Myotonic Myopathy Research Articles

Schwartz-Jampel Syndrome Type-1: Compound Heterozygosity of Two Novel Variants.

Schwartz-Jampel Syndrome (SJS) type-1 (OMIM; #255800), a rare cause of skeletal dysplasia, is characterized by myotonic myopathy, chondrodystrophy, short stature, facial and eye abnormalities. SJS Type-1 develops due to variations in the HSPG2 gene which produces the "perlecan" molecule, one of the main proteoglycans of the basement membrane. A 6-year-old girl presented with short stature, a mask face, shrunken lips, narrow palpebral opening due to blepharospasm, stiffness of facial muscles, micrognathia, overlapping teeth, a short neck, and a bell-shaped thorax due to myotonic myopathy. She was diagnosed with SJS type-1 due to compound heterozygosity of two novel variations in the HSPG2 gene. In patients with short stature and an accompanying myotonic myopathy SJS should be considered. Compound heterozygosity may cause typical clinical findings of SJS. In case of suspicion creatinine kinase levels can be measured, and the determination of myotonia may require evaluation with electromyography. Once the diagnosis is made, patients should be carefully monitored in terms of growth, neuromuscular disorders, joints problems and bone health.

Proximal myopathy: causes and associated conditions.

Proximal myopathy presents as generalized muscle weakness commonly involving the muscles of upper and/or lower limbs. Toxins, long-term use of statins, corticosteroids, alcohol, SGLT2 inhibitors, COVID-19 vaccination, and antimalarials have been attributed to its development. In endocrine and metabolic disorders, adrenal dysfunction including both overproduction and insufficiency of the adrenal gland hormones has been reported to cause myopathy. Moreover, parathyroid and thyroid disorders along with pituitary gland disorders can also directly or indirectly contribute to this condition. In idiopathic inflammatory myopathies including polymyositis, dermatomyositis, inclusion body myositis (IBM), and Systemic Lupus Erythematosus (SLE), Sjögren's Syndrome, and overlap syndromes, moderate to severe muscle weakness has been observed. IBM has been reported to be the most prevalent acquired myopathy above the age of 50. Hereditary or congenital myopathies include limb girdle muscular dystrophies, facioscapulohumeral muscular dystrophy, Duchenne and Becker muscular dystrophy, and proximal myotonic myopathy. In addition to these, glycogen storage diseases such as the McArdle disease can also cause fast exhaustion, myalgia, and cramping in working muscles. It is pertinent to mention here that a class of hereditary metabolic myopathies, referred to as "lipid deposition myopathy" causes lipids to accumulate in skeletal muscle fibers, leading to lesions and degeneration. Among viral causes, HIV, dengue virus, influenza virus, hepatitis B virus, hepatitis C virus, SARS-CoV2 are also associated with muscle weakness. Sarcoidosis, an inflammatory disease, can also manifest as muscle weakness and myalgia. Owing to this complicated pathophysiology of proximal myopathy, this review aims to summarize the existing literature on conditions associated with this phenomenon and other recent developments that have been made regarding events leading to development of generalized muscle weakness. To the authors' knowledge this is the first narrative review that discusses causes and conditions associated with proximal myopathy in thorough detail.

Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L769V Mutation in SCN4A.

The phenotypic spectrum associated with the skeletal muscle voltage-gated sodium channel gene (SCN4A) has expanded with advancements in genetic testing. Autosomal dominant SCN4A mutations were first linked to hyperkalemic periodic paralysis, then subsequently included paramyotonia congenita, several variants of myotonia, and finally hypokalemic periodic paralysis. Biallelic recessive mutations were later identified in myasthenic myopathy and in infants showing a severe congenital myopathy with hypotonia. We report a patient with a pathogenic de novo SCN4A variant, c.2386C>G p.L796V at a highly conserved leucine. The phenotype was manifest at birth with arthrogryposis multiplex congenita, severe episodes of bronchospasm that responded immediately to carbamazepine therapy, and electromyographic evidence of widespread myotonia. Another de novo case of p.L796V has been reported with hip dysplasia, scoliosis, myopathy, and later paramyotonia. Expression studies of L796V mutant channels showed predominantly gain-of-function changes, that included defects of slow inactivation. Computer simulations of muscle excitability reveal a strong predisposition to myotonia with exceptionally prolonged bursts of discharges, when the L796V defects are included. We propose L796V is a pathogenic variant, that along with other cases in the literature, defines a new dominant SCN4A disorder of myotonic myopathy with secondary congenital joint and skeletal involvement.

