Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7

<p>Abstract</p> <p>Background</p> <p>Sodium channel Na_V1.7 is preferentially expressed within dorsal root ganglia (DRG), trigeminal ganglia and sympathetic ganglion neurons and their fine-diamter axons, where it acts as a threshold channel, amplifying stimuli such as generator potentials in nociceptors. Gain-of-function mutations and variants (single amino acid substitutions) of Na_V1.7 have been linked to three pain syndromes: Inherited Erythromelalgia (IEM), Paroxysmal Extreme Pain Disorder (PEPD), and Small Fiber Neuropathy (SFN). IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling, and is caused by mutations that hyperpolarize activation, slow deactivation, and enhance the channel ramp response. PEPD is characterized by perirectal, periocular or perimandibular pain, often triggered by defecation or lower body stimulation, and is caused by mutations that severely impair fast-inactivation. SFN presents a clinical picture dominated by neuropathic pain and autonomic symptoms; gain-of-function variants have been reported to be present in approximately 30% of patients with biopsy-confirmed idiopathic SFN, and functional testing has shown altered fast-inactivation, slow-inactivation or resurgent current. In this paper we describe three patients who house the Na_V1.7/I228M variant.</p> <p>Methods</p> <p>We have used clinical assessment of patients, quantitative sensory testing and skin biopsy to study these patients, including two siblings in one family, in whom genomic screening demonstrated the I228M Na_V1.7 variant. Electrophysiology (voltage-clamp and current-clamp) was used to test functional effects of the variant channel.</p> <p>Results</p> <p>We report three different clinical presentations of the I228M Na_V1.7 variant: presentation with severe facial pain, presentation with distal (feet, hands) pain, and presentation with scalp discomfort in three patients housing this Na_V1.7 variant, two of which are from a single family. We also demonstrate that the Na_V1.7/I228M variant impairs slow-inactivation, and produces hyperexcitability in both trigeminal ganglion and DRG neurons.</p> <p>Conclusion</p> <p>Our results demonstrate intra- and interfamily phenotypic diversity in pain syndromes produced by a gain-of-function variant of Na_V1.7.</p

Co-morbidity and visual acuity are risk factors for health-related quality of life decline: five-month follow-up EQ-5D data of visually impaired older patients

<p>Abstract</p> <p>Background</p> <p>Co-morbidity is a common phenomenon in the elderly and is considered to be a major threat to quality of life (QOL). Knowledge of co-existing conditions or patient characteristics that lead to an increased QOL decline is important for individual care, and for public health purposes. In visually impaired older adults, it remains unclear which co-existing conditions or other characteristics influence their health-related QOL. Our aim was to present a risk profile of characteristics and conditions which predict deterioration of QOL in visually impaired older patients.</p> <p>Methods</p> <p>Analyses were performed on data from an observational study among 296 visually impaired older patients from four Dutch hospitals. QOL was measured with the EuroQol-5D (EQ-5D) at baseline and at five-month follow-up. Nine co-existing condition categories (musculoskeletal; diabetes; heart; hypertension; chronic obstructive pulmonary disease (COPD) or asthma; hearing impairment; stroke; cancer; gastrointestinal conditions) and six patient characteristics (age; gender; visual acuity; social status; independent living; rehabilitation type) were tested in a linear regression model to determine the risk profile. The model was corrected for baseline EQ-5D scores. In addition, baseline EQ-5D scores were compared with reference scores from a younger visually impaired population and from elderly in the general population.</p> <p>Results</p> <p>From the 296 patients, 50 (16.9%) were lost to follow-up. Patients who reported diabetes, COPD or asthma, consequences of stroke, musculoskeletal conditions, cancer, gastrointestinal conditions or higher logMAR Visual Acuity values, experienced a lower QOL. After five months, visual acuity, musculoskeletal conditions, COPD/asthma and stroke predicted a decline in QOL (R²= 0.20). At baseline, the visually impaired older patients more often reported moderate or severe problems on most EQ-5D dimensions than the two reference groups.</p> <p>Conclusion</p> <p>In visually impaired older patients, visual acuity, musculoskeletal conditions, COPD/asthma and stroke predicted a relatively rapid decline in health-related QOL. With this risk profile, a specific referral by the ophthalmologist to another sub-specialty may have a beneficial effect on the patient's health-related QOL. A referral by the ophthalmologist or optometrist to a multidisciplinary rehabilitation service seems appropriate for some patients with co-morbidity. The current results need to be confirmed in studies using pre-structured questionnaires to assess co-morbidity.</p

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.status: publishe

EURO-NMD registry: federated FAIR infrastructure, innovative technologies and concepts of a patient-centred registry for rare neuromuscular disorders

Abstract Background The EURO-NMD Registry collects data from all neuromuscular patients seen at EURO-NMD's expert centres. In-kind contributions from three patient organisations have ensured that the registry is patient-centred, meaningful, and impactful. The consenting process covers other uses, such as research, cohort finding and trial readiness. Results The registry has three-layered datasets, with European Commission-mandated data elements (EU-CDEs), a set of cross-neuromuscular data elements (NMD-CDEs) and a dataset of disease-specific data elements that function modularly (DS-DEs). The registry captures clinical, neuromuscular imaging, neuromuscular histopathology, biological and genetic data and patient-reported outcomes in a computer-interpretable format using selected ontologies and classifications. The EURO-NMD registry is connected to the EURO-NMD Registry Hub through an interoperability layer. The Hub provides an entry point to other neuromuscular registries that follow the FAIR data stewardship principles and enable GDPR-compliant information exchange. Four national or disease-specific patient registries are interoperable with the EURO-NMD Registry, allowing for federated analysis across these different resources. Conclusions Collectively, the Registry Hub brings together data that are currently siloed and fragmented to improve healthcare and advance research for neuromuscular diseases. </jats:sec