Loss Of Anterior Horn Cells Research Articles

Sporadic four-repeat tauopathy with frontotemporal lobar degeneration, Parkinsonism, and motor neuron disease: a distinct clinicopathological and biochemical disease entity

Tau is the pathological protein in several neurodegenerative disorders classified as frontotemporal lobar degeneration (FTLD), including corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). We report an unusual tauopathy in three Japanese patients presenting with Parkinsonism and motor neuron disease (neuroimaging revealed frontotemporal cerebral atrophy in two patients who were examined). At autopsy, all cases showed FTLD with the most severe neuronal loss and gliosis evident in the premotor and precentral gyri. Although less severe, such changes were also observed in other brain regions, including the basal ganglia and substantia nigra. In the spinal cord, loss of anterior horn cells and degeneration of the corticospinal tract were evident. In addition, the affected regions exhibited neuronal cytoplasmic inclusions resembling neurofibrillary tangles. Immunostaining using antibodies against hyperphosphorylated tau and 4-repeat tau revealed widespread occurrence of neuronal and glial cytoplasmic inclusions in the central nervous system; the astrocytic tau lesions were unique, and different in morphology from astrocytic plaques in CBD, or tufted astrocytes in PSP. However, immunoblotting of frozen brain samples available in two cases revealed predominantly 4R tau, with the approximately 37-kDa and 33-kDa low-molecular mass tau fragments characteristic of CBD and PSP, respectively. No mutations were found in the tau gene in either of the two cases. Based on these clinicopathological, biochemical, and genetic findings, we consider that the present three patients form a distinct 4R tauopathy associated with sporadic FTLD.

Disrupted Glutamate Transporter Expression in the Spinal Cord With Acute Flaccid Paralysis Caused by West Nile Virus Infection

Neuroinvasive West Nile virus (WNV) infections may cause acute flaccid paralysis (AFP); in fatal cases, anterior horn cell loss is presumed to be caused by direct viral infection. In related animal models, however, glutamate excitotoxicity mediates bystander injury of uninfected anterior horn cells, suggesting additional pathogenic mechanisms. We examined expression of the principal excitatory amino acid transporter (EAAT) of astrocytes (i.e. EAAT-2 in humans, glutamate transporter 1 in hamsters) in the spinal cord of human WNV-induced AFP patients and in hamsters with WNV-induced AFP by immunohistochemistry. Glial fibrillary acidic protein, synaptic and dendritic markers (i.e. synaptophysin, microtubule-associated protein 2), immune activation (HLA-DR), and viral antigens were also evaluated. Humans and hamsters with WNV-induced AFP had decreased spinal gray matter EAAT expression despite greater numbers of glial fibrillary acidic protein-positive astrocytes compared with controls. Areas of diminished EAAT expression showed reduced synaptic and dendritic protein expression and prominent local inflammation but few infected neurons. These findings suggest that WNV infection results in local immune activation within the spinal cord that in turn causes a failure of astrocyte glutamate reuptake even as the number of astrocytes increases; rising extracellular glutamate levels may then drive excitotoxic injury of both infected and uninfected anterior horn cells. The pathogenesis of this increasingly common disorder likely involves immune response and excitotoxicity mechanisms that are potential therapeutic targets.

G.P.9.08 Insights into the pathological basis of autosomal dominant distal spinal muscular atrophy from a large Australian family

“Classical” Type 1 Spinal Muscular Atrophy (SMA) is characterised by progressive muscle weakness caused by ongoing degeneration of anterior horn cells. Clinical progression after birth is universal. It has been postulated that rarer non-progressive forms of SMA result from abnormal fetal development and/or early (fetal) loss of anterior horn cells, without ongoing postnatal cell loss. We describe a four generation family in which six family members have non-progressive distal SMA that follows clear autosomal dominant (AD) inheritance.

Spinal Muscular Atrophy with Pontocerebellar Hypoplasia Is Caused by a Mutation in the VRK1 Gene

The spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of disorders characterized by degeneration and loss of anterior horn cells in the spinal cord, leading to muscle weakness and atrophy. Spinal muscular atrophy with pontocerebellar hypoplasia (SMA-PCH, also known as pontocerebellar hypoplasia type 1 [PCH1]) is one of the rare infantile SMA variants that include additional clinical manifestations, and its genetic basis is unknown. We used a homozygosity mapping and positional cloning approach in a consanguineous family of Ashkenazi Jewish origin and identified a nonsense mutation in the vaccinia-related kinase 1 gene (VRK1) as a cause of SMA-PCH. VRK1, one of three members of the mammalian VRK family, is a serine/threonine kinase that phosphorylates p53 and CREB and is essential for nuclear envelope formation. Its identification as a gene involved in SMA-PCH implies new roles for the VRK proteins in neuronal development and maintenance and suggests the VRK genes as candidates for related phenotypes.

