Muscle pathology in myotonic dystrophy: light and electron microscopic investigation in eighteen patients

Myotonic dystrophy (DM) is the most common muscular dystrophy in adults. Two known genetic subtypes include DM1 (myotonic dystrophy type 1) and DM2 (myotonic dystrophy type 2). Genetic testing is considered as the only reliable diagnostic criterion in myotonic dystrophies. Relatively little is known about DM1 and DM2 myopathology. Thus, the aim of our study was to characterise light and electron microscopic features of DM1 and DM2 in patients with genetically proven types of the disease. We studied 3 DM1 cases and 15 DM2 cases from which muscle biopsies were taken for diagnostic purposes during the period from 1973 to 2006, before genetic testing became available at our hospital. The DM1 group included 3 males (age at biopsy 15–19). The DM2 group included 15 patients (5 men and 10 women, age at biopsy 26–60). The preferential type 1 fibre atrophy was seen in all three DM1 cases in light microscopy, and substantial central nucleation was present in two biopsies. Electron microscopy revealed central nuclei in all three examined muscle biopsies. No other structural or degenerative changes were detected, probably due to the young age of our patients. Central nucleation, prevalence of type 2 muscle fibres, and the presence of pyknotic nuclear clumps were observed in DM2 patients in light microscopy. Among the ultrastructural abnormalities observed in our DM2 group, the presence of internal nuclei, severely atrophied muscle fibres, and lipofuscin accumulation were consistent findings. In addition, a variety of ultrastructural abnormalities were identified by us in DM2. It appears that no single ultrastructural abnormality is characteristic for the DM2 muscle pathology. It seems, however, that certain constellations of morphological changes might be indicative of certain types of myotonic dystrophy. (Folia Morphol 2011; 70, 2: 121–129

Homozygous C-terminal loss-of-function NaV1.4 variant in a patient with congenital myasthenic syndrome

No abstract availabl

Abundant electrical myotonia and left ventricular noncompaction: Unusual features of Danon disease due to a novel mutation in LAMP2 gene

International audienc

Zmiany histopatologiczne w biopsji mięśnia u 31 chorych z mutacjami w genie kodującym kalpainę 3

Background and purpose At present, more than 20 different forms of limb-girdle muscular dystrophies (LGMDs) are known (at least 7 autosomal dominant and 14 autosomal recessive). Although these different forms show some typical phenotypic characteristics, the existing clinical overlap makes their differential diagnosis difficult. Limb-girdle muscular dystrophy type 2 (LGMD2A) is the most prevalent LGMD in many European as well as Brazilian communities and is caused by mutations in the gene CAPN3. Laboratory testing, such as calpain immunohistochemistry and Western-blot analysis, is not totally reliable, since up to 20% of molecularly confirmed LGMD2A show normal content of calpain 3 and a third of LGMD2A biopsies have normal calpain 3 proteolytic activity in the muscle. Thus, genetic testing is considered as the only reliable diagnostic criterion in LGMD2A. Material and methods In an attempt to find a correlation between genotype and muscle pathology in limb-girdle muscular dystrophy 2A we performed histopathological investigation of a group of 31 patients subdivided according to the type of pathologic CAPN3 gene mutation. Results In all biopsies typical features of muscular dystrophy such as fiber necrosis and regeneration, variation in fiber size and fibrosis were noted. Lobulated fibers were often encountered in the muscle biopsies of LGMD2A patients. Such fibers were more frequent in patients with 550delA mutation. Conclusions These findings may be helpful in establishing diagnostic strategies in LGMD.Wstęp i cel pracy Dotychczas opisano ponad 20 różnych form dystrofii obręczowo-kończynowej (limb girdle muscular dystrophy – LGMD) (co najmniej 7 rodzajów o dziedziczeniu autosomalnym dominującym oraz 14 o dziedziczeniu autosomalnym recesywnym). Pomimo że część z tych chorób można różnicować na podstawie obrazu klinicznego, diagnostykę utrudnia często podobieństwo objawów. Dystrofia obręczowo–kończynowa typu 2A (limb-girdle muscular dystrophy type 2 – LGMD2A), najczęstsza dystrofia mięśniowa w wielu społecznościach (np. w Europie i Brazylii), spowodowana jest przez mutacje w genie kalpainy 3 (CAPN3). Badanie immunohisto-chemiczne kalpainy czy też metodą Western blot nie są wystarczające do ustalenia właściwego rozpoznania (w odpowiednio 1/3 i 20% potwierdzonych genetycznie LGMD2A badania te wypadają prawidłowo). Podstawę rozpoznania tej miopatii stanowi badanie genetyczne. Materiał i metody W pracy przedstawiono wyniki badania zależności między genotypem a analizą histopatologiczną biopsji mięśnia u 31 chorych na LGMD2A. Chorzy podzieleni zostali na grupy według wyników badania genetycznego genu CAPN3 odpowiedzialnego za tę chorobę. Wyniki We wszystkich badanych biopsjach stwierdzano typowe zmiany dystroficzne, takie jak obecność włókien martwiczych i regenerujących, zróżnicowaną wielkość włókien oraz włóknienie. Włókna o nierównomiernym rozkładzie barwień na enzymy oddechowe (lobulated fibers) były często obserwowane w biopsjach chorych z LGMD2A. Tego typu włókna szczególnie często występowały u chorych z mutacją 550delA. Wnioski Wyniki pracy wnoszą nowe informacje ułatwiające diagnostykę LGMD

