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Resume Nous rapportons le cas d’un homme de 59 ans, pris en charge a son domicile dans un contexte de syndrome confusionnel et de crise tonicoclonique generalisee, chez lequel le diagnostic d’intoxication par l’ethylene glycol a ete etabli a l’issue de l’examen histopathologique postmortem des organes. L’intoxication par l’ethylene glycol est rare, avec une centaine de cas rapportes chaque annee en France. L’ethylene glycol est un liquide incolore et inodore principalement retrouve dans les liquides de refroidissement pour automobiles. Le diagnostic d’intoxication par l’ethylene glycol est souvent difficile et tardif, notamment en raison de l’existence d’un intervalle libre de plusieurs heures entre l’ingestion du toxique et la survenue des premiers symptomes. La toxicite de l’ethylene glycol est liee a la production de metabolites toxiques responsables d’une acidose metabolique a trou anionique augmente expliquant la majeure partie de la symptomatologie a la phase aigue. Histologiquement l’intoxication par l’ethylene glycol se manifeste par un tableau d’oxalose systemique, caracterisee par la presence d’abondants depots tissulaires de cristaux d’oxalate de calcium birefringents et irises en lumiere polarisee. L’aspect microscopique de ces cristaux ainsi que leurs distributions sont pathognomoniques d’une oxalose sans que l’examen histologique ne permette d’en determiner l’etiologie precise. En raison de sa presentation clinique et biologique parfois trompeuse, le diagnostic d’intoxication par l’ethylene glycol n’est parfois etabli qu’a l’issue d’un examen autopsique.

We aim to perform ultrastructural and histopathological analysis of muscle biopsies from a large group of systemic sclerosis (SSc) patients, including some with early/mild SSc features, and examine whether capillary pathology differentiates 'scleromyositis' (SM) from other auto-immune myositis (AIM) subsets.Muscle biopsies from a total of 60 SM patients and 43 AIM controls from two independent cohorts were examined by electron microscopy, collagen-4 immunofluorescence (Col4IF) and routine light microscopy.Ultrastructural examination revealed prominent capillary basement membrane (BM) reduplication (4+ layers in50% of capillaries) in 65% of SM vs 0% of AIM controls (p 0.001). In SM cases without prominent BM reduplication, capillary dilation was the most distinctive feature, present in 8% of capillaries in SM vs 2% in controls (p = 0.001). Accumulation of ensheathed pericyte processes was another characteristic feature of SM and closely correlated with the degree of BM reduplication (r = 0.833, p 0.001). On light microscopy, BM marker Col4IF revealed more frequent capillary enlargement in SM than in controls (84% vs 21%, p 0.001). SM cases were classified as non-inflammatory myopathy (36%), non-specific myositis (33%) or immune-mediated necrotizing myopathy (31%), but despite this histopathological heterogeneity, prominent BM reduplication remained a constant finding. In the 16 SM patients with early/mild SSc features, 63% showed prominent BM reduplication.These results show that capillary pathology, and in particular prominent capillary BM reduplication, is the hallmark histopathological feature of SM even in patients with early/mild SSc and support the concept of SM as an organ manifestation of SSc and a distinct subset of AIM.

Background: The dystonias are a heterogeneous group of hyperkinetic disorders characterized by sustained or intermittent muscle contractions that cause abnormal movements and/or postures. Although more than 200 causal genes are known, many cases of primary dystonia have no clear genetic cause.Objectives: To identify the causal gene in a consanguineous family with three siblings affected by a complex persistent generalized dystonia, generalized epilepsy, and mild intellectual disability.Methods: We performed exome sequencing in the parents and two affected siblings and characterized the expression of the identified gene by immunohistochemistry in control human and zebrafish brains.Results: We identified a novel missense variant (c.142G>A (NM_032192); p.Glu48Lys) in the protein phosphatase 1 regulatory inhibitor subunit 1B gene (PPP1R1B) that was homozygous in all three siblings and heterozygous in the parents. This gene is also known as dopamine and cAMP-regulated neuronal phosphoprotein 32 (DARPP-32) and has been involved in the pathophysiology of abnormal movements. The uncovered variant is absent in public databases and modifies the conserved glutamate 48 localized close to the serine 45 phosphorylation site. The PPP1R1B protein was shown to be expressed in cells and regions involved in movement control, including projection neurons of the caudate-putamen, substantia nigra neuropil, and cerebellar Purkinje cells. The latter cells were also confirmed to be positive for PPP1R1B expression in the zebrafish brain.Conclusions: We report the association of a PPP1R1B/DARPP-32 variant with generalized dystonia in man. It might be relevant to include the sequencing of this new gene in the diagnosis of patients with otherwise unexplained movement disorders. © 2021 International Parkinson and Movement Disorder Society.

Ethylene glycol poisoning is relatively rare, with around a hundred cases reported each year in France. Its diagnosis is often challenging and delayed because of a several hours' free interval between ingestion of the toxic and the onset of the first symptoms. Ethylene glycol is a colorless and odorless liquid primarily found in automotive coolants, whose toxicity is linked to its hepatic metabolites. Histologically, ethylene glycol poisoning is characterized by abundant tissular deposits of calcium oxalate crystals. Under polarized light, these crystals appear birefringent and iridescent. Their microscopic appearance and their distribution are pathognomonic of oxalosis. Due to its frequent misleading presentation, the diagnosis of ethylene glycol poisoning is sometimes only made after an autopsy. Hereafter, we report the case of a 59-year-old man diagnosed with ethylene glycol intoxication after a post-mortem histopathological examination of organs.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C). 163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C. A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found. Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.

Cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) is a recessively inherited multisystem ataxia compromising cerebellar, vestibular, and sensory nerves, which has been associated to a pathogenic AAGGG(n) biallelic expansion repeat in the RFC1 gene. Our objective was to assess its prevalence in a French cohort of patients with idiopathic sporadic late-onset ataxia (ILOA), idiopathic early-onset ataxia (IEOA), or Multiple System Atrophy of Cerebellar type (MSA-C).163 patients were recruited in 3 French tertiary centers: 100 ILOA, 21 IEOA, and 42 patients with possible or probable MSA-C.A pathogenic biallelic RFC1 AAGGG(n) repeat expansion was found in 15 patients: 15/100 in the ILOA group, but none in the IEOA and MSA-C subgroups. 14/15 patients had a CANVAS phenotype. Only 1/15 had isolated cerebellar ataxia, but also shorter biallelic expansions. Two RFC1 AAGGG(n) alleles were found in 78% of patients with a CANVAS phenotype. In one post-mortem case, the pathophysiological involvement of cerebellum and medullar posterior columns was found.Our study confirms the genetic heterogeneity of the CANVAS and that RFC1 repeat expansions should be searched for preferentially in case of unexplained ILOA associated with a sensory neuronopathy, but not particularly in patients classified as MSA-C.

Objectives To refine the prevalence, characteristics and response to treatment of myositis in primary SS (pSS). Methods The multicentre prospective Assessment of Systemic Signs and Evolution in Sjögren’s Syndrome (ASSESS) cohort of 395 pSS patients with ≥60 months’ follow-up was screened by the 2017 EULAR/ACR criteria for myositis. Extra-muscular complications, disease activity and patient-reported scores were analysed. Results Before enrolment and during the 5-year follow-up, myositis was suspected in 38 pSS patients and confirmed in 4 [1.0% (95% CI: 0.40, 2.6)]. Patients with suspected but not confirmed myositis had higher patient-reported scores and more frequent articular and peripheral nervous involvement than others. By contrast, disease duration in patients with confirmed myositis was 3-fold longer than without myositis. Two of the four myositis patients fulfilled criteria for sporadic IBM. Despite receiving three or more lines of treatment, they showed no muscle improvement, which further supported the sporadic IBM diagnosis. The two other patients did not feature characteristics of a myositis subtype, which suggested ‘pure’ pSS myositis. Steroids plus MTX was then efficient in achieving remission. Conclusions Myositis, frequently suspected, occurs in 1% of pSS patients. Especially when there is resistance to treatment, sporadic IBM should be considered and might be regarded as a late complication of this disease.

International audience; Objective: Glycogen storage diseases (GSDs) are severe human disorders resulting from abnormal glucose metabolism, and all previously described GSDs segregate as autosomal recessive or X-linked traits. In this study, we aimed to molecularly characterize the first family with a dominant GSD. Methods: We describe a dominant GSD family with 13 affected members presenting with adult-onset muscle weakness, and we provide clinical, metabolic, histological, and ultrastructural data. We performed exome sequencing to uncover the causative gene, and functional experiments in the cell model and on recombinant proteins to investigate the pathogenic effect of the identified mutation. Results: We identified a heterozygous missense mutation in PYGM segregating with the disease in the family. PYGM codes for myophosphorylase, the enzyme catalyzing the initial step of glycogen breakdown. Enzymatic tests revealed that the PYGM mutation impairs the AMP-independent myophosphorylase activity, whereas the AMP-dependent activity was preserved. Further functional investigations demonstrated an altered conformation and aggregation of mutant myophosphorylase, and the concurrent accumulation of the intermediate filament desmin in the myofibers of the patients. Interpretation: Overall, this study describes the first example of a dominant glycogen storage disease in humans, and elucidates the underlying pathomechanisms by deciphering the sequence of events from the PYGM mutation to the accumulation of glycogen in the muscle fibers. ANN NEUROL 2020;88:274–282.

International audience

Objective Within a complex systems biology perspective, we wished to assess whether hippocampi with established neuropathological features have distinct metabolome. Apparently normal hippocampi with no signs of sclerosis (noHS), were compared to hippocampal sclerosis (HS) type 1 (HS1) and/or type 2 (HS2). Hippocampus metabolome from patients with epilepsy-associated neuroepithelial tumors (EANTs), namely, gangliogliomas (GGs) and dysembryoplastic neuroepithelial tumors (DNTs), was also compared to noHS epileptiform tissue. Methods All patients underwent standardized temporal lobectomy. We applied 1 H high-resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) spectroscopy to 48 resected human hippocampi. NMR spectra allowed quantification of 21 metabolites. Data were analyzed using multivariate analysis based on mutual information. Results Clear distinct metabolomic profiles were observed between all studied groups. Sixteen and 18 expected metabolite levels out of 21 were significantly different for HS1 and HS2, respectively, when compared to noHS. Distinct concentration variations for glutamine, glutamate, and N-acetylaspartate (NAA) were observed between HS1 and HS2. Hippocampi from GG and DNT patients showed 7 and 11 significant differences in metabolite concentrations when compared to the same group, respectively. GG and DNT had a clear distinct metabolomic profile, notably regarding choline compounds, glutamine, glutamate, aspartate, and taurine. Lactate and acetate underwent similar variations in both groups. Significance HRMAS NMR metabolomic analysis was able to disentangle metabolic profiles between HS, noHS, and epileptic hippocampi associated with EANT. HRMAS NMR metabolomic analysis may contribute to a better identification of abnormal biochemical processes and neuropathogenic combinations underlying mesial temporal lobe epilepsy.

