Publications by authors named "Shahram Attarian"

117 Publications

Impact of a frequent nearsplice variant in amyotrophic lateral sclerosis: optimising genetic screening for gene therapy opportunities.

J Neurol Neurosurg Psychiatry 2021 Mar 30. Epub 2021 Mar 30.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM,Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, Île de France, France

Objective: Mutations in superoxide dismutase 1 gene (, encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in non-coding sequences, is pathogenic.

Methods: We analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.

Results: We identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358-10T>G nearsplice variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.

Conclusions: Our results highlighted nearsplice/intronic mutations in are responsible for a significant portion of French fALS and suggested the systematic analysis of the mRNA sequence could become the method of choice for screening, not to miss these specific cases.
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http://dx.doi.org/10.1136/jnnp-2020-325921DOI Listing
March 2021

Deep phenotyping of an international series of patients with late-onset dysferlinopathy.

Eur J Neurol 2021 Mar 13. Epub 2021 Mar 13.

Nord/Est/Ile-de-France Neuromuscular Reference Center, Institute of Myology, Pitié-Salpêtrière Hospital, APHP, Sorbonne University, Paris, France.

Background: To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients.

Methods: Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30 years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30 years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited.

Results: Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range 30-57) years and most patients showed a limb-girdle (n = 26) or distal (n = 10) phenotype. However, compared with EO dysferlinopathy patients (n = 48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p = 0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p = 0.01), and higher NSAD (p = 0.008) and ACTIVLIM scores (p = 0.016). Loss of ambulation in LO patients tended to occur later (23 ± 4.4 years after disease onset vs. 16.3 ± 6.8 years; p = 0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p = 0.021), no differences in dysferlin protein expression were found on Western blot.

Conclusions: Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.
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http://dx.doi.org/10.1111/ene.14821DOI Listing
March 2021

Impact of Coronavirus Disease 2019 in a French Cohort of Myasthenia Gravis.

Neurology 2021 Feb 10. Epub 2021 Feb 10.

Referral Center for Neuromuscular Diseases and ALS, Timone University Hospital, Aix-Marseille University, Marseille, France.

Objective: To describe the clinical characteristics and outcomes of COVID-19 among patients with MG and identify factors associated with COVID-19 severity in MG patients.

Methods: The CO-MY-COVID registry was a multicenter, retrospective, observational cohort study conducted in neuromuscular referral centers and general hospitals of the FILNEMUS network (between March 1, 2020, and June 8, 2020), including MG patients with a confirmed or highly-suspected diagnosis of COVID-19. COVID-19 was diagnosed based on a polymerase chain reaction (PCR) test from a nasopharyngeal swab and/or SARS-CoV-2 serology, thoracic computed tomography (CT-scan), or typical symptoms. The main outcome was COVID-19 severity based on location of treatment/management (home, hospitalized in a medical unit, or in an intensive care unit). We collected information on demographic variables, general history, and risk factors for severe COVID-19. Multivariate ordinal regression models were used to identify factors associated with severe COVID-19 outcomes.

Results: Among 3,558 MG patients registered in the French database for rare disorders, 34 (0.96%) had COVID-19. The mean age at COVID-19 onset was 55.0 ±19.9 years (mean MG duration: 8.5 ± 8.5 years). By the end of the study period, 28 patients recovered from COVID-19, 1 remained affected, and 5 died. Only high Myasthenia Gravis Foundation of America (MGFA) class (≥IV) before COVID-19 was associated with severe COVID-19 (p=0.004); factors that were not associated included gender, MG duration, and medium MGFA classes (≤IIIb). The type of MG treatment had no independent effect on COVID-19 severity.

Conclusions: This registry-based cohort study shows that COVID-19 had a limited effect on most patients, and immunosuppressive medications and corticosteroids used for MG management are not risk factors for poorer outcomes. However, the risk of severe COVID-19 is elevated in patients with high MGFA classes [odds ratio: 102.6 (4.4; 2,371.9)]. These results are important for establishing evidence-based guidelines for the management of MG patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1212/WNL.0000000000011669DOI Listing
February 2021

Combination of serum and CSF neurofilament-light and neuroinflammatory biomarkers to evaluate ALS.

Sci Rep 2021 Jan 12;11(1):703. Epub 2021 Jan 12.

Timone Hospital, Referral Centre for Neuromuscular Diseases and ALS, AP-HM, Marseille, France.

This monocentric prospective study of patient suffering from Amyotrophic lateral sclerosis (ALS) aims to evaluate the prognosis and diagnostic potential of both Neurofilament-Light (Nf-L) and neuroinflammatory biomarkers in serum and CSF. Candidate markers levels were measured using multiplex method in serum of 60 ALS patients, 94 healthy controls of 43 patients suffering from Inflammatory Peripheral Neuropathies (IPN). A comparative CSF analysis was performed for 20 ALS and 17 IPN patients. Among the altered biomarkers, CSF Nf-L level remains the best marker of ALS severity, while serum levels correlate strongly with disease progression. The combination of Nf-L and ICAM-1 concentrations in the CSF and IFN-γ concentration in the serum differentiate ALS patients from IPN patients with improved sensibility and specificity relative to individual biomarkers. A cutoff value of 0.49 for the fitted values of these 3 biomarkers discriminate ALS from IPN patients with a specificity of 100% (78.20-100%) and a sensibility of 85.71% (57.19-98.22%) with an AUC of 0.99 ± 0.01. The measure of Nf-L and neuroinflammatory biomarkers in CSF and serum can be useful biomarkers panel in the differential diagnosis of ALS.
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http://dx.doi.org/10.1038/s41598-020-80370-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803734PMC
January 2021

Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study.

Lancet Neurol 2021 01 16;20(1):49-59. Epub 2020 Nov 16.

