Cause Of Dystrophy Research Articles

Large TRAPPC11 gene deletions as a cause of muscular dystrophy and their estimated genesis

BackgroundTransport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and...

Bi-allelic variants in HMGCR cause an autosomal-recessive progressive limb-girdle muscular dystrophy

Statins are a mainstay intervention for cardiovascular disease prevention, yet their use can cause rare severe myopathy. HMG-CoA reductase, an essential enzyme in the mevalonate pathway, is the target of statins. We identified nine individuals from five unrelated families with unexplained limb-girdle like muscular dystrophy and bi-allelic variants in HMGCR via clinical and research exome sequencing. The clinical features resembled other genetic causes of muscular dystrophy with incidental high CPK levels (>1,000U/L), proximal muscle weakness, variable age of onset, and progression leading to impaired ambulation. Muscle biopsies in most affected individuals showed non-specific dystrophic changes with non-diagnostic immunohistochemistry. Molecular modeling analyses revealed variants to be destabilizing and affecting protein oligomerization. Protein activity studies using three variants (p.Asp623Asn, p.Tyr792Cys, and p.Arg443Gln) identified in affected individuals confirmed decreased enzymatic activity and reduced protein stability. In summary, we showed that individuals with bi-allelic amorphic (i.e., null and/or hypomorphic) variants in HMGCR display phenotypes that resemble non-genetic causes of myopathy involving this reductase. This study expands our knowledge regarding the mechanisms leading to muscular dystrophy through dysregulation of the mevalonate pathway, autoimmune myopathy, and statin-induced myopathy.

VP.08 Interests and experiences of young adults with muscular dystrophy in receiving genetic information

Little is known about the informational needs of young adults with muscular dystrophy (MD). This study aims to elucidate their needs pertaining to genetic information and genetic testing, and to explore the role of genetic counsellors in helping to meet those needs. Young adults with MD (N=226) in Canada and the U.S. were surveyed about their interests and experiences in receiving genetic information. Participants were between the ages of 16-25, recruited through patient registries and social media channels. Of 226 respondents, 33% had Duchenne MD; 9 types of MD were represented overall. There was interest in receiving information about causes of MD, the chance of having a child with MD and genetic therapies. The preferred ages to receive information about the cause of MD, and about pregnancy-related genetic testing, were 12 and 17 years respectively. Only 26% of participants reported having received information about their chance of having a child with MD, while 41% indicated that it is important to receive this information. Participants described barriers to accessing genetic information, which included: cost, confusing terminology, and limited interaction with the outside world. Respondents also commented on advantages and disadvantages of genetic testing, and experiences meeting with genetic counsellors. Nineteen percent of participants were uncertain whether they had ever met with a genetic counsellor and 25% of those who had, could not recall the topics discussed. This research provides insight as to which genetic topics are of interest to young adults with MD, as well as the age they wish to receive this information. Analysis highlights gaps between interest in, and receipt of, genetic information. It delineates barriers that participants encounter in accessing this information. Results suggest the importance of genetic counselling to this population in meeting their informational needs, and that the timing of counselling delivery should be carefully planned.

MICROMORPHOLOGICAL CHANGES IN THE ORGANS OF DOGS AFTER THE INFECTION OF DIROFILARIA REPENS

With the widespread infection of Dirofilaria repens in dogs on the territory of the Russian Federation, the morphological changes in this disease are not well described, and the carcinogenic effect of these helminths on the host has not been established. We have carried out a comprehensive study of morphological changes in the tissues of outbred dogs (the mammary gland of two females and the testes of one male) with subcutaneous dirofilariasis. Excised neoplasms were sent for histological examination, as a result, the females were diagnosed with papillary breast cancer with areas of chondroid differentiation, necrosis, diffuse type of growth, fibrocystic non-proliferative mastopathy. In the male, the histological diagnosis corresponded to chronic orchitis, sclerotic changes were expressed in the epididymis with atrophic and cystic changes in the vas deferens. The uniformity of the micromorphological picture of the neoplastic process in the mammary gland in females may have a certain relationship with the invasion of D. repens due to chronic mechanical traumatization of the host tissues by helminths, as well as their toxic and immune effects. The described impact, in our opinion, was the cause of dystrophy of the male reproductive glands. In general, the study of the relationship between infection with D. repens and the oncological process requires further, more in-depth and private study.

