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PubMed2000

Cell death in polyglutamine diseases.

An increasing number of inherited neurodegenerative diseases are known to be caused by trinucleotide repeat expansions in the respective genes. At least nine disorders result from a CAG trinucleotide repeat expansion which is translated into a polyglutamine stretch in the respective proteins: Huntington's disease (HD), dentatorubral pallidolysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and several of the spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 12). Although the molecular steps leading to the specific neuropathology of each disease are unknown and are still under intensive investigation, there is increasing evidence that some CAG repeat disorders involve the induction of apoptotic mechanisms. This review summarizes the clinical and genetic features of each CAG repeat disorder and focuses on the common mechanistic steps involved in the disease progression of these so-called polyglutamine diseases. Among the common molecular features the formation of intranuclear inclusions, the recruitment of interacting polyglutamine-containing proteins, the involvement of the proteasome and molecular chaperones, and the activation of caspases are discussed with regard to their potential implication for the induction of cell death.

Animals↗
PubMed1997

Cervical spondylotic amyotrophy associated with Hirayama's disease.

A 47-year-old man with Hirayama's disease who developed cervical spondylotic amyotrophy (CSA) is presented. The patient had noted weakness and atrophy of hand and forearm muscles bilaterally at the age of 16. At the age of 40, he developed proximal muscle atrophy and weakness bilaterally after 20 years of a non-progressive state. Myelography and computed tomography (CT)-myelography revealed that ventral cord compression at multiple levels of C4-7 vertebral bodies was increased when the neck was extended. The clinical diagnosis was CSA associated with Hirayama's disease. To our knowledge, this is the first such case to be reported.

Cervical Vertebrae↗
PubMedDate not supplied

[Neonatal muscular spinal atrophy: a case report].

Spinal Muscular Atrophy (SMA) is an autosomal recessive disease characterized by diffuse proximal and distal weakness due to deletions of the survival motor neuron (SMN) gene localised on chromosome 5q13. Pathological studies show decreased numbers of motorneurons in spinal cord. SMA was initially sub-classified clinically into three types base on age at onset and clinical course. SMA type 1, Werdnig-Hoffmann disease, has an onset within the first 6 months and death within the first two years. In contrast, SMA type II has an onset after six months of life and the children achieve the ability to sit unaided. Children with SMA type III (Kugelberg-Welander) usually have normal milestones in the first year and achieve the ability to walk but then show evidence of mild weakness. The prognosis is good and the clinical course is not (or very slowly) progressive. Recently, Dubowitz described a new form of SMA called type 0 with a neonatal onset, facial weakness, progressive and fatal clinical course. These infants show generalised hypotonia, the lower limbs are more affected than the upper with marked weakness of all axial muscles. We report a case of SMA, uncommon for the early onset and the respiratory difficulties. The diagnosis has been done by genetic analyses showing a SMN mutation.

Age Factors↗
PubMed1982

[Collagen metabolism of skeletal muscles following injuries of the peripheral nerves].

In order to elucidate the mechanisms of fibrosis and atrophy of skeletal muscles after peripheral nerve injuries, the biochemical changes in collagen from gastrocunemius muscles of adult albino rabbits have been analyzed after denervation of the proximal portion of sciatic nerve. The wet weight of gastrocunemii was found to decrease at the end of the second week after denervation, and the total collagen content in the muscles progressively increased throughout the whole observation period of 12 weeks. In contrast, the amount of connectin, an intracellular elastic protein was found to decrease after denervation. The amounts of total soluble collagen, pepsin-released collagen and the reducible cross-links were remarkably increased with the passage of time after denervation. The total glycosylated hydroxylysine, especially glucosylgalactosylhydroxylysine contents of the collagen were found to decrease after denervation. These findings strongly indicate that the progressive fibrosis of skeletal muscles after peripheral nerve injury may be mostly produced by the enhanced formation of immatured collagen fibers in tissues, rather than the decrease in the amount of structural muscle proteins as discussed before.