Centro Hospitalar Universitário do Porto, Porto, Portugal.

Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy.

Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261.

Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups.

Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Funding: Alnylam Pharmaceuticals.
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http://dx.doi.org/10.1016/S1474-4422(20)30368-9DOI Listing
January 2021

Patient-reported impact of Charcot-Marie-Tooth disease: protocol for a real-world digital lifestyle study.

Neurodegener Dis Manag 2021 02 22;11(1):21-33. Epub 2020 Oct 22.

Pharnext, Paris, France.

Charcot-Marie-Tooth disease (CMT) is a rare, chronic, progressive motor and sensory neuropathy affecting the peripheral nervous system. This study will explore the real-world impact of CMT. The trial is a digital study of approximately 2000 people in 6 countries with CMT ≥18 years. Participants will use a smartphone application to check eligibility, provide consent and contribute data. The dataset will include a personal profile, covering demographics, lifestyle, diagnosis and treatment and a selection of validated generic and disease-specific instruments. Participants will provide data for up to 2 years. Data analysis will be conducted upon registration of the 1000th participant and at 12-month intervals from launch. This study is designed to help researchers and clinicians understand the real-world impact of CMT and the unmet needs of patients. ClinicalTrials.gov identifier: NCT03782883.
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http://dx.doi.org/10.2217/nmt-2020-0044DOI Listing
February 2021

Evolving Immunologic Perspectives in Chronic Inflammatory Demyelinating Polyneuropathy.

J Inflamm Res 2020 16;13:543-549. Epub 2020 Sep 16.

Reference Centre for Neuromuscular Diseases and ALS, Centre Hospitalier Universitaire La Timone, Marseille 13385, France.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is the commonest chronic idiopathic dysimmune neuropathy. Pathophysiologic processes involve both cellular and humoral immunity. There are various known forms of CIDP, likely caused by varying mechanisms. CIDP in its different forms is a treatable disorder in the majority of patients. The diagnosis of CIDP is clinical, supported routinely by electrophysiology. Cerebrospinal fluid analysis may be helpful. Routine immunology currently rarely adds to the diagnostic process but may contribute to the identification of an associated monoclonal gammopathy with or without hematologic malignancy and the consideration of alternative diagnoses, such as POEMS syndrome, anti-myelin associated glycoprotein (MAG) neuropathy or chronic ataxic neuropathy, with ophthalmoplegia, M-protein, cold aglutinins and disialosyl antibodies (CANOMAD). The search for antibodies specific to CIDP has been unsuccessful for many years. Recently, antibodies to paranodal proteins have been identified in a minority of patients with severe CIDP phenotypes, often unresponsive to first-line therapies. In conjunction with reports of high rates of antibody responses to neural structures in CIDP, this entertains the hope that more discoveries are to come. Although still arguably for only a small minority of patients, in view of current knowledge, such progress will enable earlier accurate diagnosis with direct management implications but only if the important, unfortunately and infrequently discussed issues of immunologic technique, test reliability and reproducibility are adequately tackled.
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http://dx.doi.org/10.2147/JIR.S224781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502403PMC
September 2020

Refining NGS diagnosis of muscular disorders.

J Neurol Neurosurg Psychiatry 2021 Feb 15;92(2):223-225. Epub 2020 Sep 15.

Aix-Marseille Université, Inserm, U1251-MMG, Marseille Medical Genetics, Marseille, France.

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http://dx.doi.org/10.1136/jnnp-2018-319254DOI Listing
February 2021

Application of muscle ultrasound for the evaluation of patients with amyotrophic lateral sclerosis: An observational cross-sectional study.

Muscle Nerve 2020 10 14;62(4):516-521. Epub 2020 Aug 14.

Department of Neurology, Shariati Hospital, Tehran University of Medical Sciences, Jalal al Ahmad, Tehran, 1411713135, Iran.

Introduction: We evaluated the association between muscle ultrasound, number of motor units, and clinical parameters, and assessed their utility for distinguishing amyotrophic lateral scleorisis (ALS) patients from healthy individuals.

Methods: Three muscle pairs (abductor pollicis brevis, abductor digiti minimi, and tibialis anterior) of 18 ALS patients and 18 controls underwent muscle ultrasound (echointensity and thickness) and assessment of motor unit number index (MUNIX). The clinical and functional status of participants were also assessed.

Results: Mean age of the patients was 53.8 ± 12.1 years, and score on the ALS Functional Rating Scale-Revised was 38.9 ± 4.1. Echointensity of all tested muscles of ALS participants was significantly higher than that of controls, but there was no significant difference in muscle thickness. Muscle echointensity correlated significantly with clinical and electrophysiological parameters.

Conclusion: Echointensity of muscles was highly associated with clinical scales and MUNIX, confirming its relevance as an ancillary diagnostic test in ALS patients.
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http://dx.doi.org/10.1002/mus.27036DOI Listing
October 2020

Motor unit number index as an individual biomarker: Reference limits of intra-individual variability over time in healthy subjects.

Clin Neurophysiol 2020 Sep 9;131(9):2209-2215. Epub 2020 Jul 9.

Referral Centre for Neuromuscular Diseases and ALS, La Timone Hospital, Marseille, France.

Objective: Motor unit number index (MUNIX) is proposed to monitor neuromuscular disorders. Our objective is to determine the intra-individual variability over time of the MUNIX.

Methods: In 11 different hospital centres, MUNIX was assessed twice, at least 3 months apart (range 90-360 days), in tibialis anterior (TA), abductor pollicis brevis (APB), abductor digiti minimi (ADM) and deltoid muscles in 118 healthy subjects. MUNIX sum score 2, 3 and 4 were respectively the sum of the MUNIX of the TA and ADM, of the TA, APB and ADM and of the TA, APB, ADM and deltoid muscles.

