Calsequestrin and junctin immunoreactivity in hexagonally cross-linked tubular arrays myopathy

We report on a patient with muscle pain not associated with muscle weakness. Microscopic examination of the muscle biopsy revealed rod-like cytoplasmic bodies in many fast fibres. By electron microscopy these had a crystalloid structure identical to the hexagonally cross-linked caveolin 3-positive tubular arrays, previously described in patients with similarly benign myopathy. We found that these inclusions were positive for calsequestrin and for the calsequestrin-binding protein junctin, as well as for caveolin 3. However, the genes coding for these proteins were not mutated. For diagnostic purposes calsequestrin and caveolin 3 positivity should be checked when rods are encountered in muscle biopsy for mild myopathy.     

Myopathy with tubulin-reactive inclusions in two cats

Many types of inclusions have been described in human myopathies including but not limited to nemaline rod bodies, cylindrical spirals, tubular aggregates, cytoplasmic bodies, reducing bodies, and fingerprint bodies, and hyaline inclusions in myofibrillar myopathy and inclusion body myositis. There are very few reports describing inclusions in spontaneously occurring myopathies in cats, and these reports are limited to nemaline rod myopathy. A myopathy with tubulin-reactive crystalline inclusions has recently been reported in a human patient with a clinical presentation of myalgia and fatigue. Similarly, a myopathy with chronic, slowly progressive muscle weakness has been identified here in two unrelated cats. Inclusions were the only pathological change in skeletal muscle biopsies and, ultrastructurally, groups of crystalline structures were evident that had a subsarcolemmal or central location, rhomboid or rectangular shapes, lacked orientation, and were not membrane bound. The crystalline structures reacted positively with an antibody against tubulin. This feline myopathy may be the equivalent of the human myopathy with tubulin-positive crystalline inclusions.     

Tubular aggregate myopathy with abnormal pupils and skeletal deformities

A patient is described with a novel syndrome characterised by progressive muscular weakness, contractures, pupillary muscle dysfunction, and skeletal deformity. The main myopathological feature was an abundance of tubular aggregates in both type I and type II muscle fibres. Myopathies in which tubular aggregates are the defining feature are rare and either present with progressive muscle weakness or exercise induced myalgia. Tubular aggregate myopathy with symptomatic smooth muscle dysfunction and skeletal deformities has not been described before.     

McArdle's disease presenting with asymmetric, late-onset arm weakness

McArdle's disease or myophosphorylase deficiency is one of the most common muscle glycogenoses and typically presents in childhood or adolescence with exercise intolerance, myalgia, myoglobinuria, and cramps in exercising muscle. We describe an elderly man who developed asymmetric proximal arm weakness at age 73. He had no history of exercise-induced cramps, myalgias, or myoglobinuria. Creatine kinase levels were elevated, serum lactate did not rise on ischemic exercise testing, and muscle biopsy showed a vacuolar myopathy with absent myophosphorylase activity. This unusual case demonstrates that McArdle's disease may present with fixed, asymmetric proximal weakness at an advanced age and should be considered in this clinical setting, especially when a history of poor exercise tolerance can be elicited.     

Clinical and molecular features of encephalomyopathy due to the A3302G mutation in the mitochondrial tRNA(Leu(UUR)) gene

BACKGROUND: The mitochondrial DNA mutation A3302G in the tRNA(Leu(UUR)) gene causes respiratory chain complex I deficiency. The main clinical feature appears to be a progressive mitochondrial myopathy with proximal muscle weakness. OBJECTIVE: To report on clinical and molecular features in 4 novel patients with the A3302G mutation. DESIGN: Case reports. PATIENTS: Four patients (3 of whom are from the same family) with a myopathy caused by the A3302G mitochondrial DNA mutation. MAIN OUTCOME MEASURE: Identification of the A3302G mutation by DNA sequencing. RESULTS: All 4 patients had an adult-onset progressive mitochondrial myopathy with proximal muscle weakness, resulting in exercise intolerance. In 2 unrelated patients, upper limb reflexes were absent with preservation of at least some lower limb reflexes. Other features including hearing loss, recurrent headaches, ptosis, progressive external ophthalmoplegia, and depression were present. CONCLUSION: While the dominant clinical features of the A3302G mutation were exercise intolerance and proximal muscle weakness, other features of mitochondrial encephalomyopathies, previously not described for this mutation, were present.     

