La sclérose latérale amyotrophique est une affection dégénérative caractérisée par une dégénérescence du neurone moteur central et périphérique dans le territoire bulbaire et spinal. Le diagnostic en est souvent difficile en raison de l'hétérogénéité phénotypique et surtout de l'absence de marqueur paraclinique qui signerait l'affection. Dans la mesure où il est apparu indispensable d'établir des critères diagnostiques, trois conférences de consensus se sont tenues au cours des 20 dernières années. La première classification reposait sur l'existence de signes cliniques d'atteinte du NMc et du NMp au sein du système nerveux décomposé en quatre régions anatomiques. Compte tenu de la faible sensibilité de ces critères initiaux deux autres conférences ont eu lieu ensuite. La dernière qui s'est déroulée à Awaji en 2006 a insisté sur l'importance des données myographiques qui apportaient des informations semblables à la clinique pour dépister une atteinte du NMp ainsi que sur l'importance des fasciculations dans le diagnostic de SLA. Nous discuterons de l'intérêt et des limites de ces nouveaux critères dans le diagnostic de SLA.Amyotrophic lateral sclerosis is the most common motor neuron disorder in adults. Although the diagnosis appears obvious in theory, clinical practice shows the contrary as diagnosis is delayed in many patients; the average time between symptom onset and diagnosis can reach 12 months. The delay can be explained by the variability of the clinical presentation and by the absence of diagnostic markers. In order to standardize diagnosis for enrolment in clinical research, diagnostic criteria for ALS were created and revisited during the last 20 years. In 2006, the Awaji criteria for the diagnosis of ALS were proposed, adding two major points to the diagnostic criteria: electromyography is considered equivalent to clinical examination for the identification of LMN signs and fasciculation potentials resume their prominent place in the diagnosis. Comparisons of the accuracy of the revisited El Escorial and Awaji criteria support improved diagnostic sensitivity without any effect on specificity with the new classification. The only weakness of the new classification involves patients with UMN signs in one region and LMN in two regions; these patients were previously classified as laboratory-supported probable ALS and currently as possible ALS, a lower level of diagnostic certainty. In all other instances the accuracy appears to be improved by the Awaji criteria. Nevertheless, there is a body of evidence suggesting the need for a revision of these new criteria, giving more weight to clinical and complementary findings of UMN involvement. The need to diagnose and treat ALS quickly could be facilitated by the inclusion of complementary investigations that detect UMN signs.

Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.

The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve-conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes---NF-L and KIF1Bbeta---have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR-CMT2) provided evidence of linkage to chromosome 1q21.2-q21.3 in two families (Zmax=4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural exploration of sciatic nerves of LMNA null (i.e., -/-) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site-specific amino acid substitutions in limb-girdle muscular dystrophy type 1B, autosomal dominant Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR-CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.

Giant axonal neuropathy is a rare severe autosomal recessive childhood disorder affecting both the peripheral nerves and the central nervous system. Peripheral nerves characteristically show giant axonal swellings filled with neurofilaments. The giant axonal neuropathy gene was localised by homozygosity mapping to chromosome 16q24.1 and identified as encoding a novel, ubiquitously expressed cytoskeletal protein named gigaxonin.We describe a consanguineous Algerian family with three affected sibs aged 16, 14 and 12 years who present a mild demyelinating sensory motor neuropathy, hypoacousia and kyphoscoliosis which was moderate in the two elder patients, severe in the third one, with no sign of central nervous system involvement and normal cerebral magnetic resonance imaging. This clinical picture is different from the classical severe form, with kinky hairs and early onset of central nervous system involvement and from the less severe form, with protracted course and late involvement of central nervous system. Nerve biopsy showed a moderate loss of myelinated fibers and several giant axons with thin or absent myelin, filled with neurofilaments. This neuropathological aspect is similar to the previously described families linked to the gigaxonin gene. Genetic study in this family showed absence of linkage to chromosome 16q24.1, indicating for the first time, a genetic heterogeneity in giant axonal neuropathy. We propose to call this form of giant axonal neuropathy giant axonal neuropathy 2, and to use the name of giant axonal neuropathy 1 for the form linked to 16q24.1.

