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Peripheral Neuropathies
Published in John W. Scadding, Nicholas A. Losseff, Clinical Neurology, 2011
Gareth Llewelyn, Robert Powell
The distal hereditary motor neuropathies (HMNs) usually present with progressive weakness and wasting of the extensor muscles of the toes and feet without sensory symptoms, followed later on by upper limb involvement. The distal HMNs are clinically and genetically heterogeneous and are subdivided according to the mode of inheritance, age at onset and clinical features. Additional features, such as vocal cord and diaphragmatic involvement, and pyramidal signs may also be present. Clinically, it can be difficult to distinguish distal HMN from CMT, and neurophysiological testing is essential. Inheritance can be either autosomal dominant or recessive and a number of different genetic mutations have been identified.
Juvenile amyotrophic lateral sclerosis associated with biallelic c.757delG mutation of sorbitol dehydrogenase gene
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2022
Emilien Bernard, Antoine Pegat, Anne-Evelyne Vallet, Pascal Leblanc, Serge Lumbroso, Kevin Mouzat, Philippe Latour
We described for the first time the association between JALS and the recurrent c.757del biallelic SORD mutation, which has only been associated to date with CMT2, intermediate CMT, and dHMN (5). Clinical distinction between dHMN and JALS can be challenging, but dHMN is generally considered as a slowly progressive length-dependent and rather symmetrical condition without upper motor neuron sign, although upper motor neuron signs have been observed with SETX and BSCL2 gene mutations (6). Upper limb weakness has been noted in 59% of patients harboring SORD mutation in the original report, but with no mention of upper motor neuron signs in these patients (5). Moreover, electrophysiological investigation indicated that the right hand atrophy pattern was compatible with the ALS diagnostic, as the SHI was 5.1. An SHI below 5.2 is indeed considered to robustly differentiate ALS from mimic disorders (7), although SHI values in dHMN patients have not been evaluated. In the present case, the relative fast course and rapid upper limb involvement, asymmetrical weakness, propagation of symptoms from the right leg to the homolateral upper limb, diffuse fasciculations, and upper motor neuron signs were clearly rather in favor of JALS rather than dHMN.
Typical bulbar ALS can be linked to GARS mutation
Published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2019
P. Corcia, C. Brulard, S. Beltran, S. Marouillat, S.E. Bakkouche, C.R. Andres, H. Blasco, P. Vourc’h
More than 30 genes have associated with ALS last 20 years (1). Genetics plays also a key role in distal hereditary motor neuropathies (dHMN), characterized by the degeneration of LMN which classically predominates distally. One of the most frequent features, the dHMN V phenotype, is characterized by a distal predominant upper limb phenotype and is classically linked to mutations of the GARS gene (2).
A patent review of histone deacetylase 6 inhibitors in neurodegenerative diseases (2014-2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Charcot-Marie-Tooth (CMT) disease is the most common inherited disorder of the peripheral nervous system (PNS), caused by more than 80 different types of mutation, in which motor and sensory peripheral nerves are degenerated resulting in muscle weakness, motor problems, and sensory loss [60,61]. In 2011, the Van Den Bosch group characterized a type of transgenic mice expressing two different mutations (S135F or P182L) in the heat-shock protein gene B1 (HSPB1/HSP27) that replicate the motor and sensory deficits seen in patients with CMT type 2F (CMT2F) or distal hereditary motor neuronopathies (HMN) type 2B, demonstrated by reduced compound muscle action potentials (CMAPs) and sensory nerve action potentials (SNAPs) [62]. Secondly, dorsal root ganglion (DRG) neurons isolated from HSPB1S135F-expressing transgenic mice displayed a decrease in the number of total mitochondria and a defect in axonal transport of mitochondria compared to their wild-type littermates. Moreover, both HSPB1S135F and HSPB1P182L mice exhibit impaired acetylation of α-tubulin in the sciatic nerve. As HDAC6 recognizes α-tubulin as its preferred substrate and plays a critical role in controlling the axonal transport of mitochondria in cultured hippocampal neurons [12], a 3-week course of treatment with TubA (25 mg/kg, IP) was found to effectively restore impaired Ac-α-tubulin levels in the sciatic nerve and to rescue the CMT phenotype. Moreover, after treating DRG neurons from HSPB1S135F mice with TubA (1 µM) for 12 h, the total number of mitochondria and the number of moving mitochondria were elevated, thus rescuing axonal transport defects [62]. In 2016, the Kozikowski and Van Den Bosch groups disclosed a second generation HDAC6 inhibitor, Benzimidazole 23d (10), which showed an improved ability to acetylate α-tubulin in N2a cells as well improved mitochondrial axonal transport in DRG neurons isolated from HSPB1S135F mice compared to TubA [56]. In 2017, the Van Den Bosch group further conducted an evaluation of ACY-1215 (30 mg/kg, IP), ACY-738 (3 mg/kg, IP), and ACY-775 (3 mg/kg, IP) for three weeks in CMT2F mice expressing HSPB1S135F. The compounds reversed the axonal deficits in motor and sensory nerves and induced reinnervation of the neuromuscular junction.