Introduction Le cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS) correspond a une ataxie plurisystemique, de transmission recessive, associee a une expansion biallelique pathogene AAGGG(n) dans le gene RFC1. Objectifs Notre objectif etait d’evaluer la prevalence de cette expansion dans une population francaise de patients ataxiques divises en 3 sous-groupes. Patients et methodes Cent soixante-trois patients ont ete recrutes de maniere prospective dans 3 centres tertiaires francais pour les ataxies, et divises en 3 sous-groupes : 100 ataxies diopathiques de debut tardif (ILOA), 21 ataxies idiopathiques de debut precoce (IEOA) et 42 patients ayant une atrophie multisystematisee de type C (AMS-C) possible or probable. L’âge moyen etait de 55 ans (0–80). Resultats Une expansion biallelique pathogene AAGGG(n) a ete trouvee chez 15 patients (9 %) : tous dans le groupe ILOA (et aucun dans les groupes IEOA et AMS-C). Quatorze sur 15 patients avaient un phenotype CANVAS. Seul 1/15 avait une ataxie cerebelleuse isolee, mais egalement les plus courtes expansions. Une expansion biallelique a ete trouvee chez 14/18 (78 %) des patients ayant un phenotype CANVAS. Une etude post-mortem a confirme l’atteinte du cervelet et des cordons posterieurs medullaires. Discussion Notre etude confirme que le CANVAS doit etre recherche preferentiellement chez les patients presentant une ILOA. Elle pose cependant la question du role de plus courtes expansions AAGGG, qui pourraient etre a l’origine d’un phenotype incomplet. Enfin, elle souligne l’heterogeneite genetique du CANVAS puisque seuls 14/18 cas etaient porteurs de la mutation RFC1. Conclusion Le CANVAS est une cause non exceptionnelle d’ataxie cerebelleuse tardive et doit etre recherche preferentiellement en cas de neuropathie sensitive associee. Des phenotypes incomplets pourraient etre dus a de plus courtes expansions AAGGG.

We aimed to assess stereoelectroencephalography (SEEG) seizure-onset and interictal patterns associated with MRI-negative epilepsy and investigate their possible links with histology, extent of the epileptogenic zone (EZ) and surgical outcome. We retrospectively analysed a cohort of 59 consecutive MRI-negative surgical candidates, who underwent SEEG recordings followed by cortectomy between 2000 and 2016. Most of the eight distinct seizure-onset patterns could be encountered both in confirmed focal cortical dysplasia (FCD) and in histologically non-specific or normal cases. We found strong correlation (p = 0.008) between seizure-onset pattern and histology for: (1) slow-wave/DC-shift prior to low voltage fast activity (LVFA), associated with normal/non-specific histology, and (2) bursts of polyspikes prior to LVFA, exclusively observed in FCD. Three interictal patterns were identified: periodic slow-wave/gamma burst, sub-continuous rhythmic spiking and irregular spikes. Both “periodic” patterns were more frequent in but not specific to FCD. Surgical outcome depended on the EZ complete removal, regardless electrophysiological features. Histologically normal and FCD-associated epileptogenic zones share distinct interictal and ictal electrophysiological phenotypes, with common patterns between FCD subtypes and between dysplastic and apparently normal brain. Some specific seizure-onset patterns seem to be predictive of the underlying histology and may help to detect an MRI-invisible FCD.

Mutations in genes encoding aminoacyl‐tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl‐tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl‐tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments. Here, we report on a patient with severe neurological and neurosensory disease investigated by whole‐exome sequencing and found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val), the second one being novel, in the KARS gene. The patient presented with an atypical clinical presentation with an optic neuropathy not previously reported. At the cellular level, we show that cytoplasmic KARS was expressed at a lower level in patient cells and displayed decreased interaction with MSC. In vitro, these two KARS variants have a decreased aminoacylation activity compared with wild‐type KARS, the p.Pro228Leu being the most affected. Our data suggest that dysfunction of cytoplasmic KARS resulted in a decreased level of translation of the nuclear‐encoded lysine‐rich proteins belonging to the respiratory chain complex, thus impairing mitochondria functions.

Background:Dermatomyositis (DM) is a rare autoimmune muscle disease characterized by an atrophy and a type-I interferon signature in perifascicular fibers. We recently showed that muscle mitochondrial dysfunction is also a characteristic of this disease that participates to both decrease exercise capacity and maintenance of inflammation (1). Pathophysiological mechanisms underlying these characteristics are unknown.Objectives:The objective of this study is to reveal the mechanisms underlying the modifications of perifascicular fibers during DM, taking advantage of a method combining transcriptomic and topographical information.Methods:Fourteen patients with recent (http://david.abcc.ncifcrf.gov) were used to determine the deregulated molecular pathways in the perifascicular fibers during DM.Results:482 transcripts were differently expressed in perifascicular fibers of patients with DM compared to perifascicular fibers of the 2 other groups (348 overexpressed and 134 underexpressed). The most overexpressed transcripts were involved in the type I interferon response while the most underexpressed transcripts were involved in mitochondria and in proteasome functioning. The study of the transcripts differentially expressed in perifasicular versus endofascicular fibers revealed that there is a physiological perifascicular signature: in patients without myopathy, 83 genes were overexpressed and 54 were underexpressed in perifascicular fibers compared to endofascicular fibers. This physiological perifascicular signature was abolished in patient with myositis (DM and other myositis). In the group of patients with DM (but not other myositis), a specific perifascicular signature (18 genes overexpressed and 10 genes underexpressed in perifascicular fibers compared to endofascicular fibers) was identified. The most deregulated transcripts in DM perifascicular fibers were involved in autophagy/mitophagy, mitochondria and proteasome pathways.Conclusion:In the physiological state, perifascicular fibers are characterized by a different transcriptomic profile from endofascicular fibers. During DM, this physiological perifascicular signature is abolished and replaced by a transcriptomic signature that reveal a potential role of proteasome and autophagy deregulation in the pathophysiology of DM.References:[1]Meyer et al. IFN-β-induced reactive oxygen species and mitochondrial damage contribute to muscle impairment and inflammation maintenance in dermatomyositis Acta Neuropathol. 2017;134:655-666.[2]Huang, D. W. et al. The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol 8, R183 (2007).Disclosure of Interests:None declared