脂质沉积性肌病的临床、神经电生理和病理学特征

目的研究脂质沉积性肌病(LSM)的临床、神经电生理及病理学特点。方法回顾性分析5例LSM患者的临床、神经电生理及病理学资料。结果本组发病年龄平均为25.6岁;均为亚急性或慢性起病,病情缓慢进展或出现缓解复发;2例有家族史;主要表现为运动耐受差和不同程度的肌无力(5/5)、腱反射减弱或消失(5/5)、肌痛或肌压痛(4/5)、肌萎缩(3/5)、末梢型感觉障碍(2/5);肌酶轻至中度升高(4/5),肌电图表现周围神经源性损害合并肌源性损害(2/5),或者单纯肌源性损害(1/5);肌肉病理学显示纤维间、肌膜下、胞核周围大量排列成串的或成团的脂滴,无炎性细胞浸润。高肉碱、低脂肪饮食、以及糖皮质激素治疗有效。结论LSM临床以肌无力和运动不耐受为主要症状,神经电生理表现为肌源性损害和/或周围神经损害,肌肉活检为诊断脂质沉积性肌病所必需。     

Caveolinopathy--new mutations and additional symptoms

Mutations in the caveolin-3 gene (CAV3) can lead to a broad spectrum of clinical phenotypes. Phenotypes that have so far been associated with primary caveolin-3 deficiency include limb girdle muscular dystrophy, rippling muscle disease, distal myopathy and hyperCKaemia. This is the first report describing the clinical, pathological and genetic features of patients with caveolinopathy from the UK. Ten patients (six families) were identified via the National Commissioning Group (NCG) service for patients with limb girdle muscle dystrophy in Newcastle. Myalgia was the most prominent symptom in our cohort of patients and for 50% it was the reason for referral. Muscle weakness was only found in 60% of the patients, whereas rippling muscle movement was present in 80%. One of the patients reported episodes of myoglobinuria and another one episodes of hypoglycaemia. Five different mutations were identified, two of which were novel and three that had previously been described. Caveolinopathy needs to be considered as a differential diagnosis in a range of clinical situations, including in patients who do not have any weakness. Indeed, rippling muscles are a more frequent symptom than weakness, and can be detected in childhood. Presentation with myalgia is common and management of it as well as of myoglobinuria and hypoglycaemia may have a major impact on the patients' quality of life.     

Early features of zidovudine-associated myopathy: histopathological findings and clinical correlations

Zidovudine-induced myopathy is characterized by reversible muscle weakness, wasting, myalgia, fatigue, and elevated creatine kinase (CK). Some zidovudine-treated patients with normal muscle strength experience excessive fatigue, myalgia, or transient mild CK elevations that improve when zidovudine is stopped. To determine the cause of these symptoms, we studied 13 physically fit, HIV-infected men who developed fatigue, myalgia, and reduced endurance, while taking zidovudine for a mean period of 20 months (2–39 months), with neurological evaluation and muscle biopsy processed for enzyme histochemistry and electron microscopy (EM). All subjects had normal muscle strength. In 6 of the 13 patients, muscle biopsies were normal by enzyme histochemistry. EM, however, demonstrated proliferation of normal or abnormal mitochondria, and increased amounts of lipid, glycogen, and lipofuscin. Electromyographic (EMG) studies (5/5) and serum CK (6/6) were normal. The other 7 individuals had signs of moderate to severe mitochondrial abnormalities shown by both light microscopy and EM, characterized by severe destruction, vacuolization, and rare paracrystalline inclusions. Most had elevated CK (4 out of 7) and normal EMG (5 out of 7). The severity of morphological abnormalities did not correlate with duration of HIV infection, zidovudine therapy, or zidovudine dosage. We conclude that in zidovudine-treated patients, symptoms of fatigue, myalgia, reduced endurance, and exercise intolerance represent early signs of zidovuline-induced mitochondriotoxicity, which causes an energy shortage within the muscle fibers even when muscle strength is still normal. Zidovudine, a DNA chain terminator, results in overt myopathy when a critical threshold of molecular, histological, and biochemical dysfunction of mitochondria is crossed, which seems to vary between individuals.     

