Calpainopathy

Five affected siblings were referred with a probable diagnosis of proximal adult-type spinal muscular atrophy (SMA) based on lower motor neuron signs (muscle weakness and atrophy, hypotony, hypoactive or absent reflexes, and fasciculations), normal or borderline serum creatine kinase levels, and a neurogenic pattern on electromyography, compatible with motor neuron disease, in one patient. No exon 7-8 deletion in the survival motor neuron (SMN) gene was found. Linkage analysis excluded the SMN and all known autosomal recessive limb girdle muscular dystrophy loci, with the exception of LGMD-2A. A homozygous R769Q mutation in the calpain-3 gene and absence of muscle calpain-3 protein confirmed a calpainopathy. This family suggests that the clinical spectrum of calpainopathy might be broader and that this diagnosis might be considered in patients with an atypical motor neuron disease.     

Progressive spinal muscular atrophy and parathyroid adenoma. Clinico-pathologic study of a case

A 82 year-old man died 6 years after the onset of a progressive spinal muscular atrophy. Post-mortem examination disclosed a parathyroid adenoma. Weakness and wasting were prominent in the proximal lower limbs. There were no fasciculations. Involvement of the medulla was mild and late. These clinical features were also present in 16 reported cases, which were improved by treatment of primary or secondary hyperparathyroidism. Our patient differs by the involvement of the hand muscles and the loss of tendon reflexes. Neuropathological study, as in one other reported case, showed a loss of anterior horn cells. Such cases underline that calcium metabolism must be studied in syndromes of spinal muscular atrophy.     

Atypical presentations of spinal muscular atrophy type III (Kugelberg-Welander disease)

Spinal muscular atrophy type III (SMA III, Kugelberg-Welander disease) typically presents with symmetric proximal weakness, areflexia, and hypotonia. We present four children with spinal muscular atrophy type III who had atypical phenotypes. Three patients clearly had asymmetric weakness at presentation and two had upper motor neuron signs in the lower extremities (one patient had both features). Two of the patients had prolonged evaluations before the diagnosis was made. All patients had Gowers signs and two had pes planus. In patients with proximal muscle weakness the presence of asymmetrical weakness, upper motor neuron signs, or both, may be compatible with spinal muscular atrophy type III. The diagnosis of spinal muscular atrophy should be considered when other possibilities have been excluded.     

Surface EMG in the recording of fasciculations.

The usefulness of multichannel surface recording of fasciculations was evaluated by a retrospective study of 116 patients with various neurological disorders. Eight channels of a conventional electroencephalograph were used with plate electrode recordings from the upper arms and legs. Wide-spread fasciculations (defined as five or more of the eight muscle groups) were recorded in 48 of 54 patients with motor neuron disease, spinal muscular atrophy or postpolio syndrome, but noted on routine clinical examination at presentation in only 6. Eleven of 23 patients with peripheral neuropathy or myelopathy had fasciculations in five or more leads compared to one clinically, and 3 of 39 with other neurological diseases had fasciculations electrically but in only one were they clinically observed. The method is a noninvasive and sensitive adjunct to clinical examination for detecting fasciculations. Its diagnostic value is limited by the relatively high incidence of fasciculations in neuropathies and myelopathies. However, this study suggests that "false negatives" are rare and that the diagnosis of motor neuron disease should be reconsidered when less than five leads shows fasciculations.     

Kennedy syndrome--bulbo-spinal muscular atrophy

Kennedy syndrome is a late-onset, bulbar-spinal type of muscular atrophy, with X-linked recessive inheritance. The characteristic features of the disease become prominent in the 4-5th decades: proximal muscle wasting and weakness, bulbar signs, fasciculations in skeletal muscles, subtle signs of endocrine dysfunction, such as gynaecomastia or testicular atrophy. The electrophysiological examinations are the keypoint to the diagnosis. Electroneurography shows normal conduction velocity in peripheral nerves, but the sensory nerves usually show axonal degeneration, which causes only very mild or subclinical neurological deficits. Electromyography shows chronic anterior horn cell degeneration in skeletal muscles. Molecular genetic diagnosis was introduced in 1991, when on abnormal expansion of CAG repeat was found in the first exon of the androgen receptor gene on chromosome X with a frequency of 100% in the affected population. Since the progression is very slow and these patients can expect a normal life span, it is essential to distinguish this syndrome from other, often more severe diseases, such as ALS. There is no proven therapy for Kennedy's disease yet. This is the first case of Kennedy's disease published in Hungary.     