A dopamine receptor antagonist L-745,870 suppresses microglia activation in spinal cord and mitigates the progression in ALS model mice

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a selective loss of motor neurons in the motor cortex, brainstem, and spinal cord. It has been shown that oxidative stress plays a pivotal role in the progression of this motor neuron loss. We have previously reported that L-745,870, a dopamine D4 receptor antagonist, selectively inhibits oxidative stress-induced cell death in vitro and exerts a potent neuroprotective effect against ischemia-induced neural cell damage in gerbil. To investigate the efficacy of L-745,870 in the treatment of ALS, we here conducted a chronic administration of L-745,870 to transgenic mice expressing a mutated form of human superoxide dismutase gene (SOD1 H46R); a mouse model of familial ALS, and assessed whether the mice benefit from this treatment. The pre-onset administration of L-745,870 significantly delayed the onset of motor deficits, slowed the disease progression, and extended a life span in transgenic mice. These animals showed a delayed loss of anterior horn cells in the spinal cord concomitant with a reduced level of microglial activation at a late symptomatic stage. Further, the post-onset administration of L-745,870 to the SOD1 H46R transgenic mice remarkably slowed the disease progression and extended their life spans. Taken together, our findings in a rodent model of ALS may have implication that L-745,870 is a possible novel therapeutic means to the treatment of ALS.

Adenovirus‐mediated retrograde transfer of neurotrophin‐3 gene enhances survival of anterior horn neurons of twy/twy mice with chronic mechanical compression of the spinal cord

Chronic mechanical compression of the spinal cord causes neural tissue damage, including loss of anterior horn cells around the level of injury. Exogenous delivery of neurotrophins to neuronal cells could provide neuroprotection to a spinal cord subjected to mechanical injury. We investigated the efficacy of retrograde gene delivery of adenoviral vector (AdV) carrying neurotrophin-3 (NT-3) gene into twy (twy/twy) mouse spinal cord anterior horn neurons with chronic and progressive mechanical compression at C1-C2 level. AdV-NT-3 was used for retrograde delivery via the sternomastoid muscle to the cervical spinal accessory motoneurons in 16-week-old adult twy mice with relatively mild spinal cord compression. Four weeks after the AdV-NT-3 or AdV-beta-galactosidase cDNA (LacZ) as a marker gene injection, the compressed cervical spinal cord was examined histologically, immunohistologically, and by immunoblot analysis. Immunoreactivity to NT-3 was significantly enhanced in the AdV-NT-3-injected twy mice compared with the AdV-LacZ-injected mice. The numbers of anterior horn neurons of Nissl-, choline acetyltransferase (ChAT)-, and trkC-stained and wheat germ agglutinin-horseradish peroxidase (WGA-HRP)-labeled neurons at the spinal cord level with maximum compression were significantly higher in AdV-NT-3-transfected than in AdV-LacZ-transfected twy mice. Retrograde NT-3 gene transfer to twy mouse anterior horn neurons increased neurite axonal length and arborization of WGA-HRP-labeled neurons. Our results suggest that targeted retrograde NT-3 gene delivery is feasible in the intact animal and that it enhances neuronal survival even under chronic mechanical compression of the spinal cord.

Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy

X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.

OBSERVATIONS ON SPINE DEFORMITY AND SYRINGOMYELIA

Spine deformities, notably scoliosis, are known to occur in conjunction with syringomyelia. This study aims to analyze the effect of laminectomies performed in the course of treatment of syringomyelia. It examines the incidence, severity, and type of spine deformity as it relates to the extent and location of laminectomies performed. Records of 169 patients were analyzed for evidence of spinal deformity on imaging studies for the extent of the syringomyelic cavities and for previous surgical procedures on the spine. This analysis included patients with syringomyelia related to Chiari malformation, as well as patients with primary spinal pathology. Spinal deformities were encountered in 41% of Chiari-syringomyelia patients who had not undergone previous surgery and in 57% of such patients who underwent reoperation. Scoliosis, the most common type of deformity encountered, was likely to be mild in patients who had not undergone previous surgery and severe in reoperated patients. Spine deformity was significantly more common in those patients who had more extensive bone removal. Complete laminectomy should be avoided whenever possible in patients with syringomyelia because local denervation of the axial musculature, added to loss of medial anterior horn cells from syringomyelia, favors the development of spine deformities. This is particularly true of laminectomies performed at the junctional areas of the spine, i.e., cervical-thoracic and thoracolumbar. Hemilaminectomy usually suffices for shunt placement; instrumented stabilization should be considered in patients undergoing full laminectomy, especially those considered to be at high risk of developing deformity.

