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Biallelic intronic expansions (AAGGG)exp in intron 2 of the RFC1 gene have been shown to be a common cause of late-onset ataxia. Since their first description, the phenotypes, neurological damage, and pathogenic variants associated with the RFC1 gene have been frequently updated. Here, we review the various motifs, genetic variants, and phenotypes associated with the RFC1 gene. We searched PubMed for scientific articles published between March 1st, 2019, and January 15th, 2024. The motifs and phenotypes associated with the RFC1 gene are highly heterogeneous, making molecular diagnosis and clinical screening and investigation challenging. In this review we will provide clues to give a better understanding of RFC1 disease. We briefly discuss new methods for molecular diagnosis, the origin of cough in RFC1 disease, and research perspectives.
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Fenótipo , Proteína de Replicação C , Humanos , Proteína de Replicação C/genética , Ataxia/genética , Ataxia/diagnóstico , Íntrons/genéticaRESUMO
BACKGROUND: The objectives of this observational study were to report the incidence and prevalence of myasthenia gravis (MG) in France, describe patients' characteristics and treatment patterns, and estimate mortality. METHODS: A historical cohort analysis was performed using the French National Health Data System (SNDS) database between 2008 and 2020. Patients with MG were identified based on ICD-10 codes during hospitalization and/or long-term disease (ALD) status, which leads to a 100% reimbursement for healthcare expenses related to MG. The study population was matched to a control group based on age, sex and region of residence. RESULTS: The overall incidence of MG was estimated at 2.5/100,000 in 2019 and the overall prevalence at 34.2/100,000. The mean age was 58.3 years for incident patients and 58.6 for prevalent patients. Among patients with MG, 57.1% were women. In the first year after identification of MG, acetylcholinesterase inhibitors were the most commonly used treatments (87.0%). Corticosteroids were delivered to 58.3% of patients, intravenous immunoglobulin to 34.4%, and azathioprine to 29.9%. Additionally, 8% of patients underwent thymectomy. The proportions of patients with exacerbations and crises were 59.7% and 13.5% respectively in the first year after MG identification. All-cause mortality was significantly higher in patients with MG compared to matched controls (HR=1.82 (95% CI [1.74;1.90], P<0.0001)). CONCLUSION: In this study, the incidence and prevalence of MG estimated in France were found to be higher than previously reported. Most exacerbations and crises occurred within the first year after MG identification. MG was associated with increased mortality compared to a control population matched on age, gender, and geographical region.
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Acetilcolinesterase , Miastenia Gravis , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Miastenia Gravis/epidemiologia , Miastenia Gravis/terapia , Azatioprina , Estudos de Coortes , TimectomiaRESUMO
Non-dystrophic myotonias (NDM) are disabling genetic diseases that impact quality of life. To reduce the impact of NDM, patients develop coping strategies such as lifestyle adaptation and avoiding key triggers. To understand how myotonia affects patients' lives, the IMPACT survey, an online questionnaire on patient-reported outcomes, was developed based on international IMPACT questionnaire. The French IMPACT 2022 survey was completed by 47 NDM French patients. Besides muscle stiffness (98%), patients reported muscle pain (83%), falls (70%) and anxiety (77%). These issues negatively impacted abilities to work/study (49%), daily life at home (49%) and overall mobility outside (49%). Most patients (96%) reported ongoing pharmacological treatment (mexiletine, 91%) associated with improvement in muscle stiffness (100%) and reduction in falls (94%), muscle pain (87%) and anxiety (80%). Patients were moderately satisfied (19.1%), satisfied (42.6%) and very satisfied (29.8%) with the current management; 32% rated their quality of life positively (≥ 8 on 10-point scale). In conclusion, this French survey confirms the impact of myotonia on daily life and quality of life. The improvement in patient-reported outcomes in treated participants highlights the importance of managing myotonia with effective treatments. More work should be initiated to assess the importance of NDM symptom management and patients' adherence and compliance to treatment.