Hypocalcemic myopathy without tetany due to idiopathic hypoparathyroidism: case report

Myopathy due to idiopathic hypoparathyroidism is very unusual. We report on a 30 years-old man referred with complaints of sporadic muscle pain and mild global weakness for 10 years. His physical examination showed normal strength in distal muscle and slightly weakness in the pelvic and scapular girdles with no atrophy. Deep muscle reflexes were slightly hypoactive. Trousseau's and Chvostek's signs were absent. He had bilateral cataract and complex partial seizures. His laboratory tests showed decreased ionised and total calcium and parathyroid hormone and increased muscle enzymes. EMG and muscle biopsy was compatible with metabolic myopathy. After treatment with calcium and vitamin D supplementation he showed clinical, neurophysiological and laboratorial improvement. In conclusion: patients with muscle symptoms, even when non-specific and with normal neurological examination, should have serum calcium checked, as myopathy due to idiopathic hypoparathyroidism, even being rare, is treatable and easy to diagnose.     

Bedside evaluation of large motor units in childhood spinal muscular atrophy

One hundred patients with motor unit disease were examined to determine the diagnostc reliability of several clinical signs of large motor units. These signs were high-intensity, low-pitched rumbling on skeletal muscle auscultation, voluntary contraction fasciculations, contraction fasciculation trembling, and palpable contraction fasciculations. Among 22 cases of spinal muscular atrophy, contration fasciculation trembling was noted in 86 percent, abnormal muscle auscultation in 68 percent, palpable contraction fasciculations in 64 percent, and voluntary contraction fasciculations in 50 percent.     

Amyotrophic lateral sclerosis syndrome and hyperthyroidism. Cure with antithyroid drugs

We report the case of a 62-year old man presenting with generalized muscular weakness, amyotrophy, dysarthria and dysphagia. Neurological examination showed bilateral pyramidal signs and lingual fasciculations. The clinical diagnosis was amyotrophic lateral sclerosis, since only shivers and weight loss pointed to hyperthyroidism. However, after several months the patient developed typical manifestations of hyperthyroidism. After treatment of hyperthyroidism, the neurological symptoms disappeared. Although this association is extremely rare, one must have in mind the possibility of thyroid dysfunction when studying patients with amyotrophic lateral sclerosis.     

Extensive, continuous fasciculations of the lower leg as an isolated symptom--a clinical and electromyography follow-up

10 patients suffering from a widespread continuous fasciculation of the lower extremities without any other neurological signs and symptoms are presented. A follow up study of 6 of these patients could be done. The fasciculation potentials were polyphasic with changing shape from discharge to discharge and appeared irregularly in most of the muscles of the legs. In 5 patients no change of clinical and neurophysiological signs could be detected over the period of observation, whereas in one patient a sensory polyneuropathy was evident in course of time. The findings illustrate that a state of widespread continuous fasciculations without other signs and symptoms is not predicative for the development of a amyotrophic lateral sclerosis.     

Proximal myotonic myopathy

Three Swedish patients with proximal muscle weakness, myotonia and lack of CTG expansion on genetical analysis are presented. Clinical neurological and neurophysiological examination and muscle biopsy were performed. There was an indication of autosomal dominant inheritance in 2 of the 3 patients. The main symptoms and clinical findings in the 3 patients were weakness of the proximal muscles, myotonia, muscle stiffness, muscle pain and muscle atrophy. Neurophysiological examination showed myotonic bursts and muscle biopsy snowed a variation of fibre sizes, an increased number of muscle fibres with centralized nuclei and scattered atrophic muscle fibres. Laboratory data showed elevated CK, GT and LD in 1 patient. Before genetical analysis was performed, all 3 patients had been diagnosed as atypical cases of myotonic dystrophy. However, the symptoms, clinical signs, laboratory data, electrophysiological and muscle biopsy findings were compatible with proximal myotonic myopathy (PROMM).     

