Myotonic Syndrome Research Articles

1008 Excessive daytime sleepiness in myotonic dystrophy treated with modafinil

Abstract Introduction Physiology of excessive daytime sleepiness (EDS) in myotonic dystrophy type 1 (DM1) remains incompletely understood and best practice treatment approaches are unclear. Report of case(s) We present a 73-year-old man with atrial fibrillation, implantable cardioverter defibrillator for inducible ventricular tachycardia, hypertension, and severe obstructive sleep apnea (OSA) was referred after a recent diagnosis of myotonic dystrophy type 1 (DM1) for EDS. He presented with foot pain, balance issues, and falls. A subdural hemorrhage from a fall prompted thorough evaluation including electromyography. This showed length-dependent polyneuropathy type pattern with features of subacute and chronic denervation change and myotonic discharges in right vastus medialis and bilateral tibialis anterior and gastrocnemius muscles. Myotonic Syndrome Advanced Evaluation revealed with a repeat expansion mutation in DMPK gene (85 and 13 CTG repeats). He was previously diagnosed severe OSA with an AHI of 64 and titrated onto bilevel. He recalled no improvement in symptoms with bilevel. He noted sleeping 10-12 hours per night and feeling rested. However, he takes multiple times per day for hours at a time. When actively working on tasks he feels alert and focused. Epworth sleepiness scale (ESS) was 12. Polysomnogram on bilevel followed by MSLT demonstrated control of OSA and mean sleep onset latency of 8 minutes and 5 sleep onset REM periods. With relatively little impairment and a desire for intermittent improved wakefulness, he was started on modafinil 200mg daily as needed. He reported a robust response to modafinil without the need for additional naps or cardiac complications thus far. Repeat ESS only improved to 10. Conclusion This case highlights the need for a precision medicine approach as subpopulations exist even within the specific diagnosis excessive daytime sleepiness in myotonic dystrophy. People with DM1 have been similarly reported with little improvement in ESS but dramatic subjective improvement in symptoms with modafinil. A Cochrane Review and a European Medicines Agency recommendations on modafinil are not supportive of its use in DM1 despite a subpopulation with a clear response. Interestingly, clinical measures do not seem to predict response to modafinil, suggesting unmeasured and, potentially, varied pathologies of excessive daytime sleepiness in DM1. Support (if any)

Blockers of Skeletal Muscle Nav1.4 Channels: From Therapy of Myotonic Syndrome to Molecular Determinants of Pharmacological Action and Back.

The voltage-gated sodium channels represent an important target for drug discovery since a large number of physiological processes are regulated by these channels. In several excitability disorders, including epilepsy, cardiac arrhythmias, chronic pain, and non-dystrophic myotonia, blockers of voltage-gated sodium channels are clinically used. Myotonia is a skeletal muscle condition characterized by the over-excitability of the sarcolemma, resulting in delayed relaxation after contraction and muscle stiffness. The therapeutic management of this disorder relies on mexiletine and other sodium channel blockers, which are not selective for the Nav1.4 skeletal muscle sodium channel isoform. Hence, the importance of deepening the knowledge of molecular requirements for developing more potent and use-dependent drugs acting on Nav1.4. Here, we review the available treatment options for non-dystrophic myotonia and the structure-activity relationship studies performed in our laboratory with a focus on new compounds with potential antimyotonic activity.

Hypertrophie musculaire : signe de bonne santé ou de maladie ?

In order to explain muscle hypertrophy in a patient complaining of muscular symptoms one must take into account the patient’s daily professional or leisure physical activity. If muscle hypertrophy cannot be attributed to active lifestyle, an underlying neuromuscular pathology should be suspected. The check-up includes a meticulous neurological examination (looking for myotonia, rippling, myoclonus, etc.), a CK level dosage, an electromyography (for myotonic discharges), and, if necessary, it should be completed by muscle biopsy and molecular examinations. Several diagnostic hypotheses should be considered. Most are related to a genetic defect leading to dysfunction of the excitation-contraction coupling in the muscle. The diagnosis of a myotonic syndrome is the most common but caveolinopathy 3, RYR1-related myopathy or Brody’s disease are also possible.

