Publications by authors named "Sabrina Sacconi"

93 Publications

E-Health & Innovation to Overcome Barriers in Neuromuscular Diseases. Report from the 1st eNMD Congress: Nice, France, March 22-23, 2019.

J Neuromuscul Dis 2021 Apr 2. Epub 2021 Apr 2.

Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice, Peripheral Nervous System and Muscle Department, Rare Neuromuscular Disease Reference Center, ERN-Euro-NMD, Nice, France.

By definition, neuromuscular diseases are rare and fluctuating in terms of symptoms; patients are often lately diagnosed, do not have enough information to understand their condition and be proactive in their management. Usually, insufficient resources or services are available, leading to patients' social burden. From a medical perspective, the rarity of such diseases leads to the unfamiliarity of the medical staff and caregiver and an absence of consensus in disease assessment, treatment, and management. Innovations have to be developed in response to patients' and physicians' unmet needs.It is vital to improve several aspects of patients' quality of life with a better comprehension of their disease, simplify their management and follow-up, help their caregiver, and reduce the social and economic burden for living with a rare debilitating disease. Database construction regrouping patients' data and symptoms according to specific country registration on data privacy will be critical in establishing a clear consensus on neuromuscular disease treatment.Clinicians also need technological innovations to help them recognize neuromuscular diseases, find the best therapeutic approach based on medical consensus, and tools to follow patients' states regularly. Diagnosis also has to be improved by implementing automated systems to analyze a considerable amount of data, representing a significant step forward to accelerate the diagnosis and the patients' follow up. Further, the development of new tools able to precisely measure specific outcomes reliably is of the matter of importance in clinical trials to assess the efficacy of a newly developed compound.In this context, the creation of an expert community is essential to communicate and share ideas. To this end, 97 clinicians, healthcare professionals, researchers, and representatives of private companies from 9 different countries met to discuss the new perspective and challenges to develop and implement innovative tools in the field of neuromuscular diseases.Keywords.
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http://dx.doi.org/10.3233/JND-210655DOI Listing
April 2021

The FacioScapuloHumeral muscular Dystrophy Rasch-built Overall Disability Scale (FSHD-RODS).

Eur J Neurol 2021 Apr 10. Epub 2021 Apr 10.

Department of Neurology, Curaçao Medical Center, Willemstad, Curaçao.

Background: Facioscapulohumeral muscular dystrophy is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authorities' requirements. The aim of this study is to design a patient-reported Rasch-built interval scale on activity and participation for FSHD.

Methods: A pre-phase FSHD-Rasch-built overall disability scale (pre-FSHD-RODS; consisting of n=159 activity/participation items), based on the WHO international classification of disease-related functional consequences was completed by 762 FSHD patients (Netherlands: n=171; UK: n=287; USA n=221; France: n=52; Australia n=32). Part of the patients completed it twice (n=230; interval 2-4 weeks; reliability studies). The pre-FSHD-RODS was subjected to Rasch analyses to create a model fulfilling its requirements. Validity studies were performed through correlation with the Motor Function Measure.

Results: The pre-FSHD-RODS did not meet the Rasch model's expectations. Based on determinants like misfit statistics and misfit residuals, differential item functioning, and local dependency we systematically removed items until a final 38-inquiries (originating from 32 items; six items split) FSHD-RODS was constructed achieving Rasch model's expectations. Adequate test-retest reliability and (cross-cultural and external) validity scores were obtained.

Conclusions: The FSHD-RODS is a disease-specific interval measure suitable for detecting activity and participation restrictions in patients with FSHD with good items'/persons' reliability and validity scores. The use of this scale is recommended in the near future, determining the functional deterioration slope in FSHD per year as a preparation for the upcoming clinical intervention trials in FSHD.
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http://dx.doi.org/10.1111/ene.14863DOI Listing
April 2021

Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC).

Orphanet J Rare Dis 2020 11 24;15(1):330. Epub 2020 Nov 24.

Copenhagen Neuromuscular Center, Section 6921, Rigshospitalet, University of Copenhagen, 2100, Copenhagen, Denmark.

Background: The European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) was launched to register rare muscle glycogenoses in Europe, to facilitate recruitment for research trials and to learn about the phenotypes and disseminate knowledge about the diseases through workshops and websites. A network of twenty full and collaborating partners from eight European countries and the US contributed data on rare muscle glycogenosis in the EUROMAC registry. After approximately 3 years of data collection, the data in the registry was analysed.

Results: Of 282 patients with confirmed diagnoses of muscle glycogenosis, 269 had McArdle disease. New phenotypic features of McArdle disease were suggested, including a higher frequency (51.4%) of fixed weakness than reported before, normal CK values in a minority of patients (6.8%), ptosis in 8 patients, body mass index above background population and number of comorbidities with a higher frequency than in the background population (hypothyroidism, coronary heart disease).

