Congenital myasthenic syndromes in adults: clinical features, diagnosis and long-term prognosis.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous diseases caused by mutations affecting neuromuscular transmission. Even if the first symptoms mainly occur during childhood, adult neurologists must confront this challenging diagnosis and manage these patients throughout their adulthood. However, long-term follow-up data from large cohorts of CMS patients are lacking and the long-term prognosis of these patients is largely unknown. We report the clinical features, diagnostic difficulties, and long-term prognosis of a French nationwide cohort of 235 adult patients with genetically confirmed CMS followed in 23 specialized neuromuscular centres. Data were retrospectively analysed. Of the 235 patients, 123 were female (52.3%). The diagnosis was made in adulthood in 139 patients, 110 of whom presented their first symptoms before the age of 18. Mean follow-up time between first symptoms and last visit was 34 years (SD = 15.1). Pathogenic variants were found in 19 disease-related genes. CHRNE-low expressor variants were the most common (23.8%), followed by variants in DOK7 (18.7%) and RAPSN (14%). Genotypes were clustered into four groups according to the initial presentation: ocular group (CHRNE-LE, CHRND, FCCMS), distal group (SCCMS), limb-girdle group (RAPSN, COLQ, DOK7, GMPPB, GFPT1), and a variable-phenotype group (MUSK, AGRN). The phenotypical features of CMS did not change throughout life. Only four genotypes had a proportion of patients requiring intensive care unit (ICU) admission that exceeded 20%: RAPSN (54.8%), MUSK (50%), DOK7 (38.6%) and AGRN (25.0%). In RAPSN and MUSK patients most ICU admissions occurred before age 18 years and in DOK7 and AGRN patients at or after 18 years of age. Different patterns of disease course (stability, improvement and progressive worsening) may succeed one another in the same patient throughout life, particularly in AGRN, DOK7 and COLQ. At the last visit, 55% of SCCMS and 36.3% of DOK7 patients required ventilation; 36.3% of DOK7 patients, 25% of GMPPB patients and 20% of GFPT1 patients were wheelchair-bound; most of the patients who were both wheelchair-bound and ventilated were DOK7 patients. Six patients died in this cohort. The positive impact of therapy was striking, even in severely affected patients. In conclusion, even if motor and/or respiratory deterioration could occur in patients with initially moderate disease, particularly in DOK7, SCCMS and GFPT1 patients, the long-term prognosis for most CMS patients was favourable, with neither ventilation nor wheelchair needed at last visit. CHRNE patients did not worsen during adulthood and RAPSN patients, often severely affected in early childhood, subsequently improved.

Inaugural dropped head syndrome and camptocormia in inflammatory myopathies: a retrospective study.

OBJECTIVES: Inaugural axial muscle involvement, defined as dropped head syndrome (DHS) and/or camptocormia (CC), is poorly described in inflammatory myopathies (IM). This study aimed to further characterize IM patients with inaugural DHS/CC, their outcome and care management. METHODS: This retrospective study included IM patients diagnosed between 2000 and 2021. The main inclusion criterion was IM revealed by axial muscle deficit (DHS/CC). RESULTS: Twenty-seven patients were included; median (IQR) age at first symptoms was 66.0 years (55.5-75.0); 21 were female (77.8%). There were nine IBM, 33.3%, nine overlap myositis (OM, 33.3%), five DM, 18.5%, two immune checkpoint inhibitor-related myositis (7.4%), one focal myositis (3.7%) and one myositis with anti-Hu antibodies (3.7%). Age at first symptoms was ≤70 years in 16 patients (59.3%), including all DM patients and 8/9 OM patients (88.9%). In this group, partial remission of the disease was obtained in 9/16 (56.3%) and complete remission in 1/16 patients (6.3%); regression of DHS/CC was achieved in 3/16 patients (18.8%). Conversely, in the group of 11 patients aged >70 years at first symptoms, there were eight IBM (72.7%). Partial remission was obtained in 5/11 patients (45.5%), the disease was stable in 6/11 patients (54.5%); no complete remission was obtained nor regression of DHS/CC. CONCLUSION: The analysis of IM patients with inaugural DHS/CC delineates two groups of patients according to the age at first symptoms in terms of clinical and outcome specificities, and proposes an adapted diagnostic and care management approach to prevent long-term complications.