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OBJECTIVE: We aimed to describe characteristics of patients with ATTR variant polyneuropathy (ATTRv-PN) and ATTRv-mixed and assess the real-world use and safety profile of tafamidis meglumine 20mg. METHODS: Thirty-eight French hospitals were invited. Patient files were reviewed to identify clinical manifestations, diagnostic methods, and treatment compliance. RESULTS: Four hundred and thirteen patients (296 ATTRv-PN, 117 ATTRv-mixed) were analyzed. Patients were predominantly male (68.0%) with a mean age of 57.2±17.2 years. Interval between first symptom(s) and diagnosis was 3.4±4.3 years. First symptoms included sensory complaints (85.9%), dysautonomia (38.5%), motor deficits (26.4%), carpal tunnel syndrome (31.5%), shortness of breath (13.3%), and unexplained weight loss (16.0%). Mini-invasive accessory salivary gland or punch skin and nerve biopsies were most common, with a performance of 78.8-100%. TTR genetic sequencing, performed in all patients, revealed 31 TTR variants. Tafamidis meglumine was initiated in 156/214 (72.9%) ATTRv-PN patients at an early disease stage. Median treatment duration was 6.00 years in ATTRv-PN and 3.42 years in ATTRv-mixed patients. Tafamidis was well tolerated, with 20 adverse events likely related to study drug among the 336 patients. CONCLUSION: In France, ATTRv patients are usually identified early thanks to the national network and the help of diagnosis combining genetic testing and mini-invasive biopsies.
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Neuropatias Amiloides Familiares , Benzoxazóis , Humanos , Masculino , França/epidemiologia , Feminino , Pessoa de Meia-Idade , Idoso , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/tratamento farmacológico , Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/epidemiologia , Estudos Transversais , Adulto , Benzoxazóis/uso terapêutico , Benzoxazóis/efeitos adversos , Idoso de 80 Anos ou mais , Pré-Albumina/genéticaRESUMO
Inherited neuropathies are a heterogeneous group of slowly progressive disorders affecting either motor, sensory, and/or autonomic nerves. Peripheral neuropathy may be the major component of a disease such as Charcot-Marie-Tooth disease or a feature of a more complex multisystemic disease involving the central nervous system and other organs. The goal of this review is to provide the clinical clues orientating the genetic diagnosis in a patient with inherited peripheral neuropathy. This review focuses on primary inherited neuropathies, amyloidosis, inherited metabolic diseases, while detailing clinical, neurophysiological and potential treatment of these diseases.
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Doença de Charcot-Marie-Tooth , Neuropatia Hereditária Motora e Sensorial , Humanos , Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/genética , Neuropatia Hereditária Motora e Sensorial/diagnóstico , Neuropatia Hereditária Motora e Sensorial/genéticaRESUMO
Treatment strategies in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) must be adapted on a case-to-case basis. Validated and reproducible tools for monitoring treatment response are required at diagnosis, when initiating treatment and throughout follow-up. A task force of French neurologists, experts in neuromuscular disease reference centers, was assembled to provide expert advice on the management of typical CIDP with intravenous immunoglobulins (Ig), and to harmonize treatment practices in public and private hospitals. The task force also referred to the practical experience of treating CIDP with Ig at the diagnostic, induction and follow-up stages, including the assessment and management of Ig dependence, and following the recommendations of the French health agency.
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Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Humanos , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/terapia , Prova Pericial , Imunoglobulinas Intravenosas/uso terapêutico , França/epidemiologiaRESUMO
Post-radiation diaphragmatic weakness have rarely been described. We report two cases of post-radiation diaphragmatic weakness from our center, and review the other published cases, computing clinical, electromyography and magnetic resonance imaging data. Including our two cases, seven cases of post-radiation diaphragmatic weakness have been described. Most occurred after mantle-field radiotherapy for Hodgkin lymphoma (5/7), often in associations with chemotherapy (4/7). Other radiations-induced complications were found (5/7) such as brachial plexopathy, cardiac involvement or hypothyroidy. When studied, phrenic nerve conduction studies revealed different profiles, from clearly abnormal responses to limit amplitudes. Imaging can be a useful diagnostic tool, displaying abnormalities with sharp limits matching the radiation field. Data is limited about long-term evolution. Presentation of post-radiation diaphragmatic weakness seems relatively homogeneous. We propose a diagnosis work-up for post-radiation diaphragmatic weakness, to exclude potentially treatable differential diagnoses.