Introduction La dermatomyosite (DM) est une maladie autoimmune rare du muscle qui se caracterise par une atrophie et une signature interferon de type 1 dans les fibres perifasciculaires. En analysant l’ensemble du muscle des patients nous avons recemment montre que des dysfonctions mitochondriales musculaires etaient aussi une caracteristique de cette maladie. Les mecanismes physiopathologiques qui sous-tendent ces lesions sont inconnus. L’objectif de ce travail etait de reveler les mecanismes qui sous-tendent les lesions des fibres perifasciculaires au cours de la DM. Patients et methodes Quatorze patients atteints de myosites (DM : n = 7, autres myosites : n = 7), recentes ( Resultats 28 transcrits etaient differentiellement exprimes dans les fibres perifasciculaires des patients atteints DM par rapport aux fibres perifasciculaires des deux autre groupes (18 surexprimes et 10 sous exprimes), Les transcrits les plus surexprimes etaient impliques dans la reponse interferon de type 1 alors les transcrits les plus sous-exprimes etaient impliques dans le fonctionnement de la mitochondrie. L’etude des transcrits differentiellement exprimes dans les fibres perifasciculaires par rapport aux fibres endofasciculaires a montre qu’il existait une signature perifasciculaire physiologique : chez les patients sans myopathie, 83 genes etaient surexprimes et 54 sous-exprimes dans les fibres perifasciculaires par rapport aux fibres endofasciculaires. Cette signature perifasciculaire physiologique etait abolie chez les patients atteints de myosite (DM et autres myosites). Dans le groupe des patients atteint de DM, une signature perifasciculaire specifique (18 genes surexprimes et 10 genes sous-exprimes dans les fibres perifasciculaires par rapport aux endofasciculaires) a ete identifiee. Conclusion A l’etat physiologique, les fibres perifasciculaires se caracterisent par un profil transcriptomique different des fibres endofasciculaires. Au cours de la DM, cette signature perifasciculaire physiologique est abolie et remplacee par une signature transcriptomique specifique a la maladie. Ces resultats ont des implications pour le diagnostic (immunomarquages), la comprehension et l’identification de cibles therapeutiques au cours de la DM.

Most myotilinopathy patients present with a dominant late onset distal phenotype and myofibrillar pathology, although the first MYOT mutation in a family reported to have LGMD phenotype. We report here a French family affected with a late onset proximal and distal muscle weakness and myofibrillar myopathy on muscle pathology, in which the siblings known to be clinically affected were homozygous for the c.179C>T (p.Ser60Phe) myotilin gene mutation. One subjectively asymptomatic member of the family was heterozygous for this mutation. This is the first report of a family with patients being homozygous for a known dominant MYOT mutation. Dominant negative mutations are generally considered not to cause a more severe disease in homozygosity, but our data clearly demonstrate the existence of dominant MYOT mutations with a possible dose effect causing a more severe disease phenotype in homozygosity in the spectrum of myofibrillar myopathies (MFM).

ObjectiveTo refine the predictive significance of muscle granuloma in patients with myositis.MethodsA group of 23 patients with myositis and granuloma on muscle biopsy (granuloma-myositis) from 8 French and Belgian centers was analyzed and compared with (1) a group of 23 patients with myositis without identified granuloma (control-myositis) randomly sampled in each center and (2) a group of 20 patients with sporadic inclusion body myositis (sIBM) without identified granuloma (control-sIBM).ResultsAll but 2 patients with granuloma-myositis had extramuscular involvement, including signs common in sarcoidosis that were systematically absent in the control-myositis and the control-sIBM groups. Almost half of patients with granuloma-myositis matched the diagnostic criteria for sIBM. In these patients, other than the granuloma, the characteristics of the myopathy and its nonresponse to treatment were similar to the control-sIBM patients. Aside from 1 patient with myositis overlapping with systemic sclerosis, the remaining patients with granuloma-myositis did not match the criteria for a well-defined myositis subtype, suggesting pure sarcoidosis. Matching criteria for sIBM was the sole feature independently associated with nonresponse to myopathy treatment in patients with granuloma-myositis.ConclusionPatients with granuloma-myositis should be carefully screened for sIBM associated with sarcoidosis in order to best tailor their care.

Slowly progressive, levodopa-responsive multiple system atrophy (MSA) may be misdiagnosed as Parkinson's disease (PD). Deep brain stimulation (DBS) is mostly ineffective in these patients and may even worsen the clinical course. Here we assessed whether neuropathological differences between patients with MSA who were treated with DBS of the subthalamic nucleus because of a misleading clinical presentation and typical disease cases may explain the more benign disease course of the former, and also the rapid clinical decline after surgery. The post-mortem assessment included the subthalamic nucleus, the globus pallidus, the thalamus and the putamen in five patients with MSA who received DBS and nine typical disease cases. There was no evidence for distinct neuroinflammatory profiles between both groups that could be related to the surgical procedure or that could explain the rapid clinical progression during DBS. Patients who received deep brain stimulation displayed a higher proportion of α-synuclein bearing neuronal cytoplasmic inclusions in the putamen compared with typical cases, while the number of surviving neurons was not different between groups. Our findings suggest that DBS does not induce neuroinflammatory changes in patients with MSA, at least several years after the surgery. We further hypothesize that the peculiar pattern of α-synuclein pathology may contribute to differences in the clinical phenotype, with a greater proportion of neuronal inclusions in the putamen being associated to a milder, "PD-like" phenotype with sustained levodopa response and slower disease progression.