Conclusions: The EUROMAC project and registry have provided insight into new phenotypic features of McArdle disease and the variety of co-comorbidities affecting people with McArdle disease. This should lead to better management of these disorders in the future, including controlling weight, and preventive screening for thyroid and coronary artery diseases, as well as physical examination with attention on occurrence of ptosis and fixed muscle weakness. Normal serum creatine kinase in a minority of patients stresses the need to not discard a diagnosis of McArdle disease even though creatine kinase is normal and episodes of myoglobinuria are absent.
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http://dx.doi.org/10.1186/s13023-020-01562-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687836PMC
November 2020

Motor axonal neuropathy associated with GNE mutations.

Muscle Nerve 2021 03 24;63(3):396-401. Epub 2020 Dec 24.

Côte d'Azur University, Peripheral Nervous System and Muscle Department, Nice University Hospital, Nice, France.

Background: Mutations in the GNE gene have been so far described as predominantly associated with distal lower-limb myopathies. Recent reports describe mutations in this gene in patients with peripheral neuropathy and motor neuron disease.

Methods: We describe three patients displaying motor neuropathy in association with GNE mutations. Clinical, electrophysiological, imaging, pathological, and genetic data are presented in a retrospective manner.

Results: The three patients had different phenotypes, ranging from mildly progressive lower limb weakness to a rapidly progressive 4-limb weakness. Genetic testing revealed GNE gene mutations in all patients; of those mutations, p.(His186Arg) has not been previously reported. All patients showed evidence of axonal motor nerve involvement on electrodiagnostic examination and/or muscle biopsy.

Conclusions: Nerve involvement associated with GNE gene mutations may be an underdiagnosed pathology and may influence clinical presentation and disease progression.
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http://dx.doi.org/10.1002/mus.27102DOI Listing
March 2021

Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry).

Orphanet J Rare Dis 2020 10 15;15(1):187. Epub 2020 Oct 15.

Biomedical Network Research Centre on Rare Diseases (CIBERER), Instituto de Salud Carlos III, and Research Group on Neuromuscular and Mitochondrial Diseases, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Pg. Vall d'Hebron 119, 08035, Barcelona, Catalonia, Spain.

Background: International patient registries are of particular importance for rare disorders, as they may contribute to overcome the lack of knowledge derived from low number of patients and limited awareness of these diseases, and help to learn more about their geographical or population-based specificities, which is relevant for research purposes and for promoting better standards of care and diagnosis. Our objective was to create and implement a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC) and to disseminate the knowledge of these disorders.

Results: Teams from nine different countries (United Kingdom, Spain, Italy, France, Germany, Denmark, Greece, Turkey and USA) created a consortium that developed the first European registry dedicated to rare muscle glycogenoses. A work plan was implemented to design the database and platform that constitute the registry, by choosing clinical, genetics and molecular variables of interest, based on experience gained from previous national registries for similar metabolic disorders. Among dissemination activities, several teaching events were organized in different countries, especially those where the consortium considered the awareness of these diseases needs to be promoted among health professionals and patients.

Conclusion: EUROMAC represents a step forward in the knowledge of those disorders to which it is dedicated, and will have relevant clinical outcomes at the diagnostic, epidemiological, clinical and research level.
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http://dx.doi.org/10.1186/s13023-020-01455-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558742PMC
October 2020

Diagnostic challenges in metabolic myopathies.

Expert Rev Neurother 2020 12 4;20(12):1287-1298. Epub 2020 Oct 4.

Peripheral Nervous System and Muscle Department, Université Cote d'Azur, CHU , Nice, France.

Introduction: Metabolic myopathies comprise a clinically etiological diverse group of disorders caused by defects in cellular energy metabolism including the breakdown of carbohydrates and fatty acids, which include glycogen storage diseases and fatty acid oxidation disorders. Their wide clinical spectrum ranges from infantile severe multisystemic disorders to adult-onset myopathies. To suspect in adults these disorders, clinical features such as exercise intolerance and recurrent myoglobinuria need investigation while another group presents fixed weakness and cardiomyopathy as a clinical pattern.

Areas Covered: In metabolic myopathies, clinical manifestations are important to guide diagnostic tests used in order to lead to the correct diagnosis. The authors searched in literature the most recent techniques developed. The authors present an overview of the most common phenotypes of Pompe disease and what is currently known about the mechanism of ERT treatment. The most common disorders of lipid metabolism are overviewed, with their possible dietary or supplementary treatments.