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Doença de Hodgkin , Lesões por Radiação , Eletromiografia , Doença de Hodgkin/complicações , Doença de Hodgkin/radioterapia , Humanos , Debilidade Muscular/etiologia , Nervo Frênico , Lesões por Radiação/complicações , Lesões por Radiação/etiologia , Radioterapia/efeitos adversosRESUMO
INTRODUCTION: Hereditary transthyretin related amyloidosis (h-ATTR) classically presents as a small fiber neuropathy with positive family history, but can also be revealed by various other types of peripheral neuropathy. OBJECTIVE: To describe the initial electro-clinical presentation of patients from in a single region (northern France) of h-ATTR when it presents as a polyneuropathy of unknown origin. METHOD: We reviewed the records of patients referred to two neuromuscular centers from northern France with a peripheral neuropathy of unknown origin who were subsequently diagnosed with h-ATTR. RESULTS: Among 26 h-ATTR patients (10 Val30Met, 16 Ser77Tyr), only 14 patients had a suspicious family history (53.8%). The electro-clinical presentation was mostly a large-fiber sensory motor polyneuropathy (92.3%), which could be symmetric or not, length-dependent or not, or associated with nerve entrapment or not. Demyelinating signs were observed in 17 patients (70.8%), among whom nine fulfilled the criteria for a definite diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (37.5%). CONCLUSION: h-ATTR may have a wide spectrum of clinical profiles, and should be considered in the screening of polyneuropathies of unknown origin.
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Neuropatias Amiloides Familiares , Polineuropatias , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/epidemiologia , França/epidemiologia , Humanos , Polineuropatias/diagnóstico , Polineuropatias/epidemiologia , Polineuropatias/etiologia , Pré-Albumina/genéticaRESUMO
AIMS: The most common autosomal recessive limb girdle muscular dystrophy is associated with the CAPN3 gene. The exclusively recessive inheritance of this disorder has been recently challenged by the description of the recurrent variants, c.643_663del21 [p.(Ser215_Gly221del)] and c.598_612del15 [p.(Phe200_Leu204del)], associated with autosomal dominant inheritance. Our objective was to confirm the existence of autosomal dominant calpainopathies. METHODS: Through our activity as one of the reference centres for genetic diagnosis of calpainopathies in France and the resulting collaborations through the French National Network for Rare Neuromuscular Diseases (FILNEMUS), we identified four families harbouring the same CAPN3 heterozygous variant with supposedly autosomal dominant inheritance. RESULTS: We identified a novel dominantly inherited CAPN3 variant, c.1333G>A [p.(Gly445Arg)] in 14 affected patients from four unrelated families. The complementary phenotypic, functional and genetic findings correlate with an autosomal dominant inheritance in these families, emphasizing the existence of this novel transmission mode for calpainopathies. The mild phenotype associated with these autosomal dominant cases widens the phenotypic spectrum of calpainopathies and should therefore be considered in clinical practice. CONCLUSIONS: We confirm the existence of autosomal dominant calpainopathies as an entity beyond the cases related to the in-frame deletions c.643_663del21 and c.598_612del15, with the identification of a novel dominantly inherited and well-documented CAPN3 missense variant, c.1333G>A [p.(Gly445Arg)]. In addition to the consequences for genetic counselling, the confirmation of an autosomal dominant transmission mode for calpainopathies underlines the importance of re-assessing other myopathies for which the inheritance is considered as strictly autosomal recessive.
