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Friedreich’s ataxia is a progressive neurodegenerative disorder of autosomal recessive inheritance, in which gait ataxia followed by upper limb ataxia, dysarthria, nystagmus, areflexia, loss of joint position sense, and spastic paraparesis develop from the second decade of life.1 It is the commonest hereditary ataxia, with a prevalence of 1 in 50 000 and a deduced carrier frequency in European populations of 1 in 120. Recently, Friedreich’s ataxia has been associated with mutations of the frataxin gene on chromosome 9 (X25 at 9q13).2 Most patients are homozygous for expansions of a GAA triplet repeat within intron 1 of this gene. Normal alleles have between 7 and 22 repeats, whereas the range in affected patients is 200 to 900 copies. Around 5% of patients carry heterozygous mutations, a GAA expansion on one allele being accompanied by a point mutation on the other. In this report, the clinical features of a family being investigated for presumed autosomal dominant spinocerebellar degeneration, and in which GAA expansions were identified, are reported. The finding raises the possibility that heterozygous carriers of this mutation may manifest clinical symptoms and signs.
The proband (figure; III.1) is currently 28 years of age, and has a 10 year history of insidious onset and progressive unsteadiness when walking. Upper limb ataxia and dysarthria had supervened around 7 years previously. He needs the support of a single person or a rollator Zimmer for walking, and uses a wheelchair for longer distances. A week long course of synthetic gonadotrophin had been received in childhood for delayed puberty. Examination disclosed pes cavus and kyphoscoliosis. He was dysarthric. There was no optic atrophy, but horizontal gaze evoked nystagmus and bidirectional hypermetropic saccades were noted. He had intention tremor and dysmetria, worse on the left. Reflexes were retained and plantars were flexor. Gait was ataxic, with no clinical evidence of lower limb weakness or impairment of joint position sense. The following investigations gave normal or negative results: serum biochemistry, thyroid function, lipids, urinary amino acids, blood film and full blood count, serum vitamin B12, red cell folate, vitamin E, phytanic acid, syphilis serology, autoantibody profile, chest radiography, EEG, MRI of head and cervical spine, CSF cytology, biochemistry, and immunology, antiPurkinje cell antibody assay, and gene tests for spinocerebellar ataxia types 1 and 3. Nerve conduction studies showed an axonal neuropathy affecting sensory fibres. Lower limb somatosensory evoked potentials were unobtainable, and those in the upper limbs were of low amplitude but normal latency. Echocardiography disclosed mildly impaired left ventricular contractility.
The proband’s sister (III.4) is currently 24 years of age, and has had poor balance and ataxia since 15 years. Dysarthria has been present for four years. She is wheelchair bound. She has taken valproate for presumed complex partial seizures since the age of 8. Examination disclosed limb incoordination, worse on the left. Lower limb reflexes were hyperactive, especially on the left, and both plantars were upgoing.
The proband’s father (II.4) is currently 47 years of age. He sought help 4 years ago for partial and generalised seizures, and is currently taking lamotrigine. He admitted to heavy alcohol intake. Examination disclosed hepatomegaly and some memory impairment. There was sustained horizontal gaze evoked nystagmus, limb incoordination worse on the left, diminished knee jerks, absent ankle jerks, and flexor plantar responses. He has marked truncal ataxia. Brain MRI was normal.
The proband’s daughter (IV.2) was seen at the age of 8 months after becoming floppy, unable to sit, or control her head acutely. She was intermittently irritable and sleepy, and had vomited repeatedly. She was admitted to hospital, where she was afebrile and well perfused. She could not sit unsupported, was unable to reach out for toys, and was hypotonic. She had gaze dependent very fast vertical nystagmus with no failure of upgaze. Ultrasound examination of the head, blood gases, blood and urinary amino acids, liver function tests, and blood ammonia were normal. At review 6 months later, a further episode of acute ataxia in the context of a febrile infection was reported. This had settled within a few hours, and she had not been admitted to hospital. Since then she has been well (currently 3.5 years) with normal development.
Polymerase chain reaction for the GAA triplet repeat in Friedreich’s ataxia was carried out using the primers and method described by Campuzano et al. 2 III.1 showed two expanded alleles carrying 320 and 840 GAA repeats. III.4 was homozygous for two expansions of 660 repeats. II.4 and IV.2 were heterozygous for the GAA expansion, the expanded allele bearing a repeat of 840 triplets consistent with their carrier status. II.5 was also heterozygous for the expansion, and III.2 had no expanded alleles.
The presentation of this family with ataxic features in three generations had suggested a form of autosomal dominant cerebellar ataxia. However, the proband and his sister have clinical phenotypes consistent with Friedreich’s ataxia, and this diagnosis has been established by genome analysis. The carrier status of the two other members of this pedigree manifesting ataxic features has been confirmed. This finding raises the possibility that Friedreich’s ataxia carriers are at risk of developing ataxia, especially in the context of environmental insults (such as alcohol in II.4 and and viral infections in IV.2). In a recent series of 56 pedigrees, at least two heterozygous parents (both fathers) manifesting ataxic features were identified.3 No data are available on possible environmental insults in these members. The current finding lends support to the conclusion of Lamont et al,3 that a history of ataxia in preceding (or successive) generations should not preclude a diagnosis of Freidreich’s ataxia. Finally, it may be fruitful to investigate those who develop spinocerebellar ataxia secondary to recognised environmental insults for their carrier status of Friedreich’s ataxia.
We are grateful to Professor Tetsuo Ashizawa, Dr Pragna Patel, and Dr Sanjay Bidichandani at the Department of Neurology, Baylor College of Medicine, Houston, Texas for assistance with genome analysis and helpful discussion.
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