Statiineihin liittyvät itsepintaiset lihasoireet

Pääkirjoitus-editoria

Borderlines between sarcopenia and mild late-onset muscle disease

Peer reviewe

Neurologisten sairauksien vaikutus seksuaalisuuteen

Hermostolla on tärkeä merkitys seksuaalisuudessa ja seksuaalitoimintojen säätelyssä, joten moniin neurologisiin sairauksiin liittyy niiden ongelmia. Seksuaalitoimintojen vaikeutuminen voi johtua suoraan rakenteellisista muutoksista esimerkiksi selkäytimen vaurioituessa tai epäsuorasti neurologisten vaurioiden aiheuttaman toimintahäiriön kuten halvausoireiden tai koordinaatio-ongelmien vuoksi. Lisäksi toimintakykyyn vaikuttavat usein neurologisiin tauteihin tai niiden jälkitiloihin liittyvät mielialahäiriöt, kognitiiviset ongelmat ja persoonallisuuden muutokset. Merkittävimpiä seksuaalihäiriöitä aiheuttavia tekijöitä nuorilla aikuisilla ovat MS-tauti, selkäydinvammat ja osa epilepsian hoitoon käytettävistä lääkkeistä. Ikääntyneillä muun muassa aivoverenkiertohäiriöt ja neurodegeneratiiviset sairaudet, erityisesti Parkinsonin tauti, voivat heikentää seksuaalitoimintoja. Potilaan kokonaisvaltaisessa hoidossa on tärkeää muistaa seksuaalitoimintojen häiriön mahdollisuus. Hoitovaihtoehdot noudattavat samoja periaatteita kuin muissakin sairauksissa käytettävät vaihtoehdot.publishedVersionPeer reviewe

Editorial : Current and Future Developments in the Therapeutic Management of Neuromuscular Diseases

publishedVersionNon peer reviewe

Predominantly myalgic phenotype caused by the c.3466G > A p.A1156T mutation in SCN4A gene

Objective: To characterize the clinical phenotype in patients with p.A1156T sodium channel mutation. Methods: Twenty-nine Finnish patients identified with the c.3466G>A p.A1156T mutation in the SCN4A gene were extensively examined. In a subsequent study, 63 patients with similar myalgic phenotype and with negative results in myotonic dystrophy type 2 genetic screening (DM2-neg group) and 93 patients diagnosed with fibromyalgia were screened for the mutation. Functional consequences of the p.A1156T mutation were studied in HEK293 cells with whole-cell patch clamp. Results: The main clinical manifestation in p.A1156T patients was not myotonia or periodic paralysis but exercise-and cold-induced muscle cramps, muscle stiffness, and myalgia. EMG myotonic discharges were detected in most but not all. Electrophysiologic compound muscle action potentials exercise test showed variable results. The p.A1156T mutation was identified in one patient in the DM2-neg group but not in the fibromyalgia group, making a total of 30 patients so far identified. Functional studies of the p.A1156T mutation showed mild attenuation of channel fast inactivation. Conclusions: The unspecific symptoms of myalgia stiffness and exercise intolerance without clinical myotonia or periodic paralysis in p.A1156T patients make the diagnosis challenging. The symptoms of milder SCN4A mutations may be confused with other similar myalgic syndromes, including fibromyalgia and myotonic dystrophy type 2.Peer reviewe

Late-onset limb-girdle muscular dystrophy caused by GMPPB mutations

Mutations in GMPPB gene have been reported in patients with early-onset disease ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy (LGMD) with mental retardation. More recently mutations in GMPPB have been identified with congenital myasthenic syndromes as well as milder phenotypes. We report two unrelated cases with LGMD that underwent clinical, histopathological and genetic studies. In both cases, we found identical compound heterozygous GMPPB mutations c.79G>C p.D27H and c.859C>T p.R287W, leading to a glycosylation defect of alpha-dystroglycan. The onset of muscle weakness was 30-40 years and the progression rate mild to moderate. Case 2 became wheelchair-bound at the age of 60. No cognitive or behavioral symptoms were noted. These cases provide further evidence that GMPPB mutations can also cause late-onset recessive LGMD with milder phenotypes than previously reported, and thus should be considered in the differential diagnosis of patients with adult-onset muscular dystrophies. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Diagnostically important muscle pathology in DNAJB6 mutated LGMD1D

Introduction: Limb girdle muscular dystrophies are a large group of both dominantly and recessively inherited muscle diseases. LGMD1D is caused by mutated DNAJB6 and the molecular pathogenesis is mediated by defective chaperonal function leading to impaired handling of misfolded proteins which normally would be degraded. Here we aim to clarify muscle pathology of LGMD1D in order to facilitate diagnostic accuracy. After following six Finnish LGMD1D families, we analysed 21 muscle biopsies obtained from 15 patients at different time points after the onset of symptoms. All biopsies were obtained from the lower limb muscles and processed for routine histochemistry, extensive immunohistochemistry and electron microscopy. Results: Histopathological findings were myopathic or dystrophic combined with rimmed vacuolar pathology, and small myofibrillar aggregates. These myofibrillar inclusions contained abnormal accumulation of a number of proteins such as myotilin, aB-crystallin and desmin on immunohistochemistry, and showed extensive myofibrillar disorganization with excess of Z-disk material on ultrastructure. Later in the disease process the rimmed vacuolar pathology dominated with rare cases of pronounced larger pleomorphic myofibrillar aggregates. The rimmed vacuoles were reactive for several markers of defect autophagy such as ubiquitin, TDP-43, p62 and SMI-31. Conclusions: Since DNAJB6 is known to interact with members of the chaperone assisted selective autophagy complex (CASA), including BAG3 - a known myofibrillar myopathy causing gene, the molecular muscle pathology is apparently mediated through impaired functions of CASA and possibly other complexes needed for the maintenance of the Z-disk and sarcomeric structures. The corresponding findings on histopathology offer clues for the diagnosis.Peer reviewe

Absence of NEFL in patient-specific neurons in early-onset Charcot-Marie-Tooth neuropathy

Objective: We used patient-specific neuronal cultures to characterize the molecular genetic mechanism of recessive nonsense mutations in neurofilament light (NEFL) underlying early-onset Charcot-Marie-Tooth (CMT) disease. Methods: Motor neurons were differentiated from induced pluripotent stem cells of a patient with early-onset CMT carrying a novel homozygous nonsense mutation in NEFL. Quantitative PCR, protein analytics, immunocytochemistry, electron microscopy, and single-cell transcriptomics were used to investigate patient and control neurons. Results: We show that the recessive nonsense mutation causes a nearly total loss of NEFL messenger RNA (mRNA), leading to the complete absence of NEFL protein in patient's cultured neurons. Yet the cultured neurons were able to differentiate and form neuronal networks and neurofilaments. Single-neuron gene expression fingerprinting pinpointed NEFL as the most downregulated gene in the patient neurons and provided data of intermediate filament transcript abundancy and dynamics in cultured neurons. Blocking of nonsense-mediated decay partially rescued the loss of NEFL mRNA. Conclusions: The strict neuronal specificity of neurofilament has hindered the mechanistic studies of recessive NEFL nonsense mutations. Here, we show that such mutation leads to the absence of NEFL, causing childhood-onset neuropathy through a loss-of-function mechanism. We propose that the neurofilament accumulation, a common feature of many neurodegenerative diseases, mimics the absence of NEFL seen in recessive CMT if aggregation prevents the proper localization of wild-type NEFL in neurons. Our results suggest that the removal of NEFL as a proposed treatment option is harmful in humans.Peer reviewe