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Objective:To identify the causative gene for the neurodegenerative disorder spinocerebellar ataxia type 19 (SCA19) located on chromosomal region 1p21‐q21.Methods:Exome sequencing was used to identify the causal mutation in a large SCA19 family. We then screened 230 ataxia families for mutations located in the same gene (KCND3, also known as Kv4.3) using high‐resolution melting. SCA19 brain autopsy material was evaluated, and in vitro experiments using ectopic expression of wild‐type and mutant Kv4.3 were used to study protein localization, stability, and channel activity by patch‐clamping.Results:We detected a T352P mutation in the third extracellular loop of the voltage‐gated potassium channel KCND3 that cosegregated with the disease phenotype in our original family. We identified 2 more novel missense mutations in the channel pore (M373I) and the S6 transmembrane domain (S390N) in 2 other ataxia families. T352P cerebellar autopsy material showed severe Purkinje cell degeneration, with abnormal intracellular accumulation and reduced protein levels of Kv4.3 in their soma. Ectopic expression of all mutant proteins in HeLa cells revealed retention in the endoplasmic reticulum and enhanced protein instability, in contrast to wild‐type Kv4.3 that was localized on the plasma membrane. The regulatory β subunit Kv channel interacting protein 2 was able to rescue the membrane localization and the stability of 2 of the 3 mutant Kv4.3 complexes. However, this either did not restore the channel function of the membrane‐located mutant Kv4.3 complexes or restored it only partially.Interpretation:KCND3 mutations cause SCA19 by impaired protein maturation and/or reduced channel function. ANN NEUROL 2012;72:870–880

PTH is an important health problem with a significant impact on long-term outcome of TBI patients. Several risk factors were identified, which can aid in early identification of subjects at risk for PTH.

We think that VNS is an effective treatment for pharmacoresistant epilepsy and its positive effect persists during the years of follow-up. Our results suggest that seizure reduction should not be considered as the only variable of importance to describe the outcome of VNS on epilepsy and it is worthwhile to look at other outcome measures.

SUMMARY Of a family consisting of 54 members, 44 were examined. Twenty-one showed signs of a clinically non-progressive congenital lower motor neuron disorder restricted to the lower part of the body, which resulted in arthrogryposis in 15 cases. The mode of inheritance is autosomal dominant with very varied expression of the gene.

The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with a variety of other associative features. Since 1993 ADCAs have been increasingly characterised in terms of their genetic mutation and are referred to as spinocerebellar ataxias (SCAs). Some families with ADCA cannot be assigned to any of the known genotypes, which implies further genetic heterogeneity. We investigated the clinical symptoms of 12 patients of a four-generation family with ADCA and carried out mutation and genetic linkage studies. The family showed a relatively mild cerebellar ataxic syndrome with cognitive impairment, poor performance on the Wisconsin Card Sorting Test, myoclonus, and a postural irregular tremor of slow frequency. Age at disease onset and severity of cerebellar signs and symptoms suggest anticipation. The genetic loci implicated in ADCA were excluded by mutation analyses (SCA 1, 2, 3, 6, 7, 8, 12) and genetic linkage (SCA 4, 5, 6, 10, 11). We conclude that this family represents a clinically and genetically distinct form of SCA.

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The frail elderly had worse long-term outcome, and early complaints were found to be a stronger predictor of unfavorable outcome than age. Understanding the implications of frailty on outcome could help clinicians recognize patients at risk of a poor outcome and allocate care more efficiently.