Mitochondrial myopathy: report of 12 cases with histochemical study of the skeletal muscle]

Twelve patients with histologically defined mitochondrial myopathy are described. There were 9 males and 3 females. The age of onset ranged from birth to 35 years with a median of 14 years. The most common clinical picture was that of ophthalmoplegia, ptosis and muscle weakness found in 10 patients. One presented with exercise intolerance due to muscular aches and pains, and the other besides his muscular weakness had mental retardation and an aggressive behavior. The clinical presentation and differential diagnosis of these patients are discussed.     

Muscle disease,HIV and zidovudine: the spectrum of muscle disease in HIV-infected individuals treated with zidovudine

Eleven patients with AIDS or AIDS-related complex who developed muscle-related symptoms whilst taking zidovudine were investigated. The clinical details of a further ten patients who did not undergo muscle biopsy are also outlined. The clinical features, quantitative muscle strength testing, electromyographic findings, serial creatine kinase levels, muscle biopsy appearance on light microscopy and the effects of zidovudine withdrawal and rechallenge are described. The spectrum of muscle disease encountered included four cases of frank myopathy diagnosed using clinical, electrophysiological and histological criteria, four patients with mild weakness and myalgia in whom muscle biopsies were normal, three patients with myalgia only and a mild increase in the interstitial cell infiltrate shown by biopsy. The patients presenting with myopathy showed no improvement on withdrawal of zidovudine but responded to immuno-suppressive therapy with steroids and, in one case, thalidomide prescribed incidentally. At present, it is not yet possible to clinically define a specific zidovudine-induced myopathy that is distinct from the other effects of HIV infection on muscle structure and function. Our experience suggests that zidovudine may be implicated as a myotoxin in some patients, particularly those with myalgia and mild weakness. In those patients with severe weakness, and with biopsy findings of necrosis and inflammation, the drug effects may be difficult to separate from the primary effects of HIV.     

脂质沉积性肌病的临床和病理特点

目的总结脂质沉积性肌病（lipid storage myopathy,LSM）的临床和病理特点,为早期诊断和治疗提供参考。方法对5例脂质沉积性肌病患者的临床资料进行回顾性分析。结果 5例脂质沉积性肌病患者均为慢性或亚急性起病,主要表现为不同程度的肌无力和对运动不耐受、血清肌酶均升高、神经电生理检查显示肌源性损害,病理检查发现肌纤维内空泡样变,脂滴明显增多,脂滴空泡呈＂串珠＂样排列。给予能量支持、低脂饮食、糖皮质激素等治疗后患者的临床症状好转。结论脂质沉积性肌病的确诊依靠肌肉活检,该病预后良好,及时的诊断和综合治疗可明显改善患者的生活质量。     

Proximal myotonial myopathy (PROMM): clinical and histology study

We report 13 French patients with proximal myotonic myopathy. PROMM is a recently delineated multisystem disorder with dystrophic myopathy, myotonia and cataracts. This syndrome is genetically distinct from myotonic dystrophy (DM) by the absence of abnormal CTG repeat expansion. The geographical origin varies but 4 families originated from Poland. Of late onset, muscle weakness is diffuse and predominantly affected proximal and axial muscles. Facial involvement and myotonia were moderate or absent, but in all cases myotonic discharges were detected on EMG. 6 patients suffered from myalgia. Cataracts occurred in 11 patients, mainly indistinguishable from those in DM. Cardiac arrythmia occurred in 7 patients. Muscle biopsy revealed rare structural changes of the muscle fibers and selective type I atrophy, common in DM, could not be found on morphometric analysis. PROMM has a distinct clinical spectrum from DM which includes a predominantly proximal muscle weakness, with troubling pain, a more favourable prognosis and a different histopathological pattern.     