Results: The repeatability of the MUNIX was better for sum scores than for single muscle recordings. The variability of the MUNIX was independent of sex, age, interval between measurements and was lower for experienced than non-experienced operators. The 95th percentile of the coefficient of variability of the MUNIX sum score 2, 3 and 4 were respectively 22%, 18% and 15% for experienced operators.

Conclusions: The MUNIX technique must be performed by experienced operators on several muscles to reduce its variability and improve its reliability.

Significance: A variation of the MUNIX sum score ≥20% can be interpreted as a significant change of muscle innervation.
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http://dx.doi.org/10.1016/j.clinph.2020.06.019DOI Listing
September 2020

Antibodies against the node of Ranvier: a real-life evaluation of incidence, clinical features and response to treatment based on a prospective analysis of 1500 sera.

J Neurol 2020 Dec 16;267(12):3664-3672. Epub 2020 Jul 16.

Timone Neuroscience Institute, UMR CNRS 7289, Aix-Marseille University, 13005, Marseille, France.

Introduction: IgG4 antibodies against neurofascin (Nfasc155 and Nfasc140/186), contactin (CNTN1) and contactin-associated protein (Caspr1) are described in specific subtypes of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Our objective was to assess, in a real-life practice, the incidence, the clinical features and the response to treatment of these forms of CIDP.

Methods: 1500 sera of patients suspected of having CIDP from France, Belgium and Switzerland were prospectively tested using a flow cytometry technique. The characteristics of patients with antibodies against the node of Ranvier were compared to 100 seronegative CIDP from our department.

Results: IgG4 antibodies against Nfasc155, CNTN1, and Caspr1 were, respectively, detected in 15 (prevalence 1%), 10 (0.7%) and 2 (0.2%) sera. Antibodies specific of the Nfasc140/186 were not detected. All subjects with antibodies against the node of Ranvier fulfilled diagnostic criteria for CIDP. CIDP with anti-Nfasc155 were younger, had more sensory ataxia and postural tremor than seronegative CIDP. CIDP with anti-CNTN1 had more frequent subacute onset and facial paralysis, commoner renal involvement with membranous glomerulonephritis and greater disability, than seronegative CIDP. CIDP with anti-Caspr1 had more frequent respiratory failure and cranial nerve involvement but not more neuropathic pain than seronegative CIDP. Intravenous immunoglobulins were ineffective in most seropositive patients. Rituximab produced dramatic improvement in disability and decreased antibodies titres in 13 seropositive patients (8 with anti-Nfasc155 and 5 with anti-CNTN1 antibodies).

Conclusions: Although rare, anti-paranodal antibodies are clinically valuable, because they are associated with specific phenotypes and therapeutic response.
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http://dx.doi.org/10.1007/s00415-020-10041-zDOI Listing
December 2020

Single-fiber studies for assigning pathogenicity of eight mitochondrial DNA variants associated with mitochondrial diseases.

Hum Mutat 2020 08 12;41(8):1394-1406. Epub 2020 Jun 12.

Department of Medical Genetics, National Center for Mitochondrial Diseases, Nice Teaching Hospital, Nice, France.

Whole mitochondrial DNA (mtDNA) sequencing is now systematically used in clinical laboratories to screen patients with a phenotype suggestive of mitochondrial disease. Next Generation Sequencing (NGS) has significantly increased the number of identified pathogenic mtDNA variants. Simultaneously, the number of variants of unknown significance (VUS) has increased even more, thus challenging their interpretation. Correct classification of the variants' pathogenicity is essential for optimal patient management, including treatment and genetic counseling. Here, we used single muscle fiber studies to characterize eight heteroplasmic mtDNA variants, among which were three novel variants. By applying the pathogenicity scoring system, we classified four variants as "definitely pathogenic" (m.590A>G, m.9166T>C, m.12293G>A, and m.15958A>T). Two variants remain "possibly pathogenic" (m.4327T>C and m.5672T>C) but should these be reported in a different family, they would be reclassified as "definitely pathogenic." We also illustrate the contribution of single-fiber studies to the diagnostic approach in patients harboring pathogenic variants with low level heteroplasmy.
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http://dx.doi.org/10.1002/humu.24037DOI Listing
August 2020

Management challenges for chronic dysimmune neuropathies during the COVID-19 pandemic.

Muscle Nerve 2020 07 24;62(1):34-40. Epub 2020 Apr 24.

Department of Neurology, Medical Faculty and Center of Neurology and Neuropsychiatry, LVR Klinikum, Heinrich-Heine University, Düsseldorf, Germany.

Since March 2020, the COVID-19 pandemic has led to the need to re-think the delivery of services to patients with chronic dysimmune neuropathies. Telephone/video consultations have become widespread but have compounded concerns about objective evaluation. Therapeutic decisions need, more than ever before, to be considered in the best interests of both patients, and society, while not denying function-preserving/restoring treatment. Immunoglobulin therapy and plasma exchange, for those treated outside of the home, expose patients to the hazards of hospital or outpatient infusion centers. Steroid therapy initiation and continuation pose increased infectious risk. Immunosuppressant therapy similarly becomes highly problematic, with the risks of treatment continuation enhanced by uncertainties regarding duration of the pandemic. The required processes necessitate considerable time and effort especially as resources and staff are re-deployed to face the pandemic, but are essential for protecting this group of patients and as an integral part of wider public health actions.
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http://dx.doi.org/10.1002/mus.26896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264511PMC
July 2020

Selective inhibition of anti-MAG IgM autoantibody binding to myelin by an antigen-specific glycopolymer.

J Neurochem 2020 09 23;154(5):486-501. Epub 2020 Jun 23.