Expert Commentary: The clinical suspicion is the clue to conduct in-depth investigations in suspected cases of metabolic myopathies that lead to the final diagnosis with biochemical molecular studies and often nowadays by the use of Next Generation Sequencing (NGS) to determine gene mutations.
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http://dx.doi.org/10.1080/14737175.2020.1825943DOI Listing
December 2020

Ultra-high-frequency ultrasound imaging of sural nerve: A comparative study with nerve biopsy in progressive neuropathies.

Muscle Nerve 2021 01 18;63(1):46-51. Epub 2020 Oct 18.

Ultrasound Department, CHU Nice, Université Côte d'Azur, Nice, France.

Introduction: Nerve ultrasound has been used increasingly in clinical practice as a complementary test for diagnostic assessment of neuropathies, but nerve biopsy remains invaluable in certain cases. The aim of this study was to compare ultra-high-frequency ultrasound (UHF-US) to histologic findings in progressive polyneuropathies.

Methods: Ten patients with severe, progressive neuropathies underwent ultrasound evaluation of the sural nerve before nerve biopsy. Ultrasound data were compared with histologic results in a retrospective manner.

Results: Sural nerves were easily identified on UHF-US. Nerve hyperechogenicity correlated with inflammatory infiltrates on biopsy. Nerve fascicles could be identified and measured on ultrasound in the majority of patients.

Discussion: Hyperechogenicity on UHF-US may be a marker of nerve inflammation in neuropathies. Furthermore, the UHF-US probe allows for evaluation of sensory nerves in spite of their small size, providing valuable information on their size and on their internal structure.
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http://dx.doi.org/10.1002/mus.27073DOI Listing
January 2021

Inclusion body myositis in patients with spinocerebellar ataxia types 3 and 6.

J Neurol Neurosurg Psychiatry 2020 08 23;91(8):876-878. Epub 2020 Jun 23.

Department of Neurology, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Noord-Holland, The Netherlands.

Objectives: To describe the combination of spinocerebellar ataxia (SCA) types 3 and 6 and sporadic inclusion body myositis (IBM).

Methods: A description of five patients with SCA type 3 and 6 who were diagnosed with IBM. We explore possible mechanisms explaining the coexistence of both diseases.

Results: The patients with SCA-3 (n=4) and SCA-6 (n=1) developed asymmetric muscle weakness in a pattern suggestive of IBM in the course of their disease. Based on findings of neurological examination and additional investigations (muscle ultrasound, muscle biopsy), the diagnosis of IBM was made in all patients.

Conclusion: We report on five patients with concomitant SCA and IBM. Our cases may merely illustrate coincidental co-occurrence of IBM and SCA-3/SCA-6. However, the presence of SCA mutations could predispose to the development of IBM in some SCA patients, or, the presence of toxic aggregates and malfunctioning of cellular quality control processes in both diseases could indicate a convergence of disease mechanisms.
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http://dx.doi.org/10.1136/jnnp-2020-323270DOI Listing
August 2020

Long-term benefit of enzyme replacement therapy with alglucosidase alfa in adults with Pompe disease: Prospective analysis from the French Pompe Registry.

J Inherit Metab Dis 2020 11 27;43(6):1219-1231. Epub 2020 Jul 27.

Centre de référence des maladies neuromusculaires Nord-Est-Ile de France, Service de Neurologie, CHU Raymond Poincaré, AP-HP, Garches, France.

Despite a wide clinical spectrum, the adult form of Pompe disease is the most common one, and represents more than 90% of diagnosed patients in France. Since the marketing of enzyme replacement therapy (alglucosidase alfa, Myozyme), all reports to date in adults demonstrated an improvement of the walking distance, and a trend toward stabilization of respiratory function, but the majority of these studies were less than 5 years of duration. We report here the findings from 158 treated patients included in the French Pompe Registry, who underwent regular clinical assessments based on commonly used standardized tests (6-minute walking test, MFM scale, sitting vital capacity, MIP and MEP). For longitudinal analyses, the linear mixed effects models were used to assess trends in primary endpoints over time under ERT. A two-phase model better described the changes in distance traveled in the 6-minute walk test and MFM. 6MWT showed an initial significant increase (1.4% ± 0.5/year) followed by a progressive decline (-2.3%/year), with a cut-off point at 2.2 years. A similar pattern was observed in total MFM score (6.6% ± 2.3/year followed by a - 1.1%/year decline after 0.5 years). A single-phase decline with a slope of -0.9 ± 0.1%/year (P < .001) was observed for FVC, and MEP remained stable over the all duration of follow-up. This study provides further evidence that ERT improves walking abilities and likely stabilizes respiratory function in adult patients with Pompe disease, with a ceiling effect for the 6MWT in the first 3 years of treatment.
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http://dx.doi.org/10.1002/jimd.12272DOI Listing
November 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

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

Mitochondrial function in skeletal myofibers is controlled by a TRF2-SIRT3 axis over lifetime.

