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PubMed2004

On the early diagnosis of IVIg-responsive chronic multifocal acquired motor axonopathy.

Multifocal acquired motor axonopathy (MAMA) is a treatable, immune mediated motor neuropathy with purely axonal electrophysiological features. Distinction from degenerative neuronopathies such as progressive muscular atrophy (PMA) or early motor neuron disease (MND) can be difficult because of the similar clinical and electrophysiological findings. Here, we report the clinical, electrophysiological and laboratory findings in 6 patients with MAMA. Electrophysiological testing showed purely axonal findings with evidence of pathological spontaneous activity and chronic neurogenic changes. Of particular note, pathological spontaneous activity in paraspinal myotoms was not detectable in any of the patients even though it had been documented in peripheral muscles of the corresponding myotome(s). Elevated serum ganglioside antibody levels,most frequently anti-GD1a antibodies, were present in all 6 patients. IV Ig treatment led to clinical improvement in all but one patient, who showed an allergic response when exposed to IVIg. Our findings indicate that paraspinal EMG and anti-GD1a antibodies can facilitate the early identification of treatable, IVIg responsive, patients with MAMA.

Action Potentials↗
PubMed2002

Homozygous exon 7 deletion of the SMN centromeric gene (SMN2): a potential susceptibility factor for adult-onset lower motor neuron disease.

Mutations in the telomeric copy of the SMN gene (SMN1) are responsible for almost all infantile motor neuron disease (MND). In contrast, the role of the centromeric copy of the SMN gene (SMN2) in MND remains unclear. We searched for deletions of SMN1 and SMN2 in a group of 11 patients with sporadic adult-onset lower motor neuron disease (also referred to as "progressive muscular atrophy") and found an excess of patients carrying homozygous deletions of SMN2 exon 7 (36% versus 5% in the normal population). This result suggests that SMN2 deletions could act as a susceptibility factor for sporadic lower motor neuron disease in adults.

Adolescent↗
PubMed2002

Pathophysiology and treatment for cervical flexion myelopathy.

Previous studies have suggested that spinal cord compression by the vertebral bodies and intervertebral discs during neck flexion cause cervical flexion myelopathy (CFM). However, the exact pathophysiology of CFM is still unknown, and surgical treatment for CFM remains controversial. We examined retrospectively patients with CFM based on studies of the clinical features, neuroradiological findings, and neurophysiological assessments. The objectives of this paper are to investigate the pathophysiology of CFM, and to examine an optimal surgical treatment. Twenty-three patients (20 male, three female) with age of onset ranging from 11 to 23 years (mean 15.7 years) were examined for the study. All patients were inspected by magnetic resonance imaging (MRI), myelogram, or computed tomographic myelogram (CTM) of the cervical spine. In eight patients, dynamic motor evoked potentials (MEP) studies were performed. Five patients underwent surgical treatment; two patients had cervical duraplasty with laminoplasty, two patients had musculotendinous transfer, one patient had both of these procedures, and the remaining 18 patients were treated conservatively. Amyotrophy of the hand intrinsic and flexor muscle group of the forearm except the brachioradial muscle was observed hemilaterally in 20 patients and bilaterally in three patients. In three patients, T1-weighted MRI with neck flexion showed linear high intensity regions in the epidural space. In all patients, axial MRI/CTM demonstrated flattening of the spinal cord with the posterior surface of the dura mater shifting anteriorly. The amplitude of MEPs decreased after cervical flexion in two patients with progressive muscular atrophy. In three patients, dysesthesia of the upper extremities disappeared following cervical duraplasty. Musculotendinous transfer for three patients significantly improved the performance of their upper extremity. The findings of this study suggest that degenerative changes of the dura mater may be a characteristic pathology of CFM. Cervical duraplasty with laminoplasty is effective for cases at an early stage, and musculotendinous transfer should be selected in patients at a late stage.

Adolescent↗
PubMed1994

Non-NMDA receptors in motor neuron disease (MND): a quantitative autoradiographic study in spinal cord and motor cortex using [3H]CNQX and [3H]kainate.

The distribution and density of non-NMDA receptors in spinal cord and motor cortex was compared in 10 cases of motor neuron disease (MND) and 8 neurologically normal controls by quantitative autoradiography using [3H]CNQX and [3H]kainate. In the motor cortex of MND cases, an increased density of [3H]kainate binding sites was observed which was most marked in the deep layers. No significant differences were observed in [3H]CNQX binding in the motor cortex between MND and control cases. In the spinal cord significantly increased densities of both [3H]CNQX and [3]kainate binding sites were found in the substantia gelatinosa and the intermediate grey matter in the MND group. The changes in [3H]kainate binding were observed only in the amyotrophic lateral sclerosis (ALS) subgroup of MND, while the changes in [3H]CNQX binding in the spinal cord were more marked in ALS compared to progressive muscular atrophy (PMA) cases. These findings provide evidence in support of a disturbance of glutamatergic neurotransmission in MND and suggest that there may be an increased excitatory drive to motor neurons via non-NMDA receptors. It is unclear at present whether the changes observed represent a compensatory response to loss of motor neurons in MND or a pathophysiological phenomenon contributing to motor neuron degeneration. Modulation of non-NMDA receptor activity may represent a possible target for therapeutic intervention in this disease.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1994

[3H]D-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study.

