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PubMed2005

Emerging pathways for hereditary axonopathies.

Motor neurons are affected in a number of neurological diseases. Their unifying pathological signature is degeneration of extended projecting axons and loss of motor neurons in the prefrontal cortex and/or the spinal cord. Based on clinical criteria, hereditary forms have been traditionally divided into distinct entities, such as familial amyotrophic lateral sclerosis, hereditary motor neuropathy, spinal muscular atrophy, familial spinal paraplegia, and Charcot-Marie-Tooth disease type 2, also known as hereditary motor and sensory neuropathy II. Genetic research of the last decade has revealed remarkable heterogeneity within these disorders. Most of the identified genes to date cause disease in a classic Mendelian inheritance pattern with a high phenotypic penetrance. This rich source of molecular genetic data has already provided insight into the underlying major pathways of these diseases and should continue to do so in the future. This review attempts to cross the traditional clinical classifications in order to draw an emerging picture of common pathways between causative genes, providing a different perspective of this rapidly growing scientific field.

Amyotrophic Lateral Sclerosis↗
PubMed2000

Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases.

There are several incurable diseases of motor neuron degeneration, including amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, hereditary spastic hemiplegia, spinal muscular atrophy, and bulbospinal atrophy. Advances in gene transfer techniques coupled with new insights into molecular pathology have opened promising avenues for gene therapy aimed at halting disease progression. Nonviral preparations and recombinant adenoviruses, adeno-associated viruses, herpesviruses, and lentiviruses may ultimately transduce sufficient numbers of cerebral, brainstem, and spinal cord neurons for therapeutic applications. This could be accomplished by direct injection, transduction of lower motor neurons via retrograde transport after intramuscular injection, or cell-based therapies. Studies using transgenic mice expressing mutant superoxide dismutase 1 (SOD1), a model for one form of ALS, established that several proteins were neuroprotective, including calbindin, bcl-2, and growth factors. These same molecules promoted neuronal survival in other injury models, suggesting general applicability to all forms of ALS. Potentially correctable genetic lesions have also been identified for hereditary spastic hemiplegia, bulbospinal atrophy, and spinal muscular atrophy. Finally, it may be possible to repopulate lost corticospinal and lower motor neurons by transplanting stem cells or stimulating native progenitor populations. The challenge ahead is to translate these basic science breakthroughs into workable clinical practice.

Amyotrophic Lateral Sclerosis↗
PubMed2001

[Neurodegenerative diseases of the spinal cord].

Numerous classifications have been applied to describe degenerative diseases of the spinal cord before the era of molecular analysis. The present challenge is to match in an appropriate manner old and new clinical classifications with the results of genetic analysis. This work is now well advanced for spinocerebellar degeneration but needs to be developed for hereditary spastic paraplegia, spinal muscular atrophies and amyotrophic lateral sclerosis. The widening of clinical spectrum observed in hereditary neurodegenerative diseases of the spinal cord raises the question of modulating factors (environmental or genetic). Clinicians in charge of patients with progressive spinal cord signs should bear in mind that the field of degenerative diseases is a moving one and that a degenerative aetiology has to be suspected more widely than in the past.

Amyotrophic Lateral Sclerosis↗
PubMedDate not supplied

Structure, chromosomal location, and analysis of the canine Cu/Zn superoxide dismutase (SOD1) gene.

Mutations in Cu/Zn superoxide dismutase (SOD1), a major cytosolic antioxidant enzyme in eukaryotic cells, have been reported in approximately 20% of familial amyotrophic lateral sclerosis (FALS) patients. Hereditary canine spinal muscular atrophy (HCSMA), a fatal inherited motor neuron disease in Brittany spaniels, shares many clinical and pathological features with human motor neuron disease, including FALS. The SOD1 coding region has been sequenced and cloned from several animal species, but not from the dog. We have mapped the chromosomal location, sequenced, and characterized the canine SOD1 gene. Extending this analysis, we have evaluated SOD1 as a candidate for HCSMA. The 462 bp SOD1 coding region in the dog encodes 153 amino acid residues and exhibits more than 83% and 79% sequence identity to other mammalian homologues at both the nucleotide and amino acid levels, respectively. The canine SOD1 gene maps to CFA31 close to syntenic group 13 on the radiation hybrid (RH) map in the vicinity of sodium myo/inositol transporter (SMIT) gene. The human orthologous SOD1 and SMIT genes have been localized on HSA 21q22.1 and HSA 21q21, respectively, confirming the conservation of synteny between dog syntenic group 13 and HSA 21. Direct sequencing of SOD1 cDNA from six dogs with HCSMA revealed no mutations. Northern analysis indicated no differences in steady-state levels of SOD1 mRNA.

