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PubMed2003

Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a recessive autosomal disorder characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron gene (SMN1). No curative treatment is known so far. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display skeletal muscle denervation, moderate loss of motor neuron cell bodies and severe axonal degeneration. These features, similar to those found in human SMA, strongly suggest the involvement of a dying back process of motor neurons and led us to test whether neurotrophic factors might have a protective role in SMA. We report here the therapeutic benefits of systemic delivery of cardiotrophin-1 (CT-1), a neurotrophic factor belonging to the IL-6 cytokine family. Intra-muscular injection of adenoviral vector expressing CT-1, even at very low dose, improves median survival, delays motor defect of mutant mice and exerts protective effect against loss of proximal motor axons and aberrant cytoskeletal organization of motor synaptic terminals. In spite of the severity of SMA phenotype in mutant mice, CT-1 is able to slow down disease progression. Neuroprotection could be regarded as valuable therapeutic approach in SMA.

Animals↗
PubMed1987

Morphometry of the degenerative process in the hypoglossal nerves in amyotrophic lateral sclerosis.

The peripheral hypoglossal nerves in 13 cases of amyotrophic lateral sclerosis (ALS) and five control cases were examined using morphometrical methods to demonstrate the degenerative process of motor nerve degeneration. The total number of myelinated fibers and their histograms were analyzed according to the degree of severity of the degeneration. Reduction of the total number of myelinated fibers in ALS hypoglossal nerves were graded in three groups: mild 65%-75%, moderate 50%-65% and severe 30%-50% of the myelinated fibers in controls. Each histogram of the remaining myelinated fibers showed different patterns corresponding to the degree of the degeneration and disclosed that the progressive reduction of large myelinated fibers was the fundamental change. Small myelinated fibers were not reduced, but increased, especially in the group with a moderate grade of degeneration. In plastic section, there were clusters of regenerated myelinated fibers. The transient increase of small myelinated fibers may be a reflexion of myelinated fiber regeneration during the progressive degenerative process of the motor neurons. The correlation between the degree of severity of the hypoglossal nerve degeneration and the atrophy of the tongue muscle and the duration of bulbar symptoms was examined and discussed.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Inflammatory changes in facioscapulohumeral muscular dystrophy.

Fifteen patients (10 familial and 5 sporadic cases) with facioscapulohumeral dystrophy were studied with regard to the presence of inflammatory changes. Mononuclear infiltrations were not characteristic of any stage of the disease, but they may be present in differing degrees during the whole course of the process. However, their lack or presence was uniform in the affected families, suggesting that the appearance of infiltrations may be genetically determined. Parallel with the presence of cell infiltrations, the serum creatine kinase (CK) activity was moderately increased and the progress of the disease was slightly accelerated. The relation of these phenomena to polymyositis and the diagnostic difficulties are discussed.

Adolescent↗
PubMed2002

A missense mutation in Tbce causes progressive motor neuronopathy in mice.

Mice that are homozygous with respect to the progressive motor neuronopathy (pmn) mutation (chromosome 13) develop a progressive caudio-cranial degeneration of their motor axons from the age of two weeks and die four to six weeks after birth. The mutation is fully penetrant, and expressivity does not depend on the genetic background. Based on its pathological features, the pmn mutation has been considered an excellent model for the autosomal recessive proximal childhood form of spinal muscular atrophy (SMA). Previously, we demonstrated that the genes responsible for these disorders were not orthologous. Here, we identify the pmn mutation as resulting in a Trp524Gly substitution at the last residue of the tubulin-specific chaperone e (Tbce) protein that leads to decreased protein stability. Electron microscopy of the sciatic and phrenic nerves of affected mice showed a reduced number of microtubules, probably due to defective stabilization. Transgenic complementation with a wildtype Tbce cDNA restored a normal phenotype in mutant mice. Our observations indicate that Tbce is critical for the maintenance of microtubules in mouse motor axons, and suggest that altered function of tubulin cofactors might be implicated in human motor neuron diseases.

Amino Acid Sequence↗
PubMedDate not supplied

Presenile dementia with motor neuron disease.

Seventy-one Japanese cases of presenile dementia with motor neuron disease were reviewed. The clinico-pathological features were: (1) progressive dementia with insidious onset, mostly in the presenile period: (2) neurogenic muscular wasting in the course of illness (ALS- or SPMA-like symptoms); (3) duration from the onset of the illness to death: 2-5 years (average 30.6 months); (4) extrapyramidal symptoms and definite sensory deficits are less commonly present; (5) no characteristic abnormalities in the CSF or EEG; (6) no known consanguinity or familial occurrence; (7) non-specific mild to moderate degenerative changes in the fronto-temporal cerebral cortex, hypoglossal nuclei and spinal cord, and frequently in the substantia nigra. The author was interested in discovering whether the frequency and topology of lesions in the brain of patients with presenile dementia and motor neuron disease differed characteristically from the distribution found in cases of Alzheimer's disease, Pick's disease, Creutzfeldt-Jakob disease or progressive subcortical gliosis. Presenile dementia with motor neuron disease might be a new disease entity.