The distribution and density of glutamate transporter sites was determined in human cervical and lumbar spinal cord, by quantitative autoradiography using [3H]D-aspartate. In the normal human spinal cord (n = 8) there was specific binding of [3H]D-aspartate throughout the spinal grey matter, with the highest levels observed in the substantia gelatinosa and central grey matter. In the ventral horns, particularly at the L5 level, focal hot spots of binding were observed in a distribution corresponding to that of lower motor neuron somata. Comparison of motor neuron disease (MND) cases (n = 12) with normal controls showed a reduction in the density of [3H]D-aspartate binding in the intermediate grey matter and the substantia gelatinosa of the lumbar cord. These changes were more marked in the amyotrophic lateral sclerosis (ALS) compared to the progressive muscular atrophy (PMA) subgroup, and may be due to loss of glutamatergic terminals of the corticospinal tract. The changes observed in the cervical cord were milder and did not reach statistical significance. No differences were found between [3H]D-aspartate binding in the spinal cords of the normal controls and a neurological disease control group (n = 6), suggesting that the changes observed in MND are disease specific. These findings provide further evidence in support of a disturbance of glutamatergic neurotransmission in MND.

Adult↗
PubMed1978

Lipid abnormalities in hereditary neuropathy. Part 2. Serum phospholipids.

The mean percentage of linoleate to total fatty acids in phosphatidylcholine and lysophosphatidylcholine fractions of serum phospholipids from neuropathic patients with HMN (hereditary motor neuropathy, also called distal type of progressive muscular atrophy), HMSN-I and HMSN-II (two types of peroneal muscular atrophy), and FA (Friedreich's ataxia) was reduced by approximately 10--20% (P less than 0.001). On the other hand, the mean percentage of nervonic acid in sphingomyelin was elevated by 9--20%. No significant difference was observed in phosphatidylethanolamine between neuropathic patients and control subjects. The mean concentration of phosphatidylcholine and sphingomyelin was also significantly reduced in neuropathic patients (except in HMN and HMSN-III). A significant correlation between endogenous 2-linoleoyl-sn-glycerol-3-phosphocholine and cholesteryl linoleate synthesis in vitro suggests that the decreased activity of phosphatidylcholine acyltransferase (EC 2.3.1.43; LCAT) in neuropathic patients is influenced by the fatty acid composition of their lipoprotein substrate. Furthermore, the reduction of phosphatidylcholine and of cholesteryl linoleate synthesis in vitro in neuropathic patients was affected by age and sex. It is unlikely that the reduced linoleate level in serum phosphatidylcholine for most, possibly all, of the inherited neuropathies studied here reflects a specific biochemical disorder. Possibly it reflects a more generalized biochemical alteration common to inherited neuropathy. One possibility is that biosynthesis of new membrane in axonal regeneration, segmental remyelination and Schwann cell hyperplasia may reduce the serum linoleate pool.

Adult↗
PubMed1983

Effects of polyunsaturated fatty acid diets on plasma lipids of patients with adrenomultineuronal degeneration, hepatosplenomegaly and fatty acid derangement.

The effect on plasma fatty acid composition of 3-6 weeks feeding of standard diets supplemented with various omega 6 polyenoic fatty acids (18:2, 18:3, 20:3 or 20:4) was studied in two young brothers with multineuronal degeneration plus. These boys had mental retardation or maldevelopment, neurosensory hearing loss, retinitis pigmentosa, progressive muscular atrophy, hepatosplenomegaly and adrenal failure. The study objectives were to localize the site of metabolic block and to assess the safety and short-term clinical effect of dietary treatment. Our studies have shown that the low plasma levels of 20:4 omega 6 can be corrected by feeding ethyl arachidonate and that no adverse effects were experienced. A diet enriched in ethyl linoleate produced no obvious increases of 18:2 omega 6 metabolites, indicating that these patients do not have a linoleate deficiency in their omega 6 polyenoic fatty acid pathway. Lack of incorporation of 20:4 omega 6 and a retroconversion of 20:3 omega 6 to 18:2 omega 6 after a dihomo-gamma-linolenate-enriched diet suggest that a defect of delta 5 desaturase may be involved.

Abnormalities, Multiple↗
PubMed2005

Naturally occurring Sarcocystis neurona-like infection in a dog with myositis.