Institute of Molecular Pharmacy, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.

Anti-myelin-associated glycoprotein (MAG) neuropathy is a disabling autoimmune peripheral neuropathy that is caused by circulating monoclonal IgM autoantibodies directed against the human natural killer-1 (HNK-1) epitope. This carbohydrate epitope is highly expressed on adhesion molecules such as MAG, a glycoprotein present in myelinated nerves. We previously showed the therapeutic potential of the glycopolymer poly(phenyl disodium 3-O-sulfo-β-d-glucopyranuronate)-(1→3)-β-d-galactopyranoside (PPSGG) in selectively neutralizing anti-MAG IgM antibodies in an immunological mouse model and ex vivo with sera from anti-MAG neuropathy patients. PPSGG is composed of a biodegradable backbone that multivalently presents a mimetic of the HNK-1 epitope. In this study, we further explored the pharmacodynamic properties of the glycopolymer and its ability to inhibit the binding of anti-MAG IgM to peripheral nerves. The polymer selectively bound anti-MAG IgM autoantibodies and prevented the binding of patients' anti-MAG IgM antibodies to myelin of non-human primate sciatic nerves. Upon PPSGG treatment, neither activation nor inhibition of human and murine peripheral blood mononuclear cells nor alteration of systemic inflammatory markers was observed in mice or ex vivo in human peripheral blood mononuclear cells. Intravenous injections of PPSGG to mice immunized against the HNK-1 epitope removed anti-MAG IgM antibodies within less than 1 hr, indicating a fast and efficient mechanism of action as compared to a B-cell depletion with anti-CD20. In conclusion, these observations corroborate the therapeutic potential of PPSGG for an antigen-specific treatment of anti-MAG neuropathy. Read the Editorial Highlight for this article on page 465.
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http://dx.doi.org/10.1111/jnc.15021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497077PMC
September 2020

Type 1 FSHD with 6-10 Repeated Units: Factors Underlying Severity in Index Cases and Disease Penetrance in Their Relatives Attention.

Int J Mol Sci 2020 Mar 23;21(6). Epub 2020 Mar 23.

Reference Center of Neuromuscular disorders and ALS, Timone University Hospital, AP-HM, 264 rue Saint-Pierre, Cedex 05 13385 Marseille, France.

Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared (1) the phenotype and severity of FSHD1 between patients carrying 6-8 vs. 9-10 RUs, (2) the amount of methylation in different D4Z4 regions between patients with FSHD1 with different clinical severity scores (CSS). This cross-sectional multicenter study was conducted to measure functional scales and for genetic analysis. Patients were classified into two categories according to RUs: Group 1, 6-8; Group 2, 9-10. Methylation analysis was performed in 27 patients. A total of 99 carriers of a contracted D4Z4 array were examined. No significant correlations between RUs and CSS (r = 0.04, = 0.73) and any of the clinical outcome scales were observed between the two groups. Hypomethylation was significantly more pronounced in patients with high CSS (>3.5) than those with low CSS (<1.5) (in DR1 and 5P), indicating that the extent of hypomethylation might modulate disease severity. In Group 1, the disease severity is not strongly correlated with the allele size and is mostly correlated with the methylation of D4Z4 regions.
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http://dx.doi.org/10.3390/ijms21062221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139460PMC
March 2020

Electrophysiological features of chronic inflammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodies targeting neurofascin 155 or contactin 1 glycoproteins.

Clin Neurophysiol 2020 04 6;131(4):921-927. Epub 2020 Feb 6.

Referral Centre for Neuromuscular Diseases and ALS, La Timone hospital, Marseille, France; Aix-Marseille University, Timone Neuroscience Institute, UMR CNRS 7289, 13005 Marseille, France. Electronic address:

Objective: Chronic inflammatory demyelinating polyradiculoneuropathies (CIDP) with antibodies against neurofascin 155 (Nfasc155) or contactin-1 (CNTN1) have distinctive clinical features. Knowledge on their electrophysiological characteristics is still scarce. In this study, we are investigating whether these patients have specific electrophysiological characteristics.

Methods: The electrophysiological data from 13 patients with anti-Nfasc155 IgG4 antibodies, 9 with anti-CNTN1 IgG4 antibodies were compared with those of 40 consecutive CIDP patients without antibodies.

Results: All the patients with antibodies against Nfasc155 or CNTN1 fulfilled the EFNS/PNS electrodiagnostic criteria for definite CIDP. There was no electrophysiological difference between patients with anti-CNTN1 and anti-Nfasc155 antibodies. Nerve conduction abnormalities were heterogeneously distributed along nerves trunks and roots. They were more pronounced than in CIDP without antibodies. Motor conduction velocity on median nerve <24 m/s or motor velocity on ulnar nerve <26 m/s or motor distal latency on ulnar nerve >7.4 ms were predictive of positive antibodies against the node of Ranvier with a sensitivity of 59% and a specificity of 93%.

Conclusions: Marked conduction abnormalities may suggest the presence of positive antibodies against the node of Ranvier.

Significance: Anti-Nfasc155 and anti-CNTN1 antibodies target the the paranodal axo-glial domain but are associated with nerve conduction abnormalities mimicking a "demyelinating" neuropathy.
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http://dx.doi.org/10.1016/j.clinph.2020.01.013DOI Listing
April 2020

Fat fraction distribution in lower limb muscles of patients with CMT1A: A quantitative MRI study.

Neurology 2020 04 24;94(14):e1480-e1487. Epub 2020 Jan 24.

