Timothy J. Benstead

Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) represents a family of related sensorimotor neuropathies. We studied a large family from a rural eastern Canadian community, with multiple individuals suffering from a condition clinically most similar to autosomal recessive axonal CMT, or AR-CMT2. Homozygosity mapping with high-density SNP genotyping of six affected individuals from the family excluded 23 known genes for various subtypes of CMT and instead identified a single homozygous region on chromosome 9, at 122,423,730–129,841,977 Mbp, shared identical by state in all six affected individuals. A homozygous pathogenic variant was identified in the gene encoding leucine rich repeat and sterile alpha motif 1 (LRSAM1) by direct DNA sequencing of genes within the region in affected DNA samples. The single nucleotide change mutates an intronic consensus acceptor splicing site from AG to AA. Direct analysis of RNA from patient blood demonstrated aberrant splicing of the affected exon, causing an obligatory frameshift and premature truncation of the protein. Western blotting of immortalized cells from a homozygous patient showed complete absence of detectable protein, consistent with the splice site defect. LRSAM1 plays a role in membrane vesicle fusion during viral maturation and for proper adhesion of neuronal cells in culture. Other ubiquitin ligases play documented roles in neurodegenerative diseases. LRSAM1 is a strong candidate for the causal gene for the genetic disorder in our kindred.

Progress in clinical neurosciences: Charcot-Marie-Tooth disease and related inherited peripheral neuropathies.

The classification of Charcot-Marie-Tooth disease and related hereditary motor and sensory neuropathies has evolved to incorporate clinical, electrophysiological and burgeoning molecular genetic information that characterize the many disorders. For several inherited neuropathies, the gene product abnormality is known and for others, candidate genes have been identified. Genetic testing can pinpoint a specific inherited neuropathy for many patients. However, clinical and electrophysiological assessments continue to be essential tools for diagnosis and management of this disease group. This article reviews clinical, electrophysiological, pathological and molecular aspects of hereditary motor and sensory neuropathies.

Acute endothelial swelling is induced in endoneurial microvessels by ischemia

Structural alterations of endoneurial microvessels occur in diabetic neuropathy and are statistically associated with severity of nerve fiber loss and teased fiber abnormality. It is therefore hypothesized that the microvessel alterations may cause or contribute to pathologic alterations of nerve fibers in diabetic neuropathy, possibly through hypoxic injury. The mechanism of the microvessel change in diabetic neuropathy is unknown. The role of microvessels and details of microvessel structure in other possible ischemic neuropathies has not been studied completely. Already there is evidence that hypoxia induces endothelial swelling but this has not been characterized or quantitated in nerve. To determine the acute morphologic effect of ischemia on ultrastructural features of transverse profiles of endoneurial microvessels major pelvic arteries were ligated in rats. At 36 h mean lumen and mural areas were greater in ischemic than in control nerves. All components (endothelium, pericytes and basement membrane) were on average greater in ischemic than controls. The greatest increase was in endothelial cells. In these cells swollen mitochondria were abundant. This study demonstrates that acute ischemia induces swelling of the cells and organelles of endoneurial microvessels.

EMG related anxiety and pain: a prospective study.

BACKGROUND Electromyography (EMG) is a useful test, but unfortunately also painful. We frequently encounter patients who worry about its painful nature, but tolerate it very well. OBJECTIVES We evaluated anxiety levels of patients referred for EMG to explore the possible correlating and contributing factors to high anxiety. METHODS A structured questionnaire, including the State-Trait Anxiety Inventory was completed by patients immediately before EMG testing. Emergency, hospitalized, and seriously ill patients were excluded. RESULTS Seventy-nine cases with ages ranging from 19-72 years (mean 43) were included. Thirty-five (44%) patients had a high pre-test anxiety level. The likelihood of high anxiety was increased if the patient was worried about the test (p < 0.001) or about other issues unrelated to the test or underlying diagnosis (p < 0.001), or was taking an anti-psychotic or anxiolytic drug (p = 0.008). The degree or source of knowledge regarding the test procedure, did not affect the pre-test anxiety level. CONCLUSIONS The information about EMG testing received by patients in this group did not affect pre-test anxiety levels. The patients expectations regarding the test did influence anxiety levels and this may reflect generalized anxiety regarding testing procedures or misinformation regarding the nature of the test, as patients in general reported a better than anticipated experience following the test.