Neuromyelitis Optica Spectrum Disorder Preceded by Myotonic Myopathy

Neuromyelitis Optica Spectrum Disorder Preceded by Myotonic Myopathy

Proximal myotonic dystrophy mimicking progressive muscle wasting

Introduction: Progressive myotonic dystrophy is a distinct entity from proximal myotonic myopathy, and can present with unusually prominent muscle atrophy, proximal weakness and absence of clinical myotonia. Progressive muscle wasting should to be differentiated from motor neuron disease (MND) along with other causes.

P.271 - Venous thromboembolism in adult patients with inherited myopathies: a high-risk in myotonic dystrophy

The risk of venous thromboembolism (VTE) in inherited myopathies is unknown. We identified 2,810 patients (mean age = 40.1 ± 15.4 years, women = 45,0%) referred to our institutions between January 2000 and December 2014 for the management of the 10 following genetically proven myopathies: myotonic dystrophy (DM), FSH myopathy, dystrophinopathies, mitochondrial diseases, glycogen and lipid-storage diseases, LGMD, nucleopathies, collagen VI-related disorders, myofibrillar, and congenital myopathies. We determined the incidence of VTE in each group of disease, searched for independent predictors of VTE, compared the incidence of VTE to a community-based population. Over a median 8.5 years follow-up duration, 102 patients had ≥1 VTE event, representing a cumulative incidence of 6.2%. VTE was unprovoked in 54 (52.9%) patients and occurred in patients with prior loss of ambulation due to myopathy in 15 (14.7%). The risk for VTE was the highest in DM with a cumulative incidence of 10.3%, while it was ≤4.4% in other diseases and DM patients had, compared to others, VTE events at younger age, more frequently unprovoked and unrelated to loss of ambulation, with more frequent recurrences and higher 30-days mortality. We identified 4 predictors of VTE events: increasing age, personal history of VTE, loss of ambulation, and DM with the hazard of VTE during follow-up. Incidence rates of VTE were higher in patients with DM than in a French community-based population, with the highest rate ratios for women (HR, 17.0; 95% CI, 10.0–29.1) and men (HR, 10.6; 95% CI, 6.35–17.5) aged 40 to 59 years. In patients with other myopathies, incidence rates were also higher but only for men aged 40 to 58 years and women aged up to 60 years with lower rate ratios than for DM patients. Patients with inherited myopathies have a moderately increased risk of VTE related to loss of ambulation. Patients with DM have a very high risk of VTE compared to other inherited myopathies and to the general population, requiring probably a specific management.

A case of Schwartz-Jampel syndrome

Schwartz-Jampel syndrome, also known as chondrodystrophica myotonia or myotonic myopathy is a rare, autosomal recessive disorder resulting from a defect in chromosome 1p36.1. Around 50 cases have been reported in literature. We present a 3 years old female with Schwartz-Jampel syndrome to highlight the benign course of this disease in some children.

Myotonic dystrophies: clinical presentation, pathogenesis, diagnostics and therapy

The autosomal-dominant myotonic dystrophies dystrophia myotonica type-1 (DM1, Curschmann-Steinert disease) and dystrophia myotonica type-2 (DM2, proximal myotonic myopathy (PROMM)), are, contrary to the non-dystrophic myotonias, progressive multisystem disorders. DM1 and DM2 are the most frequent of the muscular dystrophies. In both diseases the skeletal muscle is the most severely affected organ (weakness, wasting, myotonia, myalgia). Additionally, they manifest in the eye, heart, brain, endocrine glands, gastrointestinal tract, skin, skeleton, and peripheral nerves. Phenotypes of DM1 may be classified as congenital, juvenile, classical, or late onset. DM2 is a disorder of the middle or older age and usually has a milder course compared to DM1. DM1 is due to a CTG-repeat expansion > 50 repeats in the non-coding 3' UTR of the DMPK-gene. DM2 is caused by a CCTG-repeat expansion to 75 - 11 000 repeats in intron-1 of the CNBP/ZNF9 gene. Mutant pre-mRNAs of both genes aggregate within the nucleus (nuclear foci), which sequester RNA-binding proteins and result in an abnormal protein expression via alternative splicing in downstream effector genes (toxic RNA diseases). Other mechanisms seem to play an additional pathogenetic role. Clinical severity of DM1 increases from generation to generation (anticipation). The higher the repeat expansion the more severe the DM1 phenotype. In DM2 severity of symptoms and age at onset do not correlate with the expansion size. Contrary to DM2, there is a congenital form and anticipation in DM1.