From exercise intolerance to functional improvement: The second wind phenomenon in the identification of McArdle disease

McArdle disease is the most common of the glycogen storage diseases. Onset of symptoms is usually in childhood with muscle pain and restricted exercise capacity. Signs and symptoms are often ignored in children or put down to 'growing pains' and thus diagnosis is often delayed. Misdiagnosis is not uncommon because several other conditions such as muscular dystrophy and muscle channelopathies can manifest with similar symptoms. A simple exercise test performed in the clinic can however help to identify patients by revealing the second wind phenomenon which is pathognomonic of the condition. Here a patient is reported illustrating the value of using a simple 12 minute walk test.RSS is funded by Ciências sem Fronteiras/CAPES Foundation. The authors would like to thank the Association for Glycogen Storage Disease (UK), the EUROMAC Registry funded by the European Union, the Muscular Dystrophy Campaign, the NHS National Specialist Commissioning Group and the Myositis Support Group for funding

Low penetrance in facioscapulohumeral muscular dystrophy type 1 with large pathological D4Z4 alleles: a cross-sectional multicenter study.

BackgroundFacioscapulohumeral muscular dystrophy type 1(FSHD1) is an autosomal dominant disorder associated with the contraction of D4Z4 less than 11 repeat units (RUs) on chromosome 4q35. Penetrance in the range of the largest alleles is poorly known. Our objective was to study the penetrance of FSHD1 in patients carrying alleles ranging between 6 to10 RUs and to evaluate the influence of sex, age, and several environmental factors on clinical expression of the disease. Methods A cross-sectional multicenter study was conducted in six French and one Swiss neuromuscular centers. 65 FSHD1 affected patients carrying a 4qA allele of 6¿10 RUs were identified as index cases (IC) and their 119 at-risk relatives were included. The age of onset was recorded for IC only. Medical history, neurological examination and manual muscle testing were performed for each subject. Genetic testing determined the allele size (number of RUs) and the 4qA/4qB allelic variant. The clinical status of relatives was established blindly to their genetic testing results. The main outcome was the penetrance defined as the ratio between the number of clinically affected carriers and the total number of carriers. Results Among the relatives, 59 carried the D4Z4 contraction. At the clinical level, 34 relatives carriers were clinically affected and 25 unaffected. Therefore, the calculated penetrance was 57% in the range of 6¿10 RUs. Penetrance was estimated at 62% in the range of 6¿8 RUs, and at 47% in the range of 9¿10 RUs. Moreover, penetrance was lower in women than men. There was no effect of drugs, anesthesia, surgery or traumatisms on the penetrance. Conclusions Penetrance of FSHD1 is low for largest alleles in the range of 9¿10 RUs, and lower in women than men. This is of crucial importance for genetic counseling and clinical management of patients and families

ASHAM Analyse sociologique des habitudes de vie des adultes atteints de Dystrophie myotonique de type 1 ou maladie de Steinert: Rapport de recherche dans le cadre du premier appel à projets de recherche 2012 Sciences humaines et sociales et maladies rares

