[Progressive distal amyotrophy (Charcot-Marie-Tooth type) with hyperalbuminosis of the cerebrospinal fluid].
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Adolescent↗
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Characterization of Ighmbp2 in motor neurons and implications for the pathomechanism in a mouse model of human spinal muscular atrophy with respiratory distress type 1 (SMARD1).
Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is caused by recessive mutations of the IGHMBP2 gene. The role of IGHMBP2 (immunoglobulin mu-binding protein 2) in the pathomechanism of motor neuron disease is unknown. We have generated antibodies against Ighmbp2 and showed that low levels of Ighmbp2 immunoreactivity are present in the nucleus of spinal motor neurons and high levels in cell bodies, axons and growth cones. Ighmbp2 protein levels are strongly reduced in neuromuscular degeneration (nmd) mice, the mouse model of SMARD1. Mutant mice show severe motor neuron degeneration before first clinical symptoms become apparent. The loss of motor neuron cell bodies in lumbar spinal cord is followed by axonal degeneration in corresponding nerves such as the femoral quadriceps and sciatic nerve and loss of axon terminals at motor endplates. Motor neuron degeneration and clinical symptoms then slowly progress until the mice die at the age of 3-4 months. In addition, myopathic changes seem to contribute to muscle weakness and especially to respiratory failure, which is characteristic of the disorder in humans. Cultured motor neurons from embryonic nmd mice did not show any abnormality with respect to survival, axonal growth or growth cone size, thus differing from motor neurons derived from, e.g. Smn (survival motor neuron) deficient mice, the model of spinal muscular atrophy (SMA). Our data suggest that the pathomechanism in SMARD1 is clearly distinct from other motor neuron diseases such as classic SMA.
Action Potentials↗
Hereditary pure lower motor neuron disease with adult onset and rapid progression.
We describe three members each of two families presenting with a hereditary form of lower motor neuron disease with adult onset and rapid progression and compare their pathological and clinical features with hereditary lower motor neuron disease with adult onset, as described in the literature. No involvement of upper motor neurons was found either clinically or pathologically. Disease progression was rapid, and the majority of patients died from respiratory failure within 1-5 years after onset of disease. On pathological examination of the spinal cord we found ballooned neurons, neuronophagia and gliosis in family A, which have been regarded as characteristic pathological features of infantile-onset spinal muscular atrophy (SMA). In family B specific neuronal changes were observed that also occur in patients with amyotrophic lateral sclerosis (ALS). An autosomal dominant mode of inheritance would seem likely in both families. In family A the pathological findings and the clinical presentation with symmetrical proximal limb weakness show similarities with autosomal dominant SMA. Based on the finding of pathological features in family B that also occur in ALS, together with the distal asymmetrical muscle weakness and bulbar signs and a high age at onset we hypothesize that the members of family B suffered from familial ALS. The disease forms in both families in our opinion further broaden the spectrum of motor neuron disease.
Adult↗
Severe phenotype in infantile facioscapulohumeral muscular dystrophy.
While much is known about the clinical course of adult FSHD, the third most common inherited muscular dystrophy, data on the "infantile phenotype" and especially on the progression of the disease in children are limited. We have followed a cohort of 7 patients with infantile FSHD for 9-25 years and here report the clinical and genetic findings in this group. Infantile FSHD is relatively rare, amounting to 4% of all of our FSHD patients. Despite some variability in the progression, infantile FSHD has a more consistent phenotype than adult FSHD. Although they had normal motor milestones, all patients showed facial weakness from early childhood, and subsequently were severely affected with rapid progression of the disease, marked muscular wasting, weakness, and hyperlordosis. None of the patients have shown signs of nocturnal hypoventilation or cardiomyopathy so far. No correlation was found between sex and the severity of phenotype whereas all but one patient had very short fragment sizes of the D4Z4 repeat. Only two patients had a de novo mutation: 3 patients inherited the mutation from a parent with somatic mosaicism, and one was inherited from a parent with classical adult FSHD. One patient was unusual in having one allele inherited from his father who showed somatic mosaicism and one allele with an additional de novo mutation. We conclude that infantile FSHD is a severe and rapidly progressive disease, and this needs to be taken into account in the advice given to patients diagnosed in early childhood. However, our data also suggest that the risk to an individual with classical FSHD of having a child with the infantile form is low.
Adolescent↗
Radiographic demonstration of paraspinal muscle wasting in patients with chronic low back pain.
