Introduction La maladie de Parkinson est une affection neurodégénérative fréquente, l’identification des prédispositions génétiques a considérablement enrichi notre compréhension de la physiopathologie de cette dernière. Objectifs C’est de rechercher la mutation G2019S du gène LRRK2, vu la fréquence de cette mutation qu Maghreb et le deuxième objectif était de rechercher des mutations plus rares en criblant un panel sélectif ainsi par conséquent d’effectuer des corrélations phénotypes–génotypes. Méthodes Nous avons reçu dans notre consultation 320 patients, nous avons recruté 109 patients parkinsoniens, nous avons criblé la mutation G2019S étant donné que c’est la mutation la plus fréquente au Maghreb par la méthode Taqman puis nous avons utilisé la Target sequencing afin de rechercher d’autres mutations causales validé par la méthode Sanger. Résultats Nous avons retrouvé sur nos 109 patients : 21 patients présentants la mutations G2019S soit 20,2 %, 2 patients présentants la mutations GBA, 2 patients présentants la mutations PRKN, 1patients présentant la mutation DNAJ6,1 patient présentant une mutation VP35S et 69 patients avec une mutation wild type ou non porteur de la mutation G2019S. Discussion Notre étude a permis, d’une part, de confirmer que la mutation G2019S est la mutation la plus fréquente au Maghreb bien que plusieurs études ont été effectue en Algérie, notre étudié a permis de faire de corrélation phénotype-génotype dont l’implication sue la prise en charge de nos patients est certaine. Conclusion Il est fortement recommandé de réaliser une recherche systématique de mutation et notamment la G2019S dans la région du Maghreb.

ABSTRACT Background and Aims In 2019, we conducted a cross‐sectional study, collecting information on 50 patients with CMT4B, an ultrarare CMT subtype, to better define the clinical phenotype. We now aimed at investigating disease progression in 26 patients with CMT4B1/CMT4B2, recruited from the previous study and among the Inherited Neuropathy Consortium. Materials and Methods We retrospectively analysed disease progression in patients with CMT4B1/CMT4B2, collecting MRC scores from nine muscle pairs, Charcot‐Marie‐Tooth Examination Score (CMTES), and a minimal dataset of clinical information (walking difficulties, aids dependency, upper limb impairment, cranial nerves involvement) at baseline and follow‐up visits. Thirteen centres from four continents were involved. Results Thirteen CMT4B1 and 13 CMT4B2 patients were followed up for 7.1 ± 4.9 and 7.9 ± 4.5 years, respectively. During follow‐up, walking aid dependency increased: two CMT4B1 patients adopted AFOs (overall 11/12 at follow‐up), and one started using wheelchair (6/12 at follow‐up) at the age of 19; among CMT4B2 patients, two more required unilateral support in walking (4/11 at follow‐up) by the age of 33 and 49 years, respectively. We found that disease progression, as measured by CMTES, was faster in CMT4B1 as compared to CMT4B2 patients (ΔCMTES/year 0.7 vs. 0.3, p = 0.037) but tended to slow down over time as burden of disease increased. At the end of follow‐up, CMT4B1 was associated to higher disability. Conclusions This international collective effort enabled collection of relevant data for characterizing natural history and estimating disease progression of CMT4B1/CMT4B2 ultrarare diseases, aiming at improving their management and paving the way for designing future clinical trials.

Although substantial advancements have been made in genetic testing, several barriers continue to limit patient access, leading to delays in diagnosis, effective treatments, and preventative measures. The NEUROMYODredger-3billion Megaproject End the Diagnostic Odyssey grant offered free whole exome sequencing (WES) to 245 patients with undiagnosed neurodevelopmental or neuromuscular disorders in seven countries: Algeria, Chile, Egypt, France, Mexico, Peru, and Romania. We found pathogenic variants in 79 patients (diagnostic yield 32.24%)-36 neurodevelopmental (43.90%) and 43 neuromuscular (26.38%). Fifty patients harboured variants of uncertain significance (VUS, 20.40%)-14 neurodevelopmental (17.07%) and 36 neuromuscular (22.08%), and 116 patients had negative results (47.34%). NEUROMYODredger helped end the diagnostic odyssey in around 30% of patients, while ongoing functional studies and reanalysis strategies are used in order to reach more diagnoses. In conclusion, a singleton WES approach is valuable in determining the genetic diagnosis of neurodevelopmental and neuromuscular diseases, especially in low and middle-income countries.