From the Reference Center for Neuromuscular Diseases and ALS (J.B., E.D., A.P., S.A.) and CIC-CPCET (M.-N.L.), La Timone University Hospital, Aix-Marseille University; Aix-Marseille University (A.C.O., A.L.T., L.P., M.G., D.B.), CNRS, Center for Magnetic Resonance in Biology and Medicine; Aix-Marseille University (E.D.), UMR 7286, Medicine Faculty; Aix-Marseille University (S.A.), Inserm, GMGF; Aix Marseille University (A.C.O.), Université de Toulon, CNRS, LIS, Marseille; Université de Lyon (B.L.); and CREATIS CNRS UMR 5220 (B.L.), Inserm U1206, INSA-Lyon, UCBL Lyon 1, France.

Objective: To quantitatively describe the MRI fat infiltration pattern of muscle degeneration in Charcot-Marie-Tooth (CMT) type 1A (CMT1A) disease and to look for correlations with clinical variables.

Methods: MRI fat fraction was assessed in lower-limb musculature of patients with CMT1A and healthy controls. More particularly, 14 muscle compartments were selected at leg and thigh levels and for proximal, distal, and medial slices. Muscle fat infiltration profile was determined quantitatively in each muscle compartment and along the entire volume of acquisition to determine a length-dependent gradient of fat infiltration. Clinical impairment was evaluated with muscle strength measurements and CMT Examination Scores (CMTESs).

Results: A total of 16 patients with CMT1A were enrolled and compared to 11 healthy controls. Patients with CMT1A showed a larger muscle fat fraction at leg and thigh levels with a proximal-to-distal gradient. At the leg level, the largest fat infiltration was quantified in the anterior and lateral compartments. CMTES was correlated with fat fraction, especially in the anterior compartment of leg muscles. Strength of plantar flexion was also correlated with fat fraction of the posterior compartments of leg muscles.

Conclusion: On the basis of quantitative MRI measurements combined with a dedicated segmentation method, muscle fat infiltration quantified in patients with CMT1A disclosed a length-dependent peroneal-type pattern of fat infiltration and was correlated to main clinical variables. Quantification of fat fraction at different levels of the leg anterior compartment might be of interest in future clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000009013DOI Listing
April 2020

Quantitative muscle MRI study of patients with sporadic inclusion body myositis.

Muscle Nerve 2020 04 8;61(4):496-503. Epub 2020 Feb 8.

Centre de référence PACA Réunion Rhône Alpes, La Timone University Hospital, Aix-Marseille University, Marseille.

Background: Fat infiltration in individual muscles of sporadic inclusion body myositis (sIBM) patients has rarely been assessed.

Methods: Sixteen sIBM patients were assessed using MRI of the thighs and lower legs (LL). The severity of fat infiltration, proximal-to-distal and side asymmetries, and the correlations with clinical and functional parameters were investigated.

Results: All the patients had fat-infiltrated muscles, and thighs were more severely affected than LL. A proximal-to-distal gradient of fat infiltration was mainly observed for adductors, quadriceps, sartorius, and medial gastrocnemius muscles. A strong negative correlation was observed between the whole muscle fat fraction in the thighs and LL and the Inclusion Body Myositis Functional Rating Scale and Medical Research Council scores for the lower limbs.

Conclusions: Fat infiltration in individual muscles of sIBM patients is heterogeneous in terms of proximal-to-distal gradient and severity was correlated with clinical scores. These results should be considered for both natural history investigation and clinical trials.
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http://dx.doi.org/10.1002/mus.26813DOI Listing
April 2020

Methylation hotspots evidenced by deep sequencing in patients with facioscapulohumeral dystrophy and mosaicism.

Neurol Genet 2019 Dec 14;5(6):e372. Epub 2019 Nov 14.

Aix Marseille University, INSERM, MMG (S.R., C.D., N.B., C.L., M.-C.G., J.D.R., A.L., F.P., E.S.C., S.A., M.B., R.B., K.N., F.M.); Département de Génétique Médicale (A.L., C.V., C.C., R.B., K.N.), AP-HM, Hôpital de la Timone enfants, Marseille; and Centre de référence pour les maladies neuromusculaires et la SLA (E.S.C., S.A.), AP-HM, Hôpital de la Timone, Marseille, France.

Objective: To investigate the distribution of cytosine-guanine dinucleotide (CpG) sites with a variable level of DNA methylation of the D4Z4 macrosatellite element in patients with facioscapulohumeral dystrophy (FSHD).

Methods: By adapting bisulfite modification to deep sequencing, we performed a comprehensive analysis of D4Z4 methylation across D4Z4 repeats and adjacent 4qA sequence in DNA from patients with FSHD1, FSHD2, or mosaicism and controls.

Results: Using hierarchical clustering, we identified clusters with different levels of methylation and separated, thereby the different groups of samples (controls, FSHD1, and FSHD2) based on their respective level of methylation. We further show that deep sequencing-based methylation analysis discriminates mosaic cases for which methylation changes have never been evaluated previously.

Conclusions: Altogether, our approach offers a new high throughput tool for estimation of the D4Z4 methylation level in the different subcategories of patients having FSHD. This methodology allows for a comprehensive and discriminative analysis of different regions along the macrosatellite repeat and identification of focal regions or CpG sites differentially methylated in patients with FSHD1 and FSHD2 but also complex cases such as those presenting mosaicism.
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http://dx.doi.org/10.1212/NXG.0000000000000372DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878839PMC
December 2019

[Marseille welcomes the FSHD Society International Research Conference].

Med Sci (Paris) 2019 Nov 20;35 Hors série n° 2:55-59. Epub 2019 Dec 20.

Aix Marseille Univ, Inserm, MMG, Marseille Medical Genetics, Marseille, France - Centre de référence pour les maladies neuromusculaires et la SLA, Hôpital de la Timone, Marseille, France - Filnemus, Filière Neuromusculaire,.