Dystrophin genetic variants and autism

Loss-of-function variants in the dystrophin gene, a well-known cause of muscular dystrophies, have emerged as a mutational risk mechanism for autism spectrum disorder (ASD), which in turn is a highly prevalent (~ 1%) genetically heterogeneous neurodevelopmental disorder. Although the association of intellectual disability with the dystrophinopathies Duchenne (DMD) and Becker muscular dystrophy (BMD) has been long established, their association with ASD is more recent, and the dystrophin genotype-ASD phenotype correlation is unclear. We therefore present a review of the literature focused on the ASD prevalence among dystrophinopathies, the relevance of the dystrophin isoforms, and most particularly the relevance of the genetic background to the etiology of ASD in these patients. Four families with ASD-DMD/BMD patients are also reported here for the first time. These include a single ASD individual, ASD-discordant and ASD-concordant monozygotic twins, and non-identical ASD triplets. Notably, two unrelated individuals, which were first ascertained because of the ASD phenotype at ages 15 and 5 years respectively, present rare dystrophin variants still poorly characterized, suggesting that some dystrophin variants may compromise the brain more prominently. Whole exome sequencing in these ASD-DMD/BMD individuals together with the literature suggest, although based on preliminary data, a complex and heterogeneous genetic architecture underlying ASD in dystrophinopathies, that include rare variants of large and medium effect. The need for the establishment of a consortia for genomic investigation of ASD-DMD/BMD patients, which may shed light on the genetic architecture of ASD, is discussed.

Median Nail Dystrophy due to Habit Tic: A Case Report

Median dystrophy of nails may present with diagnostic difficulty. We present a case of a 30-year old male with multiple serial transverse ridges involving the median part of the bilateral great toe nails and the right thumb nail of approximately 10 years duration. On probing, the patient was found to have the habit of picking over the proximal nail folds. Habit of tic may not be noticed by the patient, however, may be the cause of dystrophy of nails.

Muscle biopsy and MRI findings in ANO5-related myopathy.

Mutations in the anoctamin 5 (ANO5) gene are a common cause of muscular dystrophy. We aimed to investigate whether inflammatory changes in muscle are present in patients with ANO5 myopathy when assessed by muscle biopsy and muscle magnetic resonance imaging (MRI). Adults with pathogenic variations in ANO5 known to cause muscular dystrophy were included in our study. Muscle biopsies of pelvic and lower extremity muscles were reviewed retrospectively. Muscle MR short-tau inversion recovery (STIR) images of a subset of these patients were obtained prospectively. Muscle biopsies from 24 patients were reviewed. MR STIR images were performed in 17 of these patients. We found inflammatory changes in muscle biopsies of three patients and MRI revealed hyperintense signals on STIR images in 14 of 17 patients. In this study, we found that muscle edema is very common in patients with ANO5 myopathy and that some patients have inflammatory changes in muscle biopsies. Further studies are needed to determine whether the STIR+ lesions reflect inflammation.

LIMB GIRDLE MUSCULAR DYSTROPHIES: P.149 ANO5-related myopathy and muscle inflammation assessed by biopsy and MRI

Anoctamin 5 (ANO5) belongs to the Anoctamin family of transmembrane proteins and has been suggested to play a part in muscle cell membrane fusion and repair. Mutations in the ANO5 gene are a common cause of muscular dystrophy. Little is known about the pathophysiology in ANO5‐related muscular dystrophy. The purpose of this study was to investigate whether inflammatory changes are present in patients with ANO5 myopathy by making a systematic histological and MRI-based evaluation of muscles. Muscle biopsies from 24 patients diagnosed with ANO5 myopathy were reviewed.