Biallelic NDUFA9 variants have hitherto been associated with disease in four individuals. Hence, clinicogenetic features of NDUFA9-related disorder remain largely unexplored. To delineate the pheno-genotypic spectrum of NDUFA9-related disorder, we screened genetic databases worldwide and collected phenotypic data on individuals with biallelic NDUFA9 variants, which were functionally investigated when possible. Eight new and four reported cases were identified. Neurodevelopmental delay followed by motor deterioration and seizures were the most common presenting features. Neurodevelopmental disorder was observed in 90% of cases surviving beyond the age of 4 months. Neurological deterioration always started in the first decade. Among ten affected surviving beyond early infancy, major clinical features included dystonia (100%), feeding difficulties/dysphagia/failure to thrive and pyramidal signs (80%), seizures and muscle weakness/atrophy (70%), and moderate-to-severe intellectual disability (60%). All showed basal ganglia MRI signal alterations, with atrophy (50%) and swelling (25%). Four individuals died by the age of 13 years. In addition to four known variants, we identified five new NDUFA9 variants and pinpointed Arg360 (NP_004993.1) as a mutational hotspot. Protein modelling suggested that variants cause NADH:ubiquinone oxidoreductase subunit A9 (NDUFA9) misfolding and/or disruption of binding interfaces. Loss of fully assembled complex I with decreased steady-state NDUFA9 levels and/or complex I activity was documented in fibroblasts from three affected individuals. Our study strengthens the evidence that biallelic NDUFA9 variants cause mitochondrial complex I deficiency presenting with a broad spectrum of progressive neurodevelopmental disorder, often accompanied by prominent dystonia, and a characteristic Leigh syndrome MRI pattern.

BACKGROUND:ANK3 encodes ankyrin-G, a key scaffolding protein essential for neuronal function. While both monoallelic and biallelic ANK3 variants have been linked to neurodevelopmental disorders (NDDs), existing evidence for their pathogenicity and clinical correlation remains limited and heterogeneous. OBJECTIVE:To delineate the clinical features associated with biallelic ANK3 predicted loss-of-function (pLOF) variants. METHODS:We employed exome sequencing, Sanger validation, detailed clinical phenotyping, and extensive international data sharing to identify patients with biallelic ANK3 variants. RESULTS:We describe five individuals from three unrelated consanguineous families with segregating homozygous ANK3 pLOF variants. These patients presented with a relatively consistent phenotype comprising developmental delay, intellectual disability, hypotonia, variable epilepsy, and cerebellar signs including ataxia, tremor, and dysarthria. Among the three patients for whom brain magnetic resonance imaging was available, cerebellar atrophy was observed, predominantly affecting the superior vermis and cerebellar hemispheres. These clinical findings align with murine models lacking the cerebellar ankyrin-G isoform, which similarly exhibit ataxic features and high cerebellar ANK3 expression. CONCLUSION:Our findings support a recognizable NDD with non-progressive cerebellar ataxia linked to biallelic ANK3 pLOF variants. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Distal hereditary motor neuropathies (dHMN) are a group of heterogeneous hereditary disorders characterized by a slowly progressive distal pure motor neuropathy. Electrophysiology, with normal motor and sensory conduction velocities, can suggest the diagnosis of dHMN and guide the genetic study. More than thirty genes are currently associated with HMNs, but around 60 to 70% of cases of dHMN remain uncharacterized genetically. Recent cohort studies showed that HSPB1, GARS, BICB2 and DNAJB2 are among the most frequent dHMN genes and that the prevalence of the disease was calculated as 2.14 and 2.3 per 100,000. The determination of the different genes involved in dHMNs made it possible to observe a genotypic overlap with some other neurogenetic disorders and other hereditary neuropathies such as CMT2, mainly with the HSPB1, HSPB8, BICD2 and TRPV4 genes of AD-inherited transmission and recently observed with SORD gene of AR transmission which seems relatively frequent and potentially curable. Distal hereditary motor neuropathy that predominates in the upper limbs is linked mainly to three genes: GARS, BSCL2 and REEP1, whereas dHMN with vocal cord palsy is associated with SLC5A7, DCTN1 and TRPV4 genes. Among the rare AR forms of dHMN like IGHMBP2 and DNAJB2, the SIGMAR1 gene mutations as well as VRK1 variants are associated with a motor neuropathy phenotype often associated with upper motoneuron involvement. The differential diagnosis of these latter arises with juvenile forms of amyotrophic lateral sclerosis, that could be caused also by variations of these genes, as well as hereditary spastic paraplegia. A differential diagnosis of dHMN related to Brown Vialetto Van Laere syndrome due to riboflavin transporter deficiency is important to consider because of the therapeutic possibility.