Adult↗
PubMed1989

Linear scleroderma. A unique presentation.

A rare case of linear scleroderma with plaques of morphea in hemicorporeal distribution and subclinical systemic involvement is presented. Its possibility of progression into systemic sclerosis, which has not been reported earlier, is discussed.

Adult↗
PubMed1996

Spinal muscular atrophy type II (intermediary) and III (Kugelberg-Welander). Evolution of 50 patients with physiotherapy and hydrotherapy in a swimming pool.

We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. Patients were reevaluated at 2-month intervals. After two years of ongoing treatment, we were able to observe that the deformities in hip, knee and foot were progressive in all SMA Type II patients, and in some Type III. Muscle strength stabilized in most SMA Type III patients, and improved in some. MMT was not done in SMA Type II. In all patients we were able to detect an improvement in the Barthel Ladder scale. This study suggests that a measurable improvement in the quality of daily living may be obtained in patients with SMA Types II and III subjected to conventional physiotherapy when associated with hydrotherapy.

Adolescent↗
PubMed1975

[Centronuclear myopathy with autosomal dominant inheritance(author's transl)].

For the first time in Germany cases of a "centronuclear myopathy" are described in a 14-year-old boy and his 18-year-old sister. First symptoms in both patients appeared at 4 to 5 years of age with a "sleepy facial expression", clumsy gait and rapid fatigue. Within few years the disease progressed to generalized muscle weakness and atrophy, ptosis, ophthalmoplegia externa and areflexia. Weakness and atrophy were most pronounced in the distal muscles of the lower extremities. Both patients were free of epilepsy and the EEG recordings were normal. Motor and sensory nerve conduction velocities were normal. Repetitive stimulation of nerves revealed a normal transmission from nerve to muscle. Muscle biopsy showed a type I muscle fiber hypotrophy and a type II muscle fibre hypertrophy in addition to a predominance of type I fibres. Both fibre types showed central nuclei, sometimes appearing as chains in longitudinal sections. In most cells with central nuclei there persists a very small pericentral zone free of myofibrils but with increased activity of oxidative enzymes and phosphorylase. 2--3% of muscle fibres in cross sections showed a decreased of absent enzyme activity in the most peripheral fibre zone. Electron microscopy showed evidence of a centrally distinct myofibrillar disintegration. The father of both children had a ptosis at least from the 20th year of age. 5 years later generalized progressive muscle atrophy was recorded. Aged 51 years he died of pneumonia. Though not proved most probably the father suffered from the same disease as the children, pointing to an autosomal dominant inheritance in this family. The disease, according to the literature, seems to be genetically heterogeneous. The clinical picture seems to be independent of the mode of inheritance. Our patients showed a relatively rapid progression of symptoms. Pathogenetically the "centronuclear myopathy" may result from a disturbance of correlated nerve-muscle structures starting during early fetal life.

Adolescent↗
PubMed2004

Respiratory capacity course in patients with infantile spinal muscular atrophy.

STUDY OBJECTIVES: To describe the clinical and respiratory course in infantile spinal muscular atrophy (SMA) type I, type II, and type III, and to evaluate the respiratory needs for these patients, using noninvasive or tracheostomy ventilation. DESIGN: Retrospective cohort study. METHODS: We report 33 patients with SMA true type I (onset before age 3 months), 35 patients with SMA intermediate type I (onset between 3 months and 6 months), 100 patients with SMA type II (onset between 6 months and 18 months), 12 patients with SMA type III (onset after age 18 months). We report the clinical symptoms, respiratory course, and respiratory management: respiratory physiotherapy, periodic hyperinsufflation, nasal nocturnal ventilation (NNV), and tracheostomy. Also, we measured the FVC over several years during childhood and adolescence. RESULTS: In patients with SMA true type I, 82% of patients died, one third of whom underwent tracheostomy. In patients with SMA intermediate type I, 43% needed NNV, 57% underwent tracheostomy, and 26% died. In patients with SMA type II, 38% needed NNV, 15% underwent tracheostomy, and 4% died. In patients with SMA type III, respiratory impairment was moderate and began during the second decade of life. CONCLUSION: This data shows the progressively worsening course of restrictive respiratory insufficiency in patients with SMA, and the importance of early respiratory management to limit pulmonary complications and improve the quality of life for these patients.

Adolescent↗
PubMed2001

Neuromuscular disorders presenting as congenital bilateral vocal cord paralysis.