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http://dx.doi.org/10.1051/medsci/2019184DOI Listing
November 2019

[Renewal of Filnemus: ambitious goals for 2019-2023].

Med Sci (Paris) 2019 Nov 20;35 Hors série n° 2:5-6. Epub 2019 Dec 20.

Presidente de la Societe Francaise de Myologie,.

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http://dx.doi.org/10.1051/medsci/2019238DOI Listing
November 2019

Comparison of MRI and motor evoked potential with triple stimulation technique for the detection of brachial plexus abnormalities in multifocal motor neuropathy.

Muscle Nerve 2020 03 20;61(3):325-329. Epub 2019 Dec 20.

Referral Centre for Neuromuscular Diseases and ALS, Hôpital La Timone, Marseille, France.

Background: Conduction blocks (CB) are the diagnostic hallmark of multifocal motor neuropathy (MMN). Conventional nerve conduction studies cannot detect CB above Erb's point. Our purpose was to compare the performance of the motor evoked potential with triple stimulation technique (MEP-TST) and MRI in the detection of abnormalities of the brachial plexus.

Methods: Examinations were performed on 26 patients with MMN (11 definite, 6 probable, 9 possible), of whom 7 had no CB.

Results: MEP-TST detected proximal CB in 19/26 patients. Plexus MRI showed T2 hyperintensity in 18/26 patients, with nerve enlargement in 14/18. A combination of both techniques increased the detection rate of brachial plexus abnormalities to 96% of patients (25/26).

Conclusions: MEP-TST and MRI have high sensitivities for detecting brachial plexus abnormalities. A combination of the two techniques increases the detection rate of supportive criteria for the diagnosis of MMN.
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http://dx.doi.org/10.1002/mus.26773DOI Listing
March 2020

An overview of motor unit number index reproducibility in amyotrophic lateral sclerosis.

Iran J Neurol 2019 Jul;18(3):119-126

Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Motor unit number index (MUNIX) is an electrophysiological technique to give an estimate of functioning motor neurons in a muscle. For any given neurophysiological technique for the use in clinical or research studies, reproducibility between different operators and in a single operator in different times is one of the most important qualities, which must be evaluated and approved by different examiners and centers. After its introduction, testing the reproducibility of MUNIX was the aim of many studies to show this quality of the technique. In this review, we aimed to summarize all the studies, which have been performed up to now to approve MUNIX reproducibility in amyotrophic lateral sclerosis comparing healthy individuals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858602PMC
July 2019

Structural Connectivity Alterations in Amyotrophic Lateral Sclerosis: A Graph Theory Based Imaging Study.

Front Neurosci 2019 2;13:1044. Epub 2019 Oct 2.

Aix Marseille Univ, CNRS, CRMBM, Marseille, France.

Background: Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. Diffusion magnetic resonance imagining (MRI) studies have consistently showed widespread alterations in both motor and non-motor brain regions. However, connectomics and graph theory based approaches have shown inconsistent results. Hub-centered lesion patterns and their impact on local and large-scale brain networks remain to be established. The objective of this work is to characterize topological properties of structural brain connectivity in ALS using an array of local, global and hub-based network metrics.

Materials And Methods: Magnetic resonance imagining data were acquired from 25 patients with ALS and 26 age-matched healthy controls. Structural network graphs were constructed from diffusion tensor MRI. Network-based statistics (NBS) and graph theory metrics were used to compare structural networks without regions of interest.

Results: Patients with ALS exhibited global network alterations with decreased global efficiency (Eglob) ( = 0.03) and a trend of reduced whole brain mean degree ( = 0.05) compared to controls. Six nodes showed significantly decreased mean degree in ALS: left postcentral gyrus, left interparietal and transverse parietal sulcus, left calcarine sulcus, left occipital temporal medial and lingual sulcus, right precentral gyrus and right frontal inferior sulcus ( < 0.01). Hub distribution was comparable between the two groups. There was no selective hub vulnerability or topological reorganization centered on these regions as the hub disruption index (κ) was not significant for the relevant metrics (degree, local efficiency and betweenness centrality). Using NBS, we identified an impaired motor subnetwork of 11 nodes and 10 edges centered on the precentral and the paracentral nodes ( < 0.01). Significant clinical correlations were identified between degree in the frontal area and the disease progression rate of ALS patients ( < 0.01).

Conclusion: Our study provides evidence that alterations of structural connectivity in ALS are primarily driven by node degree and white matter tract degeneration within an extended network around the precentral and the paracentral areas without hub-centered reorganization.
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http://dx.doi.org/10.3389/fnins.2019.01044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783612PMC
October 2019

Nailfold videocapillaroscopy alterations in dermatomyositis, antisynthetase syndrome, overlap myositis, and immune-mediated necrotizing myopathy.

Clin Rheumatol 2019 Dec 22;38(12):3451-3458. Epub 2019 Aug 22.

Department of Internal Medicine AP-HM, Hopital Timone, 264 Rue Saint Pierre, 13385, Marseille cedex, France.

Introduction/objectives: The aim of our study was to investigate possible differences in nailfold videocapillaroscopy (NVC) features between patients with dermatomyositis (DM), overlap myositis (OM), antisynthetase syndrome (ASS), and immune-mediated necrotizing myopathy (IMNM).

Methods: We performed a cross-sectional monocentric study. All patients with inflammatory myopathies (IMs) over a 6-month period were analyzed by NVC for giant and ramified capillaries, tortuosities, capillary density, disorganization, and scleroderma pattern. Clinical, biological, and pathological characteristics were retrospectively recorded. Patients were classified as having DM, OM, ASS, or IMNM for comparison. Patients were also compared with a group of patients with systemic sclerosis (SSc).