Neuromuscular Abnormalities in Ataxia Telangiectasia: A Clinical, Electrophysiological and Muscle Ultrasound Study

Thirteen classical ataxia telangiectasia (A-T) patients, varying in age from 1 to 25 years, were studied clinically, electrophysiologically as well as by muscle ultrasound to chart the development and spectrum of neuromuscular abnormalities in A-T. The most prominent finding was a progressive axonal sensorimotor polyneuropathy, apparent by electromyography and muscle ultrasound from the age of 8 years and becoming clinically discernible around 12 years of age. Before the age of 8 years decreased tendon reflexes and slightly slowed sensory nerve conduction velocities could already be observed. With routine electrophysiological techniques the severe polyneuropathy precludes conclusions about the presence of anterior horn cell loss in older patients.

Amyotrophic lateral sclerosis with dementia showing clinical parkinsonism and severe degeneration of the substantia nigra: Report of an autopsy case

An autopsy case of amyotrophic lateral sclerosis with dementia (ALS-D) showing clinically overt parkinsonism and severe degeneration of the substantia nigra is reported. The patient was a 78-year-old man who died after a 2-year clinical course characterized by parkinsonism that was responsive to Levodopa (L-DOPA) treatment. Motor neuron symptoms and dementia were not apparent ante-mortem. The autopsy demonstrated the severe degeneration of the substantia nigra without alpha-synucleinopathy-related changes. Finely granular mineralization of necrotic neurons was a unique finding in the substantia nigra. The mild loss of spinal anterior horn cells, the appearance of several Bunina bodies and the degeneration of the hippocampal subiculum and temporal cortex were also noted. A small number of ubiquitinated intra-cytoplasmic inclusions were found in neurons of the dentate fascia of the hippocampus and the temporal and frontal cortices. Although the degeneration of the substantia nigra is a common finding in ALS-D, patients seldom develop clinically overt parkinsonism. This case indicates that patients with ALS-D rarely present with predominantly parkinsonian clinical features and these symptoms and signs can be improved by L-DOPA treatment.

X-linked infantile spinal muscular atrophy: Clinical definition and molecular mapping

PurposeX-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy. We have previously reported a single family with XL-SMA that mapped to Xp11.3-q11.2. Here we report further clinical description of XL-SMA plus an additional seven unrelated (XL-SMA) families from North America and Europe that show linkage data consistent with the same region. MethodsWe first investigated linkage to the candidate disease gene region using microsatellite repeat markers. We further saturated the candidate disease gene region using polymorphic microsatellite repeat markers and single nucleotide polymorphisms in an effort to narrow the critical region. Two-point and multipoint linkage analysis was performed using the Allegro software package. ResultsLinkage analysis of all XL-SMA families displayed linkage consistent with the original XL-SMA region. ConclusionThe addition of new families and new markers has narrowed the disease gene interval for a XL-SMA locus between SNP FLJ22843 near marker DXS 8080 and SNP ARHGEF9 which is near DXS7132 (Xp11.3-Xq11.1).

Guidelines for the preclinical in vivo evaluation of pharmacological active drugs for ALS/MND: Report on the 142nd ENMC international workshop

A transgenic animal model for anterior horn cell loss was established in 1994. This model is based on the insertion of a high copy number of disease-causing human Cu/Zn SOD mutations into the intact mouse genome. It serves to establish hypotheses for the pathogenesis of anterior horn cell death, but also to test potential pharmacological approaches to therapy in human ALS. Today, more than 100 -- published and unpublished -- compounds have been tested in this animal model, a large part of them being reported as successful. However, it proved to be difficult to translate these therapeutic successes in the animal model into human trials. Also, a number of disease-modifying strategies were difficult to reproduce, even by the same group. On the other hand, the step from mice to men means a huge investment for the sponsors of clinical trials and the scientific community. Therefore, establishment of standard methods for drug testing in ALS models is mandatory. In this workshop, clinical and preclinical researchers established in the field of ALS/MND met in Holland in March 2006 in order to establish guidelines for the community for drug testing in mouse models.

