A study of the relationship between brain seizure activity, immediate early genes, and the amyloid precursor protein gene

In 2 volsAvailable from British Library Document Supply Centre-DSC:D207260 / BLDSC - British Library Document Supply CentreSIGLEGBUnited Kingdo

Guillain-Barre syndrome with involvement of the central and autonomic nervous systems

No abstract availabl

Limb girdle syndromes: Clinical, morphological and electrophysiological studies

The clinical syndrome of slowly progressive proximal limb and limb girdle muscular weakness and atrophy, or limb girdle syndromes (LGS), has a diverse aetiology. Several of the congenital, mitochondrial and other metabolic myopathies and spinal muscular atrophies are recently recognized causes of LGS. Thus the position of limb girdle muscular dystrophy (LGMD) as a discrete entity in the nosology of muscle disease deserves reappraisal. We have therefore reevaluated our experience of 33 patients in this light. Detailed clinical, electrophysiological, and pathological studies including autopsies in 2 cases, were performed. As a result we are confident that LGMD does exist as a sporadic or autosomal dominant (2 families) or recessive condition (2 families). There are therefore probably at least 2 distinct genotypes. Typical LGMD (18 patients in our series) is characterized by slowly progressive symmetrical proximal upper and lower limb girdle weakness and atrophy, elevation of the serum creatine kinase at some stage, dystrophic or less severe myopathic muscle lesions on biopsy, and myopathic EMG findings. Two minor subgroups of LGMD were identified in our series with similar clinical and laboratory features but distinguishable by the development of either facial (4 patients) or by distal limb muscle involvement (3 patients). A further group of patients with sporadic LGS (5 patients) had slowly progressive proximal symmetrical upper and lower limb-girdle weakness and atrophy with myopathic or neurogenic features on either EMG or muscle biopsy so that the precise characterization was difficult. Two of these patients had distal limb muscle involvement and contractures. One patient had upper limb-girdle muscle atrophy with normal lower limbs. A disorder affecting muscle, nerve or both remains a possibility in these cases

Butyrylcholinesterase K variant and Alzheimer's disease

This study attempted to corroborate findings on the association between butyrylcholinesterase K variant and Alzheimer’s disease. This was performed on an autopsy-confirmed series of patients with Alzheimer’s disease and controls. The butyrylcholinesterase K variant was found to be of increased allele frequency in patients with sporadic Alzheimer’s disease. When related to APOE ɛ4 typing the association was specific but not sensitive for the diagnosis of Alzheimer’s disease

CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis

Frontotemporal dementia and amyotrophic lateral sclerosis are clinically and pathologically overlapping disorders with shared genetic causes. We previously identified a disease locus on chromosome 16p12.1-q12.2 with genome-wide significant linkage in a large European Australian family with autosomal dominant inheritance of frontotemporal dementia and amyotrophic lateral sclerosis and no mutation in known amyotrophic lateral sclerosis or dementia genes. Here we demonstrate the segregation of a novel missense variant in CYLD (c.2155A>G, p.M719V) within the linkage region as the genetic cause of disease in this family. Immunohistochemical analysis of brain tissue from two CYLD p.M719V mutation carriers showed widespread glial CYLD immunoreactivity. Primary mouse neurons transfected with CYLDM719V exhibited increased cytoplasmic localization of TDP-43 and shortened axons. CYLD encodes a lysine 63 deubiquitinase and CYLD cutaneous syndrome, a skin tumour disorder, is caused by mutations that lead to reduced deubiquitinase activity. In contrast with CYLD cutaneous syndrome-causative mutations, CYLDM719V exhibited significantly increased lysine 63 deubiquitinase activity relative to the wild-type enzyme (paired Wilcoxon signed-rank test P = 0.005). Overexpression of CYLDM719V in HEK293 cells led to more potent inhibition of the cell signalling molecule NF-κB and impairment of autophagosome fusion to lysosomes, a key process in autophagy. Although CYLD mutations appear to be rare, CYLD’s interaction with at least three other proteins encoded by frontotemporal dementia and/or amyotrophic lateral sclerosis genes (TBK1, OPTN and SQSTM1) suggests that it may play a central role in the pathogenesis of these disorders. Mutations in several frontotemporal dementia and amyotrophic lateral sclerosis genes, including TBK1, OPTN and SQSTM1, result in a loss of autophagy function. We show here that increased CYLD activity also reduces autophagy function, highlighting the importance of autophagy regulation in the pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.Carol Dobson-Stone, Marianne Hallupp, Hamideh Shahheydari, Audrey M G Ragagnin, Zac Chatterton, Francine Carew-Jones ... et al