强直性肌营养不良临床特点分析

目的分析强直性肌营养不良(DM)的临床特点,以提高对DM疾病的认识及诊断水平。方法对21例DM患者的临床资料进行回顾性总结与分析。结果 21例患者均为慢性起病,以双手无力,活动不灵活起病多见,其中5例有家族史,部分病例伴有心脏、眼部、内分泌及中枢神经系统等其他多系统损害。19例行肌电图检查提示肌源性损害,其中16例发现有肌强直电位。10例行肌活检,主要表现为部分肌纤维萎缩,变性、坏死肌纤维,核内移及肌浆块形成,部分萎缩纤维内可见无结构胞浆体。1例强直性肌营养不良蛋白激酶(DMPK)基因CTG重复序列分析发现拷贝数超过正常范围。结论 DM是一种主要累及肌肉系统,以肌强直、肌无力和肌萎缩为主要临床表现并伴有多系统损害的疾病。综合评估多系统损害并结合肌肉的电生理学及病理学检查,有助于提高对DM的认识;在有条件的医疗机构可以开展DM基因诊断,对DM确诊很有意义。     

Myotonic dystrophy phenotype without expansion of (CTG)n repeat: An entity distinct from proximal myotonic myopathy (PROMM)?

Myotonic dystrophy (DM) is associated with an expansion of an unstable (CTG)n repeat in the 3' untranslated region of the DM protein kinase (DMPK) gene on chromosome 19q13.3. We studied six patients from two families who showed no expansions of the repeat, in spite of their clinical diagnosis of DM. These patients had multi-systemic manifestations that were distinguishable from those seen in other myotonic disorders, including proximal myotonic myopathy (PROMM). In one additional family, two symptomatic members showed no expanded (CTG)n repeats, while their affected relatives had the expanded repeats. DM haplotype analysis failed to exclude the DMPK locus as a possible site of mutation in each family; however,DMPK mRNA levels were normal. We conclude that a mutation(s) other than the expanded (CTG)n repeat can cause the DM phenotype. The mutation(s) in these families remain(s) to be mapped and characterized.     

Absent,unrecognized, and minimal myotonic discharges in myotonic dystrophy type 2

The purpose of this study was to describe the frequency of absent, unrecognized, or minimal myotonic discharges (MDs) in myotonic dystrophy type 2 (DM2). We performed a retrospective review of needle electromyography (EMG) data prior to genetic diagnosis in 49 DM2 patients at the Mayo Clinic. MDs were not reported on first or repeat EMG studies (n = 8) and not found in archived recordings of 4 patients (8%); archived EMG recordings (n = 4) confirmed the absence of MDs (n = 2), including 1 patient with normal insertional activity in all muscles, and misinterpretation of MDs as slow fibrillation potentials (n = 1) and complex repetitive discharge (CRD) activity (n = 1). Eight (16%) patients had minimal classic MDs with diffusely increased insertional activity, including waning‐only MDs in all patients in this group with archived EMG recordings (n = 5). Diffuse MDs were found in 33 (67%) patients. Absent or minimal MDs do not exclude DM2. Over‐reliance on diffuse MDs in patients who present with myopathy may lead to delay in genetic diagnosis of DM2. Muscle Nerve, 2010     

Phenotypic variability and molecular genetics in proximal myotonic myopathy

Introduction: Myotonic dystrophy type 2 (DM2) is an autosomal dominant inherited disorder with (CCTG)n repeat expansion in intron 1 of the CNBP gene. Methods: We studied the first 16 Greek DM2 patients who had undergone thorough evaluation. Results: The age at diagnosis ranged from 38 to 69 years. The initial symptoms were proximal weakness, myalgias, and myotonia. Clinical myotonia was elicited in 10 patients, whereas electromyographic myotonic discharges were observed in almost all patients. Subcapsular cataract was frequently present, but cardiac arrhythmias were rare. Conclusions: In this study of Greek DM2 patients, proximal weakness was the most common initial symptom. Myalgias were also reported in a few patients, yet myotonia was not a major complaint. Although DM2 is considered relatively benign, there are patients who may be affected severely. Thus, a high index of suspicion must be maintained to make a timely diagnosis, especially in those of reproductive age. Muscle Nerve 51 :686–691, 2015     

