Computerized hand grip myometry reliably measures myotonia and muscle strength in myotonic dystrophy (DM1)

The aim of this study was to develop a reliable, sensitive, quantitative measure of grip myotonia and strength and to determine whether CTG repeat length is correlated with grip myotonia and with muscle strength in myotonic dystrophy type 1 (DM1). Three maximum voluntary isometric contractions (MVICs) of the finger flexors (i.e., handgrip) were recorded on 2 successive days using a computerized handgrip myometer in 29 genetically confirmed DM1 patients and 17 normals. An automated computer program calculated MVIC peak force (PF) and relaxation times (RTs) along the declining (relaxation) phase of the force recordings at 90%, 75%, 50%, 10%, and 5% of PF. Patients also underwent quantitative strength testing (QST) manual muscle testing (MMT). The patients had longer grip RTs and lower PFs than normals. RT (90% to 5%) was above the normal mean +2.5 SD in 25 (86%) patients. In DM1, prolongation of RT was mainly in the terminal (50% to 5%), rather than the initial (90% to 50%) phase of relaxation. PFs and RTs for each patient were reproducible on consecutive days. RTs were positively correlated with leukocyte CTG repeat length, whereas measures of muscle strength, such as PF, QST, and MMT, were negatively correlated with repeat length. We conclude that computerized handgrip myometry provides a sensitive, reliable measure of myotonia and strength in DM1 and offers a method to assess natural history and response to treatment.     

Quantitative analysis of the "warm-up" phenomenon in myotonic dystrophy type 1

To quantitate improvement in hand-grip myotonia and muscle strength (i.e., the "warm-up" phenomenon) in myotonic dystrophy type 1 (DM1), six successive, standardized maximum voluntary isometric contractions (MVICs) were recorded on 2 separate days using a computerized isometric hand-grip myometer in 25 genetically confirmed DM1 patients and in 17 normal controls. An automated computer program placed cursors along the declining (relaxation) phase of the MVICs at 90%, 50%, and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. Mean 90% to 5% RT (a measure of myotonia) rapidly declined from 2.5 s in MVIC 1 to 0.8 s in MVIC 6 (warm-up = 1.7 s) in DM1; in controls, it remained 0.4 s for all six MVICs (warm-up = 0). In DM1, 70% of warm-up occurred between MVIC 1 and 2, almost exclusively in the terminal 50% to 5% phase of muscle relaxation. Day 1 warm-up was highly correlated with the severity of myotonia, and with day 2 warm-up. Improvement in myotonia was not accompanied by either transient paresis or improvement in PF. We conclude that, with this testing paradigm: warm-up of myotonia in DM1 can be reliably measured; is proportional to severity of myotonia; occurs rapidly, being most prominent between the first and second grips; mainly results from shortening of the terminal phase of muscle relaxation; and is not accompanied by significant warm-up in force output.     

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.     

Evoked myotonia can be “dialed‐up” by increasing stimulus train length in myotonic dystrophy type 1

It is unknown how evoked myotonia varies with stimulus frequency or train length, or how it compares to voluntary myotonia in myotonic dystrophy type 1 (DM1). First dorsal interosseous (FDI) tetanic contractions evoked by trains of 10–20 ulnar nerve stimuli at 10–50 HZ were recorded in 10 DM1 patients and 10 normals. For comparison, maximum voluntary handgrip contractions were also recorded. An automated computer program placed cursors along the declining (relaxation) phase of the force recordings at 90% and 5% of peak force (PF) and calculated relaxation times (RTs) between these points. For all stimulus frequencies and train lengths, evoked RTs were much shorter, and evoked PFs were much greater in normals than in DM1. In normals, evoked RT was independent of stimulus frequency and train length, while in DM1 RT was longer for train lengths of 20 stimuli (mean: 9 s in DM1; 0.20 in normals) than for 10 stimuli (mean: 3 s in DM1, 0.19 in normals), but it did not change with stimulus frequency. In both groups PF increased greatly as stimulus frequency rose from 10–50 HZ but only slightly as train length rose from 10–20 stimuli. Voluntary handgrip RT (mean: 1.9 s) was less than evoked FDI RT (mean: 9 s). In DM1, evoked RT can be “dialed up” by increasing stimulus train length. Evoked myotonia testing utilizing a stimulus paradigm of at least 20 stimuli at 30–50 HZ may be useful in antimyotonic drug trials, particularly when grip RT is normal or equivocal. Muscle Nerve, 2010     