The long dystrophin gene product Dp427 modulates retinal function and vascular morphology in response to age and retinal ischemia

Mutations in dystrophin are the major cause of muscular dystrophies. Continuous muscular degeneration and late stage complications, including cardiomyopathy and respiratory insufficiency, dominate the clinical phenotype. Gene expression and regulation of the dystrophin gene outside of muscular tissue is far more complex. Multiple tissue-specific dystrophin gene products are widely expressed throughout the body, including the central nervous system and eye, predisposing affected patients to secondary complications in non-muscular tissues. In this study, we evaluated the impact of the full-length dystrophin gene product, Dp427, on retinal homeostasis and angiogenesis. Based on the clinical case of a Duchenne muscular dystrophy (DMD) patient who developed severe fibrovascular changes in the retina in response to hypoxic stress, we hypothesized that defects in Dp427 make the retina more susceptible to stresses such as ageing and ischemia. To further study this, a mouse strain lacking Dp427 expression (Mdx) was studied during retinal development, ageing and in the oxygen-induced retinopathy (OIR) model. While retinal vascular morphology was normal during development and ageing, retinal function measured by electroretinography (ERG) was slightly reduced in young adult Mdx mice and deteriorated with age. Mdx mice also had increased retinal neovascularization in response to OIR and more pronounced long-term deterioration in retinal function following OIR. Based on these results, we suggest that DMD patients with a mutation in Dp427 may experience disturbed retinal homeostasis with increasing age and therefore be prone to develop excessive retinal neovascular changes in response to hypoxic stress. DMD patients in late disease stages should, thus, be regularly examined to detect asymptomatic retinal abnormalities and prevent visual impairment.

Profile, types, duration and severity of muscular dystrophy: a clinical study at a tertiary care hospital

Background: The cause of muscular dystrophies is genetic. It is a disorder of muscular system. The classification of the muscular dystrophies is based on the signs and symptoms. Present study was done to evaluate the profile, types, duration and severity of muscular dystrophy at a tertiary care hospital.Methods: A hospital based cross sectional study was carried out at department of General Medicine, Malla Reddy Institute of Medical Sciences, Hyderabad from October 2015 to December 2017. During the study period, it was possible to study the 20 cases of muscular dystrophy.Results: Muscular dystrophy was more common in males. Maximum cases were of Duchenne type of muscular dystrophy. Majority of the patients presented at 5-10 years of age. Muscular dystrophy was seen in early childhood. Out of 10 patients of Duchenne muscular dystrophy five patients were of grade I. There was no correlation between the duration of the disease and the severity of the disability. All patients had lower limb proximal weakness. Pathological Q wave (width > 30 ms) and Pathological Q wave (depth >more than 25% of the QRS amplitude) were present in 35% of the cases. All patients had rhythm NSR and QRS +60 to +75. Conduction abnormality was present in 5% of the cases. In half of the patients, serum creatinine kinase levels are moderately elevated.Conclusions: Muscular dystrophies are a common disorder of the childhood. Detailed studies will help to focus more light on this condition to improve outcome in future patients.

