Showing papers in "Amyotrophic Lateral Sclerosis in 2003"

Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes.

Abstract: OBJECTIVE: Since the discovery of mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) ten years ago, testing for SOD1 gene mutations has become a part of the investigation of patients with suspected motor neuron disease. We searched for novel SOD1 mutations and for clinical characteristics of patients with these mutations.METHODS: Analysis was made of patient files at the Neurogenetic DNA Diagnostic Laboratory at Massachusetts General Hospital. We also scrutinized available medical records and examined patients with the different SOD1 mutations.RESULTS: One hundred and forty eight (148) of 2045 amyotrophic lateral sclerosis (ALS) patients carried a disease‐associated mutation in the SOD1 gene. The most prevalent was the A4V missense mutation, found in 41% of those patients. Sixteen novel exonic mutations (L8V, F20C, Q22L, H48R, T54R, S59I, V87A, T88ΔTAD, A89T, V97M, S105ΔSL, V118L, D124G, G141X, G147R, I151S) were found, bringing the total number of SOD1 gene mutations in ALS to 105.CONCLUSIO...

Stem cell therapy in amyotrophic lateral sclerosis: a methodological approach in humans

Abstract: INTRODUCTION: Recently it has been shown in animal models of amyotrophic lateral sclerosis (ALS) that stem cells significantly slow the progression of the disease and prolong survival. We have evaluated the feasibility and safety of a method of intraspinal cord implantation of autologous mesenchymal stem cells (MSCs) in a few well‐monitored patients with ALS.METHOD: Bone marrow collection was performed according to the standard procedure by aspiration from the posterior iliac crest. Ex vivo expansion of mesenchymal stem cells was induced according to Pittenger's protocol. The cells were suspended in 2 ml of autologous cerebrospinal fluid and transplanted into the spinal cord by a micrometric pump injector.RESULTS: No patient manifested major adverse events such as respiratory failure or death. Minor adverse events were intercostal pain irradiation (4 patients) which was reversible after a mean period of three days after surgery, and leg sensory dysesthesia (5 patients) which was reversible after a mean pe...

Amyotrophic lateral sclerosis: A review of current concepts

Abstract: Amyotrophic lateral sclerosis (ALS), once thought to be a rare neurodegenerative disease, affects between 1.2 and 1.8/100,000 individuals. This age‐dependent disorder, similar to other major neurological disorders of the aging population (Alzheimer's and Parkinson's disease) is increasing in incidence at a rate which cannot be accounted for by population aging alone. Multiple clinical variants of ALS are now recognized which are associated with a spectrum of clinical outcomes from aggressive to rather indolent. Three variants of ALS are generally accepted, including the western Pacific type (often associated with dementia), familial (the majority of which are autosomal dominant in their inheritance) and classic sporadic ALS. Considerable biological heterogeneity underlies the disease process of ALS. By the time ALS is clinically evident, derangements at the cellular level in ALS are extensive and include alterations in the cytoskeleton, mitochondrial function, microglial activation, and the metabolism of ...

Percutaneous endoscopic gastrostomy (PEG) in patients with ALS and bulbar dysfunction.

Abstract: OBJECTIVE: To compare characteristics of ALS patients with and without percutaneous endoscopic gastrostomy (PEG).METHODS: Using the ALS Patient Care Database, data from patients with and without PEG with ALS Functional Rating Scale‐bulbar subscale (ALSFRSb) scores ≤5 were analyzed; follow‐up data were also collected.RESULTS: PEG use was markedly increased with declining ALSFRSb scores. Demographics did not differ, but ALSFRS composite scores and bulbar and arm subscale scores were lower (P<0.0001). PEG patients used significantly more assistive devices, multidisciplinary care, home care nurses and aides, had more frequent physician and emergency department visits and hospital admissions (P<0.0001), and had lower health status based on the mini‐SIP scale (P=0.0047). PEG use varied greatly between ALS centers. In the follow‐up study, positive impact of PEG was noted in 79 % of PEG patients but in only 37.5% of patients who received PEG later, based on a small number of patients. PEG use showed no survival b...

Nocturnal pulse oximetry: a new approach to establish the appropriate time for non-invasive ventilation in ALS patients.