Genetic characterization of non-5q proximal spinal muscular atrophy in a French cohort: the place of whole exome sequencing.

Proximal spinal muscular atrophy (SMA) is defined by a degeneration of the anterior horn cells resulting in muscle weakness predominantly in the proximal lower limbs. While most patients carry a biallelic deletion in the SMN1 gene (localized in chromosome 5q), little is known regarding patients without SMN1-mutation, and a genetic diagnosis is not always possible. Here, we report a cohort of 24 French patients with non-5q proximal SMA from five neuromuscular centers who all, except two, had next-generation sequencing (NGS) gene panel, followed by whole exome sequencing (WES) if gene panel showed a negative result. The two remaining patients benefited directly from WES or whole genome sequencing (WGS). A total of ten patients with causative variants were identified, nine of whom were index cases (9/23 families = 39%). Eight variants were identified by gene panel: five variants in DYNC1H1, and three in BICD2. Compound heterozygous causative variants in ASAH1 were identified directly by WES, and one variant in DYNC1H1 was identified directly by WGS. No causative variant was found using WES in patients with a previous panel with negative results (14 cases). We thus recommend using primarily NGS panels in patients with non-5q-SMA and using WES, especially when several members of the same family are affected and/or when trio analyses are possible, or WGS as second-line testing if available.

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.

Trigeminal Nerve Involvement in Bulbar-Onset Anti-IgLON5 Disease.

OBJECTIVES: Anti-IgLON5 disease (IgLON5-D) may present with a bulbar-onset motor neuron disease-like phenotype, mimicking bulbar-onset amyotrophic lateral sclerosis. Recognition of their distinctive clinical and paraclinical features may help for differential diagnosis. We report 2 cases of atypical trigeminal neuropathy in bulbar-onset IgLON5-D. METHODS: Trigeminal nerve involvement was assessed using comprehensive clinical, laboratory, electrophysiologic, and MRI workup. RESULTS: Both patients were referred for progressive dysphagia, sialorrhea, and hoarseness. They were treated with bilevel positive airway pressure for nocturnal hypoventilation. Patient 1 complained of continuous facial burning pain with allodynia, exacerbated by mastication and prolonged speech. Patient 2 reported no facial pain. Anti-IgLON5 autoantibodies (IgLON5-Abs) were positive in serum for both patients and CSF for patient 1. Cerebral MRI revealed bilateral T2 fluid-attenuated inversion recovery (FLAIR) hyperintensity and enlargement of trigeminal nerves without gadolinium enhancement in both patients. Needle myography showed fasciculations in masseter muscles. Blink-reflex study confirmed bilateral trigeminal neuropathy only in patient 2. Cortical laser-evoked potentials showed a bilateral small-fiber dysfunction in the trigeminal nerve ophthalmic branch in patient 1. DISCUSSION: In case of progressive atypical bulbar symptoms, the presence of a trigeminal neuropathy or trigeminal nerve abnormalities on MRI should encourage the testing of IgLON5-Abs in serum and CSF.

Immune-Mediated Rippling Muscle Disease Associated With Thymoma and Anti-MURC/Cavin-4 Autoantibodies.

