Long-term prognosis of fatty-acid oxidation disorders in adults: Optimism despite the limited effective therapies available.

INTRODUCTION: Fatty-acid oxidation disorders (FAODs) are recessive genetic diseases. MATERIALS AND METHODS: We report here clinical and paraclinical data from a retrospective study of 44 adults with muscular FAODs from six French reference centers for neuromuscular or metabolic diseases. RESULTS: The study cohort consisted of 44 adult patients: 14 with carnitine palmitoyl transferase 2 deficiency (32%), nine with multiple acyl-CoA deficiency (20%), 13 with very long-chain acyl-CoA dehydrogenase deficiency (30%), three with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (7%), and five with short-chain acyl-CoA dehydrogenase deficiency (11%). Disease onset occurred during childhood in the majority of patients (59%), with a mean age at onset of 15 years (range = 0.5-35) and a mean of 12.6 years (range = 0-58) from disease onset to diagnosis. The principal symptoms were acute muscle manifestations (rhabdomyolysis, exercise intolerance, myalgia), sometimes associated with permanent muscle weakness. Episodes of rhabdomyolysis were frequent (84%), with a mean creatinine kinase level of 68,958 U/L (range = 660-300,000). General metabolic complications were observed in 58% of patients, respiratory manifestations in 18% of cases, and cardiological manifestations in 9% of cases. Fasting acylcarnitine profile was used to orient genetic explorations in 65% of cases. After a mean follow-up of 10 years, 33% of patients were asymptomatic and 56% continued to display symptoms after exercise. The frequency of rhabdomyolysis decreased after diagnosis in 64% of cases. CONCLUSION: A standardized register would complete this cohort description of muscular forms of FAODs with exhaustive data, making it possible to assess the efficacy of therapeutic protocols in real-life conditions and during the long-term follow-up of patients.

Clinical and electrophysiological characteristics of women with X-linked Charcot-Marie-Tooth disease.

BACKGROUND: X-Linked Charcot-Marie-Tooth disease type 1 (CMTX1) is characterized by gender differences in clinical severity. Women are usually clinically affected later and less severely than men. However, their clinical presentation appears to be heterogenous. Our aim was to extend the phenotypic description in a large series of women with CMTX1. METHODS: We retrospectively evaluated 263 patients with CMTX1 from 11 French reference centers. Demographic, clinical, and nerve conduction data were collected. The severity was assessed by CMT Examination Score (CMTES) and Overall Neuropathy Limitations Scale (ONLS) scores. We looked for asymmetrical strength, heterogeneous motor nerve conduction velocity (MNCV), and motor conduction blocks (CB). RESULTS: The study included 137 women and 126 men from 151 families. Women had significantly more asymmetric motor deficits and MNCV than men. Women with an age of onset after 19 years were milder. Two groups of women were identified after 48 years of age. The first group represented 55%, with women progressing as severely as men, however, with a later onset age. The second group had mild or no symptoms. Some 39% of women had motor CB. Four women received intravenous immunoglobulin before being diagnosed with CMTX1. CONCLUSIONS: We identified two subgroups of women with CMTX1 who were over 48 years of age. Additionally, we have demonstrated that women with CMTX can exhibit an atypical clinical presentation, which may result in misdiagnosis. Therefore, in women presenting with chronic neuropathy, the presence of clinical asymmetry, heterogeneous MNCV, and/or motor CB should raise suspicion for X-linked CMT, particularly CMTX1, and be included in the differential diagnosis.

SORD-related peripheral neuropathy in a French and Swiss cohort: Clinical features, genetic analyses, and sorbitol dosages.

