Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disorder usually characterized by progressive early-onset ataxia. The most common ophthalmic manifestation of FRDA is optic neuropathy, which is usually late in onset, is slowly progressive, and rarely causes severe visual loss.1 The genetic basis of FRDA in most patients is the homozygous expansion of a GAA trinucleotide repeat within the first intron of the FRDA gene, which encodes the mitochondrial protein frataxin. Mutations in frataxin cause progressive iron accumulation in mitochondria. Four percent of patients are compound heterozygotes for the GAA expansion on one allele and a point mutation on the other.2 We describe a patient with FRDA who was a compound heterozygote for the GAA expansion and a Gly130Val missense mutation, developed rapid-onset catastrophic visual loss, and was found to have clinical, electrophysiological, and radiological evidence of a severe optic neuropathy. In addition, she had pattern dystrophy.To our knowledge, this is the first description of a patient with FRDA with this phenotype.
A 59-year-old woman with known FRDA and diabetes was referred for investigation of progressive loss of vision in the left eye. Two months previously, her visual acuities were 6/6 OU. On her first visit to the ophthalmology department,her visual acuities were 6/6 OD and 6/24 OS. Electrophysiology revealed normal rod, cone, and pattern electroretinographic results. The electro-oculographic results were normal, but the pattern reversal visual evoked potential showed increased latency in the right eye and no response in the left eye, consistent with optic nerve or optic tract disease. Clinical examination and autofluorescence imaging revealed multiple yellowish deposits at both posterior poles, consistent with pattern dystrophy (Figure). There were no signs of diabetic retinopathy. Twelve months later, her visual acuities were bilateral light perception only, with pale featureless optic discs. A computed tomographic scan of the brain and orbits excluded mass lesions or intraorbital abnormalities, and magnetic resonance imaging revealed severe atrophy of the optic nerves, optic chiasm, and optic tract.
Color image montages of the right (A)and left (B) posterior poles showing a pale optic nerve and scattered, flecklike,yellowish deposits. Autofluorescence image montages of the right (C) and left (D) posterior poles showing an increased autofluorescence signal in the areas of the flecklike deposits.
Genetic analysis revealed compound heterozygosity, with a GAA expansion on one allele and a G-to-T base substitution in exon 4 (Gly130Val) on the other. The mitochondrial point mutations associated with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) or MIDD (maternally inherited diabetes and deafness), MERRF (myoclonic epilepsy with ragged-red fibers), NARP (neuropathy, ataxia, and retinitis pigmentosa), and Leber hereditary optic neuropathy were not identified.
This patient with FRDA had visual loss of a rapidity and severity not previously described in FRDA. She was also noted to have a pattern dystrophy but had normal electroretinographic results and pattern electroretinographic results, suggesting that it is the optic nerve or optic tract disease that is causing the visual loss rather than the pattern dystrophy. Macular abnormalities have been described in autosomal dominant spinocerebellar ataxia type 7 but not previously in FRDA; thus, this may be a coincidental finding in our patient.3 It is possible that the pattern dystrophy observed in this case could be associated with a mutation in peripherin/RDS gene,4 the ELOVL4 gene,5 or as-yet-unknown genes.
The cause of optic atrophy in FRDA is unknown, but it occurs more frequently in patients with larger GAA repeats and also more frequently in compound heterozygotes than homozygotes.2 Furthermore, optic neuropathy emerges late in the course of disease and may be more frequent in compound heterozygotes who tend to survive longer. Optic atrophy is a heterogeneous disorder often caused by inherited or acquired abnormalities of mitochondrial function. Further investigation of the molecular mechanisms causing FRDA in compound heterozygotes may provide important insights into the underlying pathogenesis that leads to optic atrophy.
Correspondence: Dr Németh, Department of Clinical Genetics, Churchill Hospital, Churchill Drive, Oxford OX37LJ,England (email@example.com).
Financial Disclosure: None reported.
Porter N, Downes SM, Fratter C, Anslow P, Németh AH. Catastrophic Visual Loss in a Patient With Friedreich Ataxia. Arch Ophthalmol. 2007;125(2):273-274. doi:10.1001/archopht.125.2.273