Muscle pathology in 57 patients with myotonic dystrophy type 2

We evaluated muscle biopsies from 57 patients with genetically confirmed myotonic dystrophy type 2/proximal myotonic myopathy (DM2/PROMM). Light microscopy showed myopathic together with "denervation-like" changes in almost all biopsies obtained from four different muscles: increased fiber size variation, internal nuclei, small angulated fibers, pyknotic nuclear clumps, and predominant type 2 fiber atrophy. Quantitative morphometry in 18 biopsies that were immunostained for myosin heavy chain confirmed a predominance of nonselective type 2 fiber atrophy. These histological changes were similar in all patients regardless of the site of biopsy, the predominant clinical symptoms and signs, and the clinical course. It is likely that, in a number of undiagnosed patients, DM2 is the underlying disorder. With a better understanding of the histopathological pattern in DM2, biopsies from patients with undiagnosed neuromuscular disorders can now be reevaluated.     

Unusual clinical, laboratory, and muscle histopathological findings in a family with myotonic dystrophy type 2

Myotonic dystrophy type 2 (DM2) is a multisystem degenerative disorder with distinctive clinical and electrophysiological features. Recently, genetic confirmation has become available with the identification of the molecular defect, an expansion of a CCTG repeat located in intron 1 of the zinc finger protein 9 (ZNF9) gene. We present two first-degree relatives with an athletic clinical phenotype, pathological evidence of subsarcolemmal vacuolation, and molecular genetic confirmation of DM2. When found in the proper clinical context, athleticism and pathological subsarcolemmal vacuoles should not dissuade the clinician from the possible diagnosis of DM2.     

Myotonic dystrophy and proximal myotonic myopathy

Myotonic dystrophy (DM) is a well-known multisystem disorder with dominant inheritance. Proximal myotonic myopathy (PROMM) has been defined only recently, it is rather similar to but distinct from DM. Molecular genetic testing of the CTG trinucleotide repeat expansion is a reliable diagnostic method in DM. In PROMM these CTG repeats are normal, and no genetic test is so far available. Comparing the phenotypes of DM and PROMM, an important point seems to be that PROMM is a more benign disorder. There are almost no obvious mental changes in PROMM patients; premature death is extremely rare; anticipation appears to be present but to a milder degree; a severe congenital type of PROMM apparently is very rare if it occurs at all. On the other hand, at least in the German population, the frequency of PROMM may be almost equal to that of DM. Received: 10 July 1998 Accepted: 23 July 1998     

Severity, type, and distribution of myotonic discharges are different in type 1 and type 2 myotonic dystrophy

To characterize and compare electrical myotonia in myotonic dystrophy type 1 (DM1) and type 2 (DM2), 16 patients with genetically confirmed DM1 and 17 patients with DM2 underwent standardized concentric needle electromyography of deltoid, biceps, extensor digitorum communis, first dorsal interosseous, tensor fascia lata (TFL), vastus lateralis (VL), tibialis anterior, and thoracic paraspinal muscles. Eight needle insertions per muscle were made by electromyographers blinded to DM type who recorded the presence and type of myotonia (e.g., classic waxing-waning or less specific waning discharges). Manual muscle testing was performed by a physical therapist. Overall, myotonia was more elicitable in DM1 than DM2; only in VL and TFL was myotonia more elicitable in DM2 than DM1. The major type of myotonia was waxing-waning in DM1, and waning in DM2. Four DM2 (24%), but no DM1 patients had only waning myotonia. In the arms, myotonia was distally predominant in both DM1 and DM2. In the legs, it was distally predominant in DM1, but both proximal and distal in DM2. The severity of myotonia was positively correlated with muscle weakness and with the presence of waxing and waning discharges in DM1, but with neither in DM2. Thus, myotonia is qualitatively and quantitatively different in DM1 than DM2. Except for proximal leg muscles, myotonia is more evocable in DM1 than DM2. It tends to be waxing-waning in DM1 but waning in DM2, thus making electrodiagnosis of DM2 more challenging. Its severity correlates with muscle weakness and the presence of waxing-waning discharges in DM1 but not DM2.     