BACKGROUND AND PURPOSE: Biallelic variants in SORD have been reported as one of the main recessive causes for hereditary peripheral neuropathies such as Charcot-Marie-Tooth disease type 2 (CMT2) and distal hereditary motor neuropathy (dHMN) resulting in lower limb (LL) weakness and muscular atrophy. In this study, phenotype and genotype landscapes of SORD-related peripheral neuropathies were described in a French and Swiss cohort. Serum sorbitol dosages were used to classify SORD variants. METHODS: Patients followed at neuromuscular reference centres in France and Switzerland were ascertained. Sanger sequencing and next generation sequencing were performed to sequence SORD, and mass spectrometry was used to measure patients' serum sorbitol. RESULTS: Thirty patients had SORD peripheral neuropathy associating LL weakness with muscular atrophy, foot deformities (87%), and sometimes proximal LL weakness (20%) or distal upper limb weakness (50%). Eighteen had dHMN, nine had CMT2, and three had intermediate CMT. Most of them had a mild or moderate disease severity. Sixteen carried a homozygous c.757delG (p.Ala253Glnfs*27) variant, and 11 carried compound heterozygous variants, among which four variants were not yet reported: c.403C > G, c.379G > A, c.68_100 + 1dup, and c.850dup. Two unrelated patients with different origins carried a homozygous c.458C > A variant, and one patient carried a new homozygous c.786 + 5G > A variant. Mean serum sorbitol levels were 17.01 mg/L ± 8.9 SD for patients carrying SORD variants. CONCLUSIONS: This SORD-inherited peripheral neuropathy cohort of 30 patients showed homogeneous clinical presentation and systematically elevated sorbitol levels (22-fold) compared to controls, with both diagnostic and potential therapeutic implications.

Expanding the phenotypic variability of MORC2 gene mutations: From Charcot-Marie-Tooth disease to late-onset pure motor neuropathy.

MORC2 gene encodes a ubiquitously expressed nuclear protein involved in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous mutations in MORC2 gene have been associated with a spectrum of disorders affecting the peripheral nervous system such as Charcot-Marie-Tooth (CMT2Z), spinal muscular atrophy-like with or without cerebellar involvement, and a developmental syndrome associated with impaired growth, craniofacial dysmorphism and axonal neuropathy (DIGFAN syndrome). Such variability in clinical manifestations associated with the increasing number of variants of unknown significance detected by next-generation sequencing constitutes a serious diagnostic challenge. Here we report the characterization of an in vitro model to evaluate the pathogenicity of variants of unknown significance based on MORC2 overexpression in a neuroblastoma cell line SH-EP or cortical neurons. Likewise, we show that MORC2 mutants affect survival and trigger apoptosis over time in SH-EP cell line. Furthermore, overexpression in primary cortical neurons increases apoptotic cell death and decreases neurite outgrowth. Altogether, these approaches establish the pathogenicity of two new variants p.Gly444Arg and p.His446Gln in three patients from two families. These new mutations in MORC2 gene are associated with autosomal dominant CMT and with adult late onset proximal motor neuropathy, further increasing the spectrum of clinical manifestations associated with MORC2 mutations.

Genotype-phenotype correlations in valosin-containing protein disease: a retrospective muticentre study.

BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Paget's disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC <70% and being a full-time wheelchair user were associated with death. CONCLUSION: This study expands the knowledge on the phenotypic presentation, natural history, genotype-phenotype correlations and risk factors for disease progression of VCP disease and is useful to improve the care provided to patient with this complex disease.

No effect of resveratrol on fatty acid oxidation or exercise capacity in patients with fatty acid oxidation disorders: A randomized clinical cross-over trial.