Abstract B16: Dystrophin is a tumor suppressor in peripheral nerve sheath tumors

Abstract Introduction: We previously demonstrated that dystrophin inactivation results from genomic DMD 5-end deletions in advanced GIST and leiomyosarcoma, fostering migration, invasion, anchorage independence, and invadopodia formation. Hence, dystrophin inactivation, the most common cause of muscular dystrophy, is also a tumorigenic mechanism in sarcoma. CDKN2A/CDKN2B inactivation is an early event in peripheral nerve sheath tumor (PNST) progression, associated with progression from neurofibroma (NF) to atypical NF. PRC2 inactivation is a later event during progression of some MPNST. Additional biologic markers are needed to distinguish NF from low-grade MPNST. In the present study, we identify and characterize dystrophin dysregulation at an early phase in PNST progression. Methods: Dystrophin immunohistochemistry (IHC) was performed in FFPE sections using the DYS1 monoclonal antibody. DYS1 and other dystrophin monoclonals were used in immunoblotting (IB) studies of snap-frozen PNST. Genomic analyses were performed by targeted gene capture and sequencing (Haloplex custom panel of 812 cancer-associated genes) and Cytoscan HD SNPs. Dystrophin restorations were performed in MPNST cultures using Dp116 (puromycin resistance) and Dp427 (neomycin resistance), either singly or in combination. Results: Dystrophin IHC against TMAs containing common subtypes of benign and malignant soft-tissue tumors showed that most soft-tissue tumor subtypes lacked detectable dystrophin expression whereas 18 of 19 schwannomas expressed dystrophin strongly and diffusely, at levels comparable to that in non-neoplastic skeletal muscle. Dystrophin was also expressed strongly in the neoplastic Schwann-cell component of neurofibromas (NF), whereas dystrophin expression was absent or weak in each of 17 MPNST. IB studies in a separate series of snap-frozen specimens showed that the dystrophin expressed strongly in schwannomas (classic histology = 4; cellular = 6) was coexpression of 427kDa (so-called myogenic) and 116kDa Schwann-cell specific isoforms. IB studies in snap-frozen MPNST showed loss of dystrophin 116kDa and 427kDa expression in 16 cases, retained expression in 1 case, and retained expression of 427kDa only, in 1 case. Genomic surveys demonstrated intragenic DMD deletions or inactivating mutations in 4 of 11 MPNST. Each of 3 NF transitioning to MPNST had strong dystrophin expression in the NF component but not in the associated MPNST. Conjoined restoration of 116kDa and 427kDa dystrophin isoforms (but not restoration of the 116kDa isoform, on its own) inhibited MPNST migration. IHC and IB studies (in progress) suggest that PNST dystrophin inactivation occurs concurrent with or subsequent to CDKN2A/CDKN2B inactivation during transition from NF to low-grade MPNST, and prior to PRC2 inactivation. Conclusions: We show that Dp116 and Dp427 dystrophin isoforms have tumor-suppressor properties in PNST. Extinction of these isoforms occurs in most MPNST, and in laboratory models is associated with increased cell migration. Dystrophin inactivation coincides with transition from NF to low-grade MPNST; therefore, dystrophin IHC might be useful in diagnostic distinction between atypical NF and MPNST. Citation Format: Inga-Marie Schaefer*, Armelle Dufresne*, Nacef Bahri, Marije A. J. de Rooij, Stacy M. Yanofsky, Yuexiang Wang, Chandrajit P. Raut, Laurence H. Baker, Adrian Marino-Enriquez, Matt van de Rijn, Jonathan A. Fletcher. Dystrophin is a tumor suppressor in peripheral nerve sheath tumors [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B16.

Identification of a novel frameshift mutation in the DMD gene as the cause of muscular dystrophy in a Norfolk terrier dog.

BackgroundA Norfolk terrier was referred to the Animal Health Trust neurology department with suspected dystrophin-deficient muscular dystrophy (DD-MD), which was confirmed by clinical workup and immunohistochemistry.FindingsExon resequencing of the canine Duchenne Muscular Dystrophy (DMD) gene was undertaken to screen for potential disease causing mutations. The sequence data generated from all coding DMD exons revealed a 1 bp deletion in exon 22, causing a frameshift and premature termination of the coding sequence. Gene expression analysis indicated reduced levels of dystrophin transcript in the DD-MD case and western blot confirmed the absence of full length protein.ConclusionsThe finding represents a novel mutation causing DD-MD in the dog.Electronic supplementary materialThe online version of this article (doi:10.1186/s40575-015-0019-4) contains supplementary material, which is available to authorized users.

Misdiagnosis of cystic fibrosis based on transient pancreatic insufficiency and elevated sweat chloride.

Exocrine pancreatic insufficiency (PI) is a rare cause of dystrophy. Fecal elastase 1 (FE1) and 72-h fecal fat collection are the recommended indirect tests for pancreatic function. The most common cause of PI in children is cystic fibrosis (CF). PI is highly specific to CF and affects 85% of all CF patients (Borowitz D et al., J Pediatr 2004; 145: 322–326) Diagnosis of CF is based on confirmation of cystic fibrosis transmembrane regulator (CFTR) protein dysfunction based on a sweat chloride level of>60 mml/l on at least 2 occasions, detection of 2 CF-causing mutations, and/or an abnormal nasal potential difference measurement (NPD) (DeBoeck K et al., Thorax 2006; 61: 627–635). We report our experience with a patient who was misdiagnosed with CF based on dystrophy attributed to transient PI and transiently elevated sweat chloride.

The intracellular Ca²⁺ channel MCOLN1 is required for sarcolemma repair to prevent muscular dystrophy.