Aging Cell 2020 03 28;19(3):e13097. Epub 2020 Jan 28.

Université Côte d'Azur, CNRS, Inserm, Institut for Research on Cancer and Aging, Nice (IRCAN), Medical School of Nice, Nice, France.

Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere-capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene (SIRT3) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2-compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the Terf2 gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2-compromised human myotubes. Altogether, these results reveal a TRF2-SIRT3 axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism.
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http://dx.doi.org/10.1111/acel.13097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059141PMC
March 2020

Bilateral scapulothoracic arthrodesis for facioscapulohumeral muscular dystrophy: function, fusion, and respiratory consequences.

J Shoulder Elbow Surg 2020 May 22;29(5):931-940. Epub 2020 Jan 22.

Department of Orthopaedics, University Institute for Locomotion and Sports, Pasteur 2 Hospital, Nice, France.

Background: Scapulothoracic arthrodesis (STA) has been proposed for the treatment of painful scapular winging in patients with facioscapulohumeral muscular dystrophy (FSHD). However, the rate of osseous fusion is variable, and there is a theoretical risk of reduced respiratory function after bilateral STA.

Methods: This was a retrospective study of 10 STAs, performed sequentially, in 5 FSHD patients. The surgical technique involved use of a semitubular plate and wire construct with autograft (iliac crest) interposed between the scapula and rib cage. Osseous fusion, respiratory function, and shoulder function were evaluated. The mean follow-up period was 141 ± 67 months (range, 24-225 months).

Results: Early complications included 1 pneumothorax and 1 pleural effusion. No late complications occurred, and no patients underwent reoperation. On postoperative computed tomography images, complete bony union of the scapula to the ribs was observed in 90% of shoulders (9 of 10). Comparison of preoperative and postoperative pulmonary function test results showed no significant difference in vital capacity (from 87% ± 14% to 85% ± 12%) and forced vital capacity (from 86% ± 16% to 77% ± 15%). Patients gained on average 40° of active forward elevation (from 62° ± 20° to 102° ± 4°) and 22° of abduction (from 58° ± 21° to 89° ± 7°) (P < .001). The mean Subjective Shoulder Value increased from 25% ± 8% to 72% ± 18% (P < .001). All patients were pleased with the results and would recommend the procedure to other persons.

Conclusion: In patients with FSHD, bilateral STA provides satisfactory shoulder function with a high rate of scapulothoracic fusion and few or no significant respiratory repercussions.
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http://dx.doi.org/10.1016/j.jse.2019.10.006DOI Listing
May 2020

Intronic variants in FSHD: testing the potential for CRISPR-Cas9 genome editing.

J Med Genet 2019 12 1;56(12):828-837. Epub 2019 Nov 1.

Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

Background: Facioscapulohumeral dystrophy (FSHD) is associated with partial chromatin relaxation of the retrogene containing D4Z4 macrosatellite repeats on chromosome 4, and transcriptional de-repression of in skeletal muscle. The common form of FSHD, FSHD1, is caused by a D4Z4 repeat array contraction. The less common form, FSHD2, is generally caused by heterozygous variants in .

Methods: We employed whole exome sequencing combined with Sanger sequencing to screen uncharacterised FSHD2 patients for extra-exonic mutations. We also used CRISPR-Cas9 genome editing to repair a pathogenic intronic variant from patient myoblasts.

Results: We identified intronic variants in two FSHD families. In the first family, an intronic variant resulted in partial intron retention and inclusion of the distal 14 nucleotides of intron 13 into the transcript. In the second family, a deep intronic variant in intron 34 resulted in exonisation of 53 nucleotides of intron 34. In both families, the aberrant transcripts are predicted to be non-functional. Deleting the pseudo-exon by CRISPR-Cas9 mediated genome editing in primary and immortalised myoblasts from the index case of the second family restored wild-type SMCHD1 expression to a level that resulted in efficient suppression of .

Conclusions: The estimated intronic mutation frequency of almost 2% in FSHD2, as exemplified by the two novel intronic variants identified here, emphasises the importance of screening for intronic variants in . Furthermore, the efficient suppression of after restoring SMCHD1 levels by genome editing of the mutant allele provides further guidance for therapeutic strategies.
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http://dx.doi.org/10.1136/jmedgenet-2019-106402DOI Listing
December 2019

Deep morphological analysis of muscle biopsies from type III glycogenesis (GSDIII), debranching enzyme deficiency, revealed stereotyped vacuolar myopathy and autophagy impairment.

