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Intrafamilial Phenotypic Variability in Friedreich Ataxia Associated With a G130V Mutation in the FRDA Gene
Dominick J. H. McCabe, MRCPI;
Nicholas W. Wood, FRCP;
Fergus Ryan, PhD;
Michael G. Hanna, MD;
Sean Connolly, MD;
David P. Moore, MRCPI;
Janice Redmond, MD;
David E. Barton, PhD;
Raymond P. Murphy, FRCP
Arch Neurol. 2002;59:296-300.
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 progressive
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.
From the Departments of Neurology (Drs McCabe and Murphy) and Cardiology
(Dr Moore), The Adelaide and Meath Hospital, incorporating The National Children's
Hospital, Dublin, Ireland; Department of Clinical Neurology, Institute of
Neurology, National Hospital for Neurology and Neurosurgery, London, England
(Drs McCabe, Wood, and Hanna); Department of Biological Sciences, Dublin Institute
of Technology (Dr Ryan); Departments of Clinical Neurophysiology (Dr Connolly)
and Neurology (Dr Redmond), St James's Hospital, and National Centre for Medical
Genetics (Drs Ryan and Barton) and University College Dublin Department of
Paediatrics (Dr Barton), Our Lady's Hospital for Sick Children, Dublin.
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