Duchenne muscular dystrophy: Gene and gene product; mechanism of mutation in the gene

Summary The X-linked gene responsible for Duchenne muscular dystrophy encodes dystrophin, a high-molecular-weight cytoskeletal protein. Studies in several laboratories have revealed deletion of one or more exons in 60% of affected boys; quantitative analysis in our laboratory has detected duplication of exons in another 6%. The severe Duchenne phenotype is associated with deletions or duplications that shift the reading frame of the message, whereas the milder Becker muscular dytrophy is associated with deletions or duplications that maintain the reading frame. Patients who have neither deletion nor duplication may have nonsense mutations, one of which has been detected by predicting the site of the mutation from the size of the truncated protein. Rare females with the disease have a translocation that disrupts the dystrophin gene on one X chromosome and causes non-random inactivation of the normal X, resulting in the expression of the disease.The high frequency of new mutation provides an opportunity to study the mechanism of chromosomal rearrangement that is characteristic of the disease. Our laboratory has focused on the translocations in females and on duplications in affected males. The X-autosome translocations of affected females are allde novo events that originated in the paternal set of chromosomes. Molecular characterization of the translocation junctions revealed reciprocal translocation with both deletion and addition of nucleotides at the junction, suggestive of a breakage and reunion mechanism. Duplications studied to date are all tandem in nature and sequence analysis of duplication junctions has revealed both homologous and non-homologous recombination. Marker segregation analysis has revealed that five out of five duplications originated in a single X chromosome of one of the maternal grandparents, suggesting that the recombination event is unequal sister chromatid exchange.     

Anesthetic management with remimazolam for a pediatric patient with Duchenne muscular dystrophy

Rationale:With Duchenne muscular dystrophy (DMD) being the most common and most severe type of muscular dystrophy, DMD patients are at risk for complications from general anesthesia due to impaired cardiac and respiratory functions as the pathological condition progresses. In recent years, advances in multidisciplinary treatment have improved the prognosis of DMD patients, and the number of patients requiring surgery has increased. Remimazolam is a benzodiazepine derivative similar to midazolam. Its circulatory stability and the fact that it has an antagonist make it superior to propofol.There are no reports of pediatric patients with DMD undergoing total intravenous anesthesia with remimazolam.Patient concerns:A 4-year boy was scheduled for single-incision laparoscopic percutaneous extraperitoneal closure for inguinal hernia under general anesthesia, but the surgery was postponed because his serum creatine phosphokinase level was extremely high.Diagnosis:He was diagnosed with DMD. According to the results of the genetic test, exon deletion of the DMD gene was detected using multiplex ligation-dependent probe amplification, although he had no symptoms of DMD except for elevated serum levels of creatine phosphokinase, etc.Intervention:He was admitted for the same surgical purpose. Anesthesia was induced with 3 mg of intravenously administered remimazolam. He lost the ability to respond to verbal commands. After the intravenous administration of 100 μg of fentanyl, a continuous infusion of remifentanil (1.0 μg/kg/min) and remimazolam (15 mg/h) was started, and the endotracheal tube was inserted smoothly after the administration of 10 mg of rocuronium with which the muscle twitches disappeared in train-of-four monitoring. At the end of the surgery, 15 mg of flurbiprofen was administered intravenously. After surgery, we injected 40 mg of sugammadex to confirm a train-of-four count of 100%.Outcomes:Although the dose of remimazolam was reduced to 5 mg/h 30 minutes before the end of the surgery, it took 20 minutes after the discontinuation of remimazolam for the patient to open his eyes upon verbal command. On postoperative Day 2, he was discharged from the hospital without any complications.Lessons:Remimazolam was shown to be safe to use for general anesthesia in a pediatric patient with DMD.     

1例肝豆状核变性合并杜兴型肌营养不良症及其家系报道

YAN Jian-guo;CHEN Da-wei;DONG Yi;XU Zhi-qiang;WANG Li-min;GAN Yu;WANG Fu-chuan;ZHANG Min(Pediatric Liver Disease Treatment and Research Center,the Fifth Medical Center of Chinese PLA General Hospital,Beijing 100039,China)     

Limb-girdle muscular dystrophy in a Portuguese patient caused by a mutation in the telethonin gene

Limb-girdle muscular dystrophy 2G is caused by mutations in the telethonin (TCAP) gene in chromosome 17q11-12. This rare form of hereditary muscle disease was originally described in Brazilian patients and was recently identified in Chinese and Moldavian patients. We present the first Portuguese patient with a limb-girdle muscular dystrophy caused by a mutation in the TCAP gene. A Caucasian male, 50 years old, presented in his early twenties, slowly progressive weakness in upper and lower limbs. Neurologic examination revealed severe atrophy and weakness in the muscles of the arms, thighs and legs' anterior compartment. Muscle MRI of the thighs and legs revealed severe atrophy of all the muscles of the thighs and legs' anterolateral compartment, in a symmetrical way. Molecular studies identified the homozygous c.157C > T (p.Gln53X) mutation in exon 2 of the TCAP gene, already described in Brazilian patients.     