This study investigated whether paraspinal muscle wasting occurs in association with chronic low back pain (LBP). Cross-sectional areas (CSA) of spinal and paraspinal structures were measured radiographically, at the level of L4, in 43 patients with recent and 44 with chronic LBP. Crude anthropometry demonstrated no differences between the groups with regard to L4 and paraspinal and psoas muscle CSAs, but inter-individual differences were large. Since body weight correlated significantly with L4 CSA this dimension was used as an 'internal standard' and further inter-individual comparisons were made using paraspinal: L4 and psoas: L4 (i.e. muscle to bone) CSA ratios. Muscle assessments made in this 'relative' fashion revealed significant reductions in paraspinal and psoas dimensions in patients with chronic compared to recent onset LBP. These changes could cause paraspinal and psoas muscle weakness and thereby predispose to spinal instability and progressive dysfunction.
Adult↗
[A case of Charcot-Marie-Tooth disease 1 B with Val 146Phe mutation of myelin protein zero showing a severe clinical phenotype].
A 15-year-old boy had complaints of progressive gait disturbance and foot deformity. He started to walk at the age of 18 months. Since two years of age, he had noticed unstable gait. He showed evident scoliosis and enlarged great auricular nerves. Moderate to slight degrees of muscular atrophy and weakness of distal upper, and proximal and distal lower limbs were observed. Pes equinovarus deformity of both feet was obvious. Muscle stretch reflexes were absent in both limbs except decreased triceps brachii reflex. Vibratory sensation was decreased severely in the toes and mildly in the fingers. In cerebrospinal fluid, protein was mildly elevated. Median nerve motor conduction velocity was 5.0 m/sec. On sural nerve biopsy, both demyelinated and remyelinated axons and onion-bulbs without hypomyelination were observed. Therefore, the diagnosis of Charcot-Marie-Tooth disease 1 was made. The direct sequencing of the genomic DNA encoding the Po gene revealed a mutant allele, a guanine to thymine substitution of nucleotide position 436, which caused a substitution of phenylalanine for valine at amino acid position 146. This type of Po mutation is different from any type of Po mutation reported in the literature.
Adolescent↗
Diagnostic value of satellite potentials in clinical EMG.
Complex motor unit potentials (CMUPs) with satellites were recorded and analysed in 231 electromyograms of patients with spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), Duchenne muscular dystrophy (DMD) and a healthy control group. In the control adult group only few CMUPs with satellites were found; no CMUP were found in children. In SMA and DMD patients the CMUPs were present with similar frequency but their morphology, i.e. shape, duration, amplitude of the main and satellite spike components and number of satellites was different. In ALS patients a significant difference between severely involved interosseous muscle and proximal muscles was found. The pathomechanism of CMUPs with satellites is different in myopathic and neurogenic processes, in both however they reflect remodelling of the motor unit. In myopathy they reflect muscle fiber diameter variability and distribution of preserved muscle fibers within the motor unit under study. In neurogenic lesion the CMUPs with satellites are the result of increasing desynchronisation during progressive de- and reinnervation.
Adolescent↗
Mapping of the bovine spinal muscular atrophy locus to Chromosome 24.
A hereditary form of spinal muscular atrophy (SMA) caused by an autosomal recessive gene has been reported for American Brown-Swiss cattle and in advanced backcrosses between American Brown-Swiss and many European brown cattle breeds. Bovine SMA (bovSMA) bears remarkable resemblance to the human SMA (SMA1). Affected homozygous calves also show progressive symmetric weakness and neurogenic atrophy of proximal muscles. The condition is characterized by severe muscle atrophy, quadriparesis, and sternal recumbency as result of neurogenic atrophy. We report on the localization of the gene causing bovSMA within a genomic interval between the microsatellite marker URB031 and the telomeric end of bovine Chromosome (Chr) 24 (BTA24). Linkage analysis of a complex pedigree of German Braunvieh cattle revealed a recombination fraction of 0.06 and a three-point lod score of 11.82. The results of linkage and haplotyping analysis enable a marker-assisted selection against bovSMA based on four microsatellite markers most telomeric on BTA24 to a moderate accuracy of 89-94%. So far, this region is not orthologous to any human chromosome segments responsible for twelve distinct disease phenotypes of autosomal neuropathies. Our results indicate the apoptosis-inhibiting protein BCL2 as the most promising positional candidate gene causing bovSMA. Our findings offer an attractive animal model for a better understanding of human forms of SMA and for a probable anti-apoptotic synergy of SMN-BCL2 aggregates in mammals.