КЛИНИКО-ДИАГНОСТИЧЕСКИЕ ПРИЗНАКИ НЕДИФФЕРЕНЦИРОВАННОЙ ДИСПЛАЗИИ СОЕДИНИТЕЛЬНОЙ ТКАНИ У ДЕТЕЙ С ДИСПЛАЗИЕЙ ТАЗОБЕДРЕННЫХ СУСТАВОВ

Developmental dysplasia of the hip (DDH) is characterized by varying degrees of underdevelopment of the hip joint (HJ) and para-articular tissues with numerous variants of clinical and anatomical criteria. It is now considered one of the manifestations of undifferentiated connective tissue dysplasia (UCTD), which is confirmed by genetic testing. Undoubtedly, children with DDH also have other manifestations of UCTD, the clinical combination of which must be taken into account for the overall prognosis of the patient's quality of life, as well as the determination of control points in the treatment and prevention of the disease. Materials and methods of research: a singlestage observational screening study was carried out involving 785 children (578 girls and 207 boys) from 2 to 14 years old (7,5±1,5 years) with a radiographically confirmed diagnosis of DDH of various variants (torsion-valgus deformity, subluxation , dislocation in the vehicle). The control group consisted of 259 children (140 girls and 119 boys) without HJ pathology, who were examined at the Research Institute of Traumatology, Orthopedics and Neurosurgery for preparation for a kindergarten/school/sports section, comparable in age (6,5±1,3 years). The criteria for selecting UCTD was the Bayesian classifier modified by T.I. Kadurina and V.N. Gorbunova, including the 50 most common clinical markers. For analysis the clinical anamnestic method, instrumental data of somatic symptom disorder test was used. Results: after summing up the scores in children with DDH, grade I UCTD was diagnosed in 40,0% (314), grade II – in 36,1% (283) and grade III – in 23,9% (188). In most cases, symptoms of UCTD with an Ehlers-Danlos-like syndrome were noted, which are characterized by changes in the musculoskeletal system, skin, connective tissue elements of internal organs (hypermobility of the joints, stretchable skin, anatomical disorders of the heart valves, bile ducts, etc.) or signs of UCTD with an unclassifiable phenotype when there is a variety of stigmas. All children in this group have joint hypermobility, myotonic syndrome, and various types of posture disorders. In the control group with DDH, 27,4% (71) noted the burdened heredity in the pathology of the musculoskeletal system on the mother's or father's side. In the control group the signs of UCTD stigma were also diagnosed, however, the degree of their severity and occurrence were significantly lower (p<0,05). In these children, the most significant were changes in the organ of vision, nervous system, maxillofacial region, digestive tract and a decrease in immune function. Conclusion: manifestations of UCTD are significantly more common in children with DDH compared with healthy children; pathology of the musculoskeletal and cardiovascular systems prevails in the structure of UCTD stigmas. In the pathogenesis of DDH, a genetic predisposition is realized (45,5%, 357 children), hypermobility of joints, myatonic syndrome were observed in all children in the study group. Manifestations of UCTD were also found in the control group, however, the stigmas were of a visceral nature of lesions and impairments from the sense organs, which is not the subject of a pediatric orthopedist's study. Thus, the features of UCTD in children with DDH are considered as a predictor of the pathology severity.

P.Asn1180Ile mutation of SCN4A gene in an Italian family with myopathy and myotonic syndrome.

Mutations of the skeletal muscle sodium channel gene SCN4A are associated with several neuromuscular disorders including hyper/hypokaliemic periodic paralysis, paramyotonia congenita and sodium channel myotonia. These disorders are distinguished from dystrophic myotonias by the absence of progressive weakness and extramuscular systemic involvement. We present an Italian family with 2 subjects carrying a p.Asn1180Ile mutation in SCN4A gene showing a peculiar clinical picture characterized by the association of myopathic features and myotonia. The clinical, electromyographic and histological findings of these patients are reported. The possible pathogenicity of the mutation was tested by three different software, all giving positive results. This is the first report of a dominant, heterozygous mutation in SCN4A causing a complex phenotype of non-congenital myopathy and myotonic syndrome. We suggest that, in patients with myotonia and myopathy not related to dystrophic myotonias, the sequence analysis of SCN4A gene should be performed.