Animals↗
PubMed1977

Lower motor neuron disease with spinocerebellar degeneration.

A patient with polymyositis responded initially to steroid therapy. A muscle biopsy disclosed features of primary myopathy and group atrophy. The patient became refractory to therapy and died with relentlessly progressive weakness. The autopsy disclosed lower motor neuron involvement and degeneration of the spinocerebellar tracts. There was loss of Purkinje cells, which may have occurred secondary to an anoxic episode prior to death. The case is unique because of the limited involvement of the lower motor and spinocerebellar systems.

Cerebellum↗
PubMed2005

Rehabilitation after the replantation on a 2-year-old girl with both amputated legs.

We had an opportunity to perform replantation of both legs on a 2-year-old girl, and our decision to perform replantation rather than amputation surgery was carefully made taking her age, degree of crushing injury, ischaemic time and level of the amputation into consideration. Painstakingly designed rehabilitation treatments were continuously performed on this girl from the early stage after the operation, and the treatments were comprised of four parts; that is, flexion and extension exercise for the ankle in order to prevent it from stiffness or contracture, functional electrical stimulation (FES) in order to prevent muscular atrophy on the lower extremities, muscle strengthening exercise for the lower extremities, and electrical stimulation to regenerate the damaged nerves and to prevent muscular atrophy from occurring. For an objective assessment of the postoperative conditions, total active motion angles of the ankle joint were measured, and also EMG and NCV were conducted at the end of the first month as well as at the end of the 6th month. Total active motion angles of the ankle joint were increased progressively as time went on, from 15 to 60 degrees on the right and from 10 to 45 degrees on the left. NCV did not show any sensation or response from motor nerves, or amplitude decreased considerably 1 month after the operation; however, at the end of the 6th month conditions improved a great deal with both amplitude and latency. And most muscles that did not show any signals on EMG or showed less than normal at the end of the first month after the operation eventually recovered at the end of the 6th month. The patient had no particular difficulties in walking after 6 months or rather she started running in small steps showing her legs functioning superbly. An infant with both of lower extremities amputated is quite a rare case. We believe that the replantation surgery was successful due to the fact that carefully selected preoperative factors were taken into consideration and well designed postoperative rehabilitation program consisted of four parts was carried out continuously.

Amputation, Traumatic↗
PubMed1987

Mitochondrial encephalomyopathy and partial cytochrome c oxidase deficiency.

A 52-year-old man had slowly progressive weakness and wasting of limb-muscles, sensorineural hearing loss, and complex partial seizures. CT showed cerebral atrophy, but he was not demented. Muscle biopsy showed ragged-red fibers and decreased histochemical stain for cytochrome c oxidase. Biochemical studies showed decreased cytochrome c oxidase activity in crude muscle extracts and in isolated mitochondria (44 and 30% of normal), while other mitochondrial enzymes were normal. A comparable decrease of immunologically reactive enzyme protein was shown by immunotitration with antibodies against human heart cytochrome c oxidase. Partial defects of cytochrome c oxidase may cause adult-onset, slowly progressive mitochondrial encephalomyopathies.

Atrophy↗
PubMed1981

Human neurolathyrism, a follow-up study of 200 patients. Part I: Clinical investigation.

Two hundred patients with chronic neurolathyrism were clinically examined, 25 to 35 years after exposure to the lathyrus sativus pea. All the patients were prisoners in a labour camp under similar nutritional and physical conditions at the outbreak of the syndome. The main symptoms were spastic paraparesis and a neurogenic bladder, both of varying degree. In addition lower motor neuron involvement with muscular atrophies was noticed in 14 cases and simulated amyotrophic lateral sclerosis. A lathyric sensory neuropathy was found in 12 patients. No cranial lesions or psychiatric disorders were found. Laboratory tests including 5 CSF specimens were normal. HLA typing was unremarkable. Our overall impression was that chronic neurolathyrism in the long run shows a gradually slow progressive course.

