A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype–phenotype correlations based on available evidence

Rasch-ionale for neurologists

Outcome measures are considered the most important tools to monitor patients’ outcome in both clinical and research settings. Measuring the clinical state of patients is a fundamental part of our daily clinical practice and research that sometimes is taken for granted. In peripheral neuropathies, there are many scales available, but most of these are at the ordinal level. This paper will systematically address the types of scales available (being nominal, ordinal, interval, or ratio data-based) in terms of their strengths and weaknesses. The differences between classical test theory-based and modern test method-based outcome measures will be addressed with emphasis on Rasch methodology. Various steps will be highlighted as part of the evaluation and construction of outcome measures using the Rasch method, with the aim to increase the knowledge and utility of this technique. We argue that Rasch-built outcome measures should be used for future studies in neuromuscular disorders and their method of construction could be easily extrapolated to other neurological illnesses

196th ENMC international workshop: Outcome measures in inflammatory peripheral neuropathies 8-10 February 2013, Naarden, The Netherlands

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Outcome measures in MMN revisited: further improvement needed

The objectives of this study were to provide an overview of the outcome measures (OMs) applied in clinical trials in multifocal motor neuropathy (MMN) and to determine the responsiveness of a core set of selected OMs as part of the peripheral neuropathy outcome measures standardization (PeriNomS) study. The following OMs were serially applied in 26 patients with newly diagnosed or relapsing MMN, receiving intravenous immunoglobulin (assessments: T0/T3/T12months): 14 muscle pairs MRC (Medical Research Council) scale, the Neuropathy Impairment Scale motor-subset, a self-evaluation scale, grip strength, and MMN-RODS(C) (Rasch-built overall disability scale). All data, except the grip strength, were subjected to Rasch analyses before determining responsiveness. For grip strength, responsiveness was examined using a combined anchor- (SF-36 question-2) and distribution-based (1/2xSD) minimum clinically important difference (MCID) techniques, determining the proportion of patients exceeding both the identified cut-offs. For the remaining scales, the magnitude of change for each patient on each scale was determined using the MCID related to the individual SE (responder definition: MCID-SE1.96). Overall, a great assortment of measures has been used in MMN trials with different responsiveness definitions. For the selected OMs, responsiveness was poor and only seen in one fourth to one third of the patients, the grip strength being more responsive. Despite the efforts taken to standardize outcome assessment, further clinimetric responsiveness studies are needed in MM

Implications of Genetic Testing in Dilated Cardiomyopathy

Background: Genetic analysis is a first-tier test in dilated cardiomyopathy (DCM). Electrical phenotypes are common in genetic DCM, but their exact contribution to the clinical course and outcome is unknown. We determined the prevalence of pathogenic gene variants in a large unselected DCM population and determined the role of electrical phenotypes in association with outcome. Methods: This study included 689 patients with DCM from the Maastricht Cardiomyopathy Registry, undergoing genetic evaluation using a 48 cardiomyopathy-associated gene-panel, echocardiography, endomyocardial biopsies, and Holter monitoring. Upon detection of a pathogenic variant in a patient with DCM, familial segregation was performed. Outcome was defined as cardiovascular death, heart transplantation, heart failure hospitalization, and/or occurrence of life-threatening arrhythmias. Results: A (likely) pathogenic gene variant was found in 19% of patients, varying from 36% in familial to 13% in nonfamilial DCM. Family segregation analysis showed familial disease in 46% of patients with DCM who were initially deemed nonfamilial by history. Overall, 18% of patients with a nongenetic risk factor had a pathogenic gene variant. Almost all pathogenic gene variants occurred in just 12 genes previously shown to have robust disease association with DCM. Genetic DCM was independently associated with electrical phenotypes such as atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block and inversely correlated with the presence of a left bundle branch block (P Conclusions: One in 5 patients with an established nongenetic risk factor or a nonfamilial disease still carries a pathogenic gene variant. Genetic DCM is characterized by a profile of electrical phenotypes (atrial fibrillation, nonsustained ventricular tachycardia, and atrioventricular block), which carries increased risk for adverse outcomes. Based on these findings, we envisage a broader role for genetic testing in DCM

Rasch-built Overall Disability Scale for Multifocal motor neuropathy (MMN-RODS(©) )

Clinical trials in multifocal motor neuropathy (MMN) have often used ordinal-based measures that may not accurately capture changes. We aimed to construct a disability interval outcome measure specifically for MMN using the Rasch model and to examine its clinimetric properties. A total of 146 preliminary activity and participation items were assessed twice (reliability studies) in 96 clinically stable MMN patients. These patients also assessed the ordinal-based overall disability sum score (construct, sample-dependent validity). The final Rasch-built overall disability scale for MMN (MMN-RODS(©) ) was serially applied in 26 patients with newly diagnosed or relapsing MMN, treated with intravenous immunoglobulin (IVIg) (1-year follow-up; responsiveness study). The magnitude of change for each patient was calculated using the minimum clinically important difference technique related to the individually obtained standard errors. A total of 121 items not fulfilling Rasch requirements were removed. The final 25-item MMN-RODS(©) fulfilled all Rasch model's expectations and showed acceptable reliability and validity including good discriminatory capacity. Most serially examined patients improved, but its magnitude was low, reflecting poor responsiveness. The constructed MMN-RODS(©) is a disease-specific, interval measure to detect activity limitations in patients with MMN and overcomes the shortcomings of ordinal scales. However, future clinimetric studies are needed to improve the MMN-RODS(©) 's responsiveness by longer observations and/or more rigorous treatment regimens

De novo variants in CAMTA1 cause a syndrome variably associated with spasticity, ataxia, and intellectual disability

Previously, intragenic CAMTA1 copy number variants (CNVs) have been shown to cause non-progressive, congenital ataxia with or without intellectual disability (OMIM#614756). However, ataxia, intellectual disability, and dysmorphic features were all incompletely penetrant, even within families. Here, we describe four patients with de novo nonsense, frameshift or missense CAMTA1 variants. All four patients predominantly manifested features of ataxia and/or spasticity. Borderline intellectual disability and dysmorphic features were both present in one patient only, and other neurological and behavioural symptoms were variably present. Neurodevelopmental delay was found to be mild. Our findings indicate that also nonsense, frameshift and missense variants in CAMTA1 can cause a spastic ataxia syndrome as the main phenotype