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1.  Clinical and genetic analysis of the first known Asian family with myotonic dystrophy type 2 
Journal of Human Genetics  2014;59(3):129-133.
Myotonic dystrophy type 2 (DM2) is more common than DM1 in Europe and is considered a rare cause of myotonic dystrophies in Asia. Its clinical course is also milder with more phenotypic variability than DM1. We herein describe the first known Asian family (three affected siblings) with DM2 based on clinical and genetic analyses. Notably, two of the affected siblings were previously diagnosed with limb-girdle muscular dystrophy. Myotonia (the inability of the muscle to relax) was absent or only faintly present in these individuals. The third sibling had grip myotonia and is the first known Asian DM2 patient. The three DM2 siblings share several systemic characteristics, including late-onset, proximal-dominant muscle weakness, diabetes, cataracts and asthma. Repeat-primed PCR across the DM2 repeat revealed a characteristic ladder pattern of a CCTG expansion in all siblings. Southern blotting analysis identified the presence of 3400 repeats. Further DM2 studies in Asian populations are needed to define the clinical presentation of Asian DM2 and as yet unidentified phenotypic differences from Caucasian patients.
PMCID: PMC3973124  PMID: 24430576
Asian; CCTG repeat; clinical spectrum; haplotype; limb-girdle muscular dystrophy; myotonia; myotonic dystrophy type 2 (DM2)
2.  ZNF9 Activation of IRES-Mediated Translation of the Human ODC mRNA Is Decreased in Myotonic Dystrophy Type 2 
PLoS ONE  2010;5(2):e9301.
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.
PMCID: PMC2823779  PMID: 20174632
3.  Myotonia and flaccid dysarthria in patients with adult onset myotonic dystrophy 
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.
PMCID: PMC1738733  PMID: 15377703
4.  The heart and cardiac pacing in Steinert disease 
Acta Myologica  2012;31(2):110-116.
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.
PMCID: PMC3476856  PMID: 23097601
myotonic dystrophy type 1; arrhythmias; cardiac pacing
5.  Reversible model of RNA toxicity and cardiac conduction defects in myotonic dystrophy 
Nature genetics  2006;38(9):1066-1070.
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.
PMCID: PMC2909745  PMID: 16878132
6.  Hypothesis: neoplasms in myotonic dystrophy 
Cancer causes & control : CCC  2009;20(10):2009-2020.
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.
PMCID: PMC3110730  PMID: 19642006
Tumorigenesis; Myotonic dystrophy; Repeat expansion disorders; Pilomatricoma; β-Catenin
7.  Best practice guidelines and recommendations on the molecular diagnosis of myotonic dystrophy types 1 and 2 
European Journal of Human Genetics  2012;20(12):1203-1208.
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.
PMCID: PMC3499739  PMID: 22643181
8.  Upper Thoracic Myelopathy Caused by Delayed Neck Extensor Weakness in Myotonic Dystrophy 
Annals of Rehabilitation Medicine  2012;36(4):569-572.
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.
PMCID: PMC3438427  PMID: 22977786
Myotonic dystrophy; Neck weakness; Thoracic myelopathy
9.  Apathy and hypersomnia are common features of myotonic dystrophy 
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 medical literature.
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.

PMCID: PMC2170039  PMID: 9576545
10.  Cerebral and Muscle MRI Abnormalities in Myotonic Dystrophy 
Neuromuscular Disorders  2012;22(6):483-491.
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.
PMCID: PMC3350604  PMID: 22290140
Myotonic dystrophy; DM; DM1; DM2; diffusion tensor imaging; magnetic resonance imaging; MRI; cerebral white matter; cerebral gray matter; craniofacial muscle; pterygoid; temporalis; masseter
11.  Ultrasound-enhanced delivery of Morpholino with Bubble liposomes ameliorates the myotonia of myotonic dystrophy model mice 
Scientific Reports  2013;3:2242.
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.
PMCID: PMC3718203  PMID: 23873129
12.  Electrophysiological evaluation of oropharyngeal swallowing in myotonic dystrophy 
OBJECTIVE—Oropharyngeal 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 myotonic dystrophy.
METHODS—Eighteen 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 myotonic dystrophy.
CONCLUSION—Both 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.