Proximal myotonic myopathy: a syndrome with a favourable prognosis?

Cardiac involvement in myotonic dystrophy type 1 (DM1) is well known. In contrast, the severity and frequency of cardiac abnormalities in proximal myotonic myopathy (PROMM) are still unclear. To identify similarities and differences in the rate of progression of muscle weakness and cardiac disturbances in these two disorders, 16 patients with PROMM (3q-unlinked PROMM: n=10; uniformative for linkage: n=6) were compared to 33 patients with moderately severe myotonic dystrophy type 1 (DM1). There was no significant difference in disease duration between PROMM and DM1. Patients underwent serial manual muscle strength testing, EKG, 24-h Holter monitoring, 2D-echocardiography. Muscle weakness progressed slowly in both groups. Most DM1 patients developed conduction defects. No significant atrioventricular disturbances on initial and follow-up examinations were found in PROMM patients. One patient developed right bundle branch block. Many families with PROMM appear to have more benign cardiac manifestations and less severe prognosis compared to DM1. Further studies of subgroups of PROMM (linked to the 3q21 locus and without linkage) are necessary to determine whether the cardiac conduction disturbances are more common in a specific genotype of PROMM.     

Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2

Abstract. Cranial magnetic resonance imaging (MRI) in 19 German patients with genetically proven myotonic dystrophy Type 1 (DM1, n = 10) or Type 2 (DM2, n = 9) showed pathological findings consisting of white matter lesions (WML) and/or brain atrophy in 9/10 DM1 and 8/9 DM2 patients. Anterior temporal WML (ATWML) were exclusively seen in DM1 patients. Our findings indicate a high frequency of central nervous system (CNS) involvement in both disorders. However, temporopolar pathology, previously associated with intellectual dysfunction, seems to be restricted to DM1.     

Improvement of the diagnostic procedure in proximal myotonic myopathy/myotonic dystrophy type 2

Proximal myotonic myopathy/myotonic dystrophy type 2 (PROMM/DM 2) is caused by an expansion of the (TG)_n(TCTG)_n(CCTG)_n repeat tract in intron 1 of the ZNF9 gene located on chromosome 3q21. Because these expansions show a marked mitotic instability, expanded alleles are often difficult to detect. In order to improve the diagnostic procedure, we applied a combination of pulsed-field gel electrophoresis and semi-quantitative Southern blot analysis with a novel hybridization probe. The combination of these methods led to unequivocal results in about 98% of cases with a clinical diagnosis of PROMM/DM 2. Furthermore, we report the genotype/phenotype correlation in a patient lacking a normal ZNF9 allele and a further proband with a grey zone allele.     

强直性肌营养不良1型患者的临床特点及CTG重复次数分析

目的总结强直性肌营养不良1型患者的临床、神经电生理和遗传学特点。方法收集3例强直性肌营养不良1型患者的临床症状、肌电图、肌肉病理及基因检测结果。结果 3例患者(男性1例)均为成年起病,慢性病程。临床表现为四肢远端无力和肌强直; 2例患者存在眼外肌或面肌无力; 1例伴随前额脱发; 2例存在心脏传导紊乱如阵发性室性心动过速、左前束支传导阻滞、右束支传导阻滞; 2例出现脑白质病变。3例强直性肌营养不良1型患者DMPK基因3’非翻译区的突变CTG重复次数分别为104、150、299,均大于50次。3例患者肌电图检查所检肌肉均可见肌强直放电。结论强直性肌营养不良1型患者肌无力主要出现在远端肌群,心脏传导紊乱和脑白质病变是其多系统受累的显著表现。肌电图可以发现临床下肌强直放电,是最敏感的筛查手段。     

