Myotonic dystrophy types 1 and 2 (DM1 and DM2) are forms of muscular dystrophy that share similar clinical and molecular manifestations, such as myotonia, muscle weakness, cardiac anomalies, cataracts, and the presence of defined RNA-containing foci in muscle nuclei. DM2 is caused by an expansion of the tetranucleotide CCTG repeat within the first intron of ZNF9, although the mechanism by which the expanded nucleotide repeat causes the debilitating symptoms of DM2 is unclear. Conflicting studies have led to two models for the mechanisms leading to the problems associated with DM2. First, a gain-of-function disease model hypothesizes that the repeat expansions in the transcribed RNA do not directly affect ZNF9 function. Instead repeat-containing RNAs are thought to sequester proteins in the nucleus, causing misregulation of normal cellular processes. In the alternative model, the repeat expansions impair ZNF9 function and lead to a decrease in the level of translation. Here we examine the normal in vivo function of ZNF9. We report that ZNF9 associates with actively translating ribosomes and functions as an activator of cap-independent translation of the human ODC mRNA. This activity is mediated by direct binding of ZNF9 to the internal ribosome entry site sequence (IRES) within the 5′UTR of ODC mRNA. ZNF9 can activate IRES-mediated translation of ODC within primary human myoblasts, and this activity is reduced in myoblasts derived from a DM2 patient. These data identify ZNF9 as a regulator of cap-independent translation and indicate that ZNF9 activity may contribute mechanistically to the myotonic dystrophy type 2 phenotype.
Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment.
myotonic dystrophy type 1; arrhythmias; cardiac pacing
Myotonic dystrophy type 1 (DM1) is the commonest muscular dystrophy in adults, affecting multiple organs in addition to skeletal muscles. Cardiac conduction system abnormalities are well recognized as an important component of DM1 phenotype; however, primary structural myocardial abnormalities, which may predispose these patients to congestive heart failure, are not as well characterized. We reviewed the retrospective analysis of the clinical and echocardiographic findings in adult patients with DM1. Among 27 patients (16 male; age 19–61 years) with DM1, the echocardiogram (ECHAO) was abnormal in 10 (37%) including one of 6 patients (16%) with congenital myotonic dystrophy. Reduced left ventricular ejection fraction (LVEF ≤50%) was noted in 5, diastolic dysfunction in 4, left atrial dilatation in 3, left ventricular hypertrophy in 2, apical hypokinesia in 1 and mitral valve prolapse in 3 patients. One patient had paradoxical septal movement in the setting of left bundle branch block. Echocardiographic abnormalities significantly correlated with older age; however, patients with systolic dysfunction on echocardiogram ranged in age from 27 to 52 years including 2 patients aged 27 and 34 years. We can conclude that echocardiographic abnormalities are frequent in adult patients with DM1. The incidence is similar in the classical and congenital type of DM1. Overall, echocardiographic abnormalities in DM1 correlate with increasing age; however, reduced LVEF is observed even at young age. Cardiac assessment and monitoring in adult patients with DM1 should include evaluation for primary myocardial involvement.
cardiac involvement; echocardiogram; myopathy; myotonic dystrophy.
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.
Objective: To specify and quantify possible defects in speech execution in patients with adult onset myotonic dystrophy.
Methods: Studies on speech production were done on 30 mildly affected patients with myotonic dystrophy. Special attention was paid to myotonia. Because muscle activity can result in a decrease of myotonia, speech characteristics were measured before and after warm up. The possibility that warming up causes increased weakness was also assessed.
Results: As with other motor skills, a warm up effect was found in speech production, resulting in an increase in repetition rate and a decrease in variability of repetition rate. Signs of fatigue did not occur.
Conclusions: Warming up is valuable for patients with myotonic dystrophy in reducing the influence of myotonia on speech production.
Myotonic dystrophy (DM1), the most common muscular dystrophy in adults, is caused by an expanded (CTG)n tract in the 3′ UTR of the gene encoding myotonic dystrophy protein kinase (DMPK)1, which results in nuclear entrapment of the ‘toxic’ mutant RNA and interacting RNA-binding proteins (such as MBNL1) in ribonuclear inclusions2. It is unclear if therapy aimed at eliminating the toxin would be beneficial. To address this, we generated transgenic mice expressing the DMPK 3′ UTR as part of an inducible RNA transcript encoding green fluorescent protein (GFP). We were surprised to find that mice overexpressing a normal DMPK 3′ UTR mRNA reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, histopathology and RNA splicing defects in the absence of detectable nuclear inclusions. However, we observed increased levels of CUG-binding protein (CUG-BP1) in skeletal muscle, as seen in individuals with DM1. Notably, these effects were reversible in both mature skeletal and cardiac muscles by silencing transgene expression. These results represent the first in vivo proof of principle for a therapeutic strategy for treatment of myotonic dystrophy by ablating or silencing expression of the toxic RNA molecules.