PMCID: PMC1737233  PMID: 11181860
13.  A Case of Myotonic Dystrophy with Electrolyte Imbalance 
Journal of Korean Medical Science  2013;28(7):1111-1113.
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.
PMCID: PMC3708088  PMID: 23853500
Myotonic Dystrophy; Hypernatremia; Hyperkalemia
14.  Manumycin A corrects aberrant splicing of Clcn1 in myotonic dystrophy type 1 (DM1) mice 
Scientific Reports  2013;3:2142.
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.
PMCID: PMC3701899  PMID: 23828222
15.  Increased Cancer Risks in Myotonic Dystrophy 
Mayo Clinic Proceedings  2012;87(2):130-135.
To estimate cancer risks for patients with myotonic dystrophy, given that increased risks for neoplasms in association with myotonic dystrophy type 1 and type 2 have been suggested in several studies but the risks of cancers have not been quantified.
Patients and Methods
A cohort of 307 patients with myotonic dystrophy identified from medical records of Mayo Clinic in Rochester, MN, from January 1, l993, through May 28, 2010, was retrospectively analyzed. We estimated standardized incidence ratios (SIRs) of specific cancers for patients with myotonic dystrophy compared with age- and sex-specific cancer incidences of the general population. Age-dependent cumulative risks were calculated using the Kaplan-Meier method.
A total of 53 cancers were observed at a median age at diagnosis of 55 years. Patients with myotonic dystrophy had an increased risk of thyroid cancer (SIR, 5.54; 95% confidence interval [CI], 1.80-12.93; P=.001) and choroidal melanoma (SIR, 27.54; 95% CI, 3.34-99.49; P<.001). They may also have an increased risk of testicular cancer (SIR, 5.09; 95% CI, 0.62-18.38; P=.06) and prostate cancer (SIR, 2.21; 95% CI, 0.95-4.35; P=.05). The estimated cumulative risks at age 50 years were 1.72% (95% CI, 0.64%-4.55%) for thyroid cancer and 1.00% (95% CI, 0.25%-3.92%) for choroidal melanoma. There was no statistical evidence of an increased risk of brain, breast, colorectal, lung, renal, bladder, endometrial, or ovarian cancer; lymphoma; leukemia; or multiple myeloma.
Patients with myotonic dystrophy may have an increased risk of thyroid cancer and choroidal melanoma and, possibly, testicular and prostate cancers.
PMCID: PMC3498332  PMID: 22237010
16.  Structural myocardial involvement in adult patients with type 1 myotonic dystrophy 
Neurology International  2013;5(1):e5.
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.
PMCID: PMC3661985  PMID: 23717784
cardiac involvement; echocardiogram; myopathy; myotonic dystrophy.
17.  Myotonic dystrophy: relative sensitivity of symptoms signs and abnormal investigations. 
The Ulster Medical Journal  1994;63(2):151-154.
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.
PMCID: PMC2448763  PMID: 8650827
18.  Myotonic dystrophy: molecular windows on a complex etiology. 
Nucleic Acids Research  1998;26(6):1363-1368.
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.
PMCID: PMC147423  PMID: 9490778
19.  Clinical evidence for heterogeneity in myotonic dystrophy. 
Journal of Medical Genetics  1982;19(5):341-348.
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.
PMCID: PMC1048918  PMID: 7143387
20.  Modulation of skeletal muscle sodium channels by human myotonin protein kinase. 
Journal of Clinical Investigation  1995;95(5):2379-2384.
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.
PMCID: PMC295863  PMID: 7738201
21.  Decreased insulin sensitivity of forearm muscle in myotonic dystrophy. 
Journal of Clinical Investigation  1978;62(4):857-867.