Adult↗
PubMed1998

Nutritional aspects of neuromuscular diseases.

Evidence suggests that individuals with DMD have reduced skeletal development, including decreased linear growth and bone mineral density, compared to normal subjects. Despite their reduced muscle mass, a high percentage of DMD patients are overweight. Body composition measurements can assist with monitoring changes in fat mass and skeletal muscle mass as the disease progresses. Weight management in overweight DMD patients is indicated because excess adiposity burdens mobility and breathing, but only one study in two DMD patients has documented that weight reduction can be done safely. In the latter stages of the disease most DMD subjects become underweight because of an acceleration in skeletal muscle protein degradation relative to its synthesis. Studies of energy, protein and branched chain amino acid supplementation in DMD have yielded promising but inconclusive results, and more well-designed studies are needed in this area. Although there is currently no cure for DMD, studies on the role of nutritional therapy in increasing the quality of life in these patients are urgently needed. Studies in adults with various SP-NMDs indicate a reduction in fat-free mass and an increase in fat mass relative to controls. The newly developed method of air displacement plethysmography for measuring body composition is ideally suited for SP-NMD subjects because it requires very little effort and the measurement procedure is relatively fast. Dual energy x-ray absorptiometry technology has been proposed for distinguishing myogenic from neurogenic SP-NMDs from calculation of the fat-to-lean soft tissue ratio, which is higher in patients with myogenic muscular atrophy. Studies on the energy metabolism of ambulatory SP-NMD subjects indicate that their basal metabolic rate is either similar to or slightly lower than controls, but 24-hour energy expenditure is about 25% lower than controls. This reduction in 24-hour energy expenditure is due to a reduction in physical activity in SP-NMD. Studies examining the roles of energy expenditure, physical activity, and diet in the development of adiposity and risk for secondary chronic diseases in SP-NMD subjects are currently underway.

Adolescent↗
PubMed2003

Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA).

Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

Animals↗
PubMed2005

Tumor necrosis factor alpha signaling in skeletal muscle: effects of age and caloric restriction.

Past the age of 50 years, aging individuals lose muscle mass at an approximate rate of 1-2% per year. This age-related muscle atrophy, termed sarcopenia, can have significant effects on individual health and quality of life and can also impact the socioeconomic status. Sarcopenia is due to both a decrease in the number of fibers and the atrophy of the remaining fibers. The mechanisms causing loss of fibers have not been clearly defined, but may likely involve apoptosis. Elevated levels of circulating tumor necrosis factor alpha (TNF-alpha) and adaptations in TNF-alpha signaling in aged skeletal muscle may be contributing factors for the activation of apoptosis. These adaptations may be fiber-type specific, which could explain the selective loss of type II fibers, vs. type I fibers, in the aging process. Caloric restriction, a proven antiaging intervention, is known to attenuate the loss of muscle mass and function with age. Furthermore, caloric restriction has been shown to attenuate the age-associated adaptations in TNF-alpha signaling in skeletal muscle, which may be a possible mechanism by which CR prevents apoptosis and the loss of muscle fibers with age. The potential role of TNF-alpha in the progression of sarcopenia will be discussed, as well as the effects of life-long caloric restriction on TNF-alpha signaling.

Aged↗
PubMed1992

[Lymphangion in health and in lymphedema].

Comparative analysis of lymphangion construction in different organs and sites of human body is performed. Quantitative parameters of lymphangions (length, width, volume) are found to have age and site peculiarities. Myo-myocyte contacts of the nexus type and fascicular-reticular organizational principle of the cells underly myocyte association into functional syncytium. The valve consists of a muscleless fold and valvular bolster containing muscles. Restructuring of lymphangions in lower limb lymphedema are observed. In the course of the disease progression myocyte atrophy occurs which is followed by lymphangion wall collagenization. The alterations in lower limb lymphangions are proportional to the gravity of the disease.