Type 1 myotonic dystrophy (DM1) is an autosomal-dominant inherited disorder with a multisystem involvement, caused by an abnormal expansion of the CTG sequence of the dystrophic myotonia protein kinase (DMPK) gene. DM1 is a variable multisystem disorder with muscular and nonmuscular abnormalities. Increasingly, endocrine abnormalities, such as gonadal, pancreatic, and adrenal dysfunction are being reported. But, Electrolytes imbalance is a very rare condition in patients with DM1 yet. Herein we present a 42-yr-old Korean male of DM1 with abnormally elevated serum sodium and potassium. The patient had minimum volume of maximally concentrated urine without water loss. It was only cured by normal saline hydration. The cause of hypernatremia was considered by primary hypodipsia. Hyperkalemic conditions such as renal failure, pseudohyperkalemia, cortisol deficiency and hyperkalemic periodic paralysis were excluded. Further endocrine evaluation suggested selective hyperreninemic hypoaldosteronism as a cause of hyperkalemia.
Myotonic Dystrophy; Hypernatremia; Hyperkalemia
Tumorigenesis is a multi-step process due to an accumulation of genetic mutations in multiple genes in diverse pathways which ultimately lead to loss of control over cell growth. It is well known that inheritance of rare germline mutations in genes involved in tumorigenesis pathways confer high lifetime risk of neoplasia in affected individuals. Furthermore, a substantial number of multiple malformation syndromes include cancer susceptibility in their phenotype. Studies of the mechanisms underlying these inherited syndromes have added to the understanding of both normal development and the pathophysiology of carcinogenesis. Myotonic dystrophy (DM) represents a group of autosomal dominant, multisystemic diseases that share the clinical features of myotonia, muscle weakness, and early-onset cataracts. Myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2) result from unstable nucleotide repeat expansions in their respective genes. There have been multiple reports of tumors in individuals with DM, most commonly benign calcifying cutaneous tumors known as pilomatricomas. We provide a summary of the tumors reported in DM and a hypothesis for a possible mechanism of tumorigenesis. We hope to stimulate further study into the potential role of DM genes in tumorigenesis, and help define DM pathogenesis, and facilitate developing novel treatment modalities.
Tumorigenesis; Myotonic dystrophy; Repeat expansion disorders; Pilomatricoma; β-Catenin
Myotonic dystrophy is the most common autosomal dominant myopathy in adults. Our patient, a 41 year-old female suffering from myotonic muscular dystrophy, developed upper thoracic myelopathy due to hypertrophy of the ligamentum flavum and the posterior longitudinal ligament. She had a typical hatchet face and ptosis with "head hanging forward" appearance caused by neck weakness. Motor weakness, sensory changes and severe pain below T4 level, along with urinary incontinence began 3 months ago. Genetic and electrodiagnostic studies revealed myotonic dystrophy type 1. Magnetic resonance imaging of the spine showed loss of cervical lordosis and spinal cord compression due to hypertrophied ligamentum flavum and posterior longitudinal ligament at T1 to T3 level. We concluded that her upper thoracic myelopathy was likely related to the thickness of the ligamentum flavum and posterior longitudinal ligament due to repetitive mechanical stress on her neck caused by neck muscle weakness with myotonic dystrophy.
Myotonic dystrophy; Neck weakness; Thoracic myelopathy
Pathophysiological mechanisms underlying the clinically devastating CNS features of myotonic dystrophy (DM) remain more enigmatic and controversial than do the muscle abnormalities of this common form of muscular dystrophy. To better define CNS and cranial muscle changes in DM, we used quantitative volumetric and diffusion tensor MRI methods to measure cerebral and masticatory muscle differences between controls (n=5) and adults with either congenital (n=5) or adult onset (n=5) myotonic dystrophy type 1, myotonic dystrophy type 2 (n=5). Muscle volumes were diminished in DM1 and strongly correlated with reduced white matter integrity and gray matter volume. Moreover, correlation of reduced fractional anisotropy (white matter integrity) and gray matter volume in both DM1 and DM2 suggests that these abnormalities may share a common underlying pathophysiological mechanism. Further quantitative temporal and spatial characterization of these features will help delineate developmental and progressive neurological components of DM, and help determine the causative molecular and cellular mechanisms.