Animals↗
The reciprocal change of neurotrophin-4 and glial cell line-derived neurotrophic factor protein in the muscles, spinal cord and cerebellum of the dy mouse.
Laminin alpha2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration, probably due to a lower formation of multinucleated myotubes due to an adhesion defect of myoblasts to each other. Some recent studies found that CMD patients have a white matter disorder and cerebellum atrophy. In the spinal cord of dy mice, a model of CMD, inducible nitric oxide synthase (iNOS) was markedly expressed. Using Western blotting and immunohistochemical analyses, we investigated the levels of neurotrophin-4 (NT-4), brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) in the central nervous system and skeletal muscles of dy mice. In the dy mice, the microtubule-associated protein-2 (MAP-2) protein level was markedly decreased in the Purkinje and granule cells of the cerebellum, and in lumbar motoneurons of the spinal cord. The motoneurons and axons of dy mice possessed lower expressions of phosphorylated tau. The amount of NT-4 was markedly lower in the cerebellum, spinal cord and hindlimb muscles of dy mice. In dy mice, GDNF was markedly enhanced in the Purkinje and granule cells of the cerebellum, in many lumbar motoneurons, and in the regenerating atrophied fibers. The CNTF protein level did not differ in the hindlimb muscles between the normal and dy mice. Therefore, GDNF could act to inhibit the death of Purkinje and granular neurons, and motoneurons, and to promote the remodeling of the neuromuscular junction of atrophied muscle fibers of dy mice. Furthermore, dy mice include neurogenic abnormalities in the cerebellum and spinal cord along with myogenic disorder of muscle fibers.
Animals↗
Nationwide survey of juvenile muscular atrophy of distal upper extremity (Hirayama disease) in Japan.
Juvenile muscular atrophy of the distal upper extremity (JMADUE, Hirayama disease) was first reported in 1959 as 'juvenile muscular atrophy of unilateral upper extremity'. Since then, similar patients in their teens or 20s have been described, under a variety of names, not only in Japan, but also in other Asian countries, as well as Europe and North America. Biomechanical abnormalities associated with JMADUE have recently been reported through various imaging examinations, proposing its disease mechanism. Since JMADUE differs from motor neuron disease, or spinal muscular atrophy, this disease entity should be more widely recognized, and early detection and effective treatments should be considered. We report an epidemiological study in Japan. Two nationwide questionnaire-based surveys, conducted in Japan from 1996 to 1998, identified 333 cases. The numbers of patients per year, distribution of ages at onset, mode of onset, time lapse between onset and quiescence, neurological signs and symptoms, imaging findings, and the effects of conservative treatments were analyzed. The peak age was 15 to 17 years, with a marked male preponderance, usually a slow onset and progression, and quiescence six or fewer years after onset. There was a predominantly unilateral hand and forearm involvement with 'cold paresis'. The imaging findings are described.
Adolescent↗
Astrocytosis in wobbler mouse spinal cord involves a population of astrocytes which is glutamine synthetase-negative.
Mice affected by the wobbler mutation are characterized by a muscular atrophy associated with motoneuron degeneration. As soon as the first clinical signs of the disease appear, reactive astrocytes, strongly glial fibrillary acidic protein (GFAP)-positive, are observed in the spinal cord grey matter. They become prevalent at all levels with disease progression. Immunostaining of glutamine synthetase (GS) shows that these reactive astrocytes are never GS-positive. The activity and protein amounts of GS remain normal in wobbler spinal cord although astrocytosis develops. Thus, gliosis in the wobbler mouse seems to involve a subpopulation of astrocytes, which is strongly GFAP-positive but GS-negative.
Animals↗
Triplet repeat gene sequences in neuropsychiatric diseases.
The human genome has many nucleotide repeat sequences. These range from a single repeating base to entire duplicated genes. Expansion of repeating triplets of nucleotides in the genome has recently been associated with nine degenerative and developmental neuropsychiatric diseases: fragile X syndrome, fragile X-linked mental retardation, myotonic dystrophy, Friedreich's ataxia, spinal and bulbar muscular atrophy, Huntington's disease, spinocerebellar ataxia type 1, dentatorubral-pallidoluysian atrophy, and Machado-Joseph disease. These diseases are all conditions of the central nervous system; in all of them, the inheritance pattern usually exhibits the phenomenon of anticipation (defined as progressively earlier age of onset or a worsening disease severity over successive generations), and the severity of the phenotypic expression and penetrance appears to be related to the extent of the triplet expansion. Identification of this pathological genetic phenomenon solves several of the mysteries that surrounded these conditions but raises many important questions regarding pathogenic mechanisms that may be shared. There is some indication that triplet expansions may also underlie other neuropsychiatric conditions such as schizophrenia or bipolar disorder.
