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

Regulatory role of natural killer T cells in diabetes

International audienceType 1 and type 2 diabetes are growing public health problems. Despite having different pathophysiologies, both diseases are associated with defects in immune regulation. Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipids presented by CD1d. These cells not only play a key role in the defense against pathogens, but also exert potent immunoregulatory functions. The regulatory role of iNKT cells in the prevention of type 1 diabetes has been demonstrated in murine models and analyzed in diabetic patients. The decreased frequency of iNKT cells in non-obese diabetic mice initially suggested the regulatory role of this cell subset. Increasing the frequency or the activation of iNKT cells with agonists protects non-obese diabetic mice from the development of diabetes. Several mechanisms mediate iNKT regulatory functions. They can rapidly produce immunoregulatory cytokines, interleukin (IL)-4 and IL-10. They induce tolerogenic dendritic cells, thereby inducing the anergy of autoreactive anti-islet T cells and increasing the frequency of T regulatory cells (Treg cells). Synthetic agonists are able to activate iNKT cells and represent potential therapeutic treatment in order to prevent type 1 diabetes. Growing evidence points to a role of immune system in glucose intolerance and type 2 diabetes. iNKT cells are resident cells of adipose tissue and their local and systemic frequencies are reduced in obese patients, suggesting their involvement in local and systemic inflammation during obesity. With the discovery of potential continuity between type 1 and type 2 diabetes in some patients, the role of iNKT cells in these diseases deserves further investigation

Specific attentional disorders and freezing of gait in parkinson's disease

International audienceBACKGROUND: Due to its high prevalence in dual-task paradigms, freezing of gait in Parkinson's disease is thought to be associated with dysexecutive syndrome and attentional disorders. However, the role of specific attentional disorders in patients with freezing of gait is still unclear.OBJECTIVE: Here, we sought to specifically determine which basic attentional modalities are impaired in patients with freezing of gait.METHODS: Seventy-eight parkinsonian patients performed a computer-controlled reaction-time paradigm designed to measure the different attentional subcomponents, controlled for visuospatial processing and motor participation.RESULTS: The freezer (n = 42) and non-freezer (n = 36) groups were matched for age, educational level, MMSE and Mattis Dementia Rating Scale. There were no intergroup differences in simple reaction times, whereas choice reaction times were higher in the freezer group than in the non-freezer group for divided attention (p = 0.023).CONCLUSIONS: At equivalent levels of overall cognitive efficiency, freezer patients showed a greater slowdown than non-freezer patients with a specific impairment in divided attention

The interaction between cognition and motor control: A theoretical framework for dual-task interference effects on posture, gait initiation, gait and turning

Studies of dual tasks (i.e. situations during which an individual performs two tasks simultaneously) and the subsequent inter-task interference have shown that locomotion and posture involves motor and cognitive components. Dual tasks therefore constitute a promising avenue for improving the diagnosis, prevention and management of falls or cognitive impairment in populations at risk. However, tackling these major public health concerns with dual-task interventions requires a better understanding of the mechanisms underlying dual-task interference. In this context, we review (i) the main dual-task theories proposed to date and (ii) the factors that can influence dual-task interference effects in healthy young individuals and might therefore explain the current lack of consensus on the mechanisms of dual tasks. We also consider cognitive-motor dual tasks in which the motor task is a less frequently studied transition movement (such as gait initiation or turning), rather than only the often-studied gait and posture tasks. In general, the review focuses on the behavioral effects of dual tasking

Motor Preparation of Step Initiation: Error-related Cortical Oscillations

"European Union (EU)" - "Horizon 2020" - "MSCA-ITN-ETN" - "Keep Control" - "Grant number 721577"Gait initiation can vary as a function of the available and engaged attentional resources. Conflict resolution can disrupt movement preparation and lead to ‘‘errors” in motor programming. These ‘‘errors” are physiologically useful by enabling us to adapt our motor behavior to situations with conflicting information. The objective of the present study was to analyze the patterns of cortical activation associated with motor programming errors and the corresponding error corrections. Incongruent flankers around a target arrow were used to trigger errors in anticipatory postural adjustments (APAs) prior to gait initiation; i.e. perturbed motor programming but normal execution. Thirty healthy adults performed a gait initiation task. The event-related potentials (ERPs) and event-related desynchronization (ERD) after target presentation were analyzed according to the presence or absence of an APA error. The ERP was similar in both conditions, except that the Ne and P300 peak latencies were longer for APA errors. Motor programming errors during gait initiation were characterized by longer, less intense low-beta-band ERD over the sensorimotor cortex and alpha ERS followed by stronger alpha ERD during errors. APA errors were associated with a specific alpha/beta oscillation profile over the sensorimotor cortex; these beta oscillations might be sensitive markers of non-conscious motor error and correction monitoring

RFC1: Motifs and phenotypes.

International audienceBiallelic 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

Self-reported outcomes and quality of life of patients with non-dystrophic myotonia: The French IMPACT 2022 survey.

International audienceNon-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

Cognitive disorders in parkinson's disease: confirmation of a spectrum of severity

International audienceBACKGROUND: Clinical presentation and progression of cognitive disorders in Parkinson's disease (PD) is heterogeneous. Our objective was to confirm prospectively a previous exploratory cluster analysis based on retrospective data that identified five cognitive phenotypes in PD.METHODS: A model-based confirmatory cluster analysis was conducted on the results of neuropsychological tests administered in 156 PD patients from two European movement disorder centers (Lille, n = 81; Maastricht, n = 75). The number of clusters was determined on the basis of statistical criteria as well as clinical plausibility. A factorial discriminant analysis assessed the quality of the clusters' separation.RESULTS: A five-cluster model was statistically superior and clinically the most relevant. These clusters can be described as follows: 1) cognitively intact patients with high level of performance in all cognitive domains (25.64%), 2) cognitively intact patients slightly slower than those in cluster 1 (26.92%), 3) patients with deficits in executive functions (37.18%), 4) patients with severe deficits in all cognitive domains, particularly executive functions (3.20%), 5) patients with severe deficits in all cognitive domains, particularly working memory and recall in verbal episodic memory (7.05%). The groups differed in terms of age, apathy and frequency of hallucinations that were all higher in the clusters with cognitive deficits, and the duration of formal education was lower in those groups.CONCLUSIONS: We confirm our previous exploratory analysis. Cognitive disorders in PD patients are heterogeneous and can be separated in five clusters ranging from patients with performance in the normal range to patients with severe disorders in all cognitive domains

Electro-clinical presentation of hereditary transthyretin related amyloidosis when presenting as a polyneuropathy of unknown origin in northern France.

International audienceIntroductionHereditary 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.ObjectiveTo 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.MethodWe 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.ResultsAmong 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%).Conclusionh-ATTR may have a wide spectrum of clinical profiles, and should be considered in the screening of polyneuropathies of unknown origin

Cardiometabolic assessment of lamin A/C gene mutation carriers: A phenotype-genotype correlation.

International audienceMutations 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.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.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