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Abstract 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 Background Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the C9orf72 gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand. Methods We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the C9orf72 gene. Results Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in C9orf72. The analysis of the fragile X mental retardation 1 gene (FMR1) revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats). Conclusions Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller FMR1 gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for C9orf72 expansion in ataxia patients.

Background: Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the C9orf72 gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand.Methods: We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the C9orf72 gene.Results: Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in C9orf72. The analysis of the fragile X mental retardation 1 gene (FMR1) revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats).Conclusions: Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller FMR1 gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for C9orf72 expansion in ataxia patients. [ABSTRACT FROM AUTHOR]

Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type) and CaV3.2 (α1H T-type) calcium channels; KLHL1 knockdown experiments (KD) cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014). Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO) mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT); and PQ-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were reduced in the KO hippocampus; cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC) frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

Kelch-like 1 (KLHL1) is a neuronal actin-binding protein that modulates voltagegated CaV2.1 (P/Q-type) and CaV3.2 (α1H T-type) calcium channels; KLHL1 knockdown experiments (KD) cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014). Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO) mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT); and P/Q-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were also reduced in the KO hippocampus and cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC) frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition. [ABSTRACT FROM AUTHOR]

Abstract: In the last ten years, several RNAs with no protein-coding potential have been accumulating in RNA databases and are in need of further molecular characterization. At the same time, examples of non-coding RNAs (ncRNAs) such as microRNAs, small RNAs, small interfering RNAs (siRNAs) and medium/large RNAs with various functions have been described in the literature. Recent evidence points to a widespread role of these molecules in eukaryotic cells, suggesting that the majority of the new ncRNA examples might have specific functions. The aim of this review is to describe several new functional ncRNAs that have been recently identified and characterized, providing some clues that these molecules might not be produced by chance or as by-products of transcription as has been speculated. [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]

Controversial data have been reported about SCA8 since its description in 1999. The most accepted hypothesis is that CTG expansions within the CTA/CTG combined repeat expansion in the SCA8 locus causes SCA8. It is inherited as a dominant trait with reduced penetrance. The present study, reports the first data regarding SCA8 in the Spanish population and the clinical findings in patients carrying expanded alleles, including one homozygous patient. Two hundred and forty-six individuals from the Spanish population, including controls (149) and ataxic patients (97), were studied. DNA was extracted from blood samples using standard methods. Amplification of the CTA/CTG 3′untranslated region was achieved by PCR using primers SCA8-F3 and SCA8-R4 and conditions described previously. Neurological revaluation was done in individuals carrying the expanded allele. We detected five unrelated expanded alleles corresponding to three affected patients (one of them homozygous) and one healthy individual. SCA8 represents 4% of the total dominant spinocerebellar ataxias studied in our group (Spanish population) (three index patients out of 75 dominant ataxic independent nucleus). The patient that resulted homozygous for the expansion is a 25-year-old man with a clinical picture of progressive ataxia and dysarthria that began at the age of 12. On neurological examination, he showed ataxia, slight dysarthria and nystagmus to the extreme lateral gaze. A cranial MRI showed global atrophy of cerebellum but the brainstem was spared. Family history showed the presence of ataxia in his grandfather and father. His mother is healthy at the age of 52 and a molecular study of SCA8 reveals one allele that could be considered as premutated. She has no ataxia antecedents in her family. Our results provide additional information about the SCA8 expansion, within the Spanish population. These results are in agreement with the hypothesis of the CTG expansion in the SCA8 locus being... [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 8 (SCA8) is a slowly progressive ataxia causally associated with untranslated CTG repeat expansion on chromosome 13q21. However, the role of the CTG repeat in SCA8 pathology is not yet well understood. Therefore, we studied the length of the SCA8 CTA/CTG expansions (combined repeats, CRs) in 115 patients with ataxia, 64 unrelated individuals with non-triplet neuromuscular diseases, 70 unrelated patients with schizophrenia, and 125 healthy controls. Only one patient with apparently sporadic ataxia was identified with an expansion of 100 CRs. He had inherited the expansion from his asymptomatic father (140 CRs) and transmitted the mutation to his son (92 CRs). Paternal transmission in this family produced contractions of 40 and 8 CRs, respectively. None of the subjects from other studied groups had an expansion at the SCA8 locus. In the control group the number of CRs at the SCA8 locus ranged from 14 to 34. Our findings support the notion that allelic variants of the expansion mutation at the SCA8 locus can predispose to ataxia. [ABSTRACT FROM AUTHOR]