Dementia as presenting symptom of primary hyperparathyroidism: favourable outcome after surgery

The case of a 76-year-old female patient is presented with a two-year history of progressive dementia, apathy and gait impairment. Initially, Alzheimer's disease was diagnosed and she was given donepezil for one year with no significant improvement. An extensive blood and biochemical control revealed high serum calcium and parathormone levels, and normal thyroid hormones and anti-thyroid antibodies. Ultrasound of thyroid and parathyroid glands revealed an adenoma of the right parathyroid. The detailed investigation for causes of secondary hyperparathyroidism was negative. Due to the absence of clinical hyperparathyroidism she was initially treated conservatively. At referral, the neurological picture consisted of: mild signs of parkinsonism, moderate dementia (MMSE=15) and severe behavioural disturbances. Because of the continuous aggravation of the cognitive deficit, parathyroidectomy was decided although there were no clinical or laboratory signs of involvement from other organs. Three weeks after the operation the neurological picture showed dramatical improvement. Parkinsonism and behavioural disorders were remarkably reduced and the MMSE score raised to 25. In summary we report an exceptional case of primary hyperparathyroidism (PHPT) presenting as dementia and treated successfully by parathyroidectomy.     

Post-poliomyelitis syndrome: 29 cases]

The post-polio syndrome refers to new neuromuscular symptoms developed by some patients many years after recovery from acute poliomyelitis. Several groups were separated: musculo-skeletal symptoms (different from a new spinal cord disease), infraclinical signs (EMG), post-polio muscular atrophy (new lower motor neuron objective signs) with several subgroups: cramps and fasciculations, benign focal weakness and atrophy (in previously affected muscles or in unaffected muscles), progressive spinal muscular atrophy. The following examination were performed in some cases, but not all, in this retrospective study: muscle CT scan, conventional electromyography (EMG), quantifying-EMG, macro-EMG and single-fiber EMG. The serum titers of neutralising antibodies to polio virus type 1, type 2 and type 3 were negative. No oligoclonal bands were found in the CSF from 6 patients screened by electrophoresis immunoelectrophoresis. Serum creatine kinase or aldolase was high in 6 patients. The same unusual features in this syndrome were observed on muscle biopsies: muscular hypertrophy and interstitial eosinophils; two patients had rimmed vacuoles in the muscle fibers.     

Distinguishing clinical and electrodiagnostic features of X-linked bulbospinal neuronopathy

X-linked bulbospinal neuronopathy (XLBSN) or Kennedys disease is a rare inherited neuromuscular disease characterized by adult-onset muscle weakness, usually in a limb-girdle distribution. It is frequently misdiagnosed despite a distinctive clinical presentation, usually due to the absence of a clear family history, and perhaps also due to failure of recognition. Accurate diagnosis is crucial for genetic counseling purposes and because alternative diagnoses usually carry a poorer prognosis. We evaluated 4 patients with XLBSN and one symptomatic female heterozygote patient. Based on our clinical observations in these patients and a systematic review of previously reported cases, the following clinical and electrophysiologic features when present in the setting of adult-onset muscle weakness, are strongly suggestive of the disorder: 1) facial weakness, 2) facial twitching or fasciculations, 3) tongue weakness and atrophy, 4) postural hand tremor, 5) hypo- or areflexia, and 6) absent or low-amplitude sensory nerve action potentials despite clinically normal sensation. We also hypothesize regarding the possibility of partial expression of the abnormal XLBSN gene in a symptomatic heterozygote female patient.     