Results: NVC was analyzed in DM (n = 17), OM (n = 8), ASS (n = 12), and IMNM (n = 6). Vascular disorganization and avascular zones were observed only in DM (11.8%) and OM (62.5%). The percentage of patients with giant capillaries was higher in OM (n = 4/8) than in DM (n = 3/17) and absent in ASS and IMNM. Frequency of ramified capillaries, tortuosities, hemorrhages, or thrombosis was not different between subgroups. A scleroderma pattern was only observed in OM patients.

Conclusion: In this limited series of patients, we observed that DM and OM NVC abnormalities are different from ASS and IMNM. We could not determine NVC specific patterns associated with myositis-specific antibody subtypes of DM because of the small number of patients.Key Points• Nailfold videocapillaroscopy abnormalities are different in subgroups of inflammatory myopathies.• Giant capillaries, disorganization, and major capillary loss are observed in overlap myositis and dermatomyositis but not in antisynthetase syndrome (ASS) or immune-mediated necrotizing myopathy.• Nailfold videocapillaroscopy abnormalities in overlap myositis (with the exclusion of ASS) are close to systemic sclerosis.
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http://dx.doi.org/10.1007/s10067-019-04710-2DOI Listing
December 2019

Quantitative Brain Sodium MRI Depicts Corticospinal Impairment in Amyotrophic Lateral Sclerosis.

Radiology 2019 08 11;292(2):422-428. Epub 2019 Jun 11.

From the Aix Marseille University, CRMBM, UMR CNRS 7339, 27 Boulevard Jean Moulin, 13005 Marseille, France (A.M.G., B.R., A.V., A.M., S.C., E.F., M.G., J.P.R., W.Z.); APHM, Hôpital de la Timone, Referral Centre for Neuromuscular Diseases and ALS, Marseille, France (A.M.G., A.V., E.F., S.A.); APHM, Hôpital de la Timone, CEMEREM, Marseille, France (B.R., A.M., S.C., M.G., J.P.R., W.Z.); Computer Assisted Clinical Medicine, Heidelberg University, Mannheim, Germany (L.S.); and Aix Marseille University, INSERM, GMGF, Marseille, France (S.A.).

Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that mainly affects the upper and lower motor neurons. Recent sodium (Na) MRI studies have shown that abnormal sodium concentration is related to neuronal suffering in neurodegenerative conditions. Purpose To use Na MRI to investigate abnormal sodium concentrations and map their distribution in the brains of study participants with ALS as compared with healthy control subjects. Materials and Methods Twenty-seven participants with ALS (mean age, 54 years ± 10 [standard deviation], eight women) and 30 healthy control subjects (mean age, 50 years ± 10; 16 women) were prospectively recruited between September 2015 and October 2017 and were examined by using conventional proton MRI and sodium MRI at 3 T. Voxel-based statistical mapping was used to compare quantitative whole-brain total sodium concentration (TSC) maps in participants with ALS with those in control subjects and to localize regions of abnormal elevated TSC. Potential overlap of abnormal elevated TSC with regions of atrophy as detected with H MRI also was investigated. Results Voxel-based statistical mapping analyses revealed higher sodium concentration in motor regions (bilateral precentral gyri, corticospinal tracts, and the corpus callosum) of participants with ALS (two-sample test, < .005; age and sex as covariates). In these regions, mean TSC was higher in participants with ALS (mean, 45.6 mmol/L wet tissue ± 3.2) than in control subjects (mean, 41.8 mmol/L wet tissue ± 2.7; < .001; Cohen = 1.28). Brain regions showing higher TSC represented a volume of 15.4 cm that did not overlap with gray matter atrophy occupying a volume of 16.9 cm. Elevated TSC correlated moderately with corticospinal conduction failure assessed with transcranial magnetic stimulation in the right upper limb (Spearman ρ = -0.57; 95% confidence interval: -0.78, -0.16; = .005; = 23). Conclusion Quantitative Na MRI is sensitive to alterations of brain sodium homeostasis within disease-relevant regions in patients with amyotrophic lateral sclerosis (ALS). This supports further investigation of abnormal sodium concentration as a potential marker of neurodegenerative processes in patients with ALS that could be used as a secondary endpoint in clinical trials. © RSNA, 2019
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http://dx.doi.org/10.1148/radiol.2019182276DOI Listing
August 2019

Relevance of anti-HNK1 antibodies in the management of anti-MAG neuropathies.

J Neurol 2019 Aug 14;266(8):1973-1979. Epub 2019 May 14.

Immunology Laboratory, Marseille, France.

Introduction: In peripheral neuropathies with antibodies against Myelin Associated Glycoprotein (MAG), an IgM monoclonal gammopathy recognizes a specific epitope called Human Natural Killer 1 (HNK1) shared by NK lymphocytes and several components of the peripheral nerve myelin. Recently an ELISA test has been developed to detect antibodies against HNK1 epitope. Objectives were to determine the usefulness of this assay in the management of anti-MAG neuropathy.

Methods: Anti-HNK1 antibodies were assessed with the GanglioCombi™ MAG ELISA test (Buhlmann) in 41 anti-MAG neuropathies and in 118 controls: 34 chronic inflammatory demyelinating polyradiculoneuropathies, 3 Miller Fisher syndromes, 12 sensory neuronopathies, 63 length-dependent axonal sensory polyneuropathies, 6 healthy controls. Anti-HNK1 antibody was tested before and 1 year after rituximab therapy in seven patients with anti-MAG neuropathy.