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Calpaína/genética , Aberrações Cromossômicas , Proteínas Musculares/genética , Doenças Neuromusculares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , França , Genes Dominantes/genética , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo , Adulto JovemRESUMO
In classic amyotrophic lateral sclerosis (ALS), the relative degree of impairment of cortical vs spinal motor neurons serving the different body regions is highly variable. This means that an accurate, systematic assessment of the patient's clinical presentation is essential for both the diagnosis and prognosis. The patient's phenotype, rate of disease progression, time of onset (if early) of respiratory failure and nutritional status all have prognostic value, and should be specified in the nosological classification of the disease.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/fisiopatologia , Esclerose Lateral Amiotrófica/terapia , Progressão da Doença , Humanos , PrognósticoRESUMO
The target organs for familial transthyretin amyloidosis are typically the nerves, the heart or even the eyes due to the accumulation of amyloid deposits. Less frequently, these deposits can occur within the central nervous system and drive a specific phenotype of cerebral amyloid angiopathy. We report the case of a 72-year-old woman showing evidence of cerebral amyloid angiopathy, in a context of hereditary transthyretin amyloidosis (hATTR) due to p.(Ser77Tyr) mutation of the TTR gene. Her cognitive assessment on a two-year follow-up was remarkably steady. A very limited number of patients with hereditary transthyretin amyloidosis associated with a cerebral amyloid angiopathy have been reported. Few characteristics could distinguish them from classic cerebral amyloid angiopathy, and more data are needed to highlight specific features. Screening for peripheral neuropathy should be considered for patients referred to memory clinic for atypical cerebral amyloid angiopathy.
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Neuropatias Amiloides Familiares , Angiopatia Amiloide Cerebral , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/diagnóstico , Neuropatias Amiloides Familiares/genética , Sistema Nervoso Central , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/genética , Feminino , Humanos , Pré-Albumina/genéticaRESUMO
Ménétrier's disease is a protein-losing gastropathy that is uncommon in childhood. Its symptoms are unspecific, with abdominal pain, vomiting, and edema. Blood tests show hypoproteinemia and hypoalbuminemia, and upper digestive endoscopy reveals giant gastric folds. In children, cytomegalovirus has been identified as a possible cause. Here we describe two sisters presenting with Ménétrier's disease, 2 years apart. This diagnosis should be considered in the presence of hypoalbuminemia in children when a nephrotic syndrome is excluded.
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Infecções por Citomegalovirus/diagnóstico , Gastrite Hipertrófica/diagnóstico , Gastrite Hipertrófica/virologia , Criança , Pré-Escolar , Endoscopia Gastrointestinal , Feminino , Humanos , Hipoalbuminemia/etiologia , IrmãosRESUMO
AIMS: Mutations of the LMNA gene encoding lamin A/C induce heterogeneous phenotypes ranging from cardiopathies and myopathies to lipodystrophies. The aim of this study was to compare cardiometabolic complications in patients with heterozygous LMNA mutations at the 482nd codon, the 'hotspot' for partial lipodystrophy, with carriers of other, non-R482 LMNA mutations. METHODS AND RESULTS: This study included 29 patients with R482 LMNA mutations, 29 carriers of non-R482 LMNA mutation and 19 control subjects. Cardiac and metabolic phenotypes were compared between groups. A family history of either cardiac implantable electronic devices (CIEDs; P < 0.001) or sudden death (P < 0.01) was more frequent in non-R482 than R482 carriers. The non-R482 carriers also had more abnormalities on electrocardiography and received CIEDs more often than R482 carriers (P < 0.001). On cardiac ultrasound, non-R482 patients had greater frequencies of left atrial enlargement (P < 0.05) and lower left ventricular ejection fractions (P < 0.01) than R482 carriers. In contrast, R482 carriers had lower BMI (P < 0.05), leptin (P < 0.01) and fat mass (P < 0.001), but higher intra-/total abdominal fat-mass ratios (P < 0.001) and prevalences of diabetes (P < 0.01) and hypertriglyceridaemia (P < 0.05) than non-R482 carriers, with a trend towards more coronary artery disease. However, non-R482 carriers had higher intra-/total abdominal fat-mass ratios (P < 0.02) and prevalences of diabetes (P < 0.001) and hypertriglyceridaemia (P < 0.05) than the controls. CONCLUSION: Non-R482 carriers present more frequently with arrhythmias than R482 carriers, who twice as often have diabetes, suggesting that follow-up for laminopathies could be adjusted for genotype. Non-R482 mutations require ultra-specialized cardiac follow-up, and coronary artery disease should not be overlooked. Although overlapping phenotypes are found, LMNA mutations essentially lead to tissue-specific diseases, favouring genotype-specific pathophysiological mechanisms.
