friedreich's Ataxia." Movement Disorders : Official Journal of the Movement Disorder Society, vol. 16, no. 6, 2001, pp. 1153-8.
McDaniel DO, Keats B, Vedanarayanan VV, et al. Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia. Mov Disord. 2001;16(6):1153-8.
McDaniel, D. O., Keats, B., Vedanarayanan, V. V., & Subramony, S. H. (2001). Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia. Movement Disorders : Official Journal of the Movement Disorder Society, 16(6), 1153-8.
McDaniel DO, et al. Sequence Variation in GAA Repeat Expansions May Cause Differential Phenotype Display in Friedreich's Ataxia. Mov Disord. 2001;16(6):1153-8. PubMed PMID: 11748752.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sequence variation in GAA repeat expansions may cause differential phenotype display in Friedreich's ataxia. AU - McDaniel,D O, AU - Keats,B, AU - Vedanarayanan,V V, AU - Subramony,S H, PY - 2001/12/19/pubmed PY - 2002/1/26/medline PY - 2001/12/19/entrez SP - 1153 EP - 8 JF - Movement disorders : official journal of the Movement Disorder Society JO - Mov Disord VL - 16 IS - 6 N2 - Friedreich's ataxia, the most common autosomal recessive inherited ataxia, is characterized by progressive gait and limb ataxia. Friedreich's ataxia is known for its occurrence within the first or second decade of life and is associated with hypertrophic cardiomyopathy, and in some cases with diabetes. Genetically, it is identified by the expression of an unstable trinucleotide GAA repeat expansion located in the first intron of the X25 gene on chromosome 9. Two brothers with very late adult-onset ataxia, and their unaffected sister, were examined for the clinical presentation of FA and for the presence of the mutated FA gene. The relationship of the expanded gene sequence to the severity of disease and age of onset were evaluated. Clinical examination revealed that the two brothers had mild ataxia and proprioceptive loss, with age of onset between 60 and 70 years of age. DNA from peripheral blood nucleated cells demonstrated a small homozygous expansion, with approximately 120-130 GAA repeats in the X25 gene in both patients. The expanded repeats were interrupted either with GAAGAG, GAAGGA, or GAAGAAAA sequences. The unaffected sister carried a normal FA genotype with 8-uninterrupted GAA repeat, observed by sequence analysis. In addition, the levels of FA gene transcript in both brothers were relatively lower than that in the unaffected sister. No detectable cardiomyopathy or diabetes was observed. Phenotypic diversity of FA is increasingly expanding. The age of onset and the structure of GAA repeat expansion plays an important role in determining the clinical features and the differential diagnosis of FA. The confirmation of the FA gene mutation in the atypical case, broadens the clinical spectrum of FA, and supports the idea that patients with even a mild form of ataxia of late adult onset should be considered for molecular testing. SN - 0885-3185 UR - https://www.unboundmedicine.com/medline/citation/11748752/Sequence_variation_in_GAA_repeat_expansions_may_cause_differential_phenotype_display_in_Friedreich's_ataxia_ L2 - https://doi.org/10.1002/mds.1210 DB - PRIME DP - Unbound Medicine ER -