Cardiac involvement of the systemic disorder myotonic dystrophy type II - detection by CMR

Background Myotonic dystrophy type II (formerly denoted as proximal myotonic myopathy (PROMM)) is an autosomal dominantly inherited disease [1]. Sufferers are afflicted with skeletal muscle (SM) symptoms. Histopathologic changes of the SM include mild fibrosis and fatty degeneration[2]. The multisystemic disorder is also characterized by endocrine and metabolism disorder such as hypercholesterolemia and diabetes mellitus type II as well as cardiac arrhythmias [1]. The aim of this study is to evaluate myocardial structural abnormalities in preserved ejection fraction (EF).

P.12.2 Dominant distal myopathy due to slow channelopathy

Slow channel syndrome, first recognized by Engel in 1982, has distinct phenotypic features, dominant inheritance, selective weakness of cervical scapular and finger extensor weakness, ophtalmoparesis. Histochemical findings show type 1 fibers preponderance, small group of atrophic fibers of either fiber type, increased fiber size variability, tubular aggregates. We examined 3 biopsies in 3 patients (2 males – 55 years and 66 years, 1 female – 61 years) presenting a dominant distal myopathy with variable age at onset (from second to third decade). The patients had ophtalmoparesis, upper limb extensor, forearm and finger weakness and distal myopathy with a progressive slow course. The woman had also some difficulty in anterior tibial flexor muscle but also atrophy of forearms muscles. Electrophysiology on single stimulus of ulnar nerve showed repetitive CMAP. The genomic wide linkage analysis identified 3 regions co-segregating with the disease in chromosome 1, 13, 17. Next generation sequencing showed in all patients a known mutation in epsilon-subunit of AchR receptor and a mutation in phospholipase. Muscle showed mild changes consisting in atrophic fibers, mostly of type 2, some fiber type grouping, central nuclei and ring fibers. Such fibers are consistent with abnormal regeneration.We suggest that the occurrence of mutations involving both AchR receptor and phospholipase might concur in determining a new distal phenotype with permanent weakness. Our family was previously diagnosed as myotonic dystrophy or distal myopathy. The presence of the histochemical findings of both myopathy and neuropathy were present. We suggest the possibility of calcium overload due to prolonged open time of the AChR channel with a presynaptic component might determine a distal neuro-myopathy with slow evolution and muscle rearrangement due to a muscle fiber degeneration and functional denervation. The slow channel mutation should be searched in families with permanent distal weakness.

Myotonic Dystrophies type 1 and 2: anesthetic care

Myotonic dystrophy is classified as one of the myotonic syndromes although myotonia is only a minor characteristic of it. It is, in fact, also a multisystem disease with cardiac, digestive, ocular, and endocrine abnormalities. Two subgroups are currently identified with many similarities: DM1 refers to classic dystrophia myotonica (Steinert disease), while DM2, formerly called proximal myotonic myopathy has a later onset. The congenital form is present only in DM1. The genetic causes of DM1 and 2 are different but end up in a similar way of altering RNAm processing and splicing of other genes. The anesthetic risk is increased in case of DM1 type. This review summarizes current knowledge concerning the pathophysiology and anesthetic management of this disease in children and adults.

Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2

Myotonic dystrophy is an autosomal dominant, multisystem disorder that is characterized by myotonic myopathy. The symptoms and severity of myotonic dystrophy type l (DM1) ranges from severe and congenital forms, which frequently result in death because of respiratory deficiency, through to late-onset baldness and cataract. In adult patients, cardiac conduction abnormalities may occur and cause a shorter life span. In subsequent generations, the symptoms in DM1 may present at an earlier age and have a more severe course (anticipation). In myotonic dystrophy type 2 (DM2), no anticipation is described, but cardiac conduction abnormalities as in DM1 are observed and patients with DM2 additionally have muscle pain and stiffness. Both DM1 and DM2 are caused by unstable DNA repeats in untranslated regions of different genes: A (CTG)n repeat in the 3'-UTR of the DMPK gene and a (CCTG)n repeat in intron 1 of the CNBP (formerly ZNF9) gene, respectively. The length of the (CTG)n repeat expansion in DM1 correlates with disease severity and age of onset. Nevertheless, these repeat sizes have limited predictive values on individual bases. Because of the disease characteristics in DM1 and DM2, appropriate molecular testing and reporting is very important for the optimal counseling in myotonic dystrophy. Here, we describe best practice guidelines for clinical molecular genetic analysis and reporting in DM1 and DM2, including presymptomatic and prenatal testing.