Tissue stages similar to those of Sarcocystis neurona, the causative agent of equine protozoal myeloencephalitis, were identified in skeletal muscles of a dog. The dog, a 6-year-old Labrador retriever, was seropositive for Toxoplasma gondii infection and euthanized due to a history of polymyositis and progressive muscular atrophy. Histologically, 30, variably sized, microscopic, intracellular sarcocysts were observed in 60 sections of skeletal muscles taken from the neck, fore limbs and hind limbs. The cysts were only observed in inflamed skeletal muscles, but were mostly in myocytes at the periphery of areas infiltrated with leukocytes. Ultrastructurally, the cyst wall had villar protrusions consistent with sarcocysts. Immunohistochemistry with monoclonal S. neurona antibodies demonstrated positive labeling of zoites in merozoites or schizonts in the skeletal muscle interstitium, but no labeling of the sarcocysts. Initial PCR analysis with primers amplifying a genetic sequence encoding Apicomplexan 18s rRNA, and subsequent PCR analysis with differentiating primers indicated that the genetic sequences had 100% identity with sequences reported for S. neurona.

Animals↗
PubMed2005

Overexpression of MyoD-inducible lysosomal sialidase (neu1) inhibits myogenesis in C2C12 cells.

Lysosomal sialidase, encoded by neu1, is required for the removal of terminal sialic acid residues from a variety of sialoglycoconjugates. In humans, deficiency of this enzyme results in the inborn error of metabolism sialidosis, characterized by the accumulation of sialoglycoconjugates within the nervous system and in peripheral organs. A subset of sialidosis patients present with symptoms of profound muscle dysfunction, including progressive muscular atrophy. We have previously shown that the 5' regulatory region of murine neu1 is typical of skeletal muscle-specific genes due to the presence of several E-boxes and its responsiveness to stimulation by muscle regulatory factors (MRFs) such as MyoD. Here, we report that sialidase activity is increased 6-fold during the first 24 h of differentiation of C2C12 myoblasts followed by an attenuation to pre-differentiation levels by 48 h. We demonstrate that the lysosomal sialidase promoter is highly upregulated by MyoD through a mechanism that is dependent on the MyoD chromatin remodeling domain. We also show that the sialidase promoter is repressed by activated MEK. Inappropriate overexpression of sialidase 48 h after the onset of differentiation results in downregulation of myogenin as well as myosin heavy chain expression and in a halt of the differentiation cascade. This study indicates that lysosomal sialidase is a potent regulator of the early stages of myogenesis.

Animals↗
PubMed1992

Case report: selective occipital lobe hydrocephalus and agenesis of the left lobe of the liver in congenital myotonic dystrophy.

Myotonic dystrophy (Steinert's disease) is an uncommon familial autosomal dominant disease, characterized by progressive muscular atrophy and myotonia. Mental retardation, frontal baldness, cortical lenticular opacities and testicular atrophy are other prominent features of a disease that involves predominantly striated muscle. There is little information regarding this disease in the radiological literature. The present report introduces two additional findings involving the skull and the liver.

Adolescent↗
PubMed2000

Autoantibodies to acetylcholinesterase revisited.

A sensitive and specific enzyme linked immunosorbent assay (ELISA) utilizing human recombinant acetylcholinesterase has been employed for the detection of human antibodies to human acetylcholinesterase. The method can detect allogenic antibodies to the Yt(a) form of human erythrocyte AChE. Adaptation of this ELISA method allowed the IgG subclass typing of IgG anti-AChE antibodies, which could help to determine the possible role of these antibodies in the aetiology of any neurological conditions. Routine serological investigations established the AChE phenotype of each of the patients recruited, to determine whether anti-AChE antibodies were allogenic or autogenic in origin. These techniques were used to determine the incidence of autoantibodies to AChE in patients with neurological conditions, including the subtypes of motor neuron disease. The data presented are not consistent with earlier reports of a high incidence of autoantibodies to AChE in amyotrophic lateral sclerosis and progressive muscular atrophy.

Acetylcholinesterase↗
PubMed1999

Increased expression of glial cell line-derived neurotrophic factor mRNA in muscle biopsies from patients with amyotrophic lateral sclerosis.

The expression of glial cell line-derived neurotrophic factor (GDNF) mRNA and brain-derived neurotrophic factor (BDNF) mRNA were studied in muscle biopsies from five patients with amyotrophic lateral sclerosis (ALS), six patients with other neuromuscular diseases and eight healthy control persons. All five patients with ALS had higher GDNF mRNA expressions in their biopsies than the healthy control group (almost a three fold increase). Among the other patients only one, who had a rapidly progressing toxic polyneuropathy, showed a GDNF mRNA expression above those of the controls. The BDNF mRNA expressions in the biopsies from the ALS patients were in the same range as those from the healthy controls, although the mean value of the ALS patients was higher. The only biopsy that showed a markedly higher BDNF mRNA expression was taken from one patient with progressive muscular atrophy. These results suggest that increased GDNF mRNA expression in muscle is an unspecific response to ongoing denervation and that this response is maintained in ALS, at least temporarily. If increased GDNF mRNA in muscle proves to be a constant finding in ALS the rationale for the use of GDNF as a therapeutic agent in ALS must be questioned.