Congenital bilateral vocal cord paralysis (BVCP) can be associated with an underlying neuromuscular disorder, and may present before other features of the neuromuscular disorder become apparent. All infants less than 12 months of age presenting with BVCP between July 1987 and July 1999 at the Royal Children's Hospital, Melbourne, in whom a neuromuscular disorder was subsequently diagnosed were followed. Three children in whom BVCP was diagnosed soon after birth and before recognition of an underlying neuromuscular disorder were identified. All presented with upper airway obstructive symptoms at birth, had a diagnosis of bilateral abductor vocal cord paralysis made at awake flexible laryngoscopy, and had no underlying structural laryngeal abnormality on microlaryngoscopy and bronchoscopy. Two children required a tracheostomy, and 1 child was weaned from nasopharyngeal continuous positive airway pressure after 3 weeks. Subsequent neuromuscular symptoms were recognized between 4 months and 7 years later, leading to diagnoses of facioscapulohumeral myopathy, spinal muscular atrophy, and congenital myasthenia gravis. In each case, the prognosis for recovery from symptoms related to BVCP reflected that of the underlying neuromuscular disorder. This experience suggests that congenital BVCP may be a feature of an unrecognized neuromuscular condition. This possibility should be considered particularly in the presence of associated neurodevelopmental or neuromuscular dysfunction, or in cases in which BVCP is progressive.

Female↗
PubMed2001

[Equine motor neuron disease: a review based on a case report].

A 10-year-old, non-pregnant Dutch Warmblood mare was referred to the Department of Equine Science because of chronic weight loss, despite good appetite, and dullness. Clinical examination revealed muscle atrophy, trembling of the limb muscles, an abnormal stance in which all four limbs were placed under the body, and an abnormal low head carriage. The plasma vitamin E concentration was markedly decreased (0.2 mumol/l), the electromyographic (EMG) examination was consistent with denervation, and the oral glucose absorption test was below the reference value (40% increase over the resting glucose level). Because of the clinical diagnosis of equine motor neuron disease (EMND), the horse was euthanazed and post-mortem examination confirmed this diagnosis. Based on the similarity in pathological findings, EMND can be compared to amyotrophic lateral sclerosis (ALS) in humans. However, in horses, only the lower motor neurons and occasionally some nuclei of the cranial nerves are affected. Because of the low plasma vitamin E concentration found in horses with EMND, an absolute or a relative antioxidant deficiency can be involved in the pathogenesis. In general, it is a progressive disease process and stabilization of the situation is the best feasible result. There is no specific therapy other than vitamin E supplementation and the prognosis is poor.

Animals↗
PubMed1998

Shape irregularity of motor unit potentials in some neuromuscular disorders.

The aim of this study was to test whether analysis of the irregularity of the motor unit potential waveform may supplement conventional evaluation. We have found that the irregularity is not a characteristic feature of potentials either in neurogenic disorders or in myopathy. We have found, however, that within myo- and neuropathic disorders, the irregularities differ between slow (such as Becker muscle dystrophy and chronic spinal muscle atrophy) and fast progressing processes (such as amyotrophic lateral sclerosis and Duchenne muscle dystrophy). These differences depend on the different number of phases and turns contributing to wave formation. In slowly progressing processes, very irregular potentials are more often polyphasic, whereas in acute processes they may be polyturn or polyphasic. The results suggest that it is the irregularity of the potential that provides new information, not available so far, on the activity of the pathological process.

Action Potentials↗
PubMed1995

Muscle computed tomography features of motor neuron disease in late-onset GM2 gangliosidosis.

Late-onset GM2 gangliosidosis, a rare inherited neuronal storage disease, is characterized by a variety of clinical manifestations. The common clinical picture comprises neuromuscular, spinocerebellar, extrapyramidal, cognitive, and psychiatric abnormalities. Details of the extent of muscle involvement have never been reported. Eight patients with this syndrome were evaluated for the existence and extent of motor neuron disease using routine electrodiagnosis and systematic evaluation of skeletal musculature by computed tomography. Motor neuron disease was present in each and every patient regardless of the clinical manifestations and to a degree beyond that suspected on neurological examination. Muscle imaging disclosed a diffuse wasting and fatty replacement of muscles with predilection of pelvic and thigh muscles, and especially the quadriceps group. It seems that progressive motor disability in this syndrome is mainly due to motor neuron disease, as manifested by muscle atrophy, which can be easily demonstrated by muscle computed tomography.

Adipose Tissue↗
PubMed1980

Neurogenic scapuloperoneal syndrome in childhood.

Two brothers presented with a slowly progressive scapuloperoneal syndrome starting in early childhood. Initially there were myopathic EMG changes, but these changed to those of denervation. Neuromuscular biopsies at an interval of five years confirmed the neurogenic character of the muscle atrophy.

Adolescent↗