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Abstract: An increasing number of inherited neurodegenerative diseases are known to be caused by the expansion of unstable trinucleotide repeat tracts. Spinocerebellar ataxia type 8 (SCA8) has been identified as being partly caused by a CTG expansion in an untranslated, endogenous antisense RNA that overlaps the Kelch-like 1 (KLHL1) gene. Clinically, SCA8 patients show similar features to those with the other SCAs, including limb and truncal ataxia, ataxic dysarthria and horizontal nystagmus, all of which are signs of dysfunction of the cerebellar system. However, allele sizes within the SCA8 proposed pathogenic range have been reported in patients with ataxia of unknown etiology, in individuals from pedigrees with other SCA or Friedreich''s ataxia, and in patients with Alzheimer''s disease, schizophrenia or parkinsonism. These observations suggest that mutation of the SCA8 locus might affect neurons other than the cerebellum. Antisense transcripts are known to regulate complementary sense transcripts and are involved in several biologic functions, such as development, adaptive response, and viral infection. In order to test whether SCA8 affects the KLHL1 expression by antisense RNA in brain cells, we examined the expression pattern of KLHL1 and SCA8 in human tissues and in mouse brain regions. SCA8 expression was colocalized with KLHL1 transcript in many brain regions whose functions are correlated to the clinical symptoms of SCA8 patients. These findings lead to the hypothesis of a possible relevance that SCA8 transcript downregulates KLHL1 expression through an antisense mechanism, which then leads to SCA8 neuropathogenesis. [Copyright &y& Elsevier]

Spinocerebellar ataxia type 8 (SCA8) patients typically have a slowly progressive, adult-onset ataxia. SCA8 is dominantly inherited and is caused by large CTG repeat expansions in the untranslated antisense RNA of the Kelch-like 1 gene (KLHL1), but the molecular mechanism through which this expansion leads to disease is still unknown. To more fully characterize the underlying molecular mechanisms involved in SCA8, we developed a mouse model in which Klhl1 is deleted in either all tissues or is deleted specifically in Purkinje cells only. We found that mice that are either homozygous or heterozygous for the Klhl1 deletion have significant gait abnormalities at an early age and develop a significant loss of motor coordination by 24 weeks of age. This loss progresses more rapidly in homozygous knock-outs. Mice with Klhl1 specifically deleted in only Purkinje cells had a loss of motor coordination that was almost identical to the total-tissue deletion mice. Finally, we found significant Purkinje cell dendritic deficits, as measured by the thickness of the molecular layer, in all mice in which Klhl1 was deleted (both total and Purkinje cell-specific deletions) and an intermediate reduction in molecular layer thickness in mice with reduced levels of Klhl1 expression (heterozygous deletions). The results from this mouse model show that even a partial loss of Klhl1 function leads to degeneration of Purkinje cell function and indicates that loss of KLHL1 activity is likely to play a significant part in the underlying pathophysiology of SCA8. [ABSTRACT FROM AUTHOR]

Abstract: We report the case of a 29year old woman with a complex movement disorder syndrome due to the combination of coexisting pathological triplet repeat expansions of huntingtin and ATXN8 genes. The disease course was characterized by mental disturbances including cognitive decline and changes in personality starting at the age of 12years, followed by twisting motions, intentional tremor and gait ataxia. Later Parkinsonian symptoms of micrographia, bradykinesia, muscle rigidity and mental decline became dominant. Brain MRI showed hypoplasia of the nucleus caudatus and generalized atrophy; MR spectroscopy revealed a decrease of all typical metabolites except for an increased level of lactate and acetate. Therapeutic trials with pramipexole, ropinirole and tetrabenazine showed no benefit, while levetiracetam caused agitation and hallucinations. We discuss phenotype–genotype correlation and the rule of triplet repeat expansions of gene ATXN8. [Copyright &y& Elsevier]

Background: Spinocerebellar ataxia type 8 is an uncommon genetic condition and presents with gait disturbances, ataxia, dysarthria, nystagmus, and cognitive and psychiatric abnormalities. Seizures are extremely uncommon in the spinocerebellar ataxias and have been reported only once before in a patient with spinocerebellar ataxia type 8. This case report highlights the need to evaluate spells in patients with a known neurodegenerative or genetic disease to exclude seizures, and it stresses the importance of timely diagnosis and therapy.Case Presentation: The patient was a 22-year-old Caucasian woman with known spinocerebellar ataxia 8 since age 10 years. She was admitted to our hospital with new-onset left hemiparesis and encephalopathy in addition to chronic occurrence of multiple spells of confusion and oromanual automatisms with postictal lethargy. Testing confirmed that she was having recurrent seizures with episodes of nonconvulsive status epilepticus. Urgent treatment with antiepileptic therapy was initiated; her seizures resolved shortly thereafter, and her mental status improved. Her left hemiparesis has improved; she remains seizure-free; and she has returned to her baseline antiepileptic medications following physical therapy.Conclusions: Seizures have been reported extremely rarely in association with spinocerebellar ataxia 8, but they must be considered in the differential diagnosis of patients with spells of altered awareness, especially in those with a known neurodegenerative or genetic condition. Clinicoradiological correlation with symptoms can help expedite diagnosis and treatment. Expert consultation with epileptologists at the earliest signs can help establish the diagnosis quickly, minimize morbidity, and enhance recovery. [ABSTRACT FROM AUTHOR]