Brugada‐like cardiac disease in myotonic dystrophy type 2: report of two unrelated patients

Background: Myotonic dystrophy type 2 (DM2) is an autosomal dominant multisystem disorder caused by CCTG repeat expansions within intron 1 of the ZNF9 gene on chromosome 3q. Cardiac conduction disturbances, supraventricular arrhythmias, and cardiomyopathy are described in DM2 but Brugada‐like features have not yet been reported. Brugada syndrome (BS) is a genetically heterogeneous cardiac conduction disorder which is characterized by a significant ST‐segment elevation upon ECG evaluations and bears an increased risk for sudden cardiac death. Case reports: We report two unrelated patients with genetically confirmed DM2 who developed clinical relevant cardiac arrhythmias with syncopal events from 35 (patient 1) and 47 years (patient 2). Brugada‐like ECG findings were present in both patients. Family history was negative for BS, but the mothers of both index patients were also affected by DM2 and had different ventricular rhythm disturbances. SCN5A gene sequencing revealed an unknown genetic variant c.4140 C > A, p.N1380K, in patient 1, while no mutation was detected in patient 2. Discussion: Our observations may suggest that Brugada‐like cardiac arrhythmias can occur in DM2, as this seems also to be the case in DM1. The chance association of two independent inherited disorders has to be considered and cannot be excluded in one of our patients. However, on statistical grounds, this possibility cannot explain all observed cases of DM with Brugada‐like cardiac disease.     

Facial emotion recognition in myotonic dystrophy type 1 correlates with CTG repeat expansion

Objective

To investigate the ability of patients with myotonic dystrophy type 1 to recognise basic facial emotions. We also explored the relationship between facial emotion recognition, neuropsychological data, personality, and CTG repeat expansion data in the DM‐1 group.

Methods

In total, 50 patients with DM‐1 (28 women and 22 men) participated, with 41 healthy controls. Recognition of facial emotional expressions was assessed using photographs of basic emotions. A set of tests measured cognition and personality dimensions, and CTG repeat size was quantified in blood lymphocytes.

Results

Patients with DM‐1 showed impaired recognition of facial emotions compared with controls. A significant negative correlation was found between total score of emotion recognition in a forced choice task and CTG repeat size. Furthermore, specific cognitive functions (vocabulary, visuospatial construction ability, and speed) and personality dimensions (reward dependence and cooperativeness) correlated with scores on the forced choice emotion recognition task.

Conclusion

These findings revealed a CTG repeat dependent facial emotion recognition deficit in the DM‐1 group, which was associated with specific neuropsychological functions. Furthermore, a correlation was found between facial emotional recognition ability and personality dimensions associated with sociability. This adds a new clinically relevant dimension in the cognitive deficits associated with DM‐1.     

The diagnosis and treatment of myotonic disorders

Myotonia is a defining clinical symptom and sign common to a relatively small group of muscle diseases, including the myotonic dystrophies and the nondystrophic myotonic disorders. Myotonia can be observed on clinical examination, as can its electrical correlate, myotonic discharges, on electrodiagnostic testing. Research interest in the myotonic disorders continues to expand rapidly, which justifies a review of the scientific bases, clinical manifestations, and numerous therapeutic approaches associated with these disorders. We review the pathomechanisms of myotonia, the clinical features of the dystrophic and nondystrophic myotonic disorders, and the diagnostic approach and treatment options for patients with symptomatic myotonia. Muscle Nerve 47: 632–648, 2013