The objective was to investigate whether resveratrol (RSV) can improve exercise capacity in patients with fatty acid oxidation (FAO) disorders. The study was a randomized, double-blind, cross-over trial. Nine patients with very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency or carnitine palmitoyl transferase (CPT) II deficiency were randomized to receive either 8 weeks of 1000 mg day-1 RSV or placebo (P) followed by a 4-weeks wash-out period and subsequently 8 weeks of the opposite treatment. Primary outcome measures were heart rate and FAO as measured via stable isotope technique during constant workload exercise. Secondary outcome measures included fat and glucose metabolism; perceived exertion; as well as subjective measures of energy expenditure, fatigue, and daily function. Eight participants completed the trial. Heart rate did not differ at the end of exercise after treatment with RSV vs placebo (P = .063). Rate of oxidation of palmitate at end of exercise was not different with 1.5 ± 0.8 (RSV) vs 1.3 ± 0.6 (P) µmol kg-1  min-1 (P = .109). Secondary outcomes did not change except for increased plasma glycerol and decreased plasma glucose levels at the end of exercise after treatment with RSV vs placebo. A daily dose of 1000 mg resveratrol does not improve exercise capacity or FAO during exercise in patients with CPTII or VLCAD deficiencies.

Motor and respiratory decline in patients with late onset Pompe disease after cessation of enzyme replacement therapy during COVID-19 pandemic.

BACKGROUND AND PURPOSE: Data on interruption of enzyme replacement therapy (ERT) are scarce in late onset Pompe disease. Due to the COVID-19 crisis, eight neuromuscular reference centers in France were obligated to stop the treatment for 31 patients. METHODS: We collected the motor and respiratory data from our French registry, before COVID-19 and at treatment restart. RESULTS: In 2.2 months (mean), patients showed a significant deterioration of 37 m (mean) in the 6-min walk test and a loss of 210 ml (mean) of forced vital capacity, without ad integrum restoration after 3 months of ERT restart. CONCLUSIONS: This national study based on data from the French Pompe Registry shows that the interruption of ERT, even as short as a few months, worsens Pompe patients' motor and respiratory function.

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

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.

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

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.

Long term longitudinal study of muscle function in patients with glycogen storage disease type IIIa.

Glycogen storage disease type III (GSDIII) is an autosomal recessive disorder caused by mutations in the AGL gene coding for the glycogen debranching enzyme. Current therapy is based on dietary adaptations but new preclinical therapies are emerging. The identification of outcome measures which are sensitive to disease progression becomes critical to assess the efficacy of new treatments in upcoming clinical trials. In order to prepare future longitudinal studies or therapeutic trials with large cohorts, information about disease progression is required. In this study we present preliminary longitudinal data of Motor Function Measure (MFM), timed tests, Purdue pegboard test, and handgrip strength collected over 5 to 9years of follow-up in 13 patients with GSDIII aged between 13 and 56years old. Follow-up for nine of the 13 patients was up to 9years. Similarly to our previous cross-sectional retrospective study, handgrip strength significantly decreased with age in patients older than 37years. MFM scores started to decline after the age of 35. The Purdue pegboard score also significantly reduced with increasing age (from 13years of age) but with large inter-visit variations. The time to stand up from a chair or to climb 4 stairs increased dramatically in some but not all patients older than 30years old. In conclusion, this preliminary longitudinal study suggests that MFM and handgrip strength are the most sensitive muscle function outcome measures in GSDIII patients from the end of their third decade. Sensitive muscle outcome measures remain to be identified in younger GSDIII patients but is challenging as muscle symptoms remain discrete and often present as accumulated fatigue.

Cognitive profile of patients with glycogen storage disease type III: a clinical description of seven cases.

BACKGROUND: Glycogen storage disease type III (GSDIII) is a rare autosomal recessive disorder due to glycogen debranching enzyme (GDE) deficiency. It results in a multisystemic disease with predominant hepatic and myopathic symptoms. While frequent social maladjustment has been observed in our clinical practice, cognitive and psychological disturbances have never been assessed. The aim of this pilot study was to examine and characterize the cognitive profile of patients with GSDIII. METHODS: Seven patients (six women and one man, mean age: 38.7 ± 11.6 years) with GSDIII underwent a neuropsychological set of tests assessing global cognitive efficiency, executive functions, social cognition, apathy, and episodic memory. RESULTS: All patients presented previous psychopathological history. We observed attention fluctuations for each patient, and impaired global cognitive efficiency with deficiencies in executive functions in 5/7 patients. Emotional skills (social cognition) were impaired in five patients. Memory was mostly preserved. CONCLUSION: The impairment in social cognition (recognition of emotions and ability to attribute mental states to others) and executive functions observed could be a consequence of orbito-frontal dysfunction due to the abnormal glycogen metabolism characteristic of the underlying disease. These results are consistent with the hypothesis of a central nervous system involvement in patients with GSDIII, but need to be confirmed in future research. This could explain the social and economic difficulties, and the lack of compliance to the medical follow-up presented by these patients. It suggests that these disturbances need to be taken into account when planning the medical management of patients with GSDIII.

Clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in STIM1.

BACKGROUND: Tubular aggregate myopathies (TAMs) are muscle disorders characterised by abnormal accumulations of densely packed single-walled or double-walled membrane tubules in muscle fibres. Recently, STIM1, encoding a major calcium sensor of the endoplasmic reticulum, was identified as a TAM gene. METHODS: The present study aims to define the clinical, histological and ultrastructural phenotype of tubular aggregate myopathy and to assess the STIM1 mutation spectrum. RESULTS: We describe six new TAM families harbouring one known and four novel STIM1 mutations. All identified mutations are heterozygous missense mutations affecting highly conserved amino acids in the calcium-binding EF-hand domains, demonstrating the presence of a mutation hot spot for TAM. We show that the mutations induce constitutive STIM1 clustering, strongly suggesting that calcium sensing and consequently calcium homoeostasis is impaired. Histological and ultrastructural analyses define a common picture with tubular aggregates labelled with Gomori trichrome and Nicotinamide adenine dinucleotide (NADH) tetrazolium reductase, substantiating their endoplasmic reticulum origin. The aggregates were observed in both fibre types and were often accompanied by nuclear internalisation and fibre size variability. The phenotypical spectrum ranged from childhood onset progressive muscle weakness and elevated creatine kinase levels to adult-onset myalgia without muscle weakness and normal CK levels. CONCLUSIONS: The present study expands the phenotypical spectrum of STIM1-related tubular aggregate myopathy. STIM1 should therefore be considered for patients with tubular aggregate myopathies involving either muscle weakness or myalgia as the first and predominant clinical sign.

The FLNC Ala1186Val Variant Linked to Cytoplasmic Body Myopathy and Cardiomyopathy Causes Protein Instability.

Filamin C-related disorders include myopathies and cardiomyopathies linked to variants in the FLNC gene. Filamin C belongs to a family of actin-binding proteins involved in sarcomere stability. This study investigates the pathogenic impact of the FLNC c.3557C > T (p.Ala1186Val) pathogenic variant associated with an early-onset cytoplasmic body myopathy and cardiomyopathy in three unrelated patients. We performed clinical imaging and myopathologic and genetic characterization of three patients with an early-onset myopathy and cardiomyopathy. Bioinformatics analysis, variant interpretation, and protein structure analysis were performed to validate and assess the effects of the filamin C variant. All patients presented with a homogeneous clinical phenotype marked by a severe contractural myopathy, leading to loss of gait. There was prominent respiratory involvement and restrictive or hypertrophic cardiomyopathies. The Ala1186Val variant is located in the interstrand loop involved in intradomain stabilization and/or interdomain interactions with neighbor Ig-like domains. 3D modeling highlights local structural changes involving nearby residues and probably impacts the protein stability, causing protein aggregation in the form of cytoplasmic bodies. Myopathologic studies have disclosed the prominent aggregation and upregulation of the aggrephagy-associated proteins LC3B and p62. As a whole, the Ala1186Val variant in the FLNC gene provokes a severe myopathy with contractures, respiratory involvement, and cardiomyopathy due to protein aggregation in patients' muscles.

Hereditary transthyretin amyloidosis in middle-aged and elderly patients with idiopathic polyneuropathy: a nationwide prospective study.

BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv) is an adult-onset autosomal dominant disease resulting from TTR gene pathogenic variants. ATTRv often presents as a progressive polyneuropathy, and effective ATTRv treatments are available. METHODS: In this 5 year-long (2017-2021) nationwide prospective study, we systematically analysed the TTR gene in French patients with age >50 years with a progressive idiopathic polyneuropathy. RESULTS: 553 patients (70% males) with a mean age of 70 years were included. A TTR gene pathogenic variant was found in 15 patients (2.7%), including the Val30Met TTR variation in 10 cases. In comparison with patients with no TTR gene pathogenic variants (n = 538), patients with TTR pathogenic variants more often presented with orthostatic hypotension (53 vs. 21%, p = .007), significant weight loss (33 vs 11%, p = .024) and rapidly deteriorating nerve conduction studies (26 vs. 8%, p = .03). ATTRv diagnosis led to amyloid cardiomyopathy diagnosis in 11 cases, ATTRv specific treatment in all cases and identification of 15 additional ATTRv cases among relatives. CONCLUSION: In this nationwide prospective study, we found ATTRv in 2.7% of patients with age >50 years with a progressive polyneuropathy. These results are highly important for the early identification of patients in need of disease-modifying treatments.

Muscle pathology in 31 patients with calpain 3 gene mutations..

BACKGROUND AND PURPOSE: At present, more than 20 different forms of limb-girdle muscular dystrophies (LGMDs) are known (at least 7 autosomal dominant and 14 autosomal recessive). Although these different forms show some typical phenotypic characteristics, the existing clinical overlap makes their differential diagnosis difficult. Limb-girdle muscular dystrophy type 2 (LGMD2A) is the most prevalent LGMD in many European as well as Brazilian communities and is caused by mutations in the gene CAPN3. Laboratory testing, such as calpain immunohistochemistry and Western-blot analysis, is not totally reliable, since up to 20% of molecularly confirmed LGMD2A show normal content of calpain 3 and a third of LGMD2A biopsies have normal calpain 3 proteo-lytic activity in the muscle. Thus, genetic testing is considered as the only reliable diagnostic criterion in LGMD2A. MATERIAL AND METHODS: In an attempt to find a correlation between genotype and muscle pathology in limb-girdle muscular dystrophy 2A we performed histopathological investigation of a group of 31 patients subdivided according to the type of pathologic CAPN3 gene mutation. RESULTS: In all biopsies typical features of muscular dystrophy such as fiber necrosis and regeneration, variation in fiber size and fibrosis were noted. Lobulated fibers were often encountered in the muscle biopsies of LGMD2A patients. Such fibers were more frequent in patients with 550delA mutation. CONCLUSIONS: These findings may be helpful in establishing diagnostic strategies in LGMD.

Myasthenia gravis treatment in the elderly presents with a significant iatrogenic risk: a multicentric retrospective study.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease treated with acetylcholinesterase inhibitors and immunosuppressant/immunomodulatory drugs. MG is frequently diagnosed in elderly patients, a fragile population in which treatment adverse effects (TAE) have not been evaluated until now. METHODS: We retrospectively analysed the files of all MG patients with disease onset after age 70 years in four French University Hospitals, including clinical, electrophysiological, biological, and treatment data, with an emphasis on TAE. MG outcomes were assessed using the Myasthenia Gravis Foundation of America (MGFA) status scale. RESULTS: We included 138 patients (59% of men) with a mean follow-up of 4.5 years (range 1-19). Mean age at diagnosis was 78 years (70-93). Anti-acetylcholine receptor antibodies were found in 87% of cases, electrophysiological abnormalities in 82%, and thymoma in 10%. MG outcome was good in a majority of cases, with 76% of treated patients presenting with alleviated symptoms at follow-up. TAE were observed in 41% of patients, including severe TAE in 14% of cases. Seven patients (5.1%) died, including four (2.9%) from MG-related respiratory failure, and three (2.2%) from MG treatment-related complications, i.e., sepsis in 2 cases and brain toxoplasmosis in 1 case. TAE were observed in 53% of patients treated with azathioprine, 23% of patients treated with corticosteroids, and 15% of patients treated with mycophenolate mofetil. CONCLUSIONS: This retrospective study demonstrates MG in the elderly presents with a significant iatrogenic risk, including fatal immunosuppressant-related infections.