Survival in Duchenne muscular dystrophy

Objective:

To determine the survival in a population of German patients with Duchenne muscular dystrophy.

Patients and methods:

Information about 94 patients born between 1970 and 1980 was obtained by telephone interviews and questionnaires. In addition to age of death or actual age during the investigation, data concerning clinical course and medical interventions were collected.

Results:

67 patients with molecularly confirmed diagnoses had a median survival of 24.0 years. Patients without molecular confirmation (clinical diagnosis only) had a chance of 67 % to reach that age. Grouping of our patient cohort according to the year of death (before and after 2000), ventilation was recognized as main intervention affecting survival with ventilated reaching a median survival of 27.0 years. For those without ventilation it was 19.0 years.

Conclusion and clinical relevance:

our study provides survival data for a cohort of DMD patients in Germany stratified by year of death. Median survival was 24.0 years in patients confirmed by molecular testing. Ventilated patients had a median survival of 27 years. We consider this piece of information helpful in the medical care of DMD patients.Key words: duchenne muscular dystrophy, survival, ventilation     

Respiratory muscle aids during an episode of aspiration in a patient with Duchenne muscular dystrophy

We report the case of a Duchenne muscular dystrophy patient with good bulbar function but severely decreased forced vital capacity (9%) and spontaneous peak cough flow (PCF) (2.35 L/s). The patient needed continuous noninvasive ventilation (NIV) consisting of a volumetric ventilator with a nighttime nasal mask and a daytime mouthpiece. He also required application of manually assisted coughing techniques by insufflation with a resuscitation bag and chest thrust (manually assisted PCF after maximum insufflation capacity of 4.33 L/s). An episode of serious food aspiration was resolved by his main caregiver through NIV and manually assisted coughing. Bronchoscopy under sedation using NIV with a lip seal connection to his volumetric ventilator later revealed that no material remained. This case exemplifies the potential role of skilled respiratory management in some neuromuscular diseases.     

Dermatomyositis developing in a Duchenne muscular dystrophy carrier

SIR, Duchenne muscular dystrophy (DMD) is the commonest musculardystrophy and its clinical manifestations are well recognized.Less commonly female carriers can become symptomatic, with symptomsranging from mild generalized weakness to inability to walk.Manifesting carriage of DMD is a rare but important cause ofproximal muscle weakness in females, but other diagnoses needto be excluded. A 42-yr-old lady presented with a lifelong history of fluctuatingproximal muscle weakness, fevers, clumsiness and falls. Herbrother had died at 19 yr     

A female carrier of Duchenne muscular dystrophy complicated with cardiomyopathy

A 45-year-old female carrier of Duchenne muscular dystrophy (DMD) complicated with cardiomyopathy is described. She had no symptoms of muscle weakness or heart failure. Her chest X-ray film revealed marked cardiomegaly. Echocardiogram showed marked enlargement and severe hypokinesis of the left ventricle. In myocardial scintigraphic images, perfusion defects of the myocardium were revealed. Dystrophin immunostaining of myocardial biopsy specimens showed a mosaic pattern of dystrophin-negative and -positive fibers. Cardiomyopathy is sometimes the only clinical symptom in female carriers of DMD. They are thought to be in a high risk group for developing heart failure.     

Autosomal dominant Ullrich congenital muscular dystrophy due to a de novo mutation in COL6A3 gene. A case report

Mutations in the genes encoding collagen VI cause Bethlem myopathy (MIM 158810), Ullrich congenital muscular dystrophy (MIM 254090), and myosclerosis myopathy (MIM #255600). BM is a dominantly inherited disorder, characterised by proximal muscle weakness and joint contractures mainly involving the elbows, ankles, and fingers, which usually follows a relatively mild course. By contrast, UCMD is a severe muscular dystrophy characterized by early onset, rapidly progressive muscle wasting and weakness, proximal joint contractures and distal joint hyperlaxity. Rapid progression usually leads to early death due to respiratory failure. UCMD is usually inherited as an autosomal recessive trait though dominant de novo heterozygous variants have recently been reported. We describe a further patient with UCMD classical presentation who showed, at the NGS analysis, the de novo variant c.6210+1G > A in the intron 16 of the gene COL6A3, known in the literature as pathogenic (VCV0000949S6.5).Key words: collagen VI disorders, Ullrich congenital muscular dystrophy, UCMD, COL6A3     