Previous studies of patients with myotonic dystrophy have demonstrated hyperinsulinism after glucose loading. This hyperinsulinism has been attributed by some investigators to tissue insulin resistance. We have directly studied insulin sensitivity of forearm muscle in patients having such hyperinsulinism. The effect of an intrabrachial arterial insulin infusion (100 mu U/kg per min) on glucose uptake was determined in six cases of myotonic dystrophy, six normal subjects, and in seven disease control subjects with myotonia or wasting from other disorders. There was no significant difference in insulin tolerance comparing myotonic dystrophy patients to the normal and disease control groups. Glucose tolerance and basal insulin levels were normal in the myotonic dystrophy patients, but hyperinsulinism occurred after glucose ingestion. After 25 min of intra-arterial insulin, the mean peak muscle glucose uptake in myotonic dystrophy was 2.54 +/- 0.54 mu mol/min per 100 ml forearm compared to 5.24 +/- 0.86 mu mol/min per 100 ml for disease controls (P is less than 0.05). Myotonic dystrophy patients showed a peak glucose uptake increment of only 2.6 +/- 0.2-fold over basal contrasted with the disease control value of 6.5 +/- 1.0-fold (P is less than 0.02) and the normal control value of 8.8 +/- 1.1-fold (P is less than 0.01). Thus, there was an absolute as well as a relative decrease in muscle insulin sensitivity in myotonic dystrophy patients compared to both control groups. The peak increments in arterio-superficial venous glucose concentration differences after insulin infusion were not significantly different comparing myotonic dystrophy and control groups. These data suggest that in myotonic dystrophy, there is insulin insensitivity of skeletal muscle.
PMCID: PMC371838  PMID: 701484
22.  Nifedipine in the treatment of myotonia in myotonic dystrophy. 
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.
PMCID: PMC1031492  PMID: 3553433
23.  Dutch myotonic dystrophy type 2 patients and a North-African DM2 family carry the common European founder haplotype 
Myotonic dystrophy type 2 (DM2) is a progressive multisystem disease with muscle weakness and myotonia as main characteristics. The disease is caused by a repeat expansion in the zinc-finger protein 9 (ZNF9) gene on chromosome 3q21. Several reports show that patients from European ancestry share an identical haplotype surrounding the ZNF9 gene. In this study, we investigated whether the Dutch DM2 population carries the same founder haplotype. In all, 40 Dutch DM2 patients from 16 families were genotyped for eight short tandem repeat markers surrounding the ZNF9 gene. In addition, the single-nucleotide polymorphism (SNP) rs1871922 located in the first intron of DM2 was genotyped. Results were compared with previously published haplotypes from unrelated Caucasian patients. The repeat lengths identified in this study were in agreement with existing literature. In 36 patients of our population, we identified three common haplotypes. One patient showed overlap with the common haplotype for only one marker closest to the ZNF9 gene. The haplotype from a family originating from Morocco showed overlap with that of the patients of European descent for a region of 222 kb. All patients carried at least one C allele of SNP rs1871922 indicating that all patients carry the European founder haplotype. We conclude that DM2 patients from the Netherlands, including a North-African family, harbor a common haplotype surrounding the ZNF9 gene. This data show that the Dutch patients carry the common founder haplotype and strongly suggest that DM2 mutations in Europe and North Africa originate from a single ancestral founder.
PMCID: PMC3083617  PMID: 21224892
myotonic dystrophy type 2; haplotype; ZNF9
24.  Ascertainment of myotonic dystrophy through cataract by selective screening. 
Journal of Medical Genetics  1995;32(7):519-523.
Myotonic dystrophy (DM) almost always results from the expansion of an unstable (CTG)n repeat. The mutation can be detected directly. Affected patients with cataracts may have minimal additional signs of the disorder, but all are at risk of life threatening complications. We have studied the efficacy of detecting new families with myotonic dystrophy by selectively screening cataract patients. Selection criteria were: age under 60 with no obvious precipitating factor (except non-insulin dependent diabetes mellitus (NIDDM)); patients of any age with other signs suggestive of myotonic dystrophy detected by the ophthalmologist. Ninety-six patients were tested prospectively; 17 others under 55 were screened retrospectively. All patients were counselled by a clinical geneticist before testing. The patients' DNA was analysed using the DNA probe/restriction enzyme combinations GB2.6/EcoRI, KB1.4/BglI and polymerase chain reaction (PCR). Six patients have been found to have a mutation, three (3.1%) in the prospective group and three (17.6%) in the retrospective group. Three of these patients had minimal myotonic dystrophy and three had classical DM.
PMCID: PMC1050543  PMID: 7562963
25.  Grey and white matter loss along cerebral midline structures in myotonic dystrophy type 2 
Journal of neurology  2008;255(12):1904-1909.
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.
PMCID: PMC2770432  PMID: 19224318
DM2; brainstem; corpus callosum; VBM; morphometry

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