Increased Cancer Risk Among Patients with Myotonic Muscular Dystrophy

Myotonic muscular dystrophy (MMD) is a multisystem disorder characterized by myotonic myopathy, cardiac conduction disturbances, insulin resistance,

EDITORIAL WHAT ROLE FOR PROTEIN‐CONJUGATE PNEUMOCOCCAL VACCINE IN OLDER ADULTS? Invasive pneumococcal disease is a significant cause of morbidity and mortality among persons aged 65 years and older. Pneumococcal disease burden also remains high among adults over 50 years of age. In this editorial the authors discuss the priority of continued 23‐valent pneumococcal polysaccharide vaccine use in older adults, whilst

EDITORIAL WHAT ROLE FOR PROTEIN‐CONJUGATE PNEUMOCOCCAL VACCINE IN OLDER ADULTS? Invasive pneumococcal disease is a significant cause of morbidity and mortality among persons aged 65 years and older. Pneumococcal disease burden also remains high among adults over 50 years of age. In this editorial the authors discuss the priority of continued 23‐valent pneumococcal polysaccharide vaccine use in older adults, whilst

Myotonic dystrophies as a brain disorder

In their article, Romeo et al. [1] emphasize that abnormalities in blood perfusion and/or glucose metabolism are frequent in myotonic dystrophy type 1 (DM1 or Steinert’s disease). I would suggest that these abnormalities and others encompass all myotonic dystrophies. Myotonic dystrophies are autosomal dominant multisystem disorders. These include myotonic dystrophy type 1 (Steinert’s disease or DM1) due to an abnormal CTG expansion on chromosome 19 coding for protein kinase DMPK and myotonic dystrophy type 2 (proximal myotonic myopathy, PROMM or DM2), due to an abnormal CCTG expansion on chromosome 3 coding for a zinc finger protein ZNF9. These abnormal nucleotide expansions cause an abnormal accumulation of mRNA which is sequestered within the nucleus by specific binding proteins thus altering mRNA splicing of proteins involved in the disease process [2]. There are clinical, neuropsychological and neuroimaging data that support the hypothesis of central nervous system involvement also in DM2. The typical cognitive and behavioural abnormalities in DM2 are like those of the classical adult form of DM1 but in DM2 these abnormalities are less severe. Patients with DM2 have a frontal dysexecutive syndrome characterized by apathy, reduced initiative and strategic abilities. Yet global cognitive performances are normal as demonstrated by normal IQ and MMSE test scores. Neuropsychological test have demonstrated a selective involvement of visual spatial functions which do not seem to correlate with hyperintense lesions demonstrated on traditional brain MRI sequences or to the degree of cortical atrophy in the frontal and temporal poles, but indicate a selective frontal lobe involvement and a reduction of cerebral blood flow in these regions as documented by H20 PET studies [3–5]. From a behavioural point of view, the patients DM1 and DM2 have an avoidant personality trait, more rarely a passive personality trait [6]. These personality traits imply the patients tend to avoid regular outpatient visits, minimize their muscle symptoms and rarely seek medical attention. It is rather the unaffected family members who will notice difficulties during walking, stumbling and tripping over with an increase in frequency. A distinctive element between DM1 and DM2 is the absence of a congenital form in DM2 and the excessive daytime sleepiness in DM1. Extrapyramidal features like camptocormia have been described in some patients with DM2 and the dopaminergic pathway does not seem to justify extrapyramidal signs and symptoms in these patients [7]. In spite of the findings described above, advances in the study of DM1 and DM2 nervous system require development of better-designed study models. For instance, modelling of transgenic mice expressing CUG expansion RNA under the control of a strong neuronal-specific promoter, will allow the exacerbation of DM1 and DM2 neuronal manifestations. Such mouse models could serve as a basis for complete studies of DM1 and DM2 nervous system including brain anatomy analysis, behaviour and memory test, and molecular and cellular biology approach using brain samples and neuron cell cultures.