OBJECTIVES: Rippling muscle disease (RMD) is characterized by muscle stiffness, muscle hypertrophy, and rippling muscle induced by stretching or percussion. Hereditary RMD is due to sequence variants in the CAV3 and PTRF/CAVIN1 genes encoding Caveolin-3 or Cavin-1, respectively; a few series of patients with acquired autoimmune forms of RMD (iRMD) associated with AChR antibody-positive myasthenia gravis and/or thymoma have also been described. Recently, MURC/caveolae-associated protein 4 (Cavin-4) autoantibody was identified in 8 of 10 patients without thymoma, highlighting its potential both as a biomarker and as a triggering agent of this pathology. Here, we report the case of a patient with iRMD-AchR antibody negative associated with thymoma. METHODS: We suspected a paraneoplastic origin and investigated the presence of specific autoantibodies targeting muscle antigens through a combination of Western blotting and affinity purification coupled with mass spectrometry-based proteomic approaches. RESULTS: We identified circulating MURC/Cavin-4 autoantibodies and found strong similarities between histologic features of the patient's muscle and those commonly reported in caveolinopathies. Strikingly, MURC/Cavin-4 autoantibody titer strongly decreased after tumor resection and immunotherapy correlating with complete disappearance of the rippling phenotype and full patient remission. DISCUSSION: MURC/Cavin-4 autoantibodies may play a pathogenic role in paraneoplastic iRMD associated with thymoma.

A multicenter cross-sectional French study of the impact of COVID-19 on neuromuscular diseases.

BACKGROUND: Due to their health condition, patients with neuromuscular diseases (NMD) are at greater risk of developing serious complications with COVID-19. The objective of this study was to analyze the prevalence of COVID-19 among NMD patients and the risk factors for its impact and severity during the first wave of the pandemic. Clinical data were collected from NMD-COVID-19 patients, between March 25, 2020 and May 11, 2020 in an anonymous survey carried out by expert physicians from the French Health Care Network Filnemus. RESULTS: Physicians reported 84 patients, including: 34 with myasthenia gravis, 27 with myopathy and 23 with neuropathy. COVID-19 had no effect on NMD for 48 (58%) patients and 48 (58%) patients developed low COVID-19 severity. COVID-19 caused the death of 9 (11%) NMD patients. Diabetic patients were at greater risk of dying. Patients with diabetes, hypertension or severe forms of NMD had a higher risk of developing a moderate or severe form of COVID-19. In our cohort, corticosteroids and other immunosuppressants were not significantly associated with higher COVID-19 severity for acquired NMD. CONCLUSION: During this period, a small percentage of French NMD patients was affected by COVID-19 compared to the general French population and COVID-19 had a limited short-term effect on them. Diabetes, hypertension and a severe degree of NMD were identified as risk factors of unfavorable outcome following COVID-19. Conversely, in our cohort of patients with acquired NMD, corticosteroids or other immunosuppressants did not appear to be risk factors for more severe COVID-19.

Focal chronic inflammatory demyelinating polyradiculoneuropathy: Onset, course, and distinct features.

Focal chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is defined as involving the brachial or lumbosacral plexus, or one or more peripheral nerves in one upper or one lower limb (monomelic distribution). However, other auto-immune neuropathies such as Lewis-Sumner syndrome (LSS) and multifocal motor neuropathy (MMN) can also have a focal onset. From a retrospective cohort of 30 focal CIDP patients with a monomelic onset dating back at least 2 years, we distinguished patients with plexus involvement (focal demyelinating plexus neuropathy [F-PN], n = 18) from those with sensory or sensorimotor (F-SMN, n = 7), or purely motor (F-MN, n = 5) impairment located in one or several peripheral nerves. Few (39%) F-PN patients had motor nerve conduction abnormalities, but the majority showed proximal conduction abnormalities in somatosensory evoked potentials (80%), and all had focal hypertrophy and/or increased short tau inversion recovery image signal intensity on plexus MRI. Impairment remained monomelic in most (94%) F-PN patients, whereas abnormalities developed in other limbs in 57% of F-SMN, and 40% of F-MN patients (P = .015). The prognosis of F-PN patients was significantly better: none had an ONLS score > 2 at the final follow-up visit, vs 43% of F-SMN patients and 40% of F-MN patients (P = .026). Our findings from a large cohort of focal CIDP patients confirm the existence of different entities that are typically categorized under this one term: on the one hand, patients with a focal plexus neuropathy and on the other, patients with monomelic sensori-motor or motor involvement of peripheral nerves. These two last subgroups appeared to be more likely to evolve to LSS or MMN phenotype, when F-PN patients have a more distinctive long-term, focal, benign course.