Background and Objectives:To provide real-word clinical follow-up data on patients carrying variations of congenital myasthenic syndromes (CMS) and who respond to some innovative drugs.Methods:Patients recruited from the Neurology Department of the Mustapha Bacha university hospital in Algiers. Treated with innovative drugs, they were monitored and their clinical progress was evaluated on the basis of clinical arguments suggestive of CMSs, but also para clinical arguments (electromyography and genetic study).Results:Six patients carrying different mutations in different genes of CMSs were studied. They had different pathophysiologic profiles (slow or fast channel syndromes, low expressor of receptor). Their therapeutic management was based on innovative drugs, normally indicated in other, non-neurological pathologies. Their outcome was toward a clear clinical improvement.Discussion:This work relates the interest of proposing treatments (outside of Pyridostigmine) in the management of CMSs. These therapies can greatly modify the prognosis of patients suffering from this orphan disease.Classification of Evidence:This study provides Class IV evidence that for patients with congenital myasthenic syndromes, some innovative treatments are effective.

La comorbidité est un domaine d’intérêt croissant dans la sclérose en plaques (SEP). De nombreuses études ont rapporté un taux élevé, notamment avec d’autres maladies, en particulier les maladies auto-immunes. Le but de cette étude est de déterminer le nombre et le type de comorbidités associés à la sclérose en plaques (SEP) chez nos patients. Sur une base de données comportant 400 patients SEP suivis au service de neurologie du CHU Mustapha entre l’année 2012 et 2016, nous avons déterminé le nombre de patients ayant une ou plusieurs autres pathologies associées à la SEP et le type de comorbidité. Ces patients ont été comparés au groupe de patients sans comorbidités. Sur les 400 patients, 60 (15 %) patients ont présenté au moins une comorbidité. Il s’agit de 46 femmes et 14 hommes, l’âge moyen est de 46,4 ans au moment de l’extraction des données. L’hypertension artérielle est retrouvée chez 7 % des patients, une dysthyroïdie (4,5 %), le diabète (5,5 %), les cancers (1,2 %), et les maladies auto-immunes (3 %). Le délai diagnostique était plus grand chez les patients avec comorbidité. Au total, 41,6 % des patients ont un EDSS supérieur ou égale à 4 et un MSSS à 4,68. Dans notre série, 15 % des patients SEP présentent une comorbidité, dont 3 % de maladies auto-immunes. La sévérité de la maladie était plus importante dans le groupe avec comorbidités. L’existence de comorbidités associée à la SEP retarde le diagnostic de la maladie, avec des répercussions néfastes sur la démarche diagnostique, l’évolution et la prise en charge de la maladie.

Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3−/− and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR–Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function. Homozygous loss-of-function variants in phospholipase A/acyltransferase 3 (PLAAT3) underlie a new lipodystrophy syndrome. Functional studies link PLAAT3 loss with peroxisome proliferator-activated receptor gamma (PPARγ)-mediated defects in white adipose tissue differentiation and function.

Objective: To assess the availability of health workers and medications for clinical management of amyotrophic lateral sclerosis (ALS) in African hospital centers. Availability and affordability analyses of disease-modifying treatments were performed. Methods: A multicenter observational study involving African hospitals was conducted. A standard questionnaire was developed based on the European Federation of the Neurological Societies (EFNS) guidelines. We collected data on multidisciplinary care and availability of medicines. The availability and affordability were evaluated according to the WHO guidelines. Results: Nine hospital centers from eight African countries participated. We observed a low degree of implementation of multidisciplinary care in ALS management. Riluzole was only available in centers from South Africa, Senegal, Tunisia, and Togo. This treatment was unaffordable and the adjusted price was highly variable among countries. The cost of riluzole was partly or fully covered by patients, which implies a substantial economic burden. Conclusion: Our findings strengthen the need to promote multidisciplinary care in the clinical management of ALS in Africa. Disease-modifying medication should be both available and affordable. Local and international collaboration is needed to improve ALS health care access in Africa.

La maladie de Krabbe est une affection lysosomale autosomique récessive, liée à un déficit en galactosylceramidase par mutation du gène GALC, occasionnellement causée par une mutation du gène prosaposine (PSAP). Il s'agit d'un nourrisson de cinq mois, de sexe féminin, d'origine syrienne, issue d'un mariage consanguin, née sans aucun incident. On note dans la fratrie, un garçon décédé à l'âge d'un an dans un tableau d'encéphalopathie progressive et un mort in utero à 8 mois de gestation. À la naissance, une hypotonie généralisée a été constatée. Depuis l'âge de trois mois, elle présentait une hypersensibilité aux bruits et au toucher, des contractions des membres et des pleurs incessants. L'examen neurologique a retrouvé un contact pauvre, une hypotonie axiale et une légère spasticité des membres. L'évolution s'est faite rapidement vers un état grabataire et décès à l'âge de 9 mois par détresse respiratoire. Les examens complémentaires ont révélé une atrophie cortico-sous-corticale sus tentorielle à la spéctro-IRM cérébrale réalisée au début de la maladie, de petites calcifications cérébrales profondes bilatérales au scanner, un taux de galactocérébrosidase légèrement réduit, une hyperprotéinorachie, une choroïdose et une neuropathie démyélinisante. L'étude moléculaire par séquençage de l'exome a révélé la présence homozygote de la mutation : c.207_209del (p.Val70del) du gène PSAP. Nous rapportons le cas d'un nourrisson originaire du moyen Orient qui a présenté un tableau clinique évocateur de maladie de Krabbe. Le séquençage de l'exome a révélé une mutation du gène PSAP responsable d'un variant génétique de cette maladie par déficit en saposine-A. Il s'agit d'une entité exceptionnelle d'encéphalopathie infantile précoce, quelques cas seulement sont rapportés dans la littérature. La maladie de Krabbe liée au gène PSAP est extrêmement rare. Il est fortement recommandé d'évoquer ce diagnostic devant tout tableau de maladie de Krabbe non liée au gène GALC.