Living habits for individuals suffering from a debilitating chronic disease are poorly known, yet essential for effective nursing care to be delivered in the long term. Myotonic dystrophy type 1 (DM1 or Steinert’s disease) is a particular chronic rare disease: it is genetic and progressive; it affects several functions and currently treatment for it is solely symptomatic. Amidst this complexity, it is relatively easy to cater for this clinical diversity in medical terms through multidisciplinary care, but it is more complicated object-side relationship. The objective of this qualitative study was to understand the change in living habits and the social determinants of coping strategies in men and women aged over 20 whose DM1 symptoms have appeared in adulthood. This is research in social sciences and nursing science based on a care issue and an ethno-sociological set of issue. The investigation has shown that patient’s behavior varies according to a set of combined determinants: age, social and professional situation, marital status, values and beliefs, living environment, and so on. Then, there is a large gap between medical representation of disease and day-to-day experience and social life of patients. The stations they passed during their life show various adaptation strategies. That gives us an opportunity to improve their support

Muscle imaging in patients with tubular aggregate myopathy caused by mutations in STIM1

Tubular aggregate myopathy is a genetically heterogeneous disease characterized by tubular aggregates as the hallmark on muscle biopsy. Mutations in STIM1 have recently been identified as one genetic cause in a number of tubular aggregate myopathy cases. To characterize the pattern of muscle involvement in this disease, upper and lower girdles and lower limbs were imaged in five patients with mutations in STIM1, and the scans were compared with two patients with tubular aggregate myopathy not caused by mutations in STIM1. A common pattern of involvement was found in STIM1-mutated patients, although with variable extent and severity of lesions. In the upper girdle, the subscapularis muscle was invariably affected. In the lower limbs, all the patients showed a consistent involvement of the flexor hallucis longus, which is very rarely affected in other muscle diseases, and a diffuse involvement of thigh and posterior leg with sparing of gracilis, tibialis anterior and, to a lesser extent, short head of biceps femoris. Mutations in STIM1 are associated with a homogeneous involvement on imaging despite variable clinical features. Muscle imaging can be useful in identifying STIM1-mutated patients especially among other forms of tubular aggregate myopathy

Comparison of Corticosteroid Tapering Regimens in Myasthenia Gravis: A Randomized Clinical Trial

International audienceImportance: The tapering of prednisone therapy in generalized myasthenia gravis (MG) presents a therapeutic dilemma; however, the recommended regimen has not yet been validated. Objective: To compare the efficacy of the standard slow-tapering regimen of prednisone therapy with a rapid-tapering regimen. Design: From June 1, 2009, to July 31, 2013, a multicenter, parallel, single-blind randomized trial was conducted to compare 2 regimens of prednisone tapering. Data analysis was conducted from February 18, 2019, to January 23, 2020. A total of 2291 adults with a confirmed diagnosis of moderate to severe generalized MG at 7 specialized centers in France were assessed for eligibility. Interventions: The slow-tapering arm included a gradual increase of the prednisone dose to 1.5 mg/kg every other day and a slow decrease once minimal manifestation status of MG was attained. The rapid-tapering arm consisted of immediate high-dose daily administration of prednisone, 0.75 mg/kg, followed by an earlier and rapid decrease once improved MG status was attained. Azathioprine, up to a maximum dose of 3 mg/kg/d, was prescribed for all participants. Main Outcomes and Measures: The primary outcome was attainment of minimal manifestation status of MG without prednisone at 12 months and without clinical relapse at 15 months. Intention-to-treat analysis was conducted. Results: Of the 2291 patients assessed, 2086 did not fulfill the inclusion criteria, 87 declined to participate, and 1 patient registered after trial closure. A total of 117 patients (58 in the slow-tapering arm and 59 in the rapid-tapering arm) were selected for inclusion by MG specialists and were randomized. The population included 62 men (53%); median age was 65 years (interquartile range, 35-69 years). The proportion of patients having met the primary outcome was higher in the rapid- vs slow-tapering arm (23 [39%] vs 5 [9%]), with a risk ratio of 3.61 (95% CI, 1.64-7.97; P <.001) after adjusting for center and thymectomy. The rapid-tapering regimen allowed sparing of a mean of 1898 mg (95% CI, -3121 to -461 mg) of prednisone over 1 year (ie, 5.3 mg/d per patient, P =.03). The number of serious adverse events did not differ significantly between the slow- vs rapid-tapering group (13 [22%] vs 21 [36%], P =.15). Conclusions and Relevance: In patients with moderate to severe generalized MG who require high-dose prednisone with azathioprine therapy, rapid tapering of prednisone appears to be feasible, well tolerated, and associated with a good outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT00987116