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

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

Genetic variation in the hTAS2R38 taste receptor and food consumption among Finnish adults

Genetic variation in bitter taste receptors, such as hTAS2R38, may affect food preferences and intake. The aim of the present study was to investigate the association between bitter taste receptor haplotypes and the consumption of vegetables, fruits, berries and sweet foods among an adult Finnish population. A cross-sectional design utilizing data from the Cardiovascular Risk in Young Finns cohort from 2007, which consisted of 1,903 men and women who were 30-45 years of age from five different regions in Finland, was employed. DNA was extracted from blood samples, and hTAS2R38 polymorphisms were determined based on three SNPs (rs713598, rs1726866 and rs10246939). Food consumption was assessed with a validated food frequency questionnaire. The prevalence of the bitter taste-sensitive (PAV/PAV) haplotype was 11.3 % and that of the insensitive (AVI/AVI) haplotype was 39.5 % among this Finnish population. PAV homozygotic women consumed fewer vegetables than did the AVI homozygotic women, 269 g/day (SD 131) versus 301 g/day (SD 187), respectively, p = 0.03 (multivariate ANOVA). Furthermore, the intake of sweet foods was higher among the PAV homozygotes of both genders. Fruit and berry consumption did not differ significantly between the haplotypes in either gender. Individuals perceive foods differently, and this may influence their patterns of food consumption. This study showed that the hTAS2R38 taste receptor gene variation was associated with vegetable and sweet food consumption among adults in a Finnish population.Peer reviewe

CHCHD10 mutations and motor neuron disease: the distribution in Finnish patients.

Peer reviewe

Unique Exercise Lactate Profile in Muscle phosphofructokinase Deficiency (Tarui Disease); Difference Compared with McArdle Disease

Introduction: Glycogen storage disease V (GSDV, McArdle disease) and GSDVII (Tarui disease) are the most common of the rare disorders of glycogen metabolism. Both are associated with low lactate levels on exercise. Our aim was to find out whether lactate response associated with exercise testing could distinguish between these disorders. Methods: Two siblings with Tarui disease, two patients with McArdle disease and eight healthy controls were tested on spiroergometric exercise tests with follow-up of venous lactate and ammonia. Results: A late increase of lactate about three times the basal level was seen 10-30 min after exercise in patients with Tarui disease being higher than in McArdle disease and lower than in the controls. Ammonia was increased in Tarui disease. Discussion: Our results suggest that follow-up of lactate associated with exercise testing can be utilized in diagnostics to distinguish between different GSD diseases.Peer reviewe

Novel mutations in DNAJB6 gene cause a very severe early-onset limb-girdle muscular dystrophy 1D disease

DNAJB6 is the causative gene for limb-girdle muscular dystrophy 1D (LGMD1D). Four different coding missense mutations, p.F89I, p.F93I, p.F93L, and p.P96R, have been reported in families from Europe, North America and Asia. The previously known mutations cause mainly adult-onset proximal muscle weakness with moderate progression and without respiratory involvement. A Finnish family and a British patient have been studied extensively due to a severe muscular dystrophy. The patients had childhood-onset LGMD, loss of ambulation in early adulthood and respiratory involvement; one patient died of respiratory failure aged 32. Two novel mutations, c.271T > A (p.F91I) and c.271T > C (p.F91L), in DNAJB6 were identified by whole exome sequencing as a cause of this severe form of LGMD1D. The results were confirmed by Sanger sequencing. The anti-aggregation effect of the mutant DNAJB6 was investigated in a filter-trap based system using transient transfection of mammalian cell lines and polyQ-huntingtin as a model for an aggregation-prone protein. Both novel mutant proteins show a significant loss of ability to prevent aggregation. (C) 2015 Elsevier B.V. All rights reserved.Peer reviewe