Multiple sclerosis (MS) is a multifactorial disease implicating environmental factors and genetic susceptibility. The objective of this study is to describe the clinical and genetic characteristics of familial forms of MS and comparing them to sporadic forms.

Movement Disorders Clinical PracticeVolume 9, Issue 2 p. 268-271 LETTERS: GENOTYPE AND PHENOTYPEFree Access Heterozygous EIF2AK2 Variant Causes Adolescence-Onset Generalized Dystonia Partially Responsive to DBS Francesca Magrinelli MD, Corresponding Author Francesca Magrinelli MD [email protected] orcid.org/0000-0003-4706-6245 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy Correspondence to: Dr. Francesca Magrinelli, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology University College London, Queen Square, London WC1N 3BG, UK; E-mail: [email protected]Search for more papers by this authorDalila Moualek MD, Dalila Moualek MD Service de Neurologie, CHU Mustapha Bacha, Alger, Algeria Laboratoire de Recherche en Neurosciences, Université Benyoucef Benkhedda, Alger, AlgeriaSearch for more papers by this authorMeriem Tazir MD, Meriem Tazir MD Service de Neurologie, CHU Mustapha Bacha, Alger, Algeria Laboratoire de Recherche en Neurosciences, Université Benyoucef Benkhedda, Alger, AlgeriaSearch for more papers by this authorLamia Ali Pacha MD, Lamia Ali Pacha MD Service de Neurologie, CHU Mustapha Bacha, Alger, Algeria Laboratoire de Recherche en Neurosciences, Université Benyoucef Benkhedda, Alger, AlgeriaSearch for more papers by this authorAlice Verghese MBBS, MRCP, Alice Verghese MBBS, MRCP Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this authorKailash P. Bhatia MD, DM, FRCP, Kailash P. Bhatia MD, DM, FRCP orcid.org/0000-0001-8185-286X Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this authorReza Maroofian PhD, Reza Maroofian PhD Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this authorHenry Houlden MD, PhD, Henry Houlden MD, PhD orcid.org/0000-0002-2866-7777 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this author Francesca Magrinelli MD, Corresponding Author Francesca Magrinelli MD [email protected] orcid.org/0000-0003-4706-6245 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy Correspondence to: Dr. Francesca Magrinelli, Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology University College London, Queen Square, London WC1N 3BG, UK; E-mail: [email protected]Search for more papers by this authorDalila Moualek MD, Dalila Moualek MD Service de Neurologie, CHU Mustapha Bacha, Alger, Algeria Laboratoire de Recherche en Neurosciences, Université Benyoucef Benkhedda, Alger, AlgeriaSearch for more papers by this authorMeriem Tazir MD, Meriem Tazir MD Service de Neurologie, CHU Mustapha Bacha, Alger, Algeria Laboratoire de Recherche en Neurosciences, Université Benyoucef Benkhedda, Alger, AlgeriaSearch for more papers by this authorLamia Ali Pacha MD, Lamia Ali Pacha MD Service de Neurologie, CHU Mustapha Bacha, Alger, Algeria Laboratoire de Recherche en Neurosciences, Université Benyoucef Benkhedda, Alger, AlgeriaSearch for more papers by this authorAlice Verghese MBBS, MRCP, Alice Verghese MBBS, MRCP Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this authorKailash P. Bhatia MD, DM, FRCP, Kailash P. Bhatia MD, DM, FRCP orcid.org/0000-0001-8185-286X Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this authorReza Maroofian PhD, Reza Maroofian PhD Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this authorHenry Houlden MD, PhD, Henry Houlden MD, PhD orcid.org/0000-0002-2866-7777 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, United KingdomSearch for more papers by this author First published: 10 November 2021 https://doi.org/10.1002/mdc3.13371Citations: 2 Relevant disclosures and conflicts of interest are listed at the end of this article. AboutSectionsPDF 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 Eukaryotic translation initiation factor 2-alpha kinases (EIF2AK) are serine–threonine kinases involved in integrated stress response, a cytoprotective pathway which ensures adaptation of mammalian cells to stress conditions.1 Among the four members of this protein family, EIF2AK2, also known as Protein Kinase R, is activated by double-stranded RNA (primarily during viral infections), oxidative stress, endoplasmic reticulum (ER) stress, cytokines, and growth factors.2 By phosphorylating Eukaryotic Translation Initiation Factor 2 Subunit 1 (EIF2S1) in response to cellular stressors, EIF2AK2 negatively regulates mRNA translation and protein synthesis and induces apoptosis.1, 2 De novo missense variants in the EIF2AK2 gene were first linked to a complex neurological syndrome characterized by developmental delay, language impairment, various combinations of motor manifestations (including cerebellar, pyramidal, and dystonic features), and brain MRI abnormalities (encompassing dysmyelination, thin corpus callosum, and cerebral and/or vermian atrophy) in nine unrelated children in 2020.3 Intriguingly, all individuals with EIF2AK2 variants exhibited neurological deterioration in the context of febrile illness or infection.3 In 2021, Kuipers, Musacchio, and respective colleagues reported 13 individuals from six pedigrees carrying heterozygous (autosomal dominantly inherited or de novo) or homozygous EIF2AK2 missense variants which cause early-onset, mostly isolated, generalized dystonia likely through a gain-of-function mechanism.4, 5 In order to replicate the association between EIF2AK2 mutations and isolated dystonia phenotypes, we retrieved our internal database of approximately 18,000 exomes (522 belonging to subjects recruited under the diagnostic category "dystonia") and the 100,000 Genomes Project repository (1116 participants enrolled using the Human Phenotype Ontology term "dystonia") searching for EIF2AK2 variants previously found in dystonia patients and other rare variants. The missense variant NM_001135651(EIF2AK2):c.388G>C (p.Gly130Arg) was detected in the heterozygous state in a 28-year-old Algerian male who underwent whole-exome sequencing (WES) for adolescence-onset generalized dystonia with leg involvement.7 He was healthy until age 17, when he presented with dystonic posturing of the first two left fingers. Four years later he developed right hand tremor while performing fine manual tasks. Tremor spread to the head and contralateral hand over few months. At this time, he started experiencing chewing and gait difficulties and abnormal trunk posture on walking, which was alleviated by trunk anteflexion, walking backwards, carrying a heavy load, or running. His past medical history included myopia and scoliosis. There was no history of exposure to dopamine receptor antagonists. He was the eldest of five siblings born to non-consanguineous parents. His family history was negative for neurological disorders. On examination (Fig. 1A; Video 1), he had dysarthria and generalized dystonia mainly affecting the trunk and arms. Truncal dystonia showed extensor and torsional components on walking. No parkinsonian, pyramidal, cerebellar, or cognitive signs were detected. Serum copper and ceruloplasmin, iron profile, vitamin E, brain MRI and NCS/EMG were unremarkable. Dystonia did not respond to levodopa nor trihexyphenidyl but showed a 40% improvement in severity from baseline with deep brain stimulation (DBS) of the globus pallidus internus (age 24; Video 1) over a 3-year period. Prior to WES, the patient had been tested negative for TOR1A and THAP1 through single gene testing. On WES, we did not identify any other potential candidate variants in genes linked to monogenic movement disorders (MD). We acknowledge that no quantitative genetic testing was performed to rule out variants in MD-related genes potentially missed due to next-generation sequencing intrinsic limitations. Segregation analysis revealed the proband's parents did not carry the EIF2AK2 mutation detected, which is therefore assumed de novo according to the American College of Medical Genetics and Genomics (ACGM) guidelines (maternity and paternity not genetically confirmed; Fig. 1B).8 FIG. 1Open in figure viewerPowerPoint (A) Video frames showing the proband with prominent upper limb and truncal dystonia, the latter having extensor and torsional components on walking. (B) Family tree and segregation analysis revealing the NM_001135651(EIF2AK2):c.388G>C (p.Gly130Arg) missense variant occurred in the heterozygous state only in the proband (II-1). The DNA region of interest was amplified bidirectionally using the following primers (5′→3′): F-catggggaattacataggcct and R-gtggcaccctgtactctctt, with an amplicon size of 385 base pairs. Electropherograms were analyzed using the Sequencher software package. Arrow: proband. WT: wild type. Bottom right. Interspecies alignment showing lack of evolutionary conservation of the amino acid involved by the variant. (C) Functional analysis of the EIF2AK2 variant herein reported. ACMG: American College of Medical Genetics and Genomics; CADD: Combined Annotation Dependent Depletion (https://cadd.gs.washington.edu/snv); HSF: Human Splicing Finder (https://hsf.genomnis.com/home); MutationTaster (http://www.mutationtaster.org/); MutPred2 (http://mutpred.mutdb.org); PolyPhen-2: Polymorphism Phenotyping v2 (http://genetics.bwh.harvard.edu/pph2/); PROVEAN: Protein Variation Effect Analyzer (http://provean.jcvi.org/index.php); SIFT: Sorting Intolerant From Tolerant (http://sift.bii.a-star.edu.sg). This video cannot be streamed at this time, please download the video instead. VideoDownload Video (.mp4 142.7MB) First segment. The proband (age 23) presented with dysarthria and dystonia mainly affecting the trunk and arms. Truncal dystonia worsened on walking, with extensor and torsional components. Dystonic posturing of the upper limbs while writing. Second segment. The proband (age 24) with truncal dystonia. Third segment. The proband (age 27) after undergoing DBS of the globus pallidus internus at age 24 showed improvement of dysarthria, upper limb and truncal dystonia, and gait. The EIF2AK2 variant herein reported consists in a novel nucleotide change (NM_001135651:c.388G>C) causing the same amino acid substitution p.Gly130Arg previously reported in 10 affected individuals from four pedigrees who however carried a guanosine-to-adenosine substitution at the same position (NM_001135651:c.388G>A), which is due to codon redundancy.4, 5 The mutation is absent in the population database gnomAD (https://gnomad.broadinstitute.org/) and predicted benign/tolerated by most in silico tools, including a low Combined Annotation Dependent Depletion (CADD) score (Fig. 1C). This likely reflects intrinsic limitations of pathogenicity prediction algorithms when examining regions with poor evolutionary conservation, as is the case of this amino acid residue (Fig. 1B).4 The variant is pathogenic according to ACGM guidelines.8 No other rare EIF2AK2 variants associated with isolated dystonia phenotypes were identified by screening the above-mentioned datasets (Supplementary File S1). Our case further supports the inclusion of EIF2AK2 mutation analysis in the diagnostic workup of early-onset isolated generalized dystonia, including sporadic cases.4 Furthermore, it confirms that DBS is an effective treatment for EIF2AK2-associated dystonia.4, 5 Although triggers or