Multiple phenotypic manifestations of X-linked spinobulbar muscular atrophy

Recessive X-linked amyotrophic spinobulbar muscular atrophy (SBMA) or Kennedy disease is a neuroendocrine disorder with a slowly progressive phenotype, caused by an expansion of a polymorphic tandem CAG repeat of the androgen receptor gene. Classical clinical hallmarks include onset in the third decade of life, weakness and wasting predominantly in proximal extremity muscles, variable weakness of bulbar muscles, abundant muscle fasciculations, sensory nerve action potential abnormalities and signs of androgen insensitivity such as gynecomastia and testicular atrophy. The diagnosis has been recently made easier by the availability of genetic testing but Kennedy disease is probably still underdiagnosed because of phenotypic variability. We report 11 new cases, of which seven had atypical initial manifestations presenting respectively with myasthenia, cramps and fasciculation syndrome, polyneuropathy, post-trauma monomelic neuronopathy, effort-dependent muscle intolerance and/or muscular dystrophy, with the aim to enlarge the phenotypic spectrum of the published series.     

Association of myopathies and alcoholic cardiomyopathy: clinical, electroneuromyographic and histopathologic study of the skeletal muscle in 10 cases of alcoholic cardiomyopathy

Myocardial and skeletal muscle impairment caused by alcohol has been thoroughly studied. Nevertheless, the simultaneous involvement of those tissues by ethanol has not been broached in medical literature. We have studied ten patients undergoing alcoholic cardiomyopathy. They were subjected to a detailed neurological examination, muscle enzymes serum level determinations, electromyography, and muscle biopsy with analysis of the tissue by usual histological techniques and by electron microscopy. Only one of ten patients exhibited proximal weakness and atrophy of the lower limbs, the electromyographic and histological findings correlating with the clinical feature of the chronic muscle disease due to alcohol consumption. The electromyographic findings included muscle disease in eight patients, neuron disease in one patient and no changes at all in the tenth patient. In one patient only, the skeletal muscle proved normal when examined by conventional histological techniques. In the other nine patients there were several minimal changes, such as the proliferation of nuclei beneath the sarcolemma, atrophy of fibers, hyalinization, vacuolation, loss of muscle fiber striae, and atrophy of groups of fibers. Electron microscopy demonstrated the following changes in nine patients: intracellular edema, dissociation of myofilaments, alteration of the Z line, changing in the shape and increase in the number of mitochondria, thickening of sarcolemma, and vacuolation and increase of the glycogen granules. Since all patients exhibited skeletal muscle injury, we concluded that there is a close relation between alcoholic cardiomyopathy and skeletal muscle disease.     

Accuracy of muscle fasciculations for the diagnosis of later-onset spinal muscle atrophy

Diagnosis of later-onset spinal muscular atrophy (SMA) can be challenging. This study aimed to evaluate the diagnostic properties of the detection of muscle fasciculations for SMA diagnosis in adolescents and adults with proximal muscle weakness. A cross-sectional diagnostic accuracy study was performed, in which 10 subjects with SMA (5 with type II and 5 with type III) and 9 subjects with genetic muscle diseases were evaluated by physical examination, muscle ultrasound (MUS) and electromyography (EMG). Inter-rater reliability of MUS was higher than physical examination and in a sensitivity analysis of MUS, all SMA subjects and a single patient with genetic muscle disease presented fasciculations in at least 2 different muscle groups, resulting in a sensitivity of 1 (95% CI: 0.69 to 1) and a specificity of 0.89 (95% CI: 0.52 to 1) for SMA diagnosis. Forty-two percent of evaluated subjects did not agree to perform EMG, limiting this method results. Muscle ultrasound presented the best diagnostic accuracy and physical examination combined with MUS seemed to be a good strategy for screening adolescents and adults with proximal muscle weakness for SMA. These results might improve diagnostic guidelines for later-onset SMA, leading to earlier diagnosis, treatment and specific care.     