Electrophysiological findings in a cohort of old polio survivors

A population-based cohort of poliomyelitis survivors was established and followed for 15 years (mean time since polio was 40 years). Over time, the cohort demonstrated a modest decline in summated compound muscle action potential amplitudes (CMAP) and a moderate decline in the summated motor unit number estimates (MUNE). There was no association between symptoms of late deterioration and magnitude of decline. Rather, the presence of these symptoms was associated with the magnitude of the residual deficits. Two patterns of neuron loss were modeled (linear and proportional decline). The summated MUNE was a more sensitive measure of loss of motor units than was the summated CMAP and appears to be a more valid measure of attritional loss of anterior horn cells. Of these two models of neuron loss, the proportional loss of motor neurons was a better fit of the data than a linear loss.

Reflexes in prior polio and their relation to weakness and anterior horn cell loss

The aim of this study was to evaluate the reflex pattern in patients with prior polio and to relate these findings to the degree of anterior horn cell (AHC) involvement and loss of muscle force. Twenty-five prior polio subjects were investigated with electromyography (EMG), force testing and reflex studies, which included the patellar and Achilles reflex, H-reflex, T-response and interlimb reflex (ILR). The clinical reflexes, H/ M-ratio and T-response amplitude at rest were positively correlated with force and negatively correlated with the degree of AHC loss. The H/ M-ratio was decreased compared with age matched controls. ILR was present in 68% of the prior polio patients but did not exist in controls. The presence of the ILR was not correlated with the degree of AHC loss or force. The reflex studies gave two main findings. The first is reduced excitability of monosynaptic connections in the motor neuron pool, which is related to weakness. The other is the presence of ILR as an indicator of interneuronal hyper-excitability, which is not related to weakness.

Severe lethal spinal muscular atrophy variant with arthrogryposis

Spinal muscular atrophies are a clinically and genetically heterogeneous group of disorders. Atypical forms of the disease have also been described, including those with associated sensory deficits, hearing loss, cerebellar hypoplasia, congenital heart defects, arthrogryposis, and bone fractures at birth. The patient described here is a male infant, born to a 30-year-old mother at 34 weeks of gestation complicated with polyhydramnios. The first son of consanguineous parents had died with the same clinical features. The patient required ventilatory support because of respiratory failure after the birth and died on day 13. His physical examination revealed profound generalized hypotonia, absence of deep tendon and neonatal reflexes, dysmorphic facies, arthrogryposis, clinodactyly, and left femur fracture. A muscle biopsy revealed variation in fiber size with occasional hypertrophic fibers. The postmortem examination revealed loss and degeneration of anterior horn cells. We propose that the patient, who presented with severe hypotonia, femur fracture, arthrogryposis, dysmorphic features, history of early death of his brother with the same clinical features and parental consanguinity, had probable X-linked spinal muscular atrophy. However, autosomal-recessive inheritance can not be completely excluded.

Familial amyotrophic lateral sclerosis with His46Arg mutation in Cu/Zn superoxide dismutase presenting characteristic clinical features and Lewy body-like hyaline inclusions

We evaluated the characteristic clinical features of one family of familial amyotrophic sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase (SOD1). Codon 46 encodes the binding site for copper and the His46Arg mutation may result in decreased copper binding and copper toxicity. The disease duration of this family was 17.8±13.2 years (mean±S.D.) with the age at onset being 42.9±4.7 years old (mean±S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the other lower limb. An autopsy was performed on a 62-year-old female member of the family who had the mutation. Her disease duration was 23 years, and she died of tonsillar herniation caused by metastasis of colon cancer in the cerebellum. Neuropathological findings showed marked loss of large anterior horn cells and very mild degeneration of corticospinal tracts as well as posterior columns. The number of nuclei of Clark's column was reduced. Lewy body-like hyaline inclusion bodies (LBHIs) were frequently seen in the remaining anterior horn cells. Astrocytic hyaline inclusions (Ast-HIs) were also seen. This is the first autopsy report of FALS with a His46Arg mutation presenting neuronal LBHIs and Ast-HIs. The formation of LBHIs and Ast-HIs may be dependent on the phenotype of the preferential lower motor neuron involvement in FALS with a SOD mutation and long disease duration.

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.

West Nile virus infection: a new acute paralytic illness.