precipitating factors were not identifiable in our patient's history and clinical course, the association between EIF2AK2 variants and dystonia might directly link inflammatory or infectious events and phenotypic expression of dystonia in patients with causative (incompletely penetrant) or predisposing genetic makeup, thereby unveiling one of the molecular underpinnings of gene-environmental interaction in dystonia pathogenesis.9 Defective EIF2S1 signaling pathway is the shared pathobiological mechanism on which not only EIF2AK2 mutations but also other monogenic causes of dystonia, including DYT-TOR1A, DYT-THAP1, DYT-PRKRA, and DYT-SGCE converge, either directly or indirectly.4, 10 In addition, since the EIF2S1 pathway plays a role in regulating neuronal long-term synaptic plasticity, EIF2AK2 variants might represent a direct link between ER stress and aberrant synaptic plasticity, which is a well-recognized pathophysiological mechanism of dystonia.11 Finally, we speculate that EIF2AK2(NM_001135651) nucleotide 388 might be critical for EIF2AK2-related dystonia since a variant at this level segregates with the phenotype in five out of seven kindreds hitherto reported, including the present one. Further evidence is warranted to establish whether the corresponding codon or, more broadly, the second double-stranded RNA binding motif of EIF2AK2 might represent a mutational hotspot for EIF2AK2-associated dystonia.4 Acknowledgments The authors would like to thank the patient and his family for participating in this study. The Authors are grateful to Clarissa Rocca and David Murphy (UCL Queen Square Institute of Neurology, University College London, London, United Kingdom) for their valuable bioinformatic support as well as to Dr Eoin Mulroy (UCL Queen Square Institute of Neurology, University College London, London, United Kingdom) for his kind support with post-DBS assessment. Author Roles (1) Research project: A. Conception, B. Organization, C. Execution; (2) Data Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. F.M.: 1A, 1B, 1C, 2B, 3A D.M.: 1B, 1C, 3B M.T.: 1B, 1C, 3B L.A.P.: 1B, 1C, 3B A.V.: 3B K.P.B.: 1C, 2C, 3B R.M.: 1A, 1B, 1C, 2C, 3B H.H.: 1C, 2C, 3B Disclosures Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have obtained the patient consent for genetic testing on a research basis as well as for video acquisition and publication. Funding Sources and Conflicts of Interest: Biological samples from the family here reported were collected as part of the SYNaPS Study Group collaboration funded by The Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA) and research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: Francesca Magrinelli is supported by the Edmond J Safra Foundation and by the research grant "Fondo Gianesini" in collaboration with UniCredit Foundation and University of Verona, Italy. Kailash P. Bhatia has received grant support from Welcome/MRC, NIHR, Parkinson's UK and EU Horizon 2020. He receives royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008), of Marsden's Book of Movement Disorders (Oxford University Press, 2012), and of Case Studies in Movement Disorders–Common and uncommon presentations (Cambridge University Press, 2017). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals and from the American Academy of Neurology and the International Parkinson's Disease and Movement Disorders Society. Henry Houlden is funded by The MRC (MR/S01165X/1, MR/S005021/1, G0601943), The National Institute for Health Research University College London Hospitals Biomedical Research Centre, Rosetree Trust, Ataxia UK, MSA Trust, Brain Research UK, Sparks GOSH Charity, Muscular Dystrophy UK (MDUK), Muscular Dystrophy Association (MDA USA). Supporting Information Filename Description mdc313371-sup-0001-supinfo.pdfPDF document, 156.6 KB Supplementary File S1 Rare EIF2AK2 variants identified by screening our internal exome database and the rare disease sub-cohort of the 100,000 Genomes Project. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. References 1Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science 2020; 368(6489): 1– 11. 2Krishna KH, Kumar MS. Molecular evolution and functional divergence of eukaryotic translation initiation factor 2-alpha kinases. PLoS One 2018; 13(3):e0194335. 3Mao D, Reuter CM, Ruzhnikov MRZ, et al. De novo EIF2AK1 and EIF2AK2 variants are associated with developmental delay, leukoencephalopathy, and neurologic decompensation. Am J Hum Genet 2020; 106(4): 570– 583. 4Kuipers DJS, Mandemakers W, Lu CS, et al. EIF2AK2 missense variants associated with early onset generalized dystonia. Ann Neurol 2021; 89(3): 485– 497. 5Musacchio T, Zech M, Reich MM, Winkelmann J, Volkmann J. A recurrent EIF2AK2 missense variant causes autosomal-dominant isolated dystonia. Ann Neurol 2021; 89(6): 1257– 1258. 6Köhler S, Gargano M, Matentzoglu N, et al. The human phenotype ontology in 2021. Nucleic Acids Res 2021; 49(D1): D1207– D1217. 7Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: a consensus update. Mov Disord 2013; 28(7): 863– 873. 8Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5): 405– 424. 9Magrinelli F, Balint B, Bhatia KP. Challenges in clinicogenetic correlations: one gene - many phenotypes. Mov Disord Clin Pract 2021; 8(3): 299– 310. 10Gonzalez-Latapi P, Marotta N, Mencacci NE. Emerging and converging molecular mechanisms in dystonia. J Neural Transm (Vienna) 2021; 128(4): 483– 498. 11Balint B, Mencacci NE, Valente EM, et al. Dystonia. Nat Rev Dis Primers 2018; 4(1): 25. Citing Literature Volume9, Issue2February 2022Pages 268-271 This article also appears in:Genotype and Phenotype Letters FiguresReferencesRelatedInformation