DNAJB6-geenimutaatioon liittyvä LGMD1D-lihasdystrofia - kliininen ilmiasu

Lihasrappeumasairaudet ovat perinnöllisiä sairauksia, joissa lihassyyt kuolevat ennenaikaisesti ja lihaskudos korvautuu rasva- ja sidekudoksella. Seurauksena on lihaksen surkastuminen ja heikkeneminen. Satu Sandellin väitöstutkimus käsittelee DNAJB6-geenin mutaatiosta johtuvan lihasdystrofiasairauden kliinistä kuvaa ja patome-kanismeja. Hartia-lantiorenkaan lihasdystrofia (limb-girdle muscular dystrophy, LGMD) on tautiryhmä, jossa lihasheikkous kohdistuu pääasiassa raajojen tyviosien lihaksiin. Tautiryhmä jaetaan vallitsevasti (LGMD1) ja peittyvästi (LGMD2) periytyviin tautimuotoihin. Nämä sairaudet ovat kaiken kaikkiaan harvinaisia, ja vallitsevasti periytyviä tautimuotoja on vain vähän verrattuna peittyvästi periytyvien muotojen yleisyyteen. Ennen vuotta 2008 ei tiedetty LGMD1D-sairautta esiintyvän myös Suomessa. Suurehkon pirkanmaalais-satakuntalaisen perheen kohdalla oli tiedossa hitaasti etenevä, vallitsevasti periytyvä hartia-lantiolihasdystrofia kolmen sukupolven ajalta. Tämän ja toisen, pienemmän suvun kohdalla paljastui geneettinen kytkentä, joka sopi 1990-luvulla Yhdysvalloissa raportoituun kahden suvun lihasdystrofiageenipaikannukseen kromosomissa 7q36. Taudin ilmiasusta ei kuitenkaan oltu aiemmin raportoitu tarkempia tietoja. Tutkimuksen tavoitteeksi asetettiin kuvata taudin tarkempi ilmiasu, sen tyypilliset kliiniset piirteet, lihasten kuvantamis- ja patologialöydökset, tarken-taa kromosomaalista kytkentäaluetta sekä selvittää sairauden geenivirhe. LGMD1D periytyy vallitsevasti ja sen syyksi paljastui DNAJB6-geenin mutaatiovirhe, joka oli kaikilla tämän aineiston suomalaisilla potilailla sama. Vielä ei ole varmuutta siitä, miksi elimistössä kaikissa kudoksissa runsaana esiintyvän DNAJB6-proteiinin geenivirhe aiheuttaa sairauden juuri lihaskudokseen. Lihaksessa DNAJB6:n toimin-ta liittyy proteiinien laaduntarkkailujärjestelmän toimintaan. Vuonna 2010 julkaistiin Sandellin väitöstutkimukseen liittyvä ensimmäinen kattava kliininen kuvaus LGMD1D-sairauden ilmiasusta. Tutkituissa perheissä sairaus alkoi myöhäisellä aikuisiällä, joskus vasta yli 60-vuotiaana, ja eteni hitaasti. Tyypillisin ensioire oli reisilihasheikkous. Lähes kaikki potilaat säilyttivät itsenäisen liikkumiskyvyn pitkänkin sairastamisen jälkeen, jopa kahdeksankymmen vuoden ikään asti. Joillakin potilailla oli lievää puhe- tai nielemisvaikeutta. Yhdeksi sairauden tunnusomaiseksi piirteeksi paljastui lihasten magneettikuvauslöydös vuonna 2012, mikä johti useiden uusien potilaiden välittömään löytymiseen, kun kuvauslöydöksen perusteella voitiin edetä suoraan geneettiseen analyysiin. Tyypilliset lihasbiopsialöydökset raportoitiin vuonna 2014, ja myös näiden perusteella löydettiin uusia tapauksia. Tutkimuksen edetessä osoittautui, että LGMD1D on Suomen yleisin vallit-sevasti periytyvä hartia-lantiolihasdystrofia. Potilasmäärä on vielä pieni, mutta tiedossa on jo, että taudin kliininen kirjo tulee laajentumaan jatkossa uusien mutaatioiden löytymisen myötä. Lihassairauksien diagnostiikan parantaminen on ensiarvoisen tärkeää paitsi lääketieteelliseltä myös inhimilliseltä kannalta. Jokaisella lihassairauspotilaalla on oikeus tietää, mikä on hänen tautinsa perimmäinen syy, miten hänen sairastamansa lihassairaus todennäköisimmin etenee, miten se periytyy, liittyykö siihen liitännäissairauksia kuten hengitys- ja sydänkomplikaatioita, joita voidaan ennakoivasti hoitaa, ja onko sairaus elinikää lyhentävä. Vaikka sairaudelle ei parannuskeinoa lähitulevaisuudessa löytyisikään, on potilaan tärkeää saada sairaudelleen lopullinen ja täsmällinen diagnoosi.This study was designed to elucidate the clinical phenotype of Limb-girdle muscular dystrophy 1D (LGMD1D), a chaperonopathy caused by mutated DNAJB6. Muscular dystrophies are by definition inherited disorders causing progressive weakness and loss of skeletal muscle. Limb-girdle muscular dystrophy (LGMD) is one category of muscular dystrophies with preferential weakness of proximal muscle groups. LGMDs are divided in two groups based on their inheritance: autosomal dominant LGMD1 and autosomal recessive LGMD2. Dominantly inherited forms are very rare diseases. Before year 2008 LGMD1D was not known to exist in Finland. However, a large family from Pirkanmaa region had been identified with an unknown, dominantly segregating slowly progressive LGMD phenotype. In this and another smaller family we were able to confirm genetic linkage to chromosome 7q36, a muscular dystrophy gene locus reported earlier. However, the clinical features of this 7q36-linked myopathy had not been detailed. With this study we describe typical clinical features, the muscle imaging,pathology and laboratory findings, we narrowed the genetic linkage and finally unraveled the genetic defect underlying the disease. In 2010 we published the first larger clinical report of the LGMD1D disease as being typically late-onset, slowly progressive, and rarely resulting in loss of ambulation, and without cardiac or respiratory involvement. We later reported pathognomonic muscle imaging findings which, in fact, facilitated the recognition of new families. Distinct muscle biopsy findings also helped the identification of more patients and refining the morphological pathomechanism of the disease. In 2012 we reported that LGMD1D is caused by dominant mutations in the co-chaperone DNAJB6. It is still not fully understood why the defect DNAJB6, ubiquitously expressed in all tissues, causes damage to the muscle tissue only. As a co-chaperone DNAJB6 is connected to the functions of protein quality control and turnover. LGMD1D proved to be the most common dominantly inherited limb-girdle muscular dystrophy in Finland. While the total number of patients is still small, the clinical spectrum of the disease is already expanding with new mutations identified. Improved diagnostic methods are important not only from the medical point of view, but also from human perspective.Muscle disease patients have the right to know the exact cause of their disease, how the disease in likely to progress, whether it in genetic, and to know the possible additional complications that can be prevented or proactively cared for by appropriate management. Even if the cure for the disease might lie in the future, it is important for the patient to know the final diagnosis also in order to avoid false treatments due to misdiagnosis