Clinical and Molecular Landscape of ALS Patients with SOD1 Mutations: Novel Pathogenic Variants and Novel Phenotypes. A Single ALS Center Study.

Mutations in the copper zinc superoxide dismutase 1 (SOD1) gene are the second most frequent cause of familial amyotrophic lateral sclerosis (ALS). Nearly 200 mutations of this gene have been described so far. We report all SOD1 pathogenic variants identified in patients followed in the single ALS center of Lyon, France, between 2010 and 2020. Twelve patients from 11 unrelated families are described, including two families with the not yet described H81Y and D126N mutations. Splice site mutations were detected in two families. We discuss implications concerning genetic screening of SOD1 gene in familial and sporadic ALS.

Completing the Immunological Fingerprint by Refractory Proteins: Autoantibody Screening via an Improved Immunoblotting Technique.

PURPOSE: Identifying autoantigens of serological autoantibodies requires expensive methods, such as protein microarrays or IP+MS. Thus, sera are commonly pre-screened for interesting immunopatterns via immunocytochemistry/immunohistochemistry. However, distinguishing immunopatterns can be difficult and intracellular antigens are less accessible. Therefore, a simple and cheap immunoblot screening able to distinguish immunopatterns and to detect refractory proteins is presented. EXPERIMENTAL DESIGN: Five steps of immunoblotting-based autoantigen screening are revised: (1) choice of protein source, (2) protein extraction, (3) protein separation, (4) protein transfer, (5) antigen detection. Thereafter, 52 patients' sera with chronic inflammatory demyelinating polyneuropathy (CIDP) and 45 controls were screened. RESULTS: The protein source impacts the detected antigen set. Steps 2-4 can be adapted for refractory proteins. Furthermore, longitudinal cutting of protein lanes saves ≥75% of time and material and allows for exact comparison of band patterns. As the latter are individually specific and temporarily constant, we call them "immunological fingerprints". In a proof-of-principle, a 155 kDa immunoband was detected with two anti-neurofascin-155-positive CIDP sera and two further immunobands (120/220 kDa) specific to a subgroup of 3-6 of 52 CIDP patients. CONCLUSIONS AND CLINICAL RELEVANCE: Adapted immunoblotting is a cheap and simple method for accurate serum screening including refractory and intracellular antigens.

Anti-MAG antibodies in 202 patients: clinicopathological and therapeutic features.

OBJECTIVE: To assess the clinicopathological and therapeutic features of patients with low (≥1000 to <10 000 Bühlmann Titre Units) (BTU), medium (10 000-70 000) or high (≥70 000) anti-myelin-associated glycoprotein (anti-MAG) antibody titres. METHODS: We retrospectively and prospectively analysed standardised report forms and medical records of 202 patients from 14 neuromuscular centres. RESULTS: Mean age at onset and mean time between symptom onset to last follow-up were respectively 62.6 years (25-91.4) and 8.4 years (0.3-33.3). Anti-MAG antibody titres at diagnosis were low, medium or high in 11%, 51% and 38% of patients. Patients presented with monoclonal gammopathy of undetermined significance in 68% of cases. About 17% of patients presented with 'atypical' clinical phenotype independently of anti-MAG titres, including acute or chronic sensorimotor polyradiculoneuropathies (12.4%), and asymmetric or multifocal neuropathy (3%). At the most severe disease stage, 22.4% of patients were significantly disabled. Seventy-eight per cent of patients received immunotherapies. Transient clinical worsening was observed in 12% of patients treated with rituximab (11/92). Stabilisation after rituximab treatment during the 7-12-month follow-up period was observed in 29% of patients. Clinical response to rituximab during the 6-month and/or 7-12-month follow-up period was observed in 31.5% of patients and correlated with anti-MAG titre ≥10 000 BTU. CONCLUSION: Our study highlights the extended clinical spectrum of patients with anti-MAG neuropathy, which appears unrelated to antibody titre. Besides, it may also suggest beneficial use of rituximab in the early phase of anti-MAG neuropathy.