Acta Neuropathol Commun 2019 10 28;7(1):167. Epub 2019 Oct 28.

APHP, Department of Neurology, Raymond Poincaré Hospital, Garches, France.

Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene.In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model.In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples.These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.
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http://dx.doi.org/10.1186/s40478-019-0815-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819650PMC
October 2019

Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study.

BMC Neurol 2019 Sep 10;19(1):224. Epub 2019 Sep 10.

Department of Neurology, University of Rochester Medical Center, Box 673, 601 Elmwood Ave, Rochester, NY, 14642, USA.

Background: Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process.

Methods/design: The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials.

Discussion: To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics.

Trial Registration: clinicaltrials.gov NCT03458832; Date of registration: 1/11/2018.
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http://dx.doi.org/10.1186/s12883-019-1452-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734593PMC
September 2019

Mannose 6-phosphonate labelling: A key for processing the therapeutic enzyme in Pompe disease.

J Cell Mol Med 2019 09 10;23(9):6499-6503. Epub 2019 Jul 10.

NanoMedSyn, Montpellier, France.

In the search of a better enzyme therapy in Pompe disease, the conjugation of mannose 6-phosphonates to the recombinant enzyme appeared as an enhancer of its efficacy. Here, we demonstrated that the increased efficacy of the conjugated enzyme is partly due to a higher intracellular maturation because of its insensitiveness to acid phosphatases during the routing to lysosomes.
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http://dx.doi.org/10.1111/jcmm.14516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6714136PMC
September 2019

SMCHD1 mutation spectrum for facioscapulohumeral muscular dystrophy type 2 (FSHD2) and Bosma arhinia microphthalmia syndrome (BAMS) reveals disease-specific localisation of variants in the ATPase domain.

J Med Genet 2019 10 26;56(10):693-700. Epub 2019 Jun 26.

Human Genetics, Leids Universitair Medisch Centrum, Leiden, The Netherlands.

Background: Variants in the Structural Maintenance of Chromosomes flexible Hinge Domain-containing protein 1 () can cause facioscapulohumeral muscular dystrophy type 2 (FSHD2) and the unrelated Bosma arhinia microphthalmia syndrome (BAMS). In FSHD2, pathogenic variants are found anywhere in SMCHD1 while in BAMS, pathogenic variants are restricted to the extended ATPase domain. Irrespective of the phenotypic outcome, both FSHD2-associated and BAMS-associated variants result in quantifiable local DNA hypomethylation. We compared FSHD2, BAMS and non-pathogenic variants to derive genotype-phenotype relationships.

Methods: Examination of variants and methylation of the SMCHD1-sensitive FSHD locus in 187 FSHD2 families, 41 patients with BAMS and in control individuals. Analysis of variants in a three-dimensional model of the ATPase domain of SMCHD1.

Results: methylation analysis is essential to establish pathogenicity of variants. Although the FSHD2 mutation spectrum includes all types of variants covering the entire locus, missense variants are significantly enriched in the extended ATPase domain. Identification of recurrent variants suggests disease-specific residues for FSHD2 and in BAMS, consistent with a largely disease-specific localisation of variants in SMCHD1.

Conclusions: The localisation of missense variants within the ATPase domain of SMCHD1 may contribute to the differences in phenotypic outcome.
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http://dx.doi.org/10.1136/jmedgenet-2019-106168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800092PMC
October 2019

A multicenter retrospective study of charcot-marie-tooth disease type 4B (CMT4B) associated with mutations in myotubularin-related proteins (MTMRs).

Ann Neurol 2019 07 27;86(1):55-67. Epub 2019 May 27.

Institute of Experimental Neurology (InSpe), Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy.

Objective: Charcot-Marie-Tooth (CMT) disease 4B1 and 4B2 (CMT4B1/B2) are characterized by recessive inheritance, early onset, severe course, slowed nerve conduction, and myelin outfoldings. CMT4B3 shows a more heterogeneous phenotype. All are associated with myotubularin-related protein (MTMR) mutations. We conducted a multicenter, retrospective study to better characterize CMT4B.

Methods: We collected clinical and genetic data from CMT4B subjects in 18 centers using a predefined minimal data set including Medical Research Council (MRC) scores of nine muscle pairs and CMT Neuropathy Score.

Results: There were 50 patients, 21 of whom never reported before, carrying 44 mutations, of which 21 were novel and six representing novel disease associations of known rare variants. CMT4B1 patients had significantly more-severe disease than CMT4B2, with earlier onset, more-frequent motor milestones delay, wheelchair use, and respiratory involvement as well as worse MRC scores and motor CMT Examination Score components despite younger age at examination. Vocal cord involvement was common in both subtypes, whereas glaucoma occurred in CMT4B2 only. Nerve conduction velocities were similarly slowed in both subtypes. Regression analyses showed that disease severity is significantly associated with age in CMT4B1. Slopes are steeper for CMT4B1, indicating faster disease progression. Almost none of the mutations in the MTMR2 and MTMR13 genes, responsible for CMT4B1 and B2, respectively, influence the correlation between disease severity and age, in agreement with the hypothesis of a complete loss of function of MTMR2/13 proteins for such mutations.