Results: Anti-HNK1 antibodies were positive in 40/41 anti-MAG neuropathies, and in 1/118 controls (sensitivity 98%, specificity 99%). Only considering controls with IgM paraprotein, specificity was 96% (23/24). In anti-MAG neuropathies, anti-HNK1 titre was correlated with sensory deficiency evaluated with the INCAT sensory sum score (r = 0.4, p = 0.01) and with disability evaluated with the Rasch-built Overall Disability Scale (r = [Formula: see text] 0.4, p = 0.01) and Overall Neuropathy Limitation Scale (r = 0.4, p = 0.02). Anti-HNK1 titres were not related to age, disease duration, atypical clinical features and anti-MAG antibodies titres. Anti-MAG titres were not associated with disease severity. Anti-HNK1 titres were decreased by 18% 1 year after rituximab treatment.

Conclusions: Anti-HNK1 antibodies have good sensitivity and specificity for the diagnosis of anti-MAG neuropathy. Interestingly, anti-HNK1 titres are related to the disease severity and decrease after rituximab infusions.
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http://dx.doi.org/10.1007/s00415-019-09367-0DOI Listing
August 2019

Deciphering the complexity of the 4q and 10q subtelomeres by molecular combing in healthy individuals and patients with facioscapulohumeral dystrophy.

J Med Genet 2019 09 22;56(9):590-601. Epub 2019 Apr 22.

Aix Marseille Univ, INSERM, MMG, Marseille Medical Genetics U1251, Marseille, France

Background: Subtelomeres are variable regions between telomeres and chromosomal-specific regions. One of the most studied pathologies linked to subtelomeric imbalance is facioscapulohumeral dystrophy (FSHD). In most cases, this disease involves shortening of an array of D4Z4 macrosatellite elements at the 4q35 locus. The disease also segregates with a specific A-type haplotype containing a degenerated polyadenylation signal distal to the last repeat followed by a repetitive array of β-satellite elements. This classification applies to most patients with FSHD. A subset of patients called FSHD2 escapes this definition and carries a mutation in the gene. We also recently described patients carrying a complex rearrangement consisting of a -duplication of the distal 4q35 locus identified by molecular combing.

Methods: Using this high-resolution technology, we further investigated the organisation of the 4q35 region linked to the disease and the 10q26 locus presenting with 98% of homology in controls and patients.

Results: Our analyses reveal a broad variability in size of the different elements composing these loci highlighting the complexity of these subtelomeres and the difficulty for genomic assembly. Out of the 1029 DNA samples analysed in our centre in the last 7 years, we also identified 54 cases clinically diagnosed with FSHD carrying complex genotypes. This includes mosaic patients, patients with deletions of the proximal 4q region and 23 cases with an atypical chromosome 10 pattern, infrequently found in the control population and never reported before.

Conclusion: Overall, this work underlines the complexity of these loci challenging the diagnosis and genetic counselling for this disease.
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http://dx.doi.org/10.1136/jmedgenet-2018-105949DOI Listing
September 2019

Hereditary neuropathy with liability to pressure palsies.

J Neurol 2020 Aug 15;267(8):2198-2206. Epub 2019 Apr 15.

Unit of Rare Neurodegenerative and Neurometabolic Diseases, Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent sensory and motor neuropathy in individual nerves starting in adolescence or young adulthood, focal conduction abnormalities at entrapment sites on nerve conduction studies, and sausage-like swellings (tomacula) of the myelin sheaths by nerve biopsy. It is characterized genetically by the deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein-22 gene in the overwhelming majority of cases. HNPP may be frequently underdiagnosed or misdiagnosed owing to the heterogeneity of clinical and electrophysiological appearance. The main objective of this review is to describe clinical manifestations, paraclinical features such as electrodiagnostic, pathological, radiological and genetics findings, and possible treatments.
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http://dx.doi.org/10.1007/s00415-019-09319-8DOI Listing
August 2020

Characteristics of patients with vitamin B12-responsive neuropathy: a case series with systematic repeated electrophysiological assessment.

Neurol Res 2019 Jun 19;41(6):569-576. Epub 2019 Mar 19.

e Department of Neurology , Groupe Hospitalier Pellegrin , Bordeaux , France.

Background: Vitamin B12 (B12) has a fundamental role in both central and peripheral nervous system function at all ages. Neurologic manifestations may be the earliest and often the only manifestation of B12 deficiency. Mostly because of the poor sensitivity of methods of determination for B12 levels, peripheral neuropathy remains a classical but underdiagnosed complication of B12 deficiency. So the clinical and electrophysiological characteristics of B12-responsive neuropathy are not well known.

Methods: A retrospective study of patients with B12-responsive neuropathy was conducted at our hospital on a 3-year period. The criteria for inclusion were: (a) neuropathy confirmed by the electrophysiological study (nerve conduction study); and (b) improvement of at least 1 point of the total Overall Neuropathy Limitations Scale score after vitamin B12 treatment.

Results: Nine patients were identified. Serum B12 level was low in only four. Four patients had sensorimotor (predominantly sensory) axonal polyneuropathy while five had only sensory neuronopathy. Six improved in less than 1 month after B12 supplementation.

Conclusion: B12-responsive neuropathy is a more heterogeneous group of neuropathy than previously described. B12 deficiency is a cause of peripheral neuropathy and should systematically be ruled out in the clinical setting of idiopathic neuropathy or sensory neuronopathy because of potential reversibility.

Abbreviations: B12: vitamin B12; CMAP: compound muscle action potentials; DRG: dorsal root ganglia; ENMG: electroneuromyography; MCCT: motor central conduction time; MEP: motor evoked potentials; MMA: methylmalonic acid; MMCoAM: L-methylmalonyl-CoenzymeA mutase; ONLS: overall neuropathy limitations scale; SCV: sensory conduction velocities; SNAP: sensory nerve action potentials; SNN: sensory neuronopathy; SSS: SNAP sum score.
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http://dx.doi.org/10.1080/01616412.2019.1588490DOI Listing
June 2019