Myotonic dystrophy; DM; DM1; DM2; diffusion tensor imaging; magnetic resonance imaging; MRI; cerebral white matter; cerebral gray matter; craniofacial muscle; pterygoid; temporalis; masseter
In myotonic muscular dystrophy, abnormal muscle Na currents underlie myotonic discharges. Since the myotonic muscular dystrophy gene encodes a product, human myotonin protein kinase, with structural similarity to protein kinases, we tested the idea that human myotonin protein kinase modulates skeletal muscle Na channels. Coexpression of human myotonin protein kinase with rat skeletal muscle Na channels in Xenopus oocytes reduced the amplitude of Na currents and accelerated current decay. The effect required the presence of a potential phosphorylation site in the inactivation mechanism of the channel. The mutation responsible for human disease, trinucleotide repeats in the 3' untranslated region, did not prevent the effect. The consequence of an abnormal amount of the kinase would be altered muscle cell excitability, consistent with the clinical finding of myotonia in myotonic dystrophy.
dysphagia is a common feature of patients with myotonic dystrophy and
is not usually perceived due to their emotional deficits and lack of
interest. The aim was to show the existence and frequency of
subclinical electrophysiological abnormalities in oropharyngeal
swallowing and to clarify the mechanisms of dysphagia in
patients with myotonic dystrophy were examined for oropharyngeal phase
of swallowing by clinical and electrophysiological methods. Ten
patients had dysphagia whereas 11 patients had signs and symptoms
reflecting CNS involvement. Four patients with myotonia congenita and
30 healthy volunteers served as controls. Laryngeal movements were
detected by means of a piezoelectric sensor. EMG activities of the
submental muscle (SM-EMG) and needle EMG of the cricopharyngeal muscle
of the upper eosophageal sphincter (CP-EMG) were also recorded during swallowing.
RESULTS—In about 70%
of the patients with myotonic
dystrophy, the existence of oropharyngeal
dysphagia was indicated objectively by means of the technique of
"dysphagia limit" and by clinical evaluation. Duration of the
swallowing reflex as defined by the laryngeal relocation time (0-2
time interval) and submental muscle excitation as a part of the
swallowing reflex (A-C interval) were significantly prolonged in
patients with myotonic dystrophy, especially
in dysphagic patients. Triggering time of the swallowing reflex (A-0
interval) also showed significant prolongation, especially in the
patients having both dysphagia and CNS involvement. During swallowing, CP muscle activity was abnormal in 40% of the patients with
myopathic weakness and myotonia encountered in oropharyngeal muscles
play an important part in the oral and the pharyngeal phases of
swallowing dysfunction in myotonic dystrophy. It was also suggested
that CNS involvement might contribute to the delay of the triggering of
the swallowing reflex and some abnormal EMG findings in the CP
sphincter, resulting in oropharyngeal dysphagia in
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults and as yet no cure for DM1. Here, we report the potential of manumycin A for a novel DM1 therapeutic reagent. DM1 is caused by expansion of CTG repeat. Mutant transcripts containing expanded CUG repeats lead to aberrant regulation of alternative splicing. Myotonia (delayed muscle relaxation) is the most commonly observed symptom in DM1 patients and is caused by aberrant splicing of the skeletal muscle chloride channel (CLCN1) gene. Identification of small-molecule compounds that correct aberrant splicing in DM1 is attracting much attention as a way of improving understanding of the mechanism of DM1 pathology and improving treatment of DM1 patients. In this study, we generated a reporter screening system and searched for small-molecule compounds. We found that manumycin A corrects aberrant splicing of Clcn1 in cell and mouse models of DM1.