The benign acute childhood myositis presents as a marked and painful oedema of leg muscles in the days following a viral illness. This disease is often considered as occurring only in children. We report the case of a 32-year-old patient who presented with severe pain and oedema of both legs associated with motor deficit of lower extremities. He suffered from a grippal syndrome for 4 days. Creatine kinase blood level rose up to 39 394 IU/L (n

Congenital myopathies are clinically and genetically heterogeneous, and are classified based on typical structural abnormalities on muscle sections. Recessive mutations in the striated muscle preferentially expressed protein kinase (SPEG) were recently reported in patients with centronuclear myopathy (CNM) associated in most cases with dilated cardiomyopathy. Here we report the identification of novel biallelic truncating SPEG mutations in a patient with moderate congenital myopathy without clinical and histological hallmarks of CNM and without cardiomyopathy. This study expands the phenotypic spectrum of SPEG-related myopathy and prompts to consider SPEG for congenital myopathies without specific histological features.

Resume La degenerescence cortico-basale (DCB) est classee parmi les atrophies focales. Elle est tres bien definie sur le plan anatomo-pathologique, et comporte des lesions neuronales et gliales cortico-striatales, marquees par les anticorps anti-tau. Alors que la maladie a ete initialement decrite chez des patients presentant un syndrome essentiellement moteur (rigidite ou dystonie asymetriques, myoclonus focal) et des troubles corticaux plutot parietaux (apraxie unilaterale, troubles sensitifs, main capricieuse), elle se revele tres proteiforme. Les sources de discordance anatomo-cliniques sont telles qu’il est preferable de qualifier le tableau initialement decrit de « syndrome cortico-basal » et de reserver celui de DCB aux cas neuropathologiquement confirmes. Les nouveaux criteres diagnostiques de la DCB probable ou possible sont presentes.

International audience; The management of sporadic late-onset cerebellar ataxias represents a very heterogeneous group of patients and remains a challenge for neurologist in clinical practice. We aimed at describing the different causes of sporadic late-onset cerebellar ataxias that were diagnosed following standardized, exhaustive investigations and the population characteristics according to the aetiologies as well as at evaluating the relevance of these investigations. All patients consecutively referred to our centre due to sporadic, progressive cerebellar ataxia occurring after 40~years of age were included in the prospective, observational study. 80 patients were included over a 2~year period. A diagnosis was established for 52 patients (65%) corresponding to 18 distinct causes, the most frequent being cerebellar variant of multiple system atrophy (n~=~29). The second most frequent cause was inherited diseases (including spinocerebellar ataxias, late-onset Friedreich's disease, SLC20A2 mutations, FXTAS, MELAS, and other mitochondrial diseases) (n~=~9), followed by immune-mediated or other acquired causes. The group of patient without diagnosis showed a slower worsening of ataxia (p~\textless~0.05) than patients with multiple system atrophy. Patients with later age at onset experienced faster progression of ataxia (p~=~0.001) and more frequently parkinsonism (p~\textless~0.05) than patients with earlier onset. Brain MRI, DaT scan, genetic analysis and to some extent muscle biopsy, thoracic-abdominal-pelvic tomodensitometry, and cerebrospinal fluid analysis were the most relevant investigations to explore sporadic late-onset cerebellar ataxia. Sporadic late-onset cerebellar ataxias should be exhaustively investigated to identify the underlying causes that are numerous, including inherited causes, but dominated by multiple system atrophy.

Introduction McArdle disease is a glycogen storage disease caused by mutations in the PYGM gene encoding myophosphorylase. It manifests classically with childhood-onset exercise-induced pain. Methods We report the characteristics of 2 unrelated patients with a new homozygous mutation of the PYGM gene. Results Two patients, aged 76 and 79 years, presented with severe upper and lower limb atrophy and weakness. Additionally, 1 patient presented with bilateral ptosis, and the other with camptocormia. In both patients, symptoms had developed progressively in the 2 preceding years, and there was no history of exercise intolerance. Both patients demonstrated myogenic abnormalities on electromyography, multiple glycogen-containing vacuoles and undetectable muscle myophosphorylase activity on muscle biopsy, and a novel homozygous frameshift p.Lys42Profs*48 PYGM mutation. Conclusions This report expands the phenotype and genotype of McArdle disease and suggests that PYGM mutations should be looked for in patients with very late-onset myopathy with no previous history of exercise intolerance. Muscle Nerve 57: 157–160, 2018

Greater accuracy in clinical descriptions combined with advances in muscle histology and immunology have established that inflammatory myopathies (IMs), similarly to inflammatory rheumatic diseases, constitute a highly heterogeneous group of conditions. The topographic distribution, severity, and tempo of onset of the myopathy vary widely, and the histological findings distinguish at least five different profiles, which may reflect different pathophysiological processes. Most IMs are connective tissue diseases that can affect multiple organs, among which the most common targets are the skin, joints, and lungs. The extramuscular manifestations may antedate the muscular involvement and should therefore suggest a diagnosis of IM even in the absence of obvious muscle disease. About 20 different autoantibodies have been identified in patients with IM. Some are mutually exclusive and associated with specific combinations of clinical manifestations. Following the model of antisynthetase syndrome, about 10 syndromes associated with autoantibodies specific of IM have been identified. Thus, polymyositis is now emerging as a rare entity that is often mistaken for more recently described patterns of IM. No consensus exists to date about the classification of IMs. Nevertheless, the clinical manifestations, autoantibody profile, and muscle histology can be used to distinguish patient subgroups with fairly homogeneous patterns of complications, treatment responses, and outcomes. These subgroups are also characterized by specific genetic and environmental factors. The advances made in the nosology of IMs have benefited the diagnosis, personalization of treatment strategies, and understanding of pathophysiological mechanisms. They can be expected to assist in the development of specific treatments.