Refining Incidence and Characteristics of Inflammatory Myopathies: A Quadruple-Source Capture-Recapture Survey Using the 2017 European League Against Rheumatism/American College of Rheumatology Classification Criteria.

OBJECTIVE: Inflammatory myopathies (IM), characterized by muscle inflammation and weakness, are rare systemic diseases. Our previous study estimated an IM incidence rate of 7.98 cases per million people per year (95% confidence interval 7.38-8.66) and highlighted important variations that were likely because of methodologic issues rather than true epidemiologic differences. In this study, we aimed to refine the incidence of IM, using the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for IM and a quadruple-source capture-recapture method during a 6-year period in Alsace, France, a region with a population of 2 million having benefits of good access to health care and accredited IM referral centers. METHODS: Clinical data of potential IM patients were obtained from 4 sources (general practitioners and community specialists, public and private hospital records, public and private laboratories, and archives from the pathology department). Patients residing in Alsace and who fulfilled the 2017 EULAR/ACR criteria for IM between January 1, 2006, and January 1, 2013, were included. We corrected potentially incomplete ascertainment of cases with capture-recapture analyses. We studied both spatial and temporal distributions of incidence of IM. We also assessed systemic manifestations of the disease. RESULTS: Our review of 1,742 potential cases identified 106 patients with IM. No spatial or temporal heterogeneity was observed. Use of log-linear models showed an estimated 14.9 additional missed cases. Thus, the incidence rate of IM was 8.22 new cases per million inhabitants per year (95% confidence interval 6.76-9.69). Extramuscular manifestations other than dermatomyositis rash were frequently recorded. CONCLUSION: The stringent methodology used in our study provides an accurate estimation of the incidence of IM. This study also demonstrates, in a population-based cohort, the systemic nature of IM.

Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy.

Background and Objectives: Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients' series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders. Methods: Description of patients with non-5q SMA followed in the different neuromuscular reference centers in France as well as in London, United Kingdom. Patients without a genetic diagnosis had undergone at least a neuropathy or large neuromuscular gene panel. Results: Seventy-one patients from 65 different families were included, mostly sporadic cases (60.6%). At presentation, 21 patients (29.6%) showed exclusive proximal weakness (P-SMA), 35 (49.3%) showed associated distal weakness (PD-SMA), and 15 (21.1%) a scapuloperoneal phenotype (SP-SMA). Thirty-two patients (45.1%) had a genetic diagnosis: BICD2 (n = 9), DYNC1H1 (n = 7), TRPV4 (n = 4), VCP, HSBP1, AR (n = 2), VRK1, DNAJB2, MORC2, ASAH1, HEXB, and unexpectedly, COL6A3 (n = 1). The genetic diagnostic yield was lowest in P-SMA (6/21, 28.6%) compared with PD-SMA (16/35, 45.7%) and SP-SMA (10/15, 66.7%). An earlier disease onset and a family history of the disease or consanguinity were independent predictors of a positive genetic diagnosis. Neuropathy gene panels were performed in 59 patients with a 32.2% diagnostic yield (19/59). In 13 additional patients, a genetic diagnosis was achieved through individual gene sequencing or an alternative neuromuscular NGS. Discussion: Non-5q SMA is genetically heterogeneous, and neuropathy gene panels achieve a molecular diagnosis in one-third of the patients. The diagnostic yield can be increased by sequencing of other neuromuscular and neurometabolic genes. Nevertheless, there is an unmet need to cluster these patients to aid in the identification of new genes.