Multiple sclerosis (MS) is the most common chronic progressive and disabling neurological disease of the CNS. It has many impacts on social, family and professional life. These repercussions have often been discussed in terms of quality of life. The purpose of this study is to assess quality of life, fatigue, and depression in MS patients.

1Service de Neurologie, EHS El Maham Cherchell, Tipaza, Algérie. 2Centre de référence neuromusculaire, APHP, Hôpital Henri Mondor, Université Paris Est, U955 INSERM, IMRB, France. 3Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia. 4Laboratoire Central, CHU Mustapha, Alger, Algérie. 5Service de Neurologie, CHU Mustapha, Université Youcef Benkhedda, Alger Algérie. 6Institut de Myologie, Paris, France. edoardo.malfatti@aphp.fr Introduction

La neuromyélite optique de Devic (NMO) et les syndromes liés aux anti-myelin oligodendrocyte glycoprotein (MOG) sont des affections à médiation immunitaire. Nous rapportons deux cas de NMO et de MOGopathie associés à un cancer mammaire et gastrique. Mme D.O., 45 ans présenta une névrite optique bilatérale sévère et une myélite aiguë transverse longitudinalement étendue, la recherche d’anticorps anti-aquaporine 4 (AQP4) était positive signant le diagnostic de neuromyélite optique de Devic, le bilan avait concomitamment retrouvé un adénocarcinome évolutif du sein gauche jusque là méconnu, un traitement par immunothérapie associé à un traitement carcinologique ont permis le contrôle des troubles neurologiques. Mme T.K., 40 ans présenta un syndrome sensitif des quatre membres associé à un signe de Lhermitte, l’IRM cérébrale et médullaire ont mis en évidence une image en hyperT2 flair de la région bulbo-medullaire. Le diagnostic de MOGopathie a été retenu sur la positivité des anticorps anti-MOG, le bilan étiologique permit la découverte d’un cancer gastrique métastatique évolutif. Si de rares cas de NMO ont été occasionnellement décrits en association avec un cancer, principalement une néoplasie du sein, de la thyroïde et des tumeurs neuroendocrines, aucun cas de MOG+ n’ a été décrit associé à un cancer chez l’adulte ou chez l’enfant. les anti-aquaporines 4 peuvent refléter dans certains cas de NMO une réponse immunitaire paranéoplasique, pourrait-il en être de même pour les anti-MOG ? L’utilité clinique de rechercher un cancer dans ces deux entités reste justifiée.