To determine the clinical, laboratory, electrodiagnostic, radiologic, and pathologic characteristics that define the spectrum of CNS disease caused by West Nile virus (WNV) infection. The records of all patients hospitalized at the Cleveland Clinic from August 2002 to September 2002 with WNV infection were reviewed. Of 23 cases, the median age was 74 years old, and 74% were men. Symptoms included fever (100%), altered mental status (74%), gastrointestinal complaints (43%), back pain (35%), and rash (26%). In half, meningitis or encephalitis overlapped with flaccid weakness that progressed over 3 to 8 days, with a tendency to be proximal and asymmetric. Laboratory abnormalities included hyponatremia (30%) and initial CSF neutrophilic pleocytosis. Electrodiagnostic studies in two patients showed reduced motor amplitudes with normal conduction velocities and active denervation. In two other patients, reduced sensory amplitudes were also seen. MRI changes included cauda equina enhancement and parenchymal spinal cord signal abnormalities and parenchymal or leptomeningeal signal changes in the brain. Autopsy in three cases showed chronic perivascular inflammation in the brain and inflammatory changes with anterior horn cell loss in the spinal cord. An overlapping spectrum of meningitis, encephalitis, and myeloradiculitis occurs in CNS WNV infection. Fever, rash, abdominal and back pain, preceding a proximal, asymmetric flaccid weakness, with CSF pleocytosis help distinguish the motor syndrome from Guillain-Barré syndrome. Pathologic changes in the CNS resembled poliomyelitis.

Muscle cramp in Machado-Joseph disease: altered motor axonal excitability properties and mexiletine treatment.

Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.

103rd ENMC International Workshop: Designing rational therapy of SMA based on the understanding of its pathophysiology, 18–20 January 2002, Naarden, The Netherlands

A special workshop to assess the possibilities of a rational therapy of spinal muscular atrophy was convened in Naarden, attended by 24 participants. This report summarises the contributions of individual participants as well as the conclusions reached. Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder of childhood and young adults with an incidence of up to 1/10,000 live births. The main symptom of SMA is muscle weakness of varying severity according to the type of the disease. The weakness is considered to be caused by loss of anterior horn cells [1–3]. The underlying genetic defect has been localised and identified to chromosome 5q13 [4]. The gene, that localises to this region and is altered in patients with SMA, has been identified and named the SMN gene. In humans there are two different copies of this gene found at different regions of the chromosome: SMN1 gene localises to the telomeric region and SMN2 gene to the centromeric region. Only the telomeric copy of the SMN gene (SMN1) shows homozygous mutations or deletions in SMA patients, while the SMN2 gene does not seem to be affected. The two copies are not identical [4]. Full-length SMN transcripts are almost exclusively produced by SMN1, whereas the predominant form encoded by SMN2 is lacking exon 7. The truncated transcript lacking exon 7 should encode a protein lacking the last C-terminal 16 residues (SMND7). Actually, it has been recently demonstrated that SMND7 is unstable both in vitro and in vivo which explains why SMND7 protein does not protect from SMN1 defect. Nevertheless, in SMA patients where the SMN1 gene is mutated but the SMN2 gene retained, the number of copies of the SMN2 gene present is one factor that modulates the severity of the disease. The discovery of the genetic defect and the resulting alteration of SMN protein levels initiated several new and exciting lines of research giving hope for introducing a rational therapy of SMA patients. The advances in the understanding of the differences and similarities of the SMN1 and SMN2 genes and their protein products indicated that under certain conditions the SMN2 gene and its defective gene product may be modified so as to compensate for the absence of the SMN1 gene. This hope was supported by findings that in a mouse model where the complete removal of the SMN gene leads to death of the animal during embryonic development, the insertion of the human SMN2 gene allowed the survival of this lethal KO mouse [5,6]. Interestingly, the severity of the symptoms in this mouse model depended on the number of copies of the SMN2 gene reintroduced into the animal, so that the greater the number of copies the less severe were the symptoms. The sophisticated mouse models of transgenic animals where the alterations were induced either only in muscle or only in neurones [7,8] were encouraging for those interested in systems and the importance of their interactions during ontogenetic development, for they offer a model for the study of messages that are needed during development for the establishment of the normal neuromuscular system. Thus the mouse models can be useful for testing new therapeutic strategies as well as for the study of biological and biochemical mechanisms that may be altered in SMA patients and cause the ensuing paralysis. The meeting has been convened and organised to discuss these possibilities. Neuromuscular Disorders 13 (2003) 173–178