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Doenças Cardiovasculares/genética , Lamina Tipo A/genética , Doenças Metabólicas/genética , Mutação , Adulto , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Lipodistrofia/complicações , Lipodistrofia/diagnóstico , Lipodistrofia/epidemiologia , Lipodistrofia/genética , Lipodistrofia Parcial Familiar/complicações , Lipodistrofia Parcial Familiar/epidemiologia , Lipodistrofia Parcial Familiar/genética , Estudos Longitudinais , Masculino , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Freezing of gait is a paroxysmal phenomenon that is frequently reported by the parkinsonian patients or their entourage. The phenomenon significantly alters quality of life but is often difficult to characterize in the physician's office. In the present review, we focus on the clinical characterization and quantification of freezing of gait. Various biomechanical methods (based mainly on time-frequency analysis) can be used to determine time-domain characteristics of freezing of gait. Methods already used to study non-gait freezing of other effectors (the lower limbs, upper limbs and orofacial area) are also being developed for the analysis of freezing in functional magnetic resonance imaging protocols. Here, we review the reliability of these methods and compare them with reliability of information obtained from physical examination and detailed analysis of the patient's medical history.
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Transtornos Neurológicos da Marcha/diagnóstico , Doença de Parkinson/complicações , Algoritmos , Fenômenos Biomecânicos , Mapeamento Encefálico , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imageamento por Ressonância Magnética , Exame Físico , Tomografia por Emissão de Pósitrons , Sensibilidade e Especificidade , Processamento de Sinais Assistido por ComputadorRESUMO
INTRODUCTION: Freezing of gait (FoG) is a debilitating gait disorder in Parkinson's disease (PD). In advanced PD patients with FoG, the supraspinal locomotor network may be dysregulated (relative to similar patients without FoG) during gait. Here, we sought to characterize the metabolism of locomotor networks involved in FoG. METHODS: Twenty-two PD patients (11 with off-drug FoG and 11 without) each underwent two [(18)F]-fluorodeoxyglucose PET brain scans in the off-drug state: one at rest and another during radiotracer uptake while performing a standardized gait trajectory that incorporated the usual triggers for FoG. RESULTS: For the 11 freezers, FoG was present for 39% (± 23%) of the time during the gait trajectory. The FoG-associated abnormalities were characterized by (i) hypometabolism in frontal regions (the associative premotor, temporopolar and orbitofrontal areas, i.e. Brodmann areas 6 and 8), (ii) hypermetabolism in the paracentral lobule (Brodmann area 5), and (iii) deregulation of the basal ganglia output (the globus pallidus and the mesencephalic locomotor region). CONCLUSION: FoG during a real gait task was associated with impaired frontoparietal cortical activation, as characterized by abnormally low metabolic activity of the premotor area (involved in the indirect locomotor pathway) and abnormally high metabolic activity of the parietal area (reflecting the harmful effect of external cueing).
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Encéfalo/metabolismo , Transtornos Neurológicos da Marcha/etiologia , Doença de Parkinson/patologia , Idoso , Encéfalo/diagnóstico por imagem , Análise por Conglomerados , Feminino , Fluordesoxiglucose F18 , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Índice de Gravidade de Doença , Estatísticas não ParamétricasRESUMO
The gait initiation process is of particular interest in Parkinson's disease because it combines motor and cognitive components of movement preparation (referred to as anticipatory postural adjustments) and movement execution (the step by itself). Moreover, gait initiation in Parkinson's disease is often affected by motor blocks (a subtype of the "freezing of gait" phenomenon). Gait initiation disturbances in Parkinson's disease include delayed release of anticipatory postural adjustments, hypokinetic anticipatory postural adjustments (reduced scaling) and bradykinetic anticipatory postural adjustments (abnormal timing). The most extreme form is freezing of gait with sometimes the absence of anticipatory postural adjustments. Other phenomena can be also described in some freezing patients (such as multiple anticipatory postural adjustments, described clinically as "knee trembling"). The fact that emotion, attention, external triggers and dopaminergic drugs can all modify this motor program suggests the existence of a complex pathophysiological mechanism that involves not only locomotor networks but also cortical areas and the basal ganglia system. Abnormal coupling between standing posture and anticipatory postural adjustments and between the latter and step execution appears to be a crucial part of the pathophysiological mechanism. Although external cueing appears to be of interest, few studies have provided evidence of the efficacy of various rehabilitation methods in routine care.