The integrity of the plasma membrane is maintained through an active repair process, especially for skeletal and cardiac muscle cells, in which contraction-induced mechanical damage frequently occurs in vivo1,2. Muscular dystrophies (MDs) are a group of muscle diseases characterized by skeletal muscle wasting and weakness3,4. An important cause of MD is defective repair of sarcolemmal injuries, and sarcolemma repair requires Ca2+ sensor proteins5–8 and Ca2+-dependent delivery of intracellular vesicles to injury sites5,8,9. TRPML1 (ML1) is an endosomal and lysosomal Ca2+ channel and its human mutations cause Mucolipidosis IV, a neurodegenerative disease with motor disabilities10,11. Here, we report that ML1-null mice develop a primary, early-onset muscular dystrophy independent of neural degeneration. Although the dystrophin-glycoprotein complex and the known membrane repair proteins are normally expressed, membrane resealing was defective in ML1-null muscle fibers or upon acute and pharmacological inhibition of ML1 channel activity or vesicular Ca2+ release. Injury facilitated the trafficking and exocytosis of vesicles by upmodulating ML1 channel activity. In the dystrophic mdx mouse model, overexpression of ML1 decreased muscle pathology. Collectively, we have identified an intracellular Ca2+ channel that regulates membrane repair in skeletal muscle via Ca2+-dependent vesicle exocytosis.

Anoctamin 5 muscular dystrophy in Denmark: prevalence, genotypes, phenotypes, cardiac findings, and muscle protein expression

Since the initial description in 2010 of anoctamin 5 deficiency as a cause of muscular dystrophy, a handful of papers have described this disease in cases of mixed populations. We report the first large regional study and present data on new aspects of prevalence, muscular and cardiac phenotypic characteristics, and muscle protein expression. All patients in our neuromuscular unit with genetically unclassified, recessive limb girdle muscular dystrophy (LGMD2), Miyoshi-type distal myopathy (MMD) or persistent asymptomatic hyperCK-emia (PACK) were assessed for mutations in the ANO5 gene. Genetically confirmed patients were evaluated with muscular and cardiopulmonary examination. Among 40 unclassified patients (28 LGMD2, 5 MMD, 7 PACK), 20 were homozygous or compound heterozygous for ANO5 mutations, (13 LGMD2, 5 MMD, 2 PACK). Prevalence of ANO5 deficiency in Denmark was estimated at 1:100.000 and ANO5 mutations caused 11 % of our total cohort of LGMD2 cases making it the second most common LGMD2 etiology in Denmark. Eight patients complained of dysphagia and 3 dated symptoms of onset in childhood. Cardiac examinations revealed increased frequency of premature ventricular contractions. Four novel putative pathogenic mutations were discovered. Total prevalence and distribution of phenotypes of ANO5 disease in a representative regional cohort are described for the first time. A high prevalence of ANO5 deficiency was found among patients with unclassified LGMD2 (46 %) and MMD (100 %). The high incidence of reported dysphagia is a new phenotypic feature not previously reported, and cardiac investigations revealed that ANO5-patients may have an increased risk of ventricular arrhythmia.

A study of FHL1, BAG3, MATR3, PTRF and TCAP in Australian muscular dystrophy patients

FHL1, BAG3, MATR3 and PTRF are recently identified myopathy genes associated with phenotypes that overlap muscular dystrophy. TCAP is a rare reported cause of muscular dystrophy not routinely screened in most centres. We hypothesised that these genes may account for patients with undiagnosed forms of muscular dystrophy in Australia. We screened a large cohort of muscular dystrophy patients for abnormalities in FHL1 ( n = 102) and TCAP ( n = 100) and selected patients whose clinical features overlapped the phenotypes previously described for BAG3 ( n = 9), MATR3 ( n = 15) and PTRF ( n = 7). We found one FHL1 mutation (c.311G>A, p.C104Y) in a boy with rapidly progressive muscle weakness and reducing body myopathy who was initially diagnosed with muscular dystrophy. We identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP. In conclusion, we have excluded these five genes as common causes of muscular dystrophy in Australia. Patients with reducing body myopathy may be initially diagnosed as muscular dystrophy.