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 type 2 with focal asymmetric muscle weakness and no electrical myotonia

Genetically proven myotonic dystrophy type 2 (DM2) was found in a 61‐year‐old woman with creatine kinase (CK) elevation and only isolated weakness of one triceps. There was no clinical or electrical myotonia. Electromyography (EMG) showed only scattered fibrillation potentials and short duration motor unit potentials. Muscle biopsy showed nonspecific myopathic features and highly atrophic fibers with nuclear clumps. DM2 should be considered in patients with focal proximal weakness and abnormal EMG without myotonic discharges. Muscle Nerve 39: 383–385, 2009     

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.     

Therapeutics development in myotonic dystrophy type 1

Myotonic dystrophy (DM1), the most common adult muscular dystrophy, is a multisystem, autosomal dominant genetic disorder caused by an expanded CTG repeat that leads to nuclear retention of a mutant RNA and subsequent RNA toxicity. Significant insights into the molecular mechanisms of RNA toxicity have led to the previously unforeseen possibility that treating DM1 is a viable prospect. In this review, we briefly present the clinical picture in DM1, and describe how the research in understanding the pathogenesis of RNA toxicity in DM1 has led to targeted approaches to therapeutic development at various steps in the pathogenesis of the disease. We discuss the promise and current limitations of each with an emphasis on RNA-based therapeutics and small molecules. We conclude with a discussion of the unmet need for clinical tools and outcome measures that are essential prerequisites to proceed in evaluating these potential therapies in clinical trials.     

Muscle phenotype in patients with myotonic dystrophy type 1

Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand‐held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na⁺‐K⁺ pump content. Results: Muscle strength correlated with a decline in Na⁺‐K⁺ pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na⁺‐K⁺ pump content. Histopathologically, we found few centrally placed nuclei (range 0.2–6.9%). Conclusions: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1. Muscle Nerve 47:409‐415, 2013     

Distinct neuromuscular phenotypes in myotonic dystrophy types 1 and 2

Myotonic Dystrophy Type 1 (DM1) and 2 (DM2) present with distinct though overlapping clinical phenotypes. Comparative imaging data on skeletal muscle involvement are not at present available. We used the novel technique of whole body 3.0 Tesla (T) Magnetic Resonance Imaging (MRI) to further characterize musculoskeletal features in DM2 and compared the results with DM1. MRI findings of 15 DM1 and 14 DM2 patients were evaluated with respect to patterns of skeletal muscle affection and clinical data using the Muscular Impairment Rating Scale (MIRS) and Medical Research Council scale (MRC). All DM1 patients had pathological MRI compared with only 5 DM2 patients. In contrast to DM2, DM1 patients showed a characteristic distribution of muscle involvement with frequent and early degeneration of the medial heads of gastrocnemius muscles, and a perifemoral semilunar pattern of quadriceps muscle affection sparing the rectus femoris. The most frequently affected muscles in DM1 were the medial heads of gastrocnemius, soleus, and vastus medialis muscles. In DM2, however, the erector spinae and gluteus maximus muscles were most vulnerable to degeneration. MRI data were in line with the clinical grading in 12 DM1 and 3 DM2 patients. In 3 DM1 and 5 DM2 patients, MRI detected subclinical muscle involvement. 9 DM2 patients with mild to moderate proximal muscle weakness and/or myalgias had normal MRI. Pathological MRI changes in DM2 emerged with increasing age and were restricted to women. Whole body 3.0T MRI is a sensitive imaging technique that demonstrated a characteristic skeletal muscle affection in DM1. In contrast, MRI was no reliable indicator for skeletal muscle involvement in mildly affected DM2 patients since myalgia and mild paresis were usually not reflected by MRI signal alterations.     

Oculomotor involvement in myotonic dystrophy type 2

Oculomotor function has not been studied in patients with myotonic dystrophy type 2 (DM2). We report the presence of rebound nystagmus in seven of eight patients with DM2 in the absence of a structural brainstem or cerebellar lesion. The rebound nystagmus observed in these patients is very suggestive of ocular myotonia, and examination of patients using video-Frenzel goggles may be a useful method for diagnosing myotonia of the extraocular muscles.     

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.