Charcot–Marie–Tooth disease constitutes a genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. The axonal type of Charcot–Marie–Tooth is designated type 2. Six loci for autosomal dominant and three for recessive Charcot–Marie–Tooth type 2 have been reported so far. In this study we report the phenotype of autosomal recessive axonal Charcot–Marie–Tooth type 2 due to a recently-described mutation (c.892C>T–p.R298C) in a gene encoding Lamin A/C nuclear envelope proteins and the first gene in which a mutation leads to autosomal recessive Charcot–Marie–Tooth type 2. We have explored eight patients from four Algerian families. The onset is usually in the second decade and the course is rapid, involving upper limbs and proximal muscles, leading to a severe condition in less than 4 years. Many different mutations in Lamin A/C have been identified as causing variable phenotypes, such as limb girdle muscular dystrophy type 1B, autosomal dominant and recessive Emery–Dreyfuss muscular dystrophy, dilated cardiomyopathy with atrioventricular conduction defect, and Dunnigan-type familial partial lipodystrophy should prompt us to fully investigate the skeletal and cardiac muscles in patients affected with autosomal recessive Charcot–Marie–Tooth type 2 carrying a mutation in LMNA.

Annals of the New York Academy of SciencesVolume 883, Issue 1 p. 453-456 The Autosomal Recessive Form of CMT Disease Linked to 5q31-q33 A. GUILBOT, A. GUILBOT INSERM U289, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorM. KESSALI, M. KESSALI Service de Neurologie, CHU Mustapha, AlgeriaSearch for more papers by this authorN. RAVISÉ, N. RAVISÉ INSERM U289, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorT. HAMMADOUCHE, T. HAMMADOUCHE INSERM U289, Hôpital de la Salpêtrière, Paris, France Institut Pasteur, Algiers, AlgeriaSearch for more papers by this authorA. BOUHOUCHE, A. BOUHOUCHE INSERM U289, Hôpital de la Salpêtrière, Paris, France Service de Neurologie, Hôpital des Spécialités, Rabat, MoroccoSearch for more papers by this authorT. MAISONOBE, T. MAISONOBE Laboratoire de Neuropathologie R. Escourolle, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorD. GRID, D. GRID Service de Neurologie, CHU Mustapha, AlgeriaSearch for more papers by this authorA. BRICE, A. BRICE INSERM U289, Hôpital de la Salpêtrière, Paris, France Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorE. LeGUERN, Corresponding Author E. LeGUERN INSERM U289, Hôpital de la Salpêtrière, Paris, France Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, FrancegTo whom correspondence should be addressed: INSERM U289, Hôpital de la Salpêtrière, 47 Bd de l'Hôpital, 75651 Paris Cedex 13, France; 00-33-1-42-16-21-82 (voice); 00-33-1-44-24-36-58 (fax); leguern@ccr.jussieu.fr (e-mail).Search for more papers by this author A. GUILBOT, A. GUILBOT INSERM U289, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorM. KESSALI, M. KESSALI Service de Neurologie, CHU Mustapha, AlgeriaSearch for more papers by this authorN. RAVISÉ, N. RAVISÉ INSERM U289, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorT. HAMMADOUCHE, T. HAMMADOUCHE INSERM U289, Hôpital de la Salpêtrière, Paris, France Institut Pasteur, Algiers, AlgeriaSearch for more papers by this authorA. BOUHOUCHE, A. BOUHOUCHE INSERM U289, Hôpital de la Salpêtrière, Paris, France Service de Neurologie, Hôpital des Spécialités, Rabat, MoroccoSearch for more papers by this authorT. MAISONOBE, T. MAISONOBE Laboratoire de Neuropathologie R. Escourolle, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorD. GRID, D. GRID Service de Neurologie, CHU Mustapha, AlgeriaSearch for more papers by this authorA. BRICE, A. BRICE INSERM U289, Hôpital de la Salpêtrière, Paris, France Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, FranceSearch for more papers by this authorE. LeGUERN, Corresponding Author E. LeGUERN INSERM U289, Hôpital de la Salpêtrière, Paris, France Fédération de Neurologie, Hôpital de la Salpêtrière, Paris, FrancegTo whom correspondence should be addressed: INSERM U289, Hôpital de la Salpêtrière, 47 Bd de l'Hôpital, 75651 Paris Cedex 13, France; 00-33-1-42-16-21-82 (voice); 00-33-1-44-24-36-58 (fax); leguern@ccr.jussieu.fr (e-mail).Search for more papers by this author First published: 06 February 2006 https://doi.org/10.1111/j.1749-6632.1999.tb08608.xCitations: 4Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume883, Issue1CHARCOT-MARIE-TOOTH DISORDERSOctober 1999Pages 453-456 RelatedInformation