Un homme de 67 ans est adresse en Neurologie en raison de troubles du sommeil (parasomnies probables avec deambulations nocturnes) installes insidieusement 4 ans auparavant puis compliques - de facon rapidement progressive - quelques semaines avant l’hospitalisation par : – des troubles de la marche et de l’equilibre entrainant des chutes ; – un declin cognitif et des troubles du comportement ; – des episodes de rupture de contact avec automatismes ; – des myoclonies multifocales et ; – des fasciculations des membres superieurs et inferieurs. Le bilan diagnostique sera partiellement contributif. Suite au deces brutal du patient 2 ans plus tard, l’examen neuropathologique cerebral permettra une premiere conclusion diagnostique. Neanmoins, a la lumiere des connaissances actuelles, le diagnostic sera finalise 8 ans apres le deces grâce a la confrontation des elements clinico-bio-neuropathologiques conserves chez le malade.

Pompe disease is a rare metabolic affection caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase encoded by the GAA gene and responsible for the degradation of lysosomal glycogen [1]. Late-onset Pompe disease (LOPD) develops in adults and is usually limited to myopathy [1]. Cardio-cerebrovascular manifestations have been described in addition to myopathy in LOPD, including heart rythm alterations, left ventricular hypertrophy, and cerebral and aortic dilated arteriopathy [2–4]. Here, we describe for the first time a patient with Pompe disease who presented with a pure vascular phenotype of the disease. A 52-year-old male caucasian patient with no past medical or family history presented with an episode of acute left abdominal pain in 2008. Abdominal magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) demonstrated a left kidney infarct, and bilateral dilative renal and iliac arteriopathy without aortic involvement (Fig. 1). Electrocardiography (EKG) and echocardiography were normal, and treatment with aspirin 160 mg/day was introduced. In 2011, he presented with another episode of acute left abdominal pain, and abdominal MRI demonstrated an enlargement of the previously known left kidney infarct. EKG and echocardiography were normal, and aspirin treatment was replaced with an oral anticoagulant, i.e. fluindione. In 2012, the patient presented with an episode of transitory aphasia. Brain MRI revealed an acute ischemic stroke in the territory of the left middle cerebral artery, and neck MRA showed bilateral dilative carotid and vertebral arteriopathy (Fig. 1). EKG and echocardiography were normal, and treatment with fluindione was maintained. Marfan syndrome, Ehlers– Danlos syndrome and Fabry disease were excluded, and Pompe disease was considered despite the patient presenting with no sign of myopathy, i.e. normal motor examination and normal creatine kinase (CK) levels, echocardiography, pulmonary function tests, and muscle biopsy. Muscle biopsy was processed with standard methods for histology, histochemistry, and electron microscopy, including periodic acid-Schiff (PAS) staining. Motor examination included manual muscle testing, timed tests (time to climb 4 steps, to rise from a chair, and to walk 10 m), motor function measurement (MFM scale), and the 6-min walking test. Acid alpha-glucosidase deficiency was found in blood lymphocytes, cultured skin fibroblasts and skeletal muscle, and the patient was a compound heterozygote for 1 previously reported pathogenic variation in intron 1 of the GAA gene (c.-32-13T[G), and 1 newly described pathogenic variation in exon 6 of the GAA gene (p.V350M, c.1048G[A) (Table 1). Two years follow-up showed no additional cerebral or kidney infarcts with oral anticoagulation. As the patient presented with no myopathy, cardiomyopathy and respiratory insufficiency, enzyme replacement therapy was not considered [5]. This is the first description of a patient with Pompe disease presenting with a generalized dilative arteriopathy V. Quenardelle (&) M. Bataillard V. Wolff A. Echaniz-Laguna Departement de Neurologie, Hopitaux Universitaires de Strasbourg, Hopital de Hautepierre, 67098 Strasbourg, France e-mail: veronique.quenardelle@chru-strasbourg.fr

To investigate whether mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth (CMT) disease.We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2AG in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2AG on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed.Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2AG mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts.We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy.

Spasticity is a common and disabling symptom observed in patients with central nervous system diseases, including amyotrophic lateral sclerosis, a disease affecting both upper and lower motor neurons. In amyotrophic lateral sclerosis, spasticity is traditionally thought to be the result of degeneration of the upper motor neurons in the cerebral cortex, although degeneration of other neuronal types, in particular serotonergic neurons, might also represent a cause of spasticity. We performed a pathology study in seven patients with amyotrophic lateral sclerosis and six control subjects and observed that central serotonergic neurons suffer from a degenerative process with prominent neuritic degeneration, and sometimes loss of cell bodies in patients with amyotrophic lateral sclerosis. Moreover, distal serotonergic projections to spinal cord motor neurons and hippocampus systematically degenerated in patients with amyotrophic lateral sclerosis. In SOD1 (G86R) mice, a transgenic model of amyotrophic lateral sclerosis, serotonin levels were decreased in brainstem and spinal cord before onset of motor symptoms. Furthermore, there was noticeable atrophy of serotonin neuronal cell bodies along with neuritic degeneration at disease onset. We hypothesized that degeneration of serotonergic neurons could underlie spasticity in amyotrophic lateral sclerosis and investigated this hypothesis in vivo using tail muscle spastic-like contractions in response to mechanical stimulation as a measure of spasticity. In SOD1 (G86R) mice, tail muscle spastic-like contractions were observed at end-stage. Importantly, they were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists. In line with this, 5-hydroxytryptamine-2b receptor expression was strongly increased at disease onset. In all, we show that serotonergic neurons degenerate during amyotrophic lateral sclerosis, and that this might underlie spasticity in mice. Further research is needed to determine whether inverse agonists of 5-hydroxytryptamine-2b/c receptors could be of interest in treating spasticity in patients with amyotrophic lateral sclerosis.