Impact of plasma exchange on indices of demyelination in chronic inflammatory demyelinating polyradiculoneuropathy

We studied the impact of plasma exchange (PE) on indices of primary demyelination in patients of the Canadian multicenter trial of PE in chronic inflammatory demyelinating polyneuropathy (CIDP). Individual motor nerves (median, ulnar, peroneal, tibial) were studied: distal motor latencies (DMLs), proximal and distal compound muscle action potential (M‐wave) amplitudes, negative peak areas and durations, and motor conduction velocities (CVs). Proximal M‐wave amplitudes in individual motor territories, particularly in the ulnar nerve (from below elbow, above elbow, and axillary stimulating sites) demonstrated significant improvement with PE, but not sham exchange. Proximal ulnar M‐wave areas also had significant improvement with PE. Trends toward improvement of individual nerve motor CVs, M‐wave durations, and DMLs did not achieve statistical significance. Proximal M‐wave amplitudes, particularly in the ulnar motor territory, and proximal M‐wave areas (providing a measure of conduction block) were the most sensitive indices of improvement conferred by PE in CIDP. In individual patients, these indices may help judge the efficacy of therapy.

Treatment of paramyotonia congenita with acetazolamide

Treatment of paramyotonia congenita with acetazolamide has been shown to reduce myotonic symptoms but severe weakness has developed in some patients leading to a recommendation not to use the drug in this disorder. We studied a patient with the characteristic clinical and electrophysiological profile of paramyotonia congenita. Myotonia was effectively treated with a very low dose of acetazolamide and no weakness developed. We conclude that acetazolamide can be a safe and effective medication in paramyotonia congenita.

Nerve microvessel changes in diabetes are prevented by aldose reductase inhibition.

BACKGROUND Despite the potential importance of endoneurial microvessel abnormalities in diabetic neuropathy, the pathogenesis of these abnormalities is incompletely understood. We wished to evaluate the effect of experimental diabetes on endoneurial microvessels and determine if an aldose reductase inhibitor alters any of the changes induced by diabetes. METHODS We compared streptozocin diabetic rats with and without aldose reductase inhibitor treatment to non-diabetic rats after 10 months of diabetes. Transverse microvessels from the mid-sciatic level were studied by electron microscopic morphometric evaluation. RESULTS Microvessel endothelial, pericyte, basement membrane and total mural area were greater in untreated diabetic animals than non-diabetic animals. Aldose reductase inhibitor treated diabetic animals had greater endothelial area and possibly pericyte area but not basement membrane or total mural area. CONCLUSIONS This study demonstrates that endoneurial microvessel abnormalities can be detected in experimental diabetic neuropathy. Microvessel basement membrane thickening will be prevented by an aldose reductase inhibitor. One mechanism by which abnormal polyol pathway activity may contribute to diabetic neuropathy could be through damage to microvessels.

Inner perineurial cell vulnerability in ischemia

The perineurium of peripheral nerve plays important roles in anatomical organization of fiber groups, in endoneurial fluid homeostasis and in maintenance of tensile strength but little is known about the functional and structural alterations of the perineurium with injury. Large arteries of supply to lower limb of Sprague-Dawley rats were ligated to study the structural reactions of perineurium at 36 h and at 7 days after induction of ischemic injury. Lipid droplets were found to be an early reactive change to ischemia in multiple cell types including perineurial, endothelial and Schwann cells. In peripheral nerve levels showing early myelinated fiber injury the inner perineurial sheath was widened and was undergoing degeneration. The inner layers of perineurial cells showed swelling, organelle disruption and membrane dissolution while outer layers remained intact. Inner perineurial cell degeneration is a prominent early feature of ischemic injury and may be an important mechanism of altered endoneurial homeostasis, fiber function and structure.

Chapter 46 – Differential Diagnosis of Polyneuropathy

Diagnostic Yield in Assessment of Polyneuropathy Approaches to the Diagnosis of Neuropathy Pattern Class of Affected Fibers Pathophysiology Electrophysiology Temporal Profile Associated Symptoms and Signs of Disease Non-neurologic Disease Neurologic Disease Family History Laboratory Investigations Screening Tests Monoclonal Gammopathy and Antiglycolipid Antibodies Nerve Biopsy Other Investigations Disorders Simulating Peripheral Neuropathy Painful Legs and Moving Toes Erythromelalgia Myopathy Motor Neuron Disease Myelopathy Aging

Establishing a Canadian registry of patients with amyotrophic lateral sclerosis.

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating cause of progressive weakness, respiratory failure and death. To date there is no effective therapy to meaningfully extend survival but continuously emerging targets and putative treatments are studied in clinical trials. Canadian epidemiological data on ALS is scarce and the socioeconomic impact of ALS on Canadian society is unclear. The Canadian Neuromuscular Disease Registry (CNDR) is a national clinic-based registry of patients with neuromuscular diseases with the goal of facilitating the design and execution of clinical research. METHODS We conducted a national stakeholder survey to assess interest for a Canadian ALS registry and an assessment of expected case ascertainment. A dataset derivation meeting was held to establish the registry medical dataset. RESULTS We report the results of the national stakeholder survey, case ascertainment assessment, and the derived dataset that have resulted in the current implementation of a Canadian registry of patients with ALS. CONCLUSIONS The development of this long sought-after resource is a significant step forward for the Canadian ALS patient and research communities that will result in more efficient clinical trial recruitment and advancements in our understanding of ALS in Canada.