Intrafamilial Phenotypic Variability in Friedreich Ataxia Associated With a G130V Mutation in the FRDA Gene

Authors

Dominick McCabe, Adelaide and Meath Hospital
Nicholas Wood, National Hospital fo
Fergus Ryan, Technological University DublinFollow
Michael Hanna, National Hospital for Neurology and Neurosurgery, London
Sean Connolly, St. James' Hospital, Dublin
David Moore, Adelaide and Meath Hospital
Janice Redmond, Adelaide and Meath Hospital
David Barton, National Centre For Medical Genetics, Dublin
Raymond Murphy, Adelaide and Meath Hospital

Document Type

Article

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

1.6 BIOLOGICAL SCIENCES

Publication Details

Archives of Neurology, 59(2), pp.296-300.

Abstract

Background: Most patients with Friedreich ataxia (FA) have a GAA trinucleotide repeat expansion in intron 1 of the FA gene (FRDA) on both arms of chromosome 9. However, some patients are compound heterozygotes and harbor a GAA expansion on one allele and a point mutation on the other. Compound heterozygous patients with FA who have a GAA expansion and a G130V mutation have been reported to have an atypical phenotype with a slow disease progression, minimal or no ataxia, or gait spasticity. Objective: To describe intrafamilial phenotypic variability in a GAA expansion/G130V mutation compound heterozygous family with FA. Setting: Tertiary referral university hospital setting. Patients and Methods: A 34-year-old man presented to our hospital with a 24-year history of stiff legs and mild unsteadiness of gait. Clinical examination showed a spastic paraparesis with normal to pathologically brisk deep tendon reflexes and mild left upper limb ataxia. His 27-year-old sister presented with a slowly proprogressive early-onset ataxic syndrome. She had ataxia of gait, mild to severe limb ataxia, and reduced or absent deep tendon reflexes, but no evidence of spasticity on examination. Results: Neurophysiologic investigations showed evidence of a sensory axonal neuropathy, and molecular genetic analysis showed that both siblings were compound heterozygotes with a GAA expansion and a G130V mutation. Conclusions: This report confirms that compound heterozygous patients with FA who have a GAA expansion and a G130V mutation may present with an ataxic phenotype and that intrafamilial phenotypic variability in these pedigrees can occur. It also emphasizes the importance of performing molecular genetic analysis for the GAA trinucleotide expansion in patients presenting with a spastic paraparesis of undetermined etiology, especially when there is neurophysiologic evidence of a sensory axonal neuropathy.

DOI

10.1001/archneur.59.2.296

Recommended Citation

McCabe, D. et al. (2002). Intrafamilial phenotypic variability in Friedreich ataxia associated with a G130V mutation in the FRDA gene. Archives of Neurology, 59(2),pp.296-300. doi:10.1001/archneur.59.2.296