Background Mutations of the peripheral myelin protein-22 ( PMP22 ) gene are the most common cause of inherited disease of the peripheral nervous system (PNS), with its deletion resulting in hereditary neuropathy with liability to pressure palsies (HNPP), and its duplication inducing Charcot–Marie–Tooth 1A (CMT1A) disease. Although mainly expressed in the PNS, PMP22 mRNA and protein are also present in the central nervous system (CNS). Objective To investigate whether patients with PMP22 mutations present with CNS abnormalities. Methods Fifteen patients with HNPP and 15 patients with CMT1A disease were prospectively included and their brain MRI and neuropsychological assessment were compared with those of healthy subjects. We evaluated, in particular, the volumes of grey and white matter (GM and WM) and looked for metabolic changes using spectroscopy, and abnormal architecture using fractional anisotropy (FA) measurement. A post mortem examination of the CNS of a patient with PMP22 gene duplication was also performed. Results We found a decrease in the volume of WM in 70% of patients, a reduced creatine level in WM in 28% and a cognitive impairment in 70%. FA was significantly altered in several areas of WM, including the columns of the fornix. The results for WM volume, creatine level in WM and cognitive testing showed that 47% of patients (patients with HNPP and those with CMT1A) presented with at least two abnormal results. Pathological examination of the brain of a patient with PMP22 gene duplication showed diffuse hypomyelination sparing the U fibres. Conclusions This study demonstrates that altered PMP22 gene expression induces significant CNS alterations in patients with HNPP and CMT1A, including cerebral WM abnormalities and cognitive impairment.

Resume Une patiente de 63 ans qui presentait depuis une quinzaine d’annees un diabete non insulinodependant et une surdite de perception, developpa des troubles de l’equilibre et du comportement. L’IRM cerebrale montra des calcifications bilaterales des noyaux gris ainsi que la presence de multiples hypersignaux de la substance blanche periventriculaire sur les sequences ponderees en T2 et FLAIR. Le bilan biologique montra une elevation des lactates seriques. L’etude histologique et histoenzymologique d’un prelevement musculaire puis l’etude biochimique de la chaine respiratoire mitochondriale montrant un deficit partiel en complexes IV et I conduirent a l’etude du ADN mitochondrial. La presence de la mutation A3243G du ADNmt musculaire permit le diagnostic de Mitochondrial encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). Ce cas illustre l’heterogeneite phenotypique du MELAS, et rappelle les arguments cliniques et paracliniques qui doivent conduire au diagnostic de cytopathie mitochondriale.

Mutations impacting on the splicing of pre-mRNA are one important cause of genetically inherited diseases. However, detection of splice mutations, that are mainly due to intronic variations, and characterization of their effects are usually not performed as a first approach during genetic diagnosis. X-linked recessive myotubular myopathy is a severe congenital myopathy due to mutations in the MTM1 gene encoding myotubularin. Here, we screened a male patient showing an unusually mild phenotype without respiratory distress by western blot with specific myotubularin antibodies and detected a strong reduction of the protein level.The disease was subsequently linked to a hemizygous point mutation affecting the acceptor splice site of exon 8 of MTM1, proven by protein, transcript and genomic DNA analysis. Detailed analysis of the MTM1 mRNA by RT-PCR, sequencing and quantitative PCR revealed multiple abnormal transcripts with retention of a truncated exon 8, and neighboring exons 7 and 9 but exclusion of several other exons, suggesting a complex effect of this mutation on the splicing of non-adjacent exons. We conclude that the analysis of RNA by RT-PCR and sequencing is an important step to characterize the precise impact of detected splice variants. It is likely that complex splice aberrations due to a single mutation also account for unsolved cases in other diseases.

Introduction Les anticorps monoclonaux anti-PD1 (programmed cell death protein 1) comme le nivolumab et le pembrolizumab sont utilises comme anticancereux. Ils peuvent provoquer parfois des effets secondaires musculaires potentiellement fatals. Observation Un patient de 78 ans avait pour antecedent un melanome cutane traite il y a 4 ans par chirurgie. Suite a une recidive ganglionnaire inoperable, un traitement par pembrolizumab a ete debute. Trois semaines apres la premiere perfusion, un ptosis bilateral non fluctuant est apparu, suivi quelques jours plus tard d’une diplopie binoculaire, d’une dysphagie et d‘une dysphonie. L’IRM cerebrale et l’analyse du liquide cephalo-rachidien etaient normales et la recherche d’anticorps anti-neurones, anti-recepteur de l’acetylcholine et d’anticorps associes aux myosites etait negative. Les CPK etaient elevees a 11 500 UI/L (n Discussion Plusieurs cas de myopathie inflammatoire aigue fatale apres traitement par anticorps anti-PD1 ont deja ete rapportes. Ces myopathies avaient un debut quelques semaines apres la premiere cure et une predominance oculo-bulbaire et respiratoire. L’histologie musculaire retrouvait le plus souvent une myosite necrosante. L’absence de necrose dans notre cas etait peut-etre liee au fait que la biopsie a ete realisee precocement. Conclusion Le traitement par pembrolizumab peut se compliquer d’une myopathie inflammatoire aigue severe, a predominance oculo-bulbaire et respiratoire, potentiellement fatale.