Dysferlin, Annexin A1, and Mitsugumin 53 Are Upregulated in Muscular Dystrophy and Localize to Longitudinal Tubules of the T-System With Stretch

Mutations in dysferlin cause an inherited muscular dystrophy because of defective membrane repair. Three interacting partners of dysferlin are also implicated in membrane resealing: caveolin-3 (in limb girdle muscular dystrophy type 1C), annexin A1, and the newly identified protein mitsugumin 53 (MG53). Mitsugumin 53 accumulates at sites of membrane damage, and MG53-knockout mice display a progressive muscular dystrophy. This study explored the expression and localization of MG53 in human skeletal muscle, how membrane repair proteins are modulated in various forms of muscular dystrophy, and whether MG53 is a primary cause of human muscle disease. Mitsugumin 53 showed variable sarcolemmal and/or cytoplasmic immunolabeling in control human muscle and elevated levels in dystrophic patients. No pathogenic MG53 mutations were identified in 50 muscular dystrophy patients, suggesting that MG53 is unlikely to be a common cause of muscular dystrophy in Australia. Western blot analysis confirmed upregulation of MG53, as well as of dysferlin, annexin A1, and caveolin-3 to different degrees, in different muscular dystrophies. Importantly, MG53, annexin A1, and dysferlin localize to the t-tubule network and show enriched labeling at longitudinal tubules of the t-system in overstretch. Our results suggest that longitudinal tubules of the t-system may represent sites of physiological membrane damage targeted by this membrane repair complex.

P1.26 Occurrence of ANO5 mutation R758C in patients with a muscular dystrophy of unknown etiology

Recessive ANO5 gene mutations were recently reported to be the cause of limb-girdle muscular dystrophy type 2L (LGMD2L) and distal non-dysferlin Miyoshi-like myopathy. One of these mutations, c.2272C > T that leads to an amino acid substitution R758C, was found in two Finnish brothers with Miyoshi-like myopathy. R758C mutation was detected in two out of 578 Finnish control chromosomes which gives this mutation a frequency of 0.35% in Finnish population. With such frequency there should be some 50 R758C homozygote patients in Finland on a population of 5 million people. We screened 45 patients with a distal calf myopathy of unknown etiology and/or CK level over 3000. Four of these patients had ancestral origins in Germany and the rest were of Finnish origin. We identified three Finnish patients homozygous and two Finnish and three American patients heterozygous for R758C. In addition, one Finnish patient was a compound heterozygote with R758C in one chromosome and a previously unknown mutation c.2311_2312delCA in the other. R758C homozygote patients had both Miyoshi-like phenotypes and limb-girdle phenotypes as with LGMD2L. Our results indicate that R758C is a frequent cause of muscular dystrophy in Finland. Besides R758C there are at least two other ANO5 mutations in Finland, one of which is the new mutation c.2311_2312delCA. Moreover, R758C occurs also in other European populations.

P1.19 Mutational spectrum and clinical features of Korean patients with dysferlinopathy

Background: Dysferlinopathy refers to a group of autosomal recessive muscular dystrophies caused by mutations in DYSF, which encodes dysferlin working for calcium-dependent membrane repair in skeletal muscle. The disease group includes three distinct disorders; limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM) and distal anterior compartment myopathy. Since dysferlinopathy is considered as a relatively common cause of muscular dystrophy in Korea, it is needed to characterize clinical and genetic features in Korean patients of dysferlinopathy.

The neglected brain in myotonic dystrophy types 1 and 2

Myotonic dystrophy (DM), a dominantly inherited chronic progressive disease, is the most common cause of muscular dystrophy in adults, affecting 1 in 8,000 individuals worldwide. Different forms of the disease share similar features: DM1 (DM type 1) is caused by a trinucleotide (CTG) expansion within the DMPK (dystrophia myotonica protein kinase) 3′-untranslated region on chromosome 19, and DM2 (DM type 2) is caused by a tetra-nucleotide (CCTG) expansion within intron 1 of the zinc finger 9 gene on chromosome 3. The RNA transcribed from the expanded allele contains long tracts of (CUG)(n) or (CCUG)(n). The mutant toxic-RNA alters the level of RNA-binding proteins (MBNL1 [muscleblind-like 1] and CUGBP1 [CUG-binding protein 1]), forms nuclear foci in various tissues including muscle and brain, and leads to a loss-of-function normally executed by the lost RNA-binding proteins. The recently discovered mechanisms underlying these RNA disorders are compatible with the widespread features of DM1 and DM2.1 Shared core clinical features of DM1 and DM2 are autosomal dominant inheritance, limb muscle weakness, myotonia, and multiorgan involvement, including cataract, cardiac conduction defects, insulin resistance, hypothyroidism, and gonadal atrophy. DM is one of the most variable diseases; DM2 probably more so than DM1,2 but in both DM1 and DM2 symptoms and severity vary greatly among family members and between generations. Muscle pain …