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The dominantly inherited spinocerebellar ataxias (ADCAs) are a clinically and genetically heterogenous group of neurodegenerative disorders characterised by premature neuronal loss in the cerebellum. The cardinal manifestations are ataxia, dysarthia, dysmetria, and intention tremor. These clinical findings are associated with varying degrees of other neurological symptoms due to degeneration of other components of the nervous system. The similarity in the clinical presentation of the ADCAs to the mitochondrial cytopathies is widely recognised. Ptosis, ophthalmoplegia, pyramidal and extrapyramidal symptoms, optic atrophy, retinopathy, dementia, and peripheral neuropathy may variably occur in both disorders. Patients with an ADCA are therefore often investigated to exclude a mitochondrial disease.
The ADCAs are divided into three groups (ADCA I, II, III) on the basis of associated findings.1 ADCA II is characterised by the presence of a retinopathy.2 It is caused by mutations (unstable trinucleotide expansion) in the coding region in a single gene, SCA7, on the short arm of chromosome 3.3 The protein product, ataxin-7, has a nuclear localisation.3Clinically, patients with this rare condition present with visual impairment and ataxia, which may be associated with dementia, ophthalmoplegia, spasticity, and extrapyramidal symptoms.2We have identified two SCA7 families and report here on the finding of abnormal hepatic mitochondria in the index cases of the two families. This is a hitherto undescribed finding.
Patient 1 was a 20 year old black woman who presented with progressive ataxia and visual loss beginning at the age of 16 years. She had severely impaired mental functions, bilateral ptosis with external ophthalmoplegia, bilateral peripapillary and macular degeneration, distal weakness (bilateral foot drop) with depressed reflexes but intact sensation (nerve conductions studies were not done), and abnormal movements including a fixed torticollis to the right with ocular and palatal myoclonus. Brain CT and MRI showed marked cortical, cerebellar, and brainstem atrophy. Routine screens to exclude acquired causes of ataxia and retinal degeneration were carried out. Serum concentrations of pyruvate, lactate, vitamin E, and a fasting lipogram, liver function tests, assays for β-galactosidase, α-galactosidase, sphingomyelinase, β-glucosidase hexosaminidase, long chain fatty acids, copper, and caeruloplasmin were normal. Urine screened for organic amino acids, copper and heavy metals was normal or negative. There were no acanthocytes. Her CSF was normal. Histological examination of skeletal muscle showed no ragged red fibres (with Gomori trichrome stain) and no morphologically abnormal mitochondria on electron microscopy. Results from cytochrome oxidase, NADH-TR, succinic dehydrogenase, oil red O, and PAS stains were normal. Skin, conjunctival, and rectal biopsies were histologically normal and normal on electron microscopy. A liver biopsy was histologically normal. There was no fatty steatosis. On electron microscopy morphological abnormalities of the mitochondria were present. The figure shows the abnormalities of the mitochondria in shape and size. Paracrystalline inclusions, forming so called parking lot bodies were demonstrated. At least 50% of the mitochondria showed these abnormalities.
Blood samples were screened for the SCA 1, SCA 3/MJD (Machado-Joseph disease), and SCA 7 trinucleotide expansions. Polymerase chain reaction analysis of her DNA showed a SCA 7 CAG repeat length of 81 (normal 7 to 17 repeats3).
Her mother and two other siblings are affected. They did not have biochemical, histological, or genetic investigations.
Patient 2 was a 25 year old black woman who presented with progressive visual failure. She was ataxic and had bilateral peripapillary and macular degeneration with spasticity and bilateral ptosis without ophthalmoplegia. She had clinical depression but had no evidence of a dementia. Brain CT showed marked brainstem and cerebellar atrophy. Investigations were carried out as described in patient 1. All tests, including histological analyses were normal or negative, apart from the hepatic electron microscopy. This showed identical mitochondrial abnormalities. Polymerase chain reaction analysis of her DNA showed a SCA 7 CAG repeat length of 53. Her mother is clinically affected but declined investigations.
The electron microscopical changes identified in the two index cases are widely recognised as indicative of mitochondrial disease. They are usually identified in skeletal muscle as the prototype tissue involved in the mitochondrial encephalopathies. The failure to identify the abnormalities in the other tissues sampled, especially skeletal muscle, may reflect selection bias. Biochemical and molecular studies have not yet been undertaken.
Abnormal mitochondria (with paracrystalline inclusions) are not present in normal liver tissue but can be seen in various conditions, including alcoholic liver disease, diabetes mellitus, hepatocellular carcinoma, hepatocellular adenoma, Wilson's disease, and drugs including the oral contraceptive rifampicin, phenobarbital, and steroids.4These were all excluded in the two index cases. In terms of neurological diseases, Okamura et al 5 described a patient with congenital oculoskeletal myopathy, diarrhoea, deafness, and cardiac and endocrine abnormalities in whom abnormal mitochondria were found in skeletal muscle as well as in liver cells.
In SCA7, Cooles et al 2described a family in whom abnormally large mitochondria with irregular cristae were identified in the skeletal muscle of three affected members. Intramitochondrial inclusion bodies as seen in our patients were not present. Forsgren et al 6 described a large SCA7 pedigree in whom electron microscopy of skeletal muscle in affected people showed uneven distribution of mitochondria, subsarcolemmal accumulations of small rounded mitochondria, areas devoid of mitochondria, and frequent autophagic vacuoles. In a severely affected child in this family, reduced activities of complex IV and to a lesser extent of complex I were found. In the above reports, hepatic tissue was not examined.
Ptosis and opthalmoplegia were present in both our index cases and were also prominent in the affected family members (not described here). These are frequent in the mitochondrial encephalopathies but occur variably in SCA7. Enevoldson et al 2, in their extensive review of the clinical features of patients with SCA7, describe ptosis as being “quite common”. In the family of Cooles et al 2 ptosis was a feature of the disease. The external ophthalmoplegia is more uniformly present in cases described in the literature.2
The patients described here and those described in the literature suggest mitochondrial dysfunction in SCA 7. The protein ataxin-7, however, has a nuclear localisation.3 In Friedreich's ataxia, an autosomal recessive triplet repeat disorder with an unstable mutation of the X25 gene on chromosome 9q13-q21.1, the protein product frataxin is a nuclear encoded mitochondrial protein.7Mitochondrial dysfunction is therefore implicated in its pathogenesis. Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant trinucleotide expansion disorder8. Mitochondrial abnormalities have been found in the skeletal muscle of patients with OPMD.8
The relevance of mitochondrial abnormality, in patients with SCA7 as well as other triplet disorders, is therefore intriguing and requires further investigation.