Interpretation: This is the largest CMT4B series ever reported, demonstrating that CMT4B1 is significantly more severe than CMT4B2, and allowing an estimate of prognosis. ANN NEUROL 2019.
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http://dx.doi.org/10.1002/ana.25500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581441PMC
July 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

FSHD1 and FSHD2 form a disease continuum.

Neurology 2019 05 12;92(19):e2273-e2285. Epub 2019 Apr 12.

From the Peripheral Nervous System (S.S., M.G., C.C., A.P.), Muscle & ALS Department, Pasteur 2 Hospital, Centre Hospitalier Universitaire de Nice, and Institute for Research on Cancer and Aging of Nice (S.S., C.B., N.L., P.N., G.C.), CNRS, INSERM, Université Côte d'Azur; Department of Genetics and Molecular Biology (A.B.-S., S.R., M.J.), Cochin Hospital, Paris, France; Department of Human Genetics (R.J.L.F.L., S.M.v.d.M.), Leiden University Medical Center, the Netherlands; Rare Neuromuscular Diseases Centre (C.C.), Department of Human Neuroscience, Sapienza University of Rome, Italy; Pathology Department (F.C.), CHRU of Caen, INSERM U1075, University of Caen, Normandy; Myology Institute (T.S., A.B., B.E.), Center of Research in Myology, APHP, Sorbonne Université, UPMC Univ Paris 06, INSERM UMRS974, CNRS FRE3617, Paris; Electromyography and Neuromuscular Department (C.V., F.B., P.P.), Neurologic Hospital, Lyon East Hospital Group, Lyon-Bron, France; Neuromuscular Center, Department of Neuroscience (M.C., E.P.), and Clinical Genetics Unit, Department of Women's and Children's Health (L.S.), University of Padova, Italy; Institut Imagine, Imagine Bioinfomatics Platform (M.B.), Paris Descartes University; Département de Neurologie (A.E.-L.), Hôpitaux Universitaires, Strasbourg; Nord/Est/Ile de France Neuromuscular Center (P.L.), Neurology Department, Raymond Poincaré Teaching Hospital, Garches; INSERM U1179 (P.L.), END-ICAP, Versailles Saint-Quentin-en-Yvelines University, Montigny-le-Bretonneux, France; and IRP Città della Speranza (L.S.), Padova, Italy.

Objective: To compare the clinical features of patients showing a classical phenotype of facioscapulohumeral muscular dystrophy (FSHD) with genetic and epigenetic characteristics of the FSHD1 and FSHD2 loci D4Z4 and .

Methods: This is a national multicenter cohort study. We measured motor strength, motor function, and disease severity by manual muscle testing sumscore, Brooke and Vignos scores, clinical severity score (CSS), and age-corrected CSS, respectively. We correlated these scores with genetic (D4Z4 repeat size and haplotype; variant status) and epigenetic (D4Z4 methylation) parameters.

Results: We included 103 patients: 54 men and 49 women. Among them, we identified 64 patients with FSHD1 and 20 patients with FSHD2. Seven patients had genetic and epigenetic characteristics of FSHD1 and FSHD2, all carrying repeats of 9-10 D4Z4 repeat units (RU) and a pathogenic variant. In the remaining patients, FSHD was genetically excluded or remained unconfirmed. All clinically affected mutation carriers had a D4Z4 repeat of 9-16 RU on a disease permissive 4qA haplotype. These patients are significantly more severely affected by all clinical scales when compared to patients with FSHD1 with upper-sized FSHD1 alleles (8-10 RU).

Conclusion: The overlap between FSHD1 and FSHD2 patients in the 9-10 D4Z4 RU range suggests that FSHD1 and FSHD2 form a disease continuum. The previously established repeat size threshold for FSHD1 (1-10 RU) and FSHD2 (11-20 RU) needs to be reconsidered.

Clinicaltrialsgov Identifier: NCT01970735.
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http://dx.doi.org/10.1212/WNL.0000000000007456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537132PMC
May 2019

[E-Health and therapeutic innovation].

Med Sci (Paris) 2019 Mar 3;35 Hors série n° 1:42-45. Epub 2019 Apr 3.

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http://dx.doi.org/10.1051/medsci/2019052DOI Listing
March 2019

Expanding the importance of HMERF titinopathy: new mutations and clinical aspects.