How much expansion to be diseased?

Myotonic dystrophies (DMs) encompass at least two genetically distinct disorders: the classic type 1 (DM1), also known as Steiner disease, and type 2 (DM2), also referred to as proximal myotonic myopathy or Moxley-Ricker disease. Both disorders are characterized by variably expressed multisystem phenotypes with core features of progressive skeletal muscle weakness and degeneration with myotonia. DMs are caused by unstable repeat expansions: in DM1, a CTG repeat expansion in the 3′ untranslated region of DMPK in chromosome 19q13.3, and in DM2, a CCTG repeat expansion in intron 1 of ZNF9 in 3q21.3.1,2 In DM1, a reservoir of premutation alleles in the population provides the source of de novo DM1 alleles. The expanded progenitor allele has a propensity to increase the CTG repeat size in successive generations, causing anticipation. The congenital form of DM1, with a large allele and the inability to reproduce offspring, represents the endpoint of anticipation. The stoichiometric balance between de novo mutations and losses of the mutant allele may explain the relatively stable prevalence of DM1. The gender of the transmitting parent is …

Proximal myotonic myopathy

Three Swedish patients with proximal muscle weakness, myotonia and lack of CTG expansion on genetical analysis are presented. Clinical neurological and neurophysiological examination and muscle biopsy were performed. There was an indication of autosomal dominant inheritance in 2 of the 3 patients. The main symptoms and clinical findings in the 3 patients were weakness of the proximal muscles, myotonia, muscle stiffness, muscle pain and muscle atrophy. Neurophysiological examination showed myotonic bursts and muscle biopsy showed a variation of fibre sizes, an increased number of muscle fibres with centralized nuclei and scattered atrophic muscle fibres. Laboratory data showed elevated CK, GT and LD in 1 patient. Before genetical analysis was performed, all 3 patients had been diagnosed as atypical cases of myotonic dystrophy. However, the symptoms, clinical signs, laboratory data, electrophysiological and muscle biopsy findings were compatible with proximal myotonic myopathy (PROMM).

Koinzidenz einer Myasthenia gravis und einer Myotonen Dystrophie Typ 2

Wir berichten den Fall einer 68 Jahre alten Patientin mit klinischen und elektromyografischen Zeichen einer Myotonie seit dem 42. Lebensalter. Die Familienanamnese bezüglich myotoner Erkrankungen war unauffällig. Im Alter von 68 Jahren entwickelte die Patientin eine zunehmende Augenmuskel- und Extremitätenschwäche. Die Bestimmung der Azetylcholinrezeptorantikörper zeigte einen positiven Befund, die elektrophysiologischen Untersuchungen zeigten die Zeichen einer neuromuskulären Übertragungsstörung sowie elektromyografisch myotone Entladungsserien. Nach einer medikamentösen Behandlung der Myasthenie besserte sich die Muskelschwäche. Die molekulargenetische Untersuchung wies eine wiederholte CCTG-Expansion im DM2-Gen nach. Darüber hinaus zeigten sich in der Muskelbiopsie die histologischen und biochemischen Zeichen einer mitochondrialen Erkrankung mit Nachweis multipler Deletionen der mitochondrialen DNA.

G.P.13.12 Congenital myotonic dystrophy and myotubular myopathy may be differentiated by type 2C fibers and peripheral halos

G.P.13.12 Congenital myotonic dystrophy and myotubular myopathy may be differentiated by type 2C fibers and peripheral halos

Camptocormia and dropped head syndrome as a clinic picture of myotonic myopathy

Dropped head syndrome is primarily based on weakness localized at neck extensors. It may result from motor neuron disease, myasthenia gravis, and chronic inflammatory demyelinating polyneuropathy and also from various neuromuscular diseases including inflammatory, dystrophic and metabolic myopathies. Camptocormia (CC) on the other hand is an unusual condition characterized by progressive weakness of the extensor vertebral muscles and results in involuntary trunk flexion. CC may emerge as a clinical feature of many different conditions such as several myopathies and Parkinson's disease. The association of dropped head syndrome with CC has been rarely published in the literature. However, this is the only case presenting with concomitant dropped head syndrome and CC as a clinical picture of myotonic dystrophy (MD). In this report we aimed to represent a female patient, who was diagnosed as having myotonic dystrophy, with concurrent dropped head syndrome and CC.