Chapter 16 - Clinical electrophysiology of muscle diseases and episodic muscle disorders

The electrodiagnostic tests performed in a patient with suspected muscle disease should provide reliable answers to the addressed questions: (1) differentiate a myopathic disorder from a neuropathic one and (2) precise the nature and cause of the myopathy. Answer to the first question mainly requires needle electromyography (EMG) of 4-6 muscles. Recordings may include extraction and measurements of motor unit potentials (MUPs). Reduced MUP spike duration indicates a lack of active muscle fibers within the motor units, and is the most reliable sign of myopathy. Needle EMG will also guide toward the etiology of the myopathy through the topographical distribution (proximal, distal, etc.) of abnormal EMG tracings and the identification of electrical activity at rest, especially fibrillation and myotonic discharges which guide toward evolutive myopathies and myotonic syndromes, respectively. The study of sensory nerve conduction should involve two to three nerves in order to disclose the coexistence of a sensory neuropathy (particularly in mitochondrial myopathies). If the diagnosis remains uncertain, functional provocative tests should be performed: 3Hz repetitive nerve stimulation to search for a myasthenic syndrome, repeated short exercise (combined with cooling if necessary) in the case of myotonic syndrome; long exercise test if periodic paralysis is suspected.

A premature baby with bilateral pleural effusions, Turner syndrome (monosomy X) and myotonic dystrophy

Abstract Respiratory distress in the premature neonate has a variety of causes, some more common than others. Sometimes it may not be apparent that rare underlying conditions may be associated with common clinical presentations. In this case report, we describe an extremely premature neonate presenting with severe respiratory distress who was subsequently diagnosed with both myotonic dystrophy and Turner syndrome (monosomy X; 45, X0). A literature review correlating this neonate’s particular presentation with these diagnoses has been included.

THE NONDYSTROPHIC MYOTONIAS (CLINICAL CASE, DISCUSSION)

The article presents the clinical case of congenital myotonia which was newly diagnosed in patients with back pain. It has been discussed the genetics, pathophysiology, clinical features, differential diagnosis and management for myotonic syndrome due to different nondystrophic myotonias.

Regression of lumbar disk herniation

Compression of the spinal nerve root, giving rise to pain and sensory and motor disorders in the area of its innervation is the most vivid manifestation of herniated intervertebral disk. Different treatment modalities, including neurosurgery, for evolving these conditions are discussed. There has been recent evidence that spontaneous regression of disk herniation can regress. The paper describes a female patient with large lateralized disc extrusion that has caused compression of the nerve root S 1 , leading to obvious myotonic and radicular syndrome. Magnetic resonance imaging has shown that the clinical manifestations of discogenic radiculopathy, as well myotonic syndrome and morphological changes completely regressed 8 months later. The likely mechanism is inflammation-induced resorption of a large herniated disk fragment, which agrees with the data available in the literature. A decision to perform neurosurgery for which the patient had indications was made during her first consultation. After regression of discogenic radiculopathy, there was only moderate pain caused by musculoskeletal diseases (facet syndrome, piriformis syndrome) that were successfully eliminated by minimally invasive techniques.

EPA-0644 - 3p26.3 - candidate loci of intellectual disability

To date 56 reciprocal microdeletion/microduplication syndromes have been described. Due to intensive application of microarray technologies new submicroscopic rearrangements are being published. The reciprocal rearrangements are particularly valuable, since they allow to determine the dosage-sensitive pathogenic genes. To improve ID diagnostics. To identify novel candidate loci of ID. We performed the genome-wide analysis for 79 patients with idiopathic ID using CGH Microarray Kits 4×44K and 8×60K (Agilent Technologies, USA). Pathogenically significant cases were confirmed by qPCR. We present two patients with microdeletion (369 kb) and microduplication (766 kb) at 3p26.3 containing the only gene - CNTN6. The microduplication was inherited from apparently healthy father. The child with microdeletion was an orphan. Recently, the microduplication in 3p26.3 (containing CNTN6 ) has been shown to be associated with autism spectrum disorders (ASDs). Contactin 6 is also suggested to play a neuroprotective role in ischemic injury and contribute to granule cell maturation and/or synaptic formation in the developing cerebellum. Considering the experiments with mice we found myotonic syndrome, late development of sit and walk ability in the anamnesis, current fine motor skills impairment and dysarthria in patient with dup3p26.3. His IQ is 47. Dysarthria was also observed in the patient with del3p26.3 (IQ 55). Obviously, CNTN6 can be a novel pathogenic gene associated with ASDs, ID, and motor functions impairment. This study was supported by EU Seventh Framework Program, CHERISH project no. 223692 and by Federal Program of Ministry of Education and Science of Russian Federation no. 8727.

