Differential diagnosis in spinal and bulbar muscular atrophy clinical and molecular aspects

Kennedy disease is caused by an enlarged trinucleotide repeat sequence within the androgen receptor gene. We report here seven male patients with a benign motor neuron syndrome highly analogous to Kennedy disease but with a normal trinucleotide repeat

Rare functional missense variants in CACNA1H: what can we learn from Writer's cramp?

Writer's cramp (WC) is a task-specific focal dystonia that occurs selectively in the hand and arm during writing. Previous studies have shown a role for genetics in the pathology of task-specific focal dystonia. However, to date, no causal gene has been reported for task-specific focal dystonia, including WC. In this study, we investigated the genetic background of a large Dutch family with autosomal dominantinherited WC that was negative for mutations in known dystonia genes. Whole exome sequencing identified 4 rare variants of unknown significance that segregated in the family. One candidate gene was selected for follow-up, Calcium Voltage-Gated Channel Subunit Alpha1 H, CACNA1H, due to its links with the known dystonia gene Potassium Channel Tetramerization Domain Containing 17, KCTD17, and with paroxysmal movement disorders. Targeted resequencing of CACNA1H in 82 WC cases identified another rare, putative damaging variant in a familial WC case that did not segregate. Using structural modelling and functional studies in vitro, we show that both the segregating p.Arg481Cys variant and the non-segregating p.Glu1881Lys variant very likely cause structural changes to the Cav3.2 protein and lead to similar gains of function, as seen in an accelerated recovery from inactivation. Both mutant channels are thus available for re-activation earlier, which may lead to an increase in intracellular calcium and increased neuronal excitability. Overall, we conclude that rare functional variants in CACNA1H need to be interpreted very carefully, and additional studies are needed to prove that the p.Arg481Cys variant is the cause of WC in the large Dutch family.Genetics of disease, diagnosis and treatmen

The P3 event-related potential in young recent-onset schizophrenic patients

In schizophrenic patients, the amplitude of the P3 event-related potential (ERP) is usually decreased and the latency is often prolonged. Most ERP studies have compared schizophrenic patients with chronic illness or in mixed age groups with age-matched control subjects. However, P3 latency and amplitude change with age, and P3 latency increases more rapidly in schizophrenic patients than in control subjects. To investigate whether mixed age groups and chronic illness have been determining factors in ERP results, P3 was measured in 15 young patients (mean age 21.6 years) with recent-onset schizophrenia and compared with age-matched controls. P3 amplitudes were decreased in the schizophrenic group compared with the control group. P3 latencies were less significantly prolonged in the schizophrenic group than in other studies. Furthermore, in an exploratory study, the ERPs resulting from application of the irrelevant tones in some schizophrenic patients demonstrated ERP activity at latencies of 250-600 ms, while little or no activity was present at these latencies in control subjects. It is hypothesized that a defect in inhibition of incoming sensory information in the nucleus reticularis thalami may play a role in the pathogenesis of schizophrenia. Such a defect could result in a dysfunctional filter function of external stimuli and may therefore affect the social and psychological functioning of the patient. (C) 1998 Rapid Science Lt