Aging↗
PubMed1980

[Electromyographic analysis on juvenile muscular atrophy of unilateral upper extremity (author's transl)].

In 1959, this disorder was first reported by one of authors (K.H.) (6). Since then, many Japanese cases have been reported and recently some cases are also reported in other countries. Its cause and pathology are still unknown, because no autopsy case was obtained. In this report, some electromyographic findings are described and discussed. This series contain 26 cases (male 23, female 3). Age of onset: 13-33 years old (mean 19.4 years old). Clinical duration: 2-32 years old (mean 9.0 years). Only 6 cases (23%) showed trauma as the past history (Table 2). We classified 26 cases in three groups (UL: unilateral, BP: bilateral, one-side predominant, BS: bilateral symmetrical) based on the laterality of physical findings (amyotrophy, weakness, finger tremor, etc.) (Table 3). Conventional needle EMG were done in all cases and these findings were judged by the criteria which we defined as Fig. 2. In some cases, conduction velocity (MCV & SCV) were measured. Needle EMG showed more selective and localized distribution of NGP (neurogenic pattern) in the hand muscles, the forearm muscles except for M. brachioradialis, and M. triceps brachii on the atrophied sides of the arm in all clinical groups (UL, BP, BS) (Table 4.5). On the normal side of bilaterally examined cases of UL group, NGP was shown in 9/11 cases, buts its distribution seemed to be slightly restricted in the more distal part. Thus, in this disorder, 22/26 cases (77%) were electromyographically affected on the bilateral sides, although the clinical feature was mostly unilateral. The clinical features and pathological process seemed to be established in a few years after the onset without the apparent tendency of further progression. Afterwards, no apparent extension of NGP distribution and increment of grading were observed in the Clinical course. No delay was observed on MCV and SCV. The pathological lesions responsible for these electromyographic changes are discussed, either on spinal segmental origin or on brachial plexus origin, but some ambiguous portions are still remained.

Action Potentials↗
PubMedDate not supplied

Carnitine palmityltransferase deficiency with permanent weakness.

A 16-year-old male had a history of muscle pain and exercise intolerance from the age of six years. At 14 years of age, he experienced the first episode of myoglobinuria and has had eight episodes subsequently. The longest interval between episodes was 14 months. Between attacks he manifested permanent, mild proximal limb weakness, elevated serum creatine kinase activity, and myopathic features indicated by electromyography and muscle biopsies. The muscle carnitine palmityltransferase activity was 30% of normal. This patient demonstrates that carnitine palmityltransferase deficiency can be a progressive disorder leading to permanent weakness. The need for early diagnosis and treatment is stressed.

Acyltransferases↗
PubMed2006

The G526R glycyl-tRNA synthetase gene mutation in distal hereditary motor neuropathy type V.

BACKGROUND: Distal hereditary motor neuropathy (dHMN) or distal spinal muscular atrophy (dSMA) is a heterogeneous group of disorders characterized almost exclusively by degeneration of motor nerve fibers, predominantly in the distal part of the limbs. One subtype, dHMN type V (dHMN-V), is transmitted by autosomal dominant inheritance and predominantly involves the hands. It is allelic with Charcot-Marie-Tooth disease 2D (CMT2D), in which a similar phenotype is associated with sensory signs. Missense mutations in the glycyl-tRNA synthetase (GARS) gene have been recently reported in families with either dHMN-V, CMT2D, or both. METHODS: The authors searched for GARS mutations in eight dHMN-V families. RESULTS: The authors found the G526R missense mutation in three families (16 patients) of Algerian Sephardic Jewish origin. All patients shared a common disease haplotype, suggestive of a founder effect. The clinical phenotype consists of a slowly progressive, purely motor distal neuropathy. It starts in the hands in most patients, but also in both distal upper and lower limbs or in distal lower limbs alone. The age at onset in symptomatic individuals was between the second to fourth decades, but four mutation carriers were still asymptomatic, two of whom were already age 49 years. Electrophysiology showed that the motor fibers of the median nerve were the most affected in upper limbs. Sensory nerve action potentials were normal. CONCLUSIONS: The age at onset of patients with the G526R mutation in the GARS gene varied widely, but the clinical and electrophysiologic presentation was uniform and progressed slowly. Glycyl-tRNA synthetase mutations are a frequent cause of familial distal hereditary motor neuropathy type V but, because of the reduced penetrance of the disease, could also account for isolated cases.