Background/Aims: Alzheimer’s disease (AD) is characterized by extracellular Aβ peptide deposition originating from amyloid precursor protein cleavage and intracellular neurofibrillary tangles resulting from pathological tau protein aggregation. These processes are accompanied by dramatic neuronal losses, further leading to different cognitive impairments. Neuronal death signalings involve gene expression modifications that rely on transcription factor alterations. Herein, we investigated the fate of the Sp family of transcription factors in postmortem brains from patients with AD disease and in different contexts of neuronal death. Methods/Results: By immunohistochemistry we found that the Sp3 and Sp4 levels were dramatically increased and associated with neurofibrillary tangles and pathological tau presence in neurons from the CA1 region of the hippocampus, as well as the entorhinal cortex of AD patient brains. The Sp transcription factor expression levels were further analyzed in cortical neurons in which death is induced by amyloid precursor protein signaling targeting. While the Sp1 levels remained constant, the Sp4 levels were slightly upregulated in response to the death signal. The Sp3 isoforms were rather degraded. Interestingly, when overexpressed by transfection experiments, the three Sp family members induced neuronal apoptosis, Sp3 and Sp4 being the most potent proapoptotic factors over Sp1. Conclusion: Our data evidence Sp3 and Sp4 as new hallmarks of AD in postmortem human brains and further point out that Sp proteins are potential triggers of neuronal death signaling cascades.

Objectives To highlight the risk of clinical worsening after deep brain stimulation in histologically proven multiple system atrophy (MSA) patients presenting slow and relatively benign disease progression mimicking Parkinson's disease (PD). In such cases but also in more typical MSA patients, the results of deep brain stimulation have been mostly reported as case reports and small patient series. Methods The present study describes the outcome of the largest series of histologically proven MSA patients who underwent deep brain stimulation (DBS) of the subthalamic nucleus because they were considered as having PD at the time of surgery. Results Three patients showed significant improvement of motor signs after surgery while two did not. Clinical improvement was short-lasting and rapidly followed by the occurrence of disabling manifestations of MSA that counteracted DBS benefits. Conclusions Together with previous reports, our study demonstrates that DBS should not be recommended for MSA patients. It also underlines that detecting subtle red flags is crucial to avoid DBS surgery in this population.

The studies of molecular alterations in tumor cells with microarrays are often hampered by inherent tissue heterogeneity. The emergence of Laser Capture Microdissection (LCM) allowed us to overcome this challenge since it gives selective access to cancer cells that are isolated from their native tissue environment. In this report, we microdissected mesothelial cells and malignant mesothelioma cells of ex vivo resected specimens using LCM. Amplified RNA from mesothelial and mesothelioma microdissected cells allowed us to measure global gene expression with 10 K-microarrays in four independent experiments. We screened 9850 annotated human genes, 1275 of which have satisfied our data analysis requirements. They included 302 overexpressed genes and 160 downregulated genes in mesothelioma microdissected cells as compared to mesothelial microdissected cells. Among them, the expression levels of eight genes, namely BF, FTL, IGFBP7, RARRES1, RARRES2, RBP1, SAT, and TXN according to HUGO nomenclature, were increased, whereas six: ALOX5AP, CLNS1A, EIF4A2, ELK3, REQ and SYPL, were found to be underexpressed in mesothelioma microdissected cells. The ferritin light polypeptide (FTL) gene overexpression was confirmed by real time quantitative PCR. Our approach allowed a comprehensive in situ examination of mesothelioma and provided an accurate way to find new marker genes that may be useful for diagnosis and treatment of malignant pleural mesothelioma.

Arsenic trioxide (ATO) has been successfully used as a treatment for acute promyelocytic leukemia (APL) for more than a decade. Here we report a patient with APL who developed a mitochondrial myopathy after treatment with ATO. Three months after ATO therapy withdrawal, the patient was unable to walk without assistance and skeletal muscle studies showed a myopathy with abundant cytoplasmic lipid droplets, decreased activities of the mitochondrial respiratory chain complexes, multiple mitochondrial DNA (mtDNA) deletions, and increased muscle arsenic content. Six months after ATO treatment was interrupted, the patient recovered normal strength, lipid droplets had decreased in size and number, respiratory chain complex activities were partially restored, but multiple mtDNA deletions and increased muscle arsenic content persisted. ATO therapy may provoke a delayed, severe, and partially reversible mitochondrial myopathy, and a long-term careful surveillance for muscle disease should be instituted when ATO is used in patients with APL.

Eosinophilic myositis is characterized by eosinophilic infiltration of skeletal muscles. In the absence of an identifiable causative factor or source (including parasitic infection, intake of drugs or L-tryptophan, certain systemic disorders as well as malignant diseases), the diagnosis of idiopathic eosinophilic myositis is usually retained. However, some muscular dystrophies have been recently identified in this subset of eosinophilic myositis. Here, we report a patient with an 8 kb CCTG expansion in intron 1 of the CNBP gene, a mutation characteristic of myotonic dystrophy type 2 (DM2), whose first manifestation was "idiopathic" eosinophilic myositis. This report suggests that in "idiopathic" eosinophilic myositis, clinicians should consider muscular dystrophies, including DM2.