Bilaterale Augenbrauentumoren

We report about a 5-year-old boy who presented in our clinic with bilateral, slowly progressive solid tumors of the eyebrows. Histological examination of the excised tumors revealed the typical diversified picture of pilomatrixoma with basophilic and shadow cells. The bilateral or multiple manifestation of pilomatrixoma is uncommon and can be associated with myotonic dystrophy, sarcoidosis or Gardner's syndrome.

FOOT CRAMPING PAIN ??? RUNNER

HISTORY An 18-year-old male runner was referred to our sports medicine clinic with a 1-year history of cramping left foot pain. His symptoms developed insidiously when he increased his speed work training about 1 year previous, with an onset of severe left foot pain and tightness that would develop after about 20 minutes of exercise. The patient also noted occasional cramps in his calves after excessive exercise. He did not notice any swelling, numbness, tingling or burning sensations. He saw numerous private physicians and tried physical therapy, interdigital nerve block, and was immobilized in a walking cast for more than 1 month for a presumed stress fracture without effect. A family history revealed that a 29-year-old sister and uncle had symptoms of cramping in the hands with hard exercise or cold weather. PHYSICAL EXAMINATION The patient had no atrophy or fasciculations of his extremities or tongue. Neurovascular status was intact. He had no current pain associated with the foot with palpation, range of motion, or ambulation. He had full range of motion in all extremities as well as in the cervical and thoracolumbar spine. Neurologic examination, including detailed testing of mental status, cranial nerves, motor/sensory systems, muscle stretch reflexes, coordination, and gait were within normal limits, with the exception of mild proximal muscle weakness noted at the deltoids and triceps rated at 4/5 bilaterally. Distal upper and lower extremity strength were normal. DIFFERENTIAL DIAGNOSIS Compartment syndrome. Metatarsal stress fracture. Plantar fascitis. Interdigital neuroma. Myotonic syndrome. TEST AND RESULTS Blood studies, including cell count, electrolyte, chemistry panel: – Normal MRI scans of the foot: – No sign of interdigital neuroma, metatarsal stress fracture, tenosynovitis, and no evidence of tumor or mass. Stryker examination: – No abnormal pressure increase of the medial, central, and deep posterior compartments of the left and central compartment on the right foot. Serum CPK: – 687 IU/L (normal range for men, 35–232) Repeated CPK study and aldolase after rest from running for two weeks: – 669 IU/L and 9 (normal range, 1–8). Nerve conduction study – Normal Needle electromyography – At rest, abnormal sustained runs of positive sharp waves at virtually every needle site in all limbs studied – Motor unit potentials and recruitment were normal in all muscles. – Following immersion of his hands in cold water for approximately 4–5 minutes, a repeat needle examination of the patients first dorsal interossei in the hand showed a large amount of myotonic discharges. Thyroid function test, eye examination: – Normal Muscle biopsy specimen taken from quadriceps muscle: – No evidence of myotonia dystrophica, inflammation, and metabolic myopathy. FINAL/WORKING DIAGNOSIS Paramyotonia congenital. TREATMENT AND OUTCOMES Carbamazepine and mexiletine, both of which were discontinued secondary to reported adverse effects of subtle cognitive slowing. Phenytoin (400 mg q hs), which lessened the patients symptoms. The patient decided to give up running, as he was not able to maintain mileage high enough to compete successfully at an elite college level.

Report of the 84th ENMC Workshop: PROMM (Proximal Myotonic Myopathy) and Other Myotonic Dystrophy-Like Syndromes: 2nd Workshop. 13–15th October, 2000, Loosdrecht, The Netherlands

Report of the 84th ENMC Workshop: PROMM (Proximal Myotonic Myopathy) and Other Myotonic Dystrophy-Like Syndromes: 2nd Workshop. 13–15th October, 2000, Loosdrecht, The Netherlands

Proof of genetic heterogeneity in the proximal myotonic myopathy syndrome (PROMM) and its relationship to myotonic dystrophy type 2 (DM2).

Recently, myotonic dystrophy type 2 has been described as a separate disease entity that is distinctive from classical Steinert's disease since it lacks a CTG repeat expansion on chromosome 19q. A gene locus for myotonic dystrophy type 2 has been mapped to chromosome 3q. Independently, proximal myotonic myopathy has been recognized as yet another form of a multisystem myotonic disorder. Its relationship to myotonic dystrophy type 2 remains to be clarified. In our linkage study of 17 German proximal myotonic myopathy families nine of them mapped to the myotonic dystrophy type 2 locus (LOD score 18.9). However, two families with a typical proximal myotonic myopathy phenotype were excluded from this locus (LOD score -7.4). These results confirm genetic heterogeneity in the proximal myotonic myopathy syndrome. Furthermore, in the majority of the proximal myotonic myopathy families the disease phenotype may be caused by allelic mutations in the putative myotonic dystrophy type 2 gene.