Amino Acid Sequence↗
PubMed1986

MRI of normal and pathologic skeletal muscle.

Lower extremity skeletal muscle of 22 individuals (five normal volunteers and 17 patients with muscular or neuromuscular diseases) was studied with magnetic resonance imaging. Axial images generated with spin-echo pulse sequences using short repetition times (500-900 msec TR) and short echo times (30-60 msec TE) provided excellent contrast between fat (high signal intensity) and muscle (intermediate signal intensity). Seventeen patients with clinically verified muscle disorders were evaluated in a manner similar to the normal volunteers. Conditions studied include Duchenne muscular dystrophy (three patients), limb-girdle muscular dystrophy (five), facioscapulohumeral dystrophy (three), and spinal muscular atrophy, amyotrophic lateral sclerosis, hereditary sensorimotor neuropathy, cerebral palsy, poliomyelitis, and Kearn-Sayre mitochondrial muscle disease (one each). General patterns of muscle abnormality were common among the diseases and included decreased or increased muscle size and a spectrum of muscle replacement by fat. Variable patterns were observed within disease groups and for each patient. Much phosphorus-31 spectroscopy has been performed in a blind fashion with no proton map of normal/abnormal muscle distribution to guide the spectroscopist. This study emphasizes the worth of having a muscle proton map of patients with muscle dysfunction to assure that meaningful phosphorus spectroscopic information is obtained from a volume of tissue limited to an appropriate muscle.

Adult↗
PubMed2006

Genetics of motor neuron disease.

The number of genes associated with motor neuron degeneration has increased considerably over the past few years. As more gene mutations are identified, the hope arises that certain common themes and/or pathways become clear. In this overview, we focus on recent discoveries related to amyotrophic lateral sclerosis (ALS), spinal muscular atrophies (SMA), and distal hereditary motor neuropathies (dHMN). It is striking that many of the mutated genes that were linked to these diseases encode proteins that are either directly or indirectly involved in axonal transport or play a role in RNA metabolism. We hypothesize that both phenomena are not only crucial for the normal functioning of motor neurons, but that they could also be interconnected. In analogy with the situation after acute stress, axonal mRNA translation followed by retrograde transport of the signal back to the nucleus could play an important role in chronic motor neuron diseases. We hope that information on the genetic causes of these diseases and the insight into the pathologic processes involved could ultimately lead to therapeutic strategies that prevent or at least slow this degenerative process.

Amyotrophic Lateral Sclerosis↗
PubMed2003

No association with common Caucasian genotypes in exons 8, 13 and 14 of the human cytoplasmic dynein heavy chain gene (DNCHC1) and familial motor neuron disorders.

We have shown in a mouse model of motor neuron disease, the legs-at-odd-angles (Loa) mutant, and that mutations in the cytoplasmic dynein heavy chain gene (Dnchc1) cause motor neuron degeneration. Mice exhibiting the Loa phenotype suffer progressive loss of locomotor function and homozygous animals have neuronal inclusion bodies that are positive for SOD1, CDK5, neurofilament and ubiquitin proteins. As this phenotype models some aspects of human motor neuron degeneration disorders, we think there is a reasonable likelihood that dynein may be a causative gene or susceptibility factor in human motor neuron disease. Therefore we have screened exons of this gene in a set of human patients with familial forms of disparate motor neuron degeneration diseases, affecting both upper and lower motor neurons: amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), and hereditary spastic paraplegia. As part of this study, we have determined that DNCHC1 is a large gene of 78 exons spanning 86 kb genomic length. We have focused on the exons known to be mutated in Loa, and in a very similar mouse mutation, cramping 1 (Cra1); both mutations result in loss of anterior horn cells. The exons studied are highly conserved in a wide range of eukaryotes. We screened our patient samples by sequencing and although we detect single nucleotide polymorphisms, our results show these occur at the same frequency in our patient group as in control samples of unaffected individuals. Therefore we do not find any association between familial motor neuron disease and the genotypes presented here in the exons screened.