A case of brachial amyotrophic diplegia accompanied with Sj?gren's syndrome presenting good response to immunotherapies in the early course of the disease]

A 74-year-old woman suffered from progressive muscle atrophy and weakness of her arms since she was seventy two years old. Before referral to our department, she was diagnosed as having cervical spondylotic myeloradiculopathy and received spinal fusion. Though spinal decompression was successful, muscle weakness of her upper limbs were progressive even after the surgery. On admission, neurological examinations revealed marked atrophy and weakness of her bilateral upper limbs with absent deep tendon reflexes showing man-in-the-barrel syndrome. Her lower extremities had normal muscle strength, but fasciculations were seen in her all four limbs. Electrophysiologically, motor nerve conduction velocity was almost normal but the amplitude was remarkably decreased, conduction block was not detected, and electromyography showed neurogenic patterns on her all extremities. Spinal progressive musclar atrophy (SPMA) accompanied with Sj?gren's syndrome was the likely diagnosis. Because 50 kDa anti-neuronal antibodies were found in her serum, we assumed that anterior horn cells were impaired by an autoimmune mechanism. Thus we treated her with corticosteroid pulse therapy, plasma exchange (PE) and intravenous immunoglobulin infusion therapy (IVIG). Although steroid pulse therapy only had a minimal effect, PE and IVIG promoted a remarkable improvement on her weakness, and the effect lasted for about three months. This is the first case of SPMA with Sj?gren's syndrome which showed good response to PE and IVIG in the early course of the disease. We considered that some SPMA-like motor neuron syndrome accompanied with autoimmune features may require immunomodulating therapies.     

Progressive muscular atrophy: clinical and laboratory study in eleven patients

Progressive muscular atrophy (PMA), an infrequent type of motor neuron disease (MND), is a predominantly lower motor neuron degeneration, causing muscle wasting and weakness with loss of weight and fasciculations. The diagnosis is based on rigid criteria, considering clinical aspects and eletroneuromyography findings. Blood tests and radiological investigation are necessary to look for other diagnosis mimicking PMA. We herein present 11 patients with PMA (5.9% of all our MND patients), 9 men and 2 women, which onset of symptoms occurred mainly under de age of 50, with a mean of 45.5 years. Cramp was the most frequent symptom preceding muscular weakness. Muscle pain, fatigue and fasciculations were also cited as starting symptoms. Asymmetric weakness of the arms was the most frequent pattern of onset of the disease. Bulbar muscular weakness developed in all patients during the course of the disease. Predisposing factors and distinctive clinical outcome was not observed in any of the patients. Ophthalmoparesis and sphincter dysfunction were seen in two patients who had a prolonged time in artificial respiratory assistance. Immunosuppressive therapy was ineffective in all patients. Progressive course was seen in all cases and the mean survival time was 44 months.     

Sporadic amyotrophic lateral sclerosis of long duration mimicking spinal progressive muscular atrophy: a clinicopathological study

We report an autopsy case of amyotrophic lateral sclerosis (ALS) clinically diagnosed as spinal progressive muscular atrophy (SPMA). The patient was a Japanese woman without hereditary burden. She developed muscle weakness of the distal part of the left lower extremity at age 42, followed by muscle weakness and atrophy of the right lower extremity and upper extremities. At age 57, she needed transient ventilatory support. Slight weakness in the facial muscles and fasciculation of the tongue appeared at age 60. At age 61, she died of sudden respiratory arrest. During the clinical course, neurological examination revealed neither Babinski signs nor hyperreflexia. The neuropathological examination revealed not only neuronal loss with gliosis in the facial nucleus, hypoglossal nucleus, and anterior horns of the spinal cord, but also loss of Betz cells and degeneration of the pyramidal tracts. Based on these clinicopathological findings and review of literature, we conclude that sporadic ALS mimicking SPMA is present.     

The muscular pain-fasciculation syndrome

Five cases of a chronic neuromuscular syndrome consisted of muscular aching and sometimes burning pain, fasciculations, cramps, fatigue, and occasional paresthesia. The disorder affected the legs and, less commonly, the girdle, trunk, and arm muscles. The symptoms were enhanced by physical activity and were usually improved by rest. Neither muscular wasting nor weakness was found, although the condition was present for an average of 4.7 years and, in one patient, as long as 10 years. Electrophysiologic studies showed motor abnormalities indicative of axonal degeneration and muscle fiber denervation, most marked in the legs. Light microscopy of skeletal muscle and spinal cord in one case disclosed evidence of mild denervation atrophy in muscle, but no loss of anterior horn cells. The findings are compatible with a benign polyneuropathy.