Myotonic Dystrophy type 1 (DM1) is a multi-system disorder characterized by muscle wasting, myotonia, cardiac conduction defects, cataracts, and neuropsychological dysfunction. DM1 is caused by expansion of a CTG repeat in the 3´untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene. A body of work demonstrates that DMPK mRNAs containing abnormally expanded CUG repeats are toxic to several cell types. A core mechanism underlying symptoms of DM1 is that mutant DMPK RNA interferes with the developmentally regulated alternative splicing of defined pre-mRNAs. Expanded CUG repeats fold into ds(CUG) hairpins that sequester nuclear proteins including human Muscleblind-like (MBNL) and hnRNP H alternative splicing factors. DM1 cells activate CELF family member CUG-BP1 protein through hyperphosphorylation and stabilization in the cell nucleus. CUG-BP1 and MBNL1 proteins act antagonistically in exon selection in several pre-mRNA transcripts, thus MBNL1 sequestration and increase in nuclear activity of CUG-BP1 both act synergistically to missplice defined transcripts. Mutant DMPK-mediated effect on subcellular localization, and defective phosphorylation of cytoplasmic CUG-BP1, have additionally been linked to defective translation of p21 and MEF2A in DM1, possibly explaining delayed differentiation of DM1 muscle cells. Mutant DMPK transcripts bind and sequester transcription factors such as Specificity protein 1 leading to reduced transcription of selected genes. Recently, transcripts containing long hairpin structures of CUG repeats have been shown to be a Dicer ribonuclease target and Dicer-induced downregulation of the mutant DMPK transcripts triggers silencing effects on RNAs containing long complementary repeats. In summary, mutant DMPK transcripts alter gene transcription, alternative splicing, and translation of specific gene transcripts, and have the ability to trigger gene-specific silencing effects in DM1 cells. Therapies aimed at reversing these gene expression alterations should prove effective ways to treat DM1.
OBJECTIVES—Myotonic dystrophy is a disease
characterised by myotonia and muscle weakness. Psychiatric disorder and
sleep problems have also been considered important features of the
illness. This study investigated the extent to which apathy, major
depression, and hypersomnolence were present. The objective was to
clarify if the apathy reported anecdotally was a feature of CNS
involvement or if this was attributable to major depression,
hypersomnolence, or a consequence of chronic muscle weakness.
METHODS—These features were studied in 36 adults
with non-congenital myotonic dystrophy and 13 patients with
Charcot-Marie-Tooth disease. By using patients with Charcot-Marie-Tooth
disease as a comparison group the aim was to control for the disabling
effects of having an inherited chronic neurological disease causing
muscle weakness. Standardised assessment instruments were used wherever
possible to facilitate comparison with other groups reported in the
RESULTS—There was no excess of major depression on
cross sectional analysis in these patients with mild myotonic
dystrophy. However, apathy was a prominent feature of myotonic
dystrophy in comparison with a similarly disabled group of patients
with Charcot-Marie-Tooth disease (clinician rated score;
Mann Whitney U test, p=0.0005). Rates of hypersomnolence
were greater in the myotonic dystrophy group, occurring in 39% of
myotonic dystrophy patients, but there was no correlation with apathy.
CONCLUSION—These data suggest that apathy
and hypersomnia are independent and common features of myotonic
dystrophy. Apathy cannot be accounted for by clinical depression or
peripheral muscle weakness and is therefore likely to reflect CNS
involvement. These features of the disease impair quality of life and
may be treatable.
Phosphorodiamidate morpholino oligonucleotide (PMO)-mediated control of the alternative splicing of the chloride channel 1 (CLCN1) gene is a promising treatment for myotonic dystrophy type 1 (DM1) because the abnormal splicing of this gene causes myotonia in patients with DM1. In this study, we optimised a PMO sequence to correct Clcn1 alternative splicing and successfully remedied the myotonic phenotype of a DM1 mouse model, the HSALR mouse. To enhance the efficiency of delivery of PMO into HSALR mouse muscles, Bubble liposomes, which have been used as a gene delivery tool, were applied with ultrasound exposure. Effective delivery of PMO led to increased expression of Clcn1 protein in skeletal muscle and the amelioration of myotonia. Thus, PMO-mediated control of the alternative splicing of the Clcn1 gene must be important target of antisense therapy of DM1.
Myotonic dystrophy (DM) is the most common form of adult onset muscular dystrophy, with an incidence of approximately 1 in 8500 adults. DM is caused by an expanded number of trinucleotide repeats in the 3'-untranslated region (UTR) of a cAMP-dependent protein kinase (DM protein kinase, DMPK). Although a large number of transgenic animals have been generated with different gene constructions and knock-outs, none of them faithfully recapitulates the multisystemic and often severe phenotype seen in human patients. The transgenic data suggest that myotonic dystrophy is not caused simply by a biochemical deficiency or abnormality in the DM kinase gene product. Emerging studies suggest that two novel pathogenetic mechanisms may play a role in the disease: the expanded repeats appear to cause haploinsufficiency of a neighboring homeobox gene and also abnormal DMPK RNA appears to have a detrimental effect on RNA homeostasis. The complex, multisystemic phenotype may reflect an underlying multifaceted molecular pathophysiology: the facial dysmorphology may be due to pattern defects caused by haploinsufficiency of the homeobox gene, while the muscle disease and endocrine abnormalities may be due to both altered RNA metabolism and deficiency of the cAMP DMPK protein.