Age of Onset↗
PubMed2006

Neuronal-specific roles of the survival motor neuron protein: evidence from survival motor neuron expression patterns in the developing human central nervous system.

Despite recent data on the cellular function of the survival motor neuron (SMN) gene, the spinal muscular atrophy (SMA) disease gene, the role of the SMN protein in motor neurons and hence in the pathogenesis of SMA is still unclear. The spatial and temporal expression of SMN in neurons, particularly during development, could help in verifying the hypotheses on the SMN protein functions so far proposed. We have therefore investigated the expression and subcellular localization of the SMN protein in the human central nervous system (CNS) during ontogenesis with immunocytochemical, confocal immunofluorescence, and Western blot experiments using a panel of anti-SMN antibodies recognizing the full-length SMN protein. The experiments not only revealed the early SMN expression in all neurons, but also demonstrated the progressive shift in SMN subcellular localization from mainly nuclear to cytoplasmic and then to axons during CNS maturation. This finding was present in selected neuronal cell populations and it was particularly conspicuous in motor neurons. Our data support the idea of a specific role for SMN in axons, which becomes predominant in the ontogenetic period encompassing axonogenesis and axonal sprouting. In addition, the asymmetric SMN staining demonstrated in the germinative neuroepithelium suggests a possible role for SMN in neuronal migration and/or differentiation.

Adult↗
PubMed2004

Blood loss in pediatric spine surgery.

This article reviews the extent of blood loss in spine surgery for scoliosis corrections in the pediatric age group. An extensive literature review presents blood loss values in surgery for adolescent idiopathic scoliosis, cerebral palsy, Duchenne muscular dystrophy, spinal muscular atrophy, and myelomeningocoele. The underlying disorder plays a major role in determining the extent of blood loss. Blood loss is considerably higher in those patients with a neuromuscular scoliosis compared with adolescent idiopathic scoliosis. Within the neuromuscular group those with Duchenne muscular dystrophy demonstrate the highest mean levels of blood loss. Blood loss is also shown to be progressively greater with increasing numbers of vertebral levels incorporated into the fusion, with posterior fusions compared to anterior fusions, and in those patients having both anterior and posterior fusions.

Adolescent↗
PubMed1999

[Role of growth hormone underproduction and support load deficit in development of muscle atrophy and osteopenia in tail-suspended rats].

In a 20-day experiment with tail-suspended male rats histological and histomorphometric techniques were used to study the effects of growth hormone, thyroxin, and graded support loads on the progress of atrophy in soleus and gastrocnemius m.m., tibial metaphyses spongiosis, and growth of tibiae. Daily injections of growth hormone at a dose of 0.5 mg/kg of the body mass were found to restore the longitudinal growth of tibiae and to suppress osteopenia in the spongiosis of metaphyses; however, they did not have any noteworthy effect on the muscular atrophy in the suspended rats. Support loading of the hind limbs for 2 hours a day in parallel to the treatment with growth hormone and thyroxin (0.02 mg/kg of the body mass per a day) suppressed the atrophy in soleus m. but not in gastrocnemius m. They were not able to oppose to osteoporosis in tibial metaphyses spongiosis; tibial growth was not normalized. Thyroxin did not appear to markedly influence muscle and bone atrophies; moreover, it made hypofunctioning of the thyroid more intense and, when combined with the growth hormone, masked the positive effect of the latter on the rats' bones.

Animals↗