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The spinocerebellar ataxias (SCAs) are a group of autosomal dominant inherited neurodegenerative disorders characterised by progressive cerebellar dysfunction. Besides cerebellar manifestations a variety of associated neurological signs, such as ophthalmoplegia, dementia, or pyramidal and extrapyramidal signs may occur. At least 21 loci for SCAs including 11 different genes have been identified. SCA 1, 2, 3, 6, 7, and 17 are caused by expansion of a translated CAG repeat in the corresponding gene leading to an expanded polyglutamine tract in the translated protein. In contrast, Holmes and colleagues1 recently described a large pedigree with a new form of autosomal dominant ataxia (SCA12) associated with an expanded CAG tract in the 5′ untranslated region of the gene PPP2R2B, encoding a brain specific regulatory subunit of protein phosphatase PP2A. Clinical findings in SCA12 patients include upper extremity tremor, cerebellar signs and late onset dementia.2
We report on a patient with Creutzfeld-Jakob disease (CJD) carrying a 49 CAG repeat at the SCA12 locus. Additionally, we analysed a large sample of sporadic and hereditary ataxia patients for SCA12 mutations.
A 57 year old man of German origin presented subacutely with gait ataxia and a striking action tremor. Shortly after disease onset, his wife also noticed dysarthria. There was no evidence for neurological diseases in his family. His father died at 43 years from cardiac infarction, his 80 year old mother has no other children. On neurological examination, he showed no signs of cognitive impairment, oculomotor performance was normal. Deep tendon reflexes were depressed, there were no paresis, no pathological signs, and sensory testing was normal for pain, temperature, and touch. His gait was severely ataxic, there was a moderate dysmetria of the upper and lower limbs with a prominent action tremor.
An initial brain MRI was normal. Extensive blood tests including vitamins B12 and E, paraneoplastic antibodies and serum ceruloplasmin showed no pathological results. His cerebrospinal fluid was normal, except for a moderately raised protein level.
Electrophysiology showed subclinical sensory motor neuropathy. A genetic analysis of SCAs revealed a repeat expansion of 49 CAGs in the PPP2R2B gene for SCA12.
The disease rapidly progressed and after four months the patient additionally developed dementia with disorientation and paranoid hallucinations together with a deterioration of his neurological status especially for the ability to coordinate his movements. A second MRI scan now showed bilateral signal hyperintensity in the putamen and caudate nucleus, as well as the frontal, parietal, and insular cortices. EEG showed slowing of background activity with bursts of generalised θ rhythm. Additionally, CSF was positive for 14.3.3 protein leading to the assumption of a probable CJD case.
The patient died two months later because of aspiration pneumonia. Necropsy revealed a brain of 1265 g, which appeared to be unaffected macroscopically. Histological investigations showed moderate to severe spongiform changes with confluent vacuoles, a mild to moderate astrocytic gliosis, and a moderate nerve cell loss in the cerebral neocortex and, to a variable extent, in the basal ganglia, thalamic nuclei, and midbrain structures. The hippocampal formation and brain stem nuclei were comparatively free of pathological changes. Spongiform changes were seen also in the molecular layer of the cerebellum together with a granule cell loss. Kuru plaques could be detected next to Purkinje cells as a hallmark of this special subtype of CJD.3 With a monoclonal antibody against prion protein (Gö138), perivacuolar prion protein deposits were detectable in cortical areas and plaque-like or granular deposits in the cerebellum. Genetic analysis of the PRNP gene revealed the MV genotype at codon 129.
Additionally, we screened 1028 patients from northern Germany with cerebellar ataxia, including 113 patients with positive family history, and 150 healthy controls for SCA12 mutation.
Repeat expansions in all other known SCA genes had been previously excluded.
SCA12 expansions larger than 50 repeats were not detected in any of the patients or controls. In addition to the CJD patient with 49 CAG repeats, alleles of 40 respectively 41 repeats were found in two patients with late onset sporadic ataxia. All other allele sizes ranged from 4 to 28 CAG repeats with a heterozygosity of 60.7% as shown in table 1. The most common allele containing 10 CAG repeats was found in 61.7% of all chromosomes.
SCA12 is a very rare entity for autosomal dominant and sporadic ataxias with only six Indian and one American pedigree of German descent published at present.2,4,5 The expanded alleles ranged from 55 to 78 CAG repeats, whereas normal alleles ranged from 7–31 repeats. Recently, an allele of even 45 repeats was described in an Indian control subject without any neurological symptoms and with no family history of ataxia.5 We now present a case of CJD bearing a repeat of 49 CAG copies. The initial symptoms of this patient resembled those described in SCA12 patients. In particular the action tremor in combination with cerebellar signs that preceded the cognitive impairment for four months was striking. On the other hand, ataxia is also a prominent clinical feature of the Kuru-plaque variant found in this patient, which is linked to the MV genotype at codon 129 and PRPsc type 2. However, we cannot elucidate whether CJD of this patient unmasked SCA12 at a subclinical stage or whether the 49 allele is a large and rare normal allele without any influence on the phenotype and, unfortunately, there are no other family members available for genetic evaluation. What remains is the coincidence of two very rare diseases, respectively genetic variations. The protein phophatase PP2A may play a part in tau phosphorylation and apoptosis. Therefore, the possibility that a large SCA12 repeat could influence the pathogenesis of sporadic CJD, especially the Kuru-plaques variant, should be further evaluated.
The role of the 40 and 41 CAG repeats in two sporadic late onset ataxia cases is also difficult to interpret and we cannot exclude a pathogenic influence, although an even larger allele was found in a young Indian healthy control. The findings of this study implicate a more sophisticated interpretation of SCA12 alleles and raise the question about the diagnostic threshold between normal and expanded alleles.
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