Brain Diseases↗
Distal spinal muscular atrophy. A clinical and genetic study of 8 kindreds.
Twelve patients (8 kindreds) with distal SMA are described, and an analysis presented of their clinical and genetic features. Distal SMA accounted for 10% of all patients with SMA in a total population survey of this disease in North-East England. The parental consanguinity rate is high, occurring in 3 of the 8 kindreds reported; the sex ratio was 1.0; the segregation ratio of sibs did not differ from 0.25. Intrafamilial concordance for clinical features of the disease is high. This current data is consistent with a suggested aetiology of two separate autosomal recessive genes. Clinical features are discussed and a review of the literature presented. The disease is only slowly progressive, but one of the genetic types may present with infantile or early juvenile onset; there is no evidence that it shortens life. 50% of cases did not have a normal gait after 4 years of age; 50% could not run after 17 years of age; and 50% could not walk unaided after 28 years of age. Details of prognosis, and principles of genetic counselling in this disease are discussed.
Adolescent↗
[Chronic anterior polyradiculitis with a picture of progressive ascending amyotrophy, regressing with cortisone therapy. Considerations on the theme of amyotrophy following probable chronic neuroallergic phlogoses].
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Adrenal Cortex Hormones↗
Progressive sensory loss one year after bullet injury of spinal cord.
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Adult↗
[The effectiveness of physical therapy techniques. Possibilities of electromyography evaluation].
The purpose of this study is to verify the efficiency of selected physiotherapeutic techniques. EMG analysis with surface electrodes was performed in order to obtain sufficient data about the process of local strain. Furthermore, the local strain of the muscles surrounding a healthy knee is compared with the local strain of muscles after a knee injury (ACL-rupture) with resultant atrophy. The results prove modifications of progress and amplitudes of local strain and of coordination affected by atrophy/non-atrophy. On account of the first results additional research is recommended to investigate the specific aims of the different techniques.
Anterior Cruciate Ligament↗
CT muscle scanning in the evaluation of patients with spinal muscular atrophy (SMA).
One hundred patients with spinal muscular atrophy (SMA) were assessed by CT scanning using a standardised technique. The spectrum of CT abnormality occurring in SMA was observed and by overall analysis the patients were divided into 4 groups. While the CT appearances of these groups correlated well with clinical assessment of severity of disease, the disease process was usually much more widespread than clinical examination suggested. CT abnormality was first observed in the leg and gluteal muscles, progressing to the posterior spinal, thigh, shoulder girdle and sternomastoid muscles. Hypertrophy of sartorius and gracilis was observed in a significant number of patients. Fascial planes were preserved in involved muscles in over half of the patients, even in late-stage disease. Asymmetrical muscle involvement was seen with increasing frequency as the disease process increased in extent as evaluated by CT scanning. There was no discernible difference in the CT appearances in those patients who clinically had limb-girdle, facioscapulohumeral or scapuloperoneal distribution of weakness.
Adolescent↗
Neurofilament accumulation at the motor endplate and lack of axonal sprouting in a spinal muscular atrophy mouse model.
Mutations of survival of the motor neuron gene (SMN1) are responsible for spinal muscular atrophy (SMA), a common genetic cause of death in childhood. The cellular mechanism by which mutations of SMN1 are responsible for the selective neuromuscular defect and motor neuron cell degeneration observed in SMA has not been described. We have previously generated mice carrying a homozygous deletion of Smn exon 7 directed to neurons. We report here that these mutant mice display a dramatic and progressive loss of motor axons involving both proximal and terminal regions, in agreement with the skeletal muscle denervation process and disease progression. Moreover, we found massive accumulation of neurofilaments, including phosphorylated forms, in terminal axons of the remaining neuromuscular junctions. This aberrant cytoskeletal organization of synaptic terminals was associated with reduction of branched structures of the postsynaptic apparatus and defect of axonal sprouting in mutant mice. Together, these findings may be responsible for severe motor neuron dysfunction, and suggest that loss of motor neuron cell bodies results from a 'dying-back' axonopathy in SMA. Smn mutant mice should represent a valuable model for elucidating the pathway linking Smn to cytoskeletal organization.
Animals↗