Congenital myasthenic syndromes (CMS) represent phenotypically and genotypically very heterogeneous conditions. No less than 32 genes have been identified to date. CMS caused by mutations in the COL13A1 gene are very rare and have a phenotype described as severe. We present the first case of CMS described in Algeria and the Maghreb with a mutation of this gene.

Les myopathies génétiques représentent un groupe très hétérogène d’affections associant classiquement un déficit musculaire des ceintures mais aussi d’autres manifestations très variées comprenant l’insuffisance respiratoire, la cardiomyopathie, les contractures et ou les hyperlaxités ligamentaires voire des atteintes extramusculaires. Le diagnostic et le démembrement des différentes formes sont un challenge en pratique courante. Nous rapportons l’observation d’une famille consanguine comportant 5 patients atteints, caractérisée par une grande variabilité intrafamiliale associant trois phénotypes distincts : un syndrome d’Ehlers Danlos type cardiaque valvulaire chez le propositus et le frère aîné âgés respectivement de 36 ans et 60 ans, un phénotype LGMD ayant débuté à l’âge de 18 ans chez le 3éme frère âgé de 53 ans associé à une atteinte cardiaque polyvalvulaire atypique et un tableau d’intolérance à l’effort chez les deux sœurs. Ce polymorphisme clinique moteur et cardiaque au sein d’une même famille rendait le diagnostic difficile. Le dosage de l’acide alpha glucosidase par DBS était bas chez le patient porteur du phénotype LGMD avec identification de deux mutations génétiques pathogènes par PCR- amplification et séquençage du gene GAA, confirmant ainsi le diagnostic de maladie de Pompe tardive. Ces mêmes mutations étaient absentes chez les autres membres atteints de la famille. L analyse par exome chez le propositus ne retrouva pas de variants dans le gène Col1A2 habituellement délétère dans le syndrome d’Ehlers-Danlos cardiaque valvulaire mais un variant dans le gène ALX4,dont la pathogenicité devra être confirmée, a été identifié. Les mutations de ce gène sont responsables de différents syndromes malformatifs chez l’enfant incluant le syndrome de Potocki-shaffer, le syndrome de dysplasie frontonasale et la scaphocephalie isolée. L’approche diagnostique des myopathies génétiques, caractérisées par un large spectre clinique parfois au sein d’une même famille, est très complexe. Si l’analyse clinique reste indispensable, les techniques modernes de biologie moléculaire ne suffisent pas à elles seules à résoudre ce challenge diagnostique. Cette famille illustre toute la complexité diagnostique rencontrée en pratique courante par le clinicien dont l’ approche doit être consensuelle et parfois dogmatique en évoquant par exemple la maladie de Pompe, vu sa relative curabilité, devant tout tableau de myopathie non étiquetée.

Background: The demographic aging of the Algerian population increases the risk of some age-related pathologies, including dementia. It is one of the most significant public health problems. The prevalence of dementia and risk factors has not been fully investigated in Algeria. This study aims to improve the knowledge of dementia in Algiers by determining its risk factors, allowing to enrich its epidemiology and social aspects. Methods: A cross-sectional, door-to-door study in the Department of Sidi M’Hamed in Algiers “Algeria», conducted in general population, was carried out between June 2012 and August 2014. The clinical diagnosis of dementia was made according to the Diagnostic and Statistical Manual of Mental Disorders,4th Edition (DSM-IV) criteria. Possible or probable cases of Alzheimer’s Disease (AD), Mixed Dementia (MD), Vascular Dementia (VD), Frontotemporal Dementia (FTD), Parkinson’s Dementia (PD), and other dementias were identified using standard criteria. Sociodemographic characteristics, lifestyle and the pathological history were recorded. Results: 3896 subjects aged 60 years and over participated in the study. Among them, 192 had dementia. Factors strongly associated with dementia in the department of Sidi M’Hamed were advanced age, living alone, widowhood, low cultural level, family history of dementia, high blood pressure and stroke (p<10−6). Conclusion: Greater age, low social raise, low level of education and vascular risk factors (stroke and high blood pressure) increase the risk of suffering from dementia. Other more extensive studies should be conducted, both in rural and urban areas of Algeria, in order to consider comprehensive management solutions and prevention approaches adapted to our context.