Abnormal calcium transport may be implicated in the membrane defect in myotonic dystrophy. A single blind crossover trial of placebo (t.i.d.), nifedipine 10 mg (t.i.d.) and nifedipine 20 mg (t.i.d.), was performed in 10 patients with myotonic dystrophy. The severity of myotonia was assessed by measuring finger extension time after maximum voluntary finger flexion. A significant improvement in myotonia, after nifedipine, was recorded by this technique and supported by a subjective improvement in 50% of patients and clinical improvement of greater than 20% in five patients. Initial grip strength and muscle fatiguability measured by grip strength ergometry were not significantly altered.
Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. It is caused by an expanded (CTG)n tract in the 3′ UTR of the Dystrophia Myotonica Protein Kinase (DMPK) gene. This causes nuclear retention of the mutant mRNA into ribonuclear foci and sequestration of interacting RNA-binding proteins (such as muscleblind-like 1 (MBNL1)). More severe congenital and childhood-onset forms of the disease exist but are less understood than the adult disease, due in part to the lack of adequate animal models. To address this, we utilized transgenic mice over-expressing the DMPK 3′ UTR as part of an inducible RNA transcript to model early-onset myotonic dystrophy. In mice in which transgene expression was induced during embryogenesis, we found that by two weeks after birth, mice reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, muscle weakness, histopathology and mRNA splicing defects. Notably, these defects were more severe than in adult mice induced for an equivalent period of exposure to RNA toxicity. Additionally, the utility of the model was tested by over-expressing MBNL1, a key therapeutic strategy being actively pursued for treating the disease phenotypes associated with DM1. Significantly, increased MBNL1 in skeletal muscle partially corrected myotonia and splicing defects present in these mice, demonstrating the responsiveness of the model to relevant therapeutic interventions. Furthermore, these results also represent the first murine model for early-onset DM1 and provide a tool to investigate the effects of RNA toxicity at various stages of development.
Muscle degeneration and myotonia are clinical hallmarks of myotonic dystrophy type 1 (DM1), a multisystemic disorder caused by a CTG repeat expansion in the 3′ untranslated region of the myotonic dystrophy protein kinase (DMPK) gene. Transgenic mice engineered to express mRNA with expanded (CUG)250 repeats (HSALR mice) exhibit prominent myotonia and altered splicing of muscle chloride channel gene (Clcn1) transcripts. We used whole-cell patch clamp recordings and nonstationary noise analysis to compare and biophysically characterize the magnitude, kinetics, voltage dependence, and single channel properties of the skeletal muscle chloride channel (ClC-1) in individual flexor digitorum brevis (FDB) muscle fibers isolated from 1–3-wk-old wild-type and HSALR mice. The results indicate that peak ClC-1 current density at −140 mV is reduced >70% (−48.5 ± 3.6 and −14.0 ± 1.6 pA/pF, respectively) and the kinetics of channel deactivation increased in FDB fibers obtained from 18–20- d-old HSALR mice. Nonstationary noise analysis revealed that the reduction in ClC-1 current density in HSALR FDB fibers results from a large reduction in ClC-1 channel density (170 ± 21 and 58 ± 11 channels/pF in control and HSALR fibers, respectively) and a modest decrease in maximal channel open probability(0.91 ± 0.01 and 0.75 ± 0.03, respectively). Qualitatively similar results were observed for ClC-1 channel activity in knockout mice for muscleblind-like 1 (Mbnl1ΔE3/ΔE3), a second murine model of DM1 that exhibits prominent myotonia and altered Clcn1 splicing (Kanadia et al., 2003). These results support a molecular mechanism for myotonia in DM1 in which a reduction in both the number of functional sarcolemmal ClC-1 and maximal channel open probability, as well as an acceleration in the kinetics of channel deactivation, results from CUG repeat–containing mRNA molecules sequestering Mbnl1 proteins required for proper CLCN1 pre-mRNA splicing and chloride channel function.