DNA Mutational Analysis↗
PubMed2005

MEP recruitment curves in multiple sclerosis and hereditary spastic paraplegia.

OBJECTIVE: Axons remodel at multiple levels after a single inflammatory lesion in the spinal cord, which can contribute to recovery. The primary aim of this study was to investigate whether the MEP response as function of the excitatory strength, here called recruitment curves, may be used in discriminating demyelination from compensated axonal loss. Multiple sclerosis (MS) represents both demyelination and axonal degeneration. Hereditary Spastic Paraplegia (HSP) was included as a model of pure axonal loss. METHODS: To investigate both spinal and cortical recruitment, the methods used for gradual recruitment were two different test paradigms of voluntary pre-activation and stimulus intensity. The MEP-recruitment curves were obtained by means of transcranial magnetic stimulation (TMS) in 29 MS patients, 9 patients with HSP and in 30 healthy controls. RESULTS: Saturated recruitment curves were obtained in all subject groups, muscles and paradigms and were generally found to be identical. The two groups of patients had clinical signs, CMCT changes and reduced MEP amplitude reflecting relevant cortico-spinal disorder. CONCLUSIONS: We conclude that both demyelination and axonal degeneration in the CNS leads to diminished MEP amplitudes and CMCT changes. The recruitment curves of MS and HSP was identical to controls and may not be used for diagnostic or monitoring purposes.

Adult↗
PubMed1984

[Endogenous morphines in chronic progressive diseases of the central nervous system].

Using radioimmunoassay the authors studied concentrations of beta-endorphine and metenkephalin in the cerebrospinal fluid (CSF) of 65 patients with various diseases of the central nervous system (CNS)--hereditary extrapyramidal disorders, disseminated sclerosis (DS), lateral amyotrophic sclerosis (LAS), spinal tumours, senile dementia, some CNS impairments of inflammatory nature. Patients with spinal tumours showed a 4-14-fold elevation in metenkephalin levels along with a comparatively high content of beta-endorphine. In senile dementia, the concentration of both peptides was lowered. In hereditary extrapyramidal diseases, the levels of beta-endorphine were also low, while there was no concomitant decrease in the metenkephalin concentration.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Genetics of familial and sporadic amyotrophic lateral sclerosis.

Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig's disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy's disease) are a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade, identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of total cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. This review provides an overview of the genetics of both familial and sporadic forms of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1972

Transmission block in terminal nerve twigs: a single fibre electromyographic finding in man.

Single fibre electromyography has been performed in patients with partial nerve lesions, amyotrophic lateral sclerosis, progressive spinal muscle atrophy, muscular dystrophy, and distal hereditary myopathy. The recorded action potentials were often more complex than in the normal muscle due to increased fibre density in the motor unit and the individual spike components showed a large jitter and occasional blockings. Sometimes two or more spikes in a complex disappeared and reappeared simultaneously upon successive discharges. This phenomenon, called `paired blocking', has been further investigated. The jitter of the blocking potentials in relation to the rest of the complex was large, up to 500 μsec. The degree of blocking increased with increasing innervation frequency until it eventually proceeded to total block during continuous activity. Sometimes a slight effect on blocking was seen after edrophonium. This type of block is probably localized in the terminal nerve twigs, perhaps in newly formed sprouts. The phenomenon of neurogenic blocking may contribute to the fatigue clinically experienced in different denervation-reinnervation cases.

Action Potentials↗