Adult↗
PubMed1999

A novel frameshift mutation in the McLeod syndrome gene in a Japanese family.

We report a novel mutation in the XK gene (XK) in a Japanese patient with McLeod syndrome. A 50-year-old man showed progressive muscular atrophy, choreic movement, elevated level of serum creatinine kinase, and acanthocytosis. The expression level of all the Kell antigens in erythrocyte was decreased and molecular analysis revealed a single-base (T) deletion at the nucleotide position 1095 in XK. This deletion caused a frameshift in translation, leading to a premature stop codon at the amino acid position 408. We conclude this single-base deletion causes defective Kx protein, which is responsible for the McLeod phenotype in this patient.

Amino Acid Transport Systems, Neutral↗
PubMed1998

An approach to understanding the mechanisms of poliovirus persistence in infected cells of neural or non-neural origin.

BACKGROUND: Poliovirus (PV) is the etiologic agent of paralytic poliomyelitis, which is sometimes followed, after decades of clinical stability, by new symptoms, including progressive muscular atrophy, collectively known as the post-polio syndrome. This raises the question of possible PV persistence in post polio patients. OBJECTIVE: To test the capacity of PV to establish persistent infections in human cells, three models were developed. STUDY DESIGN: This review focuses on the viral and cellular parameters involved in persistent PV infection. RESULTS: Many PV strains, which are generally lytic in primate cell lines, are able to establish persistent infections in human neuroblastoma cells. During persistent infection, PV mutants (PVpi) are consistently selected, and several of their capsid substitutions occur at positions known to be involved in PV-PV receptor interactions. PVpi have a particular property: they can establish persistent infections in non-neural HEp-2 cells. PV can also persistently infect primary cultures of human fetal brain cells and the majority of cells which survive infection belong to the neuronal lineage. CONCLUSIONS: The results obtained with the three models of persistent PV infection in human cells suggest that several mechanisms are used by PV to establish and maintain persistent infections in neural and non-neural cells. The interactions of the virus with its receptor seem to be a key-step in all cases. In the future, the elucidation of the etiology of the post-polio syndrome will require the characterization of PV sequences having persisted for decades in post-polio patients.

Animals↗
PubMed1998

Amyotrophic lateral sclerosis: current issues in classification, pathogenesis and molecular pathology.

The classification of amyotrophic lateral sclerosis (ALS) is reconsidered in the light of developments in the molecular pathogenesis and histopathology of the condition. A current view is encapsulated in the El Escorial World Federation of Neurology criteria for the diagnosis of ALS. While intended for research purposes, use of these criteria for entry into clinical trials may result in the exclusion of some patient groups with related disorders that are likely to share aetiological mechanisms but which are not classified as 'definite ALS' or 'probable ALS'. The relationship between ALS and the more restricted motor disorders of progressive lateral sclerosis and progressive muscular atrophy, together with cerebral degenerations including ALS-dementia and ALS-related frontal lobe dementia, are reviewed. The possibility is raised that they all represent syndromic manifestations of a similar pathogenetic cascade whose clinical phenotype depends upon the anatomical selectivity of involvement in each individual. The new evidence regarding the central role of oxidative stress and abnormal glutamatergic neurotransmission in familial and sporadic ALS seem applicable across these disorders. New evidence regarding the molecular pathology of inclusion bodies in these various syndromes, including ubiquitinated inclusions and hyaline conglomerate inclusions, shows striking similarities between them. Marked differences in the anatomical distribution of lesions determine the predominance and type of motor and cognitive features in each syndrome. This concept of a clinicopathological spectrum is potentially of equal relevance to other late onset neurodegenerative disorders including multisystem atrophies, the Lewy body disorders and various manifestations of Alzheimer's disease. It will gain increasing importance as therapies evolve from the symptomatic to those directed at underlying pathogenetic events.

Amyotrophic Lateral Sclerosis↗
PubMedDate not supplied

[Pes valgoplanus in Friedreich and Charcot-Marie-Tooth-Hoffmann disease].

An increasingly severe hollow foot deformity is typical of Friedreich's hereditary ataxia and Charcot-Marie-Tooth's progressive muscular atrophy. However, on the basis of personal observations it has been found that in infancy, patients with either of these diseases may have an extreme pes valgoplanus. The retrospective analysis presented here is intended to draw attention to this possibility and to point out that these diseases should also be taken into consideration in the differential diagnosis of the cause of a pes valgoplanus.

Adolescent↗