Twenty-five symptoms, signs, and abnormal investigations were looked for in 20 patients with clinically-definite myotonic dystrophy. Weakness of facial muscles, neck flexors, and arm external rotators was found in all patients (sensitivity = 100%). Arm external rotation has not been reported as a frequently involved muscle in previous clinical studies on myotonic dystrophy. Careful examination of muscle strength may therefore predict which patients may or may not carry the abnormal gene for myotonic dystrophy.
In a study of 35 index patients who developed myotonic dystrophy between birth and 30 years (neonatal cases aware excluded), 30 could be categorised into two clinical types. The 13 type 1 patients had a more severe limb weakness, of patchy distribution, associated with proportional facial weakness. The 17 type 2 patients had a milder and more diffuse limb weakness; their facial weakness, however, was very pronounced and preceded the limb weakness by several years. All but one of the 25 affected relatives who were examined belonged to the same category as their index relative, providing evidence that the cause of the clinical heterogeneity was genetic. Subsequent observations showed that mental retardation, male infertility, and neonatally affected offspring were commoner in type 2 patients. Congenital myotonic dystrophy could occur among the offspring of either affected males or affected females, but neonatal symptoms were confined to the offspring of affected women. The overall risk for having neonatally affected offspring for this prospective study of young adult patients was 7 in 38, and for the offspring of affected females 7 in 27. The risk for having a surviving child whose mental or physical handicap or both required special schooling was 1 in 12 for males and 4 in 27 for females.
Myasthenia gravis (MG) and myotonic dystrophy type 2 (DM2) are rare disorders individually, and their coexistence in the same patient is very rare. We present a patient in which these two diseases coexisted.
The patient complained of diplopia, fluctuating limb weakness, and difficulties in swallowing and speaking. A neurological examination revealed diplopia, facial, weakness of the neck and proximal limb muscles, dysphagia, dysphonia, and myotonia. The patient's mother had DM2 and her maternal grandfather had cataracts. MG was confirmed in our patient by positive results for neostigmine and a repetitive nerve stimulation test, and elevated serum anti-acetylcholine-receptor antibodies, while DM2 was confirmed by electromyography and genetic testing. The patient improved remarkably after treatment with anticholinesterases, corticosteroids, and azathioprine.
This is the second reported case of the coexistence of DM2 and MG in the same patient. Since the symptoms of these two diseases overlap it is very important to keep in mind the possibility of their coexistence, so that MG is not overlooked in patients with a family history of myotonic dystrophy.
myasthenia gravis; myotonic dystrophy type 2; neuromuscular; myopathy; neuromuscular transmission
Because of its high prevalence, fibromyalgia (FM) is a major general health issue. Myotonic dystrophy type 2 (DM2) is a recently described autosomal-dominant multisystem disorder. Besides variable proximal muscle weakness, myotonia, and precocious cataracts, muscle pain and stiffness are prominent presenting features of DM2. After noting that several of our mutation-positive DM2 patients had a previous diagnosis of FM, suggesting that DM2 may be misdiagnosed as FM, we invited 90 randomly selected patients diagnosed as having FM to undergo genetic testing for DM2. Of the 63 patients who agreed to participate, 2 (3.2%) tested positive for the DM2 mutation. Their cases are described herein. DM2 was not found in any of 200 asymptomatic controls. We therefore suggest that the presence of DM2 should be investigated in a large sample of subjects diagnosed as having FM, and clinicians should be aware of overlap in the clinical presentation of these 2 distinct disorders.
Myotonic dystrophy type 2 (DM2) is an autosomal dominantly inherited multisystemic disorder and a common cause of muscular dystrophy in adults. Although neuromuscular symptoms predominate, there is clinical and imaging evidence of cerebral involvement. We used voxel-based morphometry (VBM) based on T1-weighted magnetic resonance images to investigate brain morphology in 13 DM2 patients in comparison to 13 sex- and age-matched controls. Further, we employed novel computational surface-based methods that specifically assess callosal thickness. We found grey and white matter loss along cerebral midline structures in our patient group. Grey matter reductions were present in brainstem and adjacent hypothalamic and thalamic regions, while white matter was mainly reduced in corpus callosum. The reduced callosal size was highly significant and independently confirmed by different methods. Our data provide first evidence for grey and white matter loss along brain midline structures in DM2 patients. The reduced size of the corpus callosum further extends the spectrum of white matter changes in DM2 and may represent the morphological substrate of neuropsychological abnormalities previously described in this disorder.
DM2; brainstem; corpus callosum; VBM; morphometry