Congenital myopathy with tubular aggregates and tubulofilamentous IBM-type inclusions

We report on a 16-year-old girl with a unique neuromuscular disorder characterised by progressive proximal muscle weakness and numerous tubular aggregates, intracytoplasmic, as well as intranuclear inclusions of the IBM type in her muscle biopsy. The clinical features of the presented case, as manifested by the early childhood onset of the disease, proximal weakness, lumbar hyperlordosis, and bilateral Achilles tendon contractures, were suggestive of congenital myopathy. To the best of our knowledge, the coexistence of tubular aggregates and tubulofilamentous inclusions of the IBM type in a child has never been described.     

Clinical and muscle MRI features in a family with tubular aggregate myopathy and novel STIM1 mutation

Heterozygous mutations in the stromal interaction molecule-1-gene (STIM1) cause a clinical phenotype varying from tubular aggregate myopathy with single or multiple signs of Stormorken syndrome to the full Stormorken phenotype. We identified a novel heterozygous mutation c.325C > T (p.H109Y) in the EF-hand domain of STIM1 in six patients of a large Belgian family, and performed a detailed clinical (N = 6), histopathological (N = 2) and whole-body muscle MRI (N = 3) study. The clinical phenotype was characterized by a slowly progressive, predominant proximal muscle weakness in all patients (100%), and additional exercise-induced myalgia in three (60%). Patients experienced symptom onset between 10 and 20 years, remained ambulatory into late adulthood, showed elevated serum creatine kinase levels and tubular aggregates in type 1 and type 2 fibers on muscle biopsy. Interestingly, jaw contractures and hyperlaxity, as well as non-muscular multisystemic features such as menorrhagia, easy bruising and ichthyosis occurred in one patient, and miosis in another. Whole-body muscle MRI revealed predominant involvement of superficial neck extensors, subscapularis, obliquus abdominis externus, lumbar extensors, rectus femoris, biceps femoris longus, medial head of gastrocnemius and flexor hallucis longus. Our findings in patients with myopathy with tubular aggregates and a STIM1 mutation further support the concept of a continuous spectrum with Stormorken syndrome.     

Myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy

BACKGROUND: Multicore disease and congenital fibre type disproportion myopathy are diseases assigned to the heterogeneous group of congenital myopathies. Although hypotonia and muscle weakness appearing in early life are the commonest manifestations of these diseases, distinct phenotypes and late onset cases have been described. OBJECTIVE: To report the occurrence of myalgia as the revealing symptom of multicore disease and fibre type disproportion myopathy. METHODS: The clinical cases of three patients with fibre type disproportion myopathy and one with multicore disease are described. Skeletal muscle biopsies were processed for routine histological and histochemical studies. RESULTS: The clinical picture was unusual in that the symptoms were of late onset and the predominant complaint was muscle pain exacerbated by exercise. Muscle weakness was found in only a single patient, the mother of a patient with fibre type disproportion myopathy. Physical examination was unremarkable in the other patients. Muscle biopsies from patients 1 and 2 contained type I fibres that were considerably smaller than the type II fibres, supporting the diagnosis of fibre type disproportion myopathy. Skeletal muscle of patient 4 showed multiple areas, predominantly but not exclusively in the type I fibres, from which oxidative enzyme activities were absent, as seen in multicore disease. CONCLUSIONS: Muscle pain was the main clinical manifestation in our patients. Recognition of the broader clinical expression of these myopathies is important for prognostic reasons and for genetic counselling of the family members.     