J Neurol 2019 Mar 21;266(3):680-690. Epub 2019 Jan 21.

Department of Neurology, Neuromuscular Research Center, Tampere University Hospital and University of Tampere, 33014, Tampere, Finland.

Objective: Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied.

Methods: Altogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated.

Results: Three families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF.

Conclusions: Our collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.
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http://dx.doi.org/10.1007/s00415-019-09187-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6394805PMC
March 2019

The French National Registry of patients with Facioscapulohumeral muscular dystrophy.

Orphanet J Rare Dis 2018 12 4;13(1):218. Epub 2018 Dec 4.

Aix Marseille Univ, INSERM, MMG, Bioinformatics & Genetics, Marseille, France.

Background: Facioscapulohumeral muscular dystrophy is a rare inherited neuromuscular disease with an estimated prevalence of 1/20,000 and France therefore harbors about 3000 FSHD patients. With research progress and the development of targeted therapies, patients' identification through registries can facilitate and improve recruitment in clinical trials and studies.

Results: The French National Registry of FSHD patients was designed as a mixed model registry involving both patients and physicians, through self-report and clinical evaluation questionnaires respectively, to collect molecular and clinical data. Because of the limited number of patients, data quality is a major goal of the registry and various automatic data control features have been implemented in the bioinformatics system. In parallel, data are manually validated by molecular and clinical curators. Since its creation in 2013, data from 638 FSHD patients have been collected, representing about 21% of the French FSHD population. The mixed model strategy allowed to collect 59.1% of data from both patients and clinicians; 26 and 14.9% from respectively patients and clinicians only. With the identification of the FSHD1 and FSHD2 forms, specific questionnaires have been designed. Though FSHD2 patients are progressively included, FSHD1 patients still account for the majority (94.9%). The registry is compatible with the FAIR principles as data are Findable, Accessible and Interoperable. We thus used molecular standards and standardized clinical terms used by the FILNEMUS French network of reference centers for the diagnosis and follow-up of patients suffering from a rare neuromuscular disease. The implemented clinical terms mostly map to dictionaries and terminology systems such as SNOMED-CT (75% of terms), CTV3 (61.7%) and NCIt (53.3%). Because of the sensitive nature of data, they are not directly reusable and can only be accessed as aggregated data after evaluation and approval by the registry oversight committee.

Conclusions: The French National Registry of FSHD patients belongs to a national effort to develop databases, which should now interact with other initiatives to build a European and/or an international FSHD virtual registry for the benefits of patients. It is accessible at www.fshd.fr and various useful information, links, and documents, including a video, are available for patients and professionals.
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http://dx.doi.org/10.1186/s13023-018-0960-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280451PMC
December 2018

Dynamic transcriptomic analysis reveals suppression of PGC1α/ERRα drives perturbed myogenesis in facioscapulohumeral muscular dystrophy.

Hum Mol Genet 2019 04;28(8):1244-1259

Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, King's College London, London, UK.

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic derepression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. For further analysis here, we selected pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α), the cofactor and activator of oestrogen-related receptor α (ERRα). PGC1α knock-down caused hypotrophic myotubes to form from control myoblasts. Known ERRα agonists and safe food supplements biochanin A, daidzein or genistein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1α-ERRα axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily available food supplements.
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http://dx.doi.org/10.1093/hmg/ddy405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6452176PMC
April 2019

Cis D4Z4 repeat duplications associated with facioscapulohumeral muscular dystrophy type 2.

Hum Mol Genet 2018 10;27(20):3488-3497

Department of Human Genetics, Leiden University Medical Center, Leiden, Netherlands.

Facioscapulohumeral muscular dystrophy, known in genetic forms FSHD1 and FSHD2, is associated with D4Z4 repeat array chromatin relaxation and somatic derepression of DUX4 located in D4Z4. A complete copy of DUX4 is present on 4qA chromosomes, but not on the D4Z4-like repeats of chromosomes 4qB or 10. Normally, the D4Z4 repeat varies between 8 and 100 units, while in FSHD1 it is only 1-10 units. In the rare genetic form FSHD2, a combination of a 4qA allele with a D4Z4 repeat size of 8-20 units and heterozygous pathogenic variants in the chromatin modifier SMCHD1 causes DUX4 derepression and disease. In this study, we identified 11/79 (14%) FSHD2 patients with unusually large 4qA alleles of 21-70 D4Z4 units. By a combination of Southern blotting and molecular combing, we show that 8/11 (73%) of these unusually large 4qA alleles represent duplication alleles in which the long D4Z4 repeat arrays are followed by a small FSHD-sized D4Z4 repeat array duplication. We also show that these duplication alleles are associated with DUX4 expression. This duplication allele frequency is significantly higher than in controls (2.9%), FSHD1 patients (1.4%) and in FSHD2 patients with typical 4qA alleles of 8-20 D4Z4 units (1.5%). Segregation analysis shows that, similar to typical 8-20 units FSHD2 alleles, duplication alleles only cause FSHD in combination with a pathogenic variant in SMCHD1. We conclude that cis duplications of D4Z4 repeats explain DUX4 expression and disease presentation in FSHD2 families with unusual long D4Z4 repeats on 4qA chromosomes.
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http://dx.doi.org/10.1093/hmg/ddy236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168970PMC
October 2018

