Contractures and muscle disease.

Contractures are one of a handful of signs in muscle disease, besides weakness and its distribution, whose presence can help guide us diagnostically, a welcome star on the horizon. Contractures are associated with several myopathies, some with important cardiac manifestations, and consequently are important to recognise; their presence may also provide us with a potential satisfying 'penny dropping' diagnostic moment.

Muscle diseases: mimics and chameleons.

Muscle diseases are not as common as headaches and funny turns in our general neurology clinics, but most of us will encounter them. We all pride ourselves on a methodical approach to clinical problems-discovering the where and what in neurological parlance-but any diagnostic process can unravel, particularly if one condition resembles another. Before we settle on a diagnosis, we need to ask ourselves, whether the 'ducks all line up' to avoid cases of mistaken identity.

A novel TBK1 mutation in a family with diverse frontotemporal dementia spectrum disorders.

Mutations in the TANK-binding kinase 1 (TBK1) gene have recently been shown to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioral variant FTD, primary progressive aphasia, and pure ALS. We describe the clinical, anatomical, and pathological features of a patient who developed corticobasal syndrome (CBS)/progressive nonfluent aphasia (PNFA) overlap. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic-rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with four out of seven siblings developing either dementia or ALS in their 50s and 60s. The patient died at the age of 71 and the brain was donated for postmortem analysis. Histopathological examination showed frontotemporal lobar degeneration TDP-43 type A pathology. Genetic screening did not reveal a mutation in the GRN, MAPT, or C9orf72 genes, but exome sequencing revealed a novel p.E703X mutation in the TBK1 gene. Although segregation data were not available, this loss-of-function mutation is highly likely to be pathogenic because it is predicted to disrupt TBK1/optineurin interaction and impair cellular autophagy. In conclusion, we show that TBK1 mutations can be a cause of an atypical parkinsonian syndrome and screening should be considered in CBS patients with a family history of dementia or ALS.

Facial Onset Sensory and Motor Neuronopathy: Further Evidence for a TDP-43 Proteinopathy.

Three patients with the clinical and investigation features of facial onset sensory and motor neuronopathy (FOSMN) syndrome are presented, one of whom came to a post-mortem examination. This showed TDP-43-positive inclusions in the bulbar and spinal motor neurones as well as in the trigeminal nerve nuclei, consistent with a neurodegenerative pathogenesis. These data support the idea that at least some FOSMN cases fall within the spectrum of the TDP-43 proteinopathies, and represent a focal form of this pathology.

Nerve excitability changes in chronic renal failure indicate membrane depolarization due to hyperkalaemia.

Multiple nerve excitability measurements were used to investigate axonal membrane properties in patients with chronic renal failure (CRF). Nine patients were studied during routine haemodialysis therapy. The median nerve was stimulated at the wrist and compound muscle action potentials recorded from abductor pollicis brevis. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and recovery cycle (refractoriness, superexcitability and late subexcitability) were recorded using a recently described protocol. In six patients, sequential studies were performed before, during and after haemodialysis. All patients underwent standard electrolyte and renal function tests before and after haemodialysis. Before dialysis, there were significant abnormalities in axonal excitability: reduced superexcitability; increased accommodation to depolarizing and hyperpolarizing currents; and a steeper current-threshold relationship compared with normal controls. These excitability parameters are the most sensitive to membrane potential and the abnormalities, which were all reduced by haemodialysis, closely resembled those in normal axons depolarized by ischaemia. Before dialysis, the excitability parameters correlated significantly with serum potassium (range 4.3-6.1 mM), but not with other markers of renal dysfunction: patients with normal axonal resting potentials had normal serum potassium, although urea and creatinine were elevated. We conclude that nerves are depolarized in many CRF patients and that the depolarization is primarily due to hyperkalaemia.