Inspiratory flow reserve in boys with Duchenne muscular dystrophy

Patients with advanced muscular dystrophy frequently develop ventilatory failure. Currently respiratory impairment usually is assessed by measuring vital capacity and the mouth pressure generated during a maximal inspiratory maneuver (PI,max), neither of which directly measures ventilatory capacity. We assessed inspiratory flow reserve in 26 boys [mean (SD) age 12.8 (3.8) years] with Duchenne muscular dystrophy (DMD) without ventilatory failure and in 28 normal boys [mean (SD) age 12.6 (1.9) years] by analyzing the ratio between the largest inspiratory flow during tidal breathing (V'I,max(t)) and during a forced vital capacity maneuver (V'I,max(FVC), (V'I,max(t)/V'I,maxFVC). We have compared this ratio with the forced vital capacity FVC and PI,max measured at functional residual capacity. Mean PI,max was -90(30)cmH2O, average 112% (range 57-179%) of predicted values in control boys and -31(11)cmH2O, average 40% predicted values in DMD boys (control vs DMD, P < 0.001). FVC was reduced in DMD boys [59(20)% predicted values vs 86(10)% predicted values in controls, P < 0.01]. Absolute V'I,max(FVC) was strongly related to FVC in both control and DMD boys; V'I,max(FVC) (expressed as FVC. s(-1)) was not related to PI,max in either group. The mean V'I,max(t)/V'I,max(FVC); ratio was higher in DMD 0.22 (0.08) than in controls 0.12 (0.03) (P < 0.001) indicating a reduction in inspiratory flow reserve in DMD. Inspiratory flow reserve was within the normal range in 8 of 19 DMD patients with PI,max less than 50% of predicted values. We conclude that measurement of inspiratory flow reserve (V'I,max(t)/V'I,maxFVC ratio) provides a simple and direct assessment of dynamic inspiratory muscle function which is not replicated by static measurement of PI,max or vital capacity and might be useful in assessment of respiratory impairment in boys with Duchenne muscular dystrophy. Follow-up studies are required to establish whether measures of inspiratory flow reserve are of clinical value in predicting subsequent ventilatory failure.     

Hypoxemia during sleep in Duchenne muscular dystrophy

Overnight polysomnography after acclimatization was performed on 14 patients with Duchenne muscular dystrophy (mean age, 18.3 yr; mean VC, 1.24 L). Despite their lack of sleep-related symptoms and normal daytime blood gas tensions, periods of hypopnea and/or apnea (H/A) were observed in all patients (mean frequency 9.6/h; range, 3.7 to 17.0; mean duration 23.1; range of means, 16 to 36 s). In 9 patients, between 0.5 and 12.3 oxygen desaturations of greater than 5% occurred per hour, with falls from a mean SaO2 baseline of 95.4 +/- 0.6% (SEM) to a mean nadir of 74.2 +/- 3.9% (range, 58 to 90). This desaturating group (n = 9) showed longer and more frequent H/A than did the 5 nondesaturators; the proportion of REM sleep occupied by H/A was 37.7 +/- 3.8% in the desaturating group compared with only 15.1 +/- 5.1% in the remainder (p less than 0.01). The severity of sleep-disordered breathing could not be reliably predicted from daytime pulmonary function test results, and only maximal static expiratory pressure appeared significantly lower in the desaturating group. Hypopneas were associated with reduced chest wall movement in all subjects, and with chest wall paradox in one; continued submental "inspiratory" EMG activity throughout "central" apneas in 2 subjects suggested that these episodes were not truly central in origin. Sleep hypoxemia is imputed in the progression of several chronic respiratory diseases, and its prevention in Duchenne and related neuromuscular diseases may influence morbidity and mortality.     

中国一进行性肌营养不良家系相关致病基因Dystrophin突变检测结果分析

目的 探讨进行性肌营养不良（DMD）家系相关致病基因Dystrophin基因突变情况.方法 收集一个DMD家系的临床资料,采用聚合酶链反应及直接测序法对此家系成员进行Dystrophin基因突变检测,同时对140例家系外健康对照者的该基因位点进行限制性核酸内切酶分析（PELP）.结果 在DMD家系中先证者（DMD患者1例）发现了一个纯合变异基因,即Dystrophin基因59号外显子上发现一个错义变异（G9017A）,导致代表精氨酸的2937位密码子转变为为谷氨酰胺（R2937Q）.在健康对照者中未发现此位点的变异.结论 在一个中国DMD家系先证者的Dystrophin基因上发现了一个尚未报道的基因突变位点.     

Non-compaction on autopsy in Duchenne muscular dystrophy

Left ventricular hypertrabeculation (LVHT)/non-compaction is frequently associated with neuromuscular disorders. Recently, LVHT has been detected in a 28-year patient with Duchenne muscular dystrophy. Here, the patho-anatomic findings of this patient are presented, which showed LVHT located within in the apex and the anterior and lateral wall, being the most demanded segments during systole. The septum and the left ventricular outflow tract were not involved. The patho-anatomic specimen also showed aberrant bands and false tendons, a frequent finding in hearts with LVHT. The patho-anatomic findings were in line with those of LVHT patients with or without neuromuscular disorders.