Late-onset Pompe disease in France: molecular features and epidemiology from a nationwide study.

J Inherit Metab Dis 2018 11 28;41(6):937-946. Epub 2018 Aug 28.

Centre de Référence des Maladies Neuromusculaires Nord-Est-Ile de France, Service de Neurologie, CHU Raymond Poincaré, AP-HP, 104 bd Raymond Poincaré, 92380, Garches, France.

Pompe disease (PD) is caused by a deficiency of lysosomal acid α-glucosidase resulting from mutations in the GAA gene. The clinical spectrum ranges from a rapidly fatal multisystemic disorder (classic PD, onset < 1 year) to a milder adult onset myopathy. The aims of this study were to characterize the GAA mutations, to establish the disease epidemiology, and to identify potential genotype-phenotype correlations in French late-onset PD patients (onset ≥ 2 years) diagnosed since the 1970s. Data were collected from the two main laboratories involved in PD diagnosis and from the French Pompe registry. Two hundred forty-six patients (130 females and 116 males) were included, with a mean age at diagnosis of 43 years. Eighty-three different mutations were identified in the GAA gene, among which 28 were novel. These variants were spread all over the sequence and included 42 missense (one affecting start codon), 8 nonsense, 15 frameshift, 14 splice mutations, 3 small in-frame deletions, and one large deletion. The common c.-32-13T>G mutation was detected in 151/170 index cases. Other frequent mutations included the exon 18 deletion, the c.525del, and the missense mutations c.1927G>A (p.Gly643Arg) and c.655G>A (p.Gly219Arg). Patients carrying the c.-32-13T>G mutation had an older mean age at onset than patients non-exhibiting this mutation (36 versus 25 years). Patients with the same genotype had a highly variable age at onset. We estimated the frequency of late-onset PD in France around 1/69,927 newborns. In conclusion, we characterized the French cohort of late-onset PD patients through a nationwide study covering more than 40 years.
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http://dx.doi.org/10.1007/s10545-018-0243-7DOI Listing
November 2018

New variant of necklace fibres display peculiar lysosomal structures and mitophagy.

Neuromuscul Disord 2018 10 2;28(10):846-856. Epub 2018 Jul 2.

Department of Neuropathology, Charité - Universitätsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany. Electronic address:

Here, we describe a new variant of necklace fibres with specific myopathological features that have not been described thus far. They were observed in two patients, from two independent families with identical DNM2 (dynamin 2) mutation (c.1106 G > A (p.Arg369Gln)), displaying mildly heterogeneous clinical phenotypes. The variant is characterized by lysosomal inclusions, arranged in a necklace pattern, containing homogenous material, devoid of myonuclei. The so-called necklace region has a certain characteristic distance to the sarcolemma. Electron microscopy, including three dimensional reconstructions of serial section images highlights their ultrastructural properties and relation to neighbouring organelles. This new pattern is compared to the previously reported patterns in muscle biopsies containing necklace fibres associated with MTM1- and DNM2-mutations.
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http://dx.doi.org/10.1016/j.nmd.2018.06.010DOI Listing
October 2018

Inflammatory facioscapulohumeral muscular dystrophy type 2 in 18p deletion syndrome.

Am J Med Genet A 2018 08 28;176(8):1760-1763. Epub 2018 Jul 28.

Peripheral Nervous System, Muscle and ALS Department, Nice University Hospital, Université Côte d'Azur, Nice, France.

Facioscapulohumeral muscular dystrophy (FSHD) has been shown to be related to genetic and epigenetic derepression of DUX4 (mapping to chromosome 4), a gene located within a repeat array of D4Z4 sequences of polymorphic length. FSHD type 1 (FSHD1) is associated with pathogenic D4Z4 repeat array contraction, while FSHD type 2 (FSHD2) is associated with SMCHD1 variants (a chromatin modifier gene that maps to the short arm of chromosome 18). Both FSHD types require permissive polyadenylation signal (4qA) downstream of the D4Z4 array.
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http://dx.doi.org/10.1002/ajmg.a.38843DOI Listing
August 2018