Klinisches Spektrum der Gliedergürtelmuskeldystrophie Typ 2I bei Mutation im „Fukutin-Related-Protein“-Gen

LGMD2I, linked to chromosome 19q13.3, is caused by mutations in the fukutin related protein (FKRP) gene. This myopathy has a variable clinical course with weakness and wasting of the shoulder girdle muscles and proximal extremities, calf hypertrophy, and elevated serum CK. We describe five patients from four families harboring the typical C826A mutation in the FKRP gene. Three patients showed the typical clinical features of LGMD2I. One patient had prominent exercise-induced myalgia in addition to a limb-girdle syndrome. Another patient had myalgia, cramps, elevated serum CK and dilatative cardiomyopathy without muscle weakness and wasting. Thus, the phenotype of the C826A mutation in the FKRP gene is apparently not restricted to a clinical limb girdle syndrome.     

Tubular aggregates: their association with myalgia.

Three thousand consecutive muscle biopsies were reviewed for the presence of tubular aggregates and their association with clinical symptomatology. Tubular aggregates were detected in 19 patients (0.6%). Twelve of these nineteen patients had severe myalgia, and the most abundant tubular aggregates were found in biopsies of patients with myalgia. Seven patients had only myalgia as their clinical symptomatology with normal physical examination. An additional five patients with tubular aggregates and myalgia had concomitant amyotrophic lateral sclerosis (2) or neuropathy (3). The high incidence of myalgia associated with tubular aggregates in our patients and the fact that tubular aggregates originate from sarcoplasmic reticulum suggest a role played by this structure in the pathogenesis of myalgia.     

脂质沉积性肌病的临床分析（附2例报道）

目的：对2例脂质沉积性肌病（LSM）的临床资料予以分析报道。方法：收集2例经病理检查确诊的LSM病例的临床资料,结合相关文献分析其临床表现、病理特征和实验室检查结果。结果：LSM临床以肢带肌近端无力为主要表现,有明显的运动不耐受特点,部分受累肌有压痛;肌电图示以肌源性损害为主;肌酶以肌酸激酶轻中度升高为主,对糖皮质激素反应早且明显;病理特征为肌纤维内有大量脂质颗粒沉积,并以Ⅰ型肌纤维为主。结论：LSM以肢带型肌无力综合征为临床表现时极易误诊为多发性肌炎等,确诊依赖于肌肉病理学检查。     

Lipid storage myopathy with clinical markers of Marfan syndrome: A rare association

Disorders of lipid metabolism can cause variable clinical presentations, often involving skeletal muscle, alone or together with other tissues. A 19-year-old boy presented with a 2-year history of muscle pain, cramps, exercise intolerance and progressive weakness of proximal lower limbs. Examination revealed skeletal markers of Marfan syndrome in the form of increased arm span compared with height, Kyphoscoliois, moderate pectus excavatum, high arched palate and wrist sign. He also had mild neck flexor weakness and proximal lower limb weakness with areflexia. Pathologic findings revealed lipid-laden fine vacuoles in the muscle fibers. Possibility of carnitine deficiency myopathy was considered and the patient was started on carnitine and Co Q. The patient made remarkable clinical improvement over the next 2 months. This case is reported for rarity of the association of clinical markers of Marfan syndrome and lipid storage myopathy and sparse literature on lipid storage myopathy in the Indian context.     

Autosomal dominant myopathy with congenital joint contractures,ophthalmoplegia, and rimmed vacuoles

We describe a new myopathy in a large family with 19 affected cases. Inheritance was autosomal dominant. Characteristic clinical features were congenital joint contractures, which normalized during early childhood, external ophthalmoplegia, and proximal muscle weakness. Muscle atrophy was most prominent in the pectoralis and quadriceps muscles. The clinical course was nonprogressive in childhood, but most adult cases experienced deterioration of muscle function, starting from 30 to 50 years of age. The major histopathological change of skeletal muscle in childhood was focal disorganization of myofilaments. In adults with progressive muscle weakness, the muscle biopsies showed dystrophic changes and rimmed vacuoles with cytoplasmic and intranuclear inclusions of 15- to 21-nm filaments. These findings suggests that this new disease should be classified as a variant of hereditary inclusion body myopathy.