Anaesthesia in lipid myopathy

Anaesthesia in lipid myopathy

Paramyotonia congenita: genotype to phenotype correlations in two families and report of a new mutation in the sodium channel gene

Sodium channel disorders include hyperkalemic periodic paralysis (hyperPP), paramyotonia congenita (PC) and potassium-aggravated myotonia (PAM). PC is a myotonic syndrome characterized by cold-induced muscle stiffness and weakness. In this paper, we report two families. The first is affected by PC with cold-induced stiffness and no weakness, in addition to hyperPP. This family displays the Arg1448Cys mutation in the sodium channel gene originally described in pure PC families. The fact that families with the same mutation present distinct phenotypes indicates that other factors, genetic or environmental, may modulate the expression of the disease in sodium channel disorders. The second family was unusual because patients presented cold-induced weakness without stiffness. A mutation was found in the sodium channel gene that changed an isoleucine into a threonine at position 693. These two families demonstrate that sodium channel mutations may cause either cold-induced stiffness or weakness.

A family with an unusual myotonic and myopathic phenotype and no CTG expansion (proximal myotonic myopathy syndrome): a challenge for future molecular studies

Myotonic dystrophy (DM) is a well-defined autosomal dominant disorder characterized by myotonia, muscle weakness, cardiac conduction defects, cataracts, and endocrine abnormalities. Recently a newly recognized disorder, similar to but distinct from DM, has been observed with multisystem findings including intermittent myotonia, proximal myopathy, and occasional cardiac conduction disturbances. This disorder has been called proximal myotonic myopathy (PROMM). No history of anticipation is present and there is no linkage to the gene locus for DM or to the loci for the muscle sodium or chloride channels. This report describes a family with a normal size of the CTG trinucleotide repeat expansion of the DM gene in which affected individuals have myotonia (intermittent, exacerbated by cold), bilateral cataracts, mild hypogonadism and mild temporal atrophy. Affected individuals also have proximal muscle weakness, facial involvement, nonspecific abnormalities on muscle biopsy, normal cardiac conduction, and no glucose intolerance. The absence of trinucleotide repeat expansion in the DM gene is consistent with this family being affected by a disorder distinct from DM, possibly a form of PROMM.

Proximal myotonic myopathy syndrome in the absence of trinucleotide repeat expansions

Proximal myotonic myopathy syndrome in the absence of trinucleotide repeat expansions

Neurologic complications after gastric restriction surgery for morbid obesity.

We report the occurrence of neurologic complications in 23 patients who underwent gastric restriction surgery for the treatment of morbid obesity. Complications occurred 3 to 20 months after surgery. All the patients had had protracted vomiting for the first 3 months after the operation. The following syndromes were found: chronic or subacute symmetric polyneuropathy (12 patients), acute severe polyneuropathy (1 patient), burning feet syndrome (2 patients), meralgia paresthetica (3 patients), myotonic syndrome (1 patient), posterolateral myelopathy (2 patients), and Wernicke-Korsakoff encephalopathy (2 patients). The patients suffering from burning feet syndrome and those with Wernicke-Korsakoff encephalopathy showed a clear improvement after parenteral thiamine treatment. As to the rest of the patients, the occurrence of the complications seems to be linked to nutritional causes, although no such deficiencies were detected.

Morphologic and morphometric analyses of muscle in the neonatal myotonic dystrophy syndrome

Autopsy studies of three premature siblings who died soon after birth with the neonatal myotonic dystrophy syndrome revealed pulmonary hypoplasia and congenital pleural effusions. Neither of these findings has been described previously in this condition. New ultrastructural findings include focal diaphragmatic myofiber degeneration and necrosis, which were attributed to over-stretching of the fetal diaphragm. In addition, abnormally small stores of free and intravesicular glycogen were observed in skeletal muscle fibers. The morphometric features of control fetal and neonatal skeletal muscle were recorded for comparison with muscle fiber measurements in the three infants. Fiber diameters in the latter were much smaller than expected for body weights. The morphologic and morphometric findings support the concept that fetal muscle maturation is severely retarded in this syndrome.