Abstract: Previous studies have supported non-invasive ventilation (NIV) in amyotrophic lateral sclerosis (ALS), indicating that it prolongs survival. However, criteria for the use of NIV are yet to be defined. The aim of the present study was to evaluate the potential use of nocturnal pulse oximetry (NPO) as a tool for determining the most appropriate time at which to initiate NIV in ALS patients. We conducted a prospective, comparative, historical-controlled clinical study of 64 consecutive ALS patients. Group 1 (historical control group) comprised 44 patients, 14 women and 30 men, with a mean age of 60+/-13 years, in whom we used NIV after detecting early signs of diurnal respiratory insufficiency (RI). Group 2 had 20 ALS patients, 8 women and 12 men, with a mean age of 56+/-11 years, for whom we started NIV after detecting more than 15 periods of nocturnal desaturation/hour by NPO. All patients were periodically evaluated with Norris spinal and bulbar scores, respiratory function tests (RFT) and NPO at three month intervals for one year. They were subsequently followed until death or loss of autonomy from the ventilator. We compared survival time or time to loss of autonomy from the ventilator between both groups. Survival was longer in Group 2 (p<0.002). We concluded that NPO is a valuable screening test to establish the need for NIV. Our results also suggest that the early diagnosis of RI and the early use of NIV increase patient compliance with NIV.

A survey of clinicians' practice in the symptomatic treatment of ALS.

Abstract: Symptomatic management is the mainstay of ALS patient care, but there are few controlled trials of drugs and interventions for common symptoms.METHODS: We queried ALS clinic neurologists to determine drugs and interventions of choice and neurologists' perceived efficacy for 14 symptoms.RESULTS: The results are tabulations of the physicians' four most frequent choices for each symptom, the physicians' perception of efficacy, the average doses and average daily costs. A wide range of drugs and interventions were nominated for management of ALS symptoms. Consensus on treatment was rare for individual symptoms, and efficacy for any symptom was judged moderate at best. A few drugs were recommended for multiple symptoms. Comparisons of perceived efficacy compared to drug costs are informative.DISCUSSION: The results of the survey emphasize the challenges of symptom management in ALS. These data aid clinical management and guide rational choices for randomized controlled trials.

Relevance of oxidative injury in the pathogenesis of motor neuron diseases.

Abstract: Oxidative stress, which results from a complex interplay of pro- and anti-oxidant forces, is generally considered to be the major effector of accumulation of oxidatively modified protein accumulation in cells, although reduced degradation due to impairment of proteolytic activity could also contribute. The discovery that a familial lateral sclerosis (ALS) results from mutations in the gene encoding Cu/Zn superoxide dismutase a anti-oxidant enzyme, stimulated considerable evaluation of reactive oxygen species (ROS) generation and oxidative protein damage in both familial and sporadic forms of the disease. Mutations in SOD1 do not cause disease by compromising dismutating activity, but through some toxic gain of function. Although exacerbation of other copper-catalyzed enzymatic activities has been demonstrated in vitro, there is little evidence substantiating that this property is responsible for toxicity in vivo. Studies of ROS generation and oxidative damage in vivo have produced mixed results, but collectively are consistent with oxidative stress playing a secondary role in pathogenesis of the disease. Studies of post-mortem tissue from sporadic ALS patients has yielded more consistent evidence of accumulation of oxidative damage to proteins, lipids, and DNA, but the time course of accumulation cannot be determined and the initiating causes of the disease have not been identified. The interplay between motor neurons and glial cells is important in the clinical progression of both familial and sporadic motor neuron diseases and release of reactive oxygen and nitrogen species or cytokines from microglia could contribute to the demise of motor neurons. This review describes the general mechanisms of radical-mediated cellular damage followed by the evidence for and against the contribution of oxidative injury to the pathogenesis of motor neuron diseases.

A prospective, randomized, placebo-controlled evaluation of corticoneuronal response to intrathecal BDNF therapy in ALS using magnetic resonance spectroscopy: feasibility and results.

Abstract: During the multicenter, phase III trial of intrathecal BDNF in ALS, we evaluated the neuronal marker N-acetylaspartate (NAA) as a surrogate marker of therapeutic efficacy using proton magnetic resonance spectroscopic imaging (MRSI) in a prospective and blinded manner. Selected subjects tolerated the study well without pump malfunction. The NAA to creatine (Cr) intensity ratio (NAA/Cr) was measured in the precentral and postcentral gyri, the superior parietal lobule, the supplementary motor area, and the premotor cortex. After 4.5+/-0.6 weeks treatment, NAA/Cr did not change significantly in any of the regions in the BDNF-treated group (n=5) compared to the placebo group (n=6). The lack of change in NAA correlated with the lack of clinical efficacy and supports the validity of NAA/Cr as a surrogate in this setting. MRSI is a feasible and safe method to evaluate intrathecal therapies in ALS.

Riluzole for ALS: what is the evidence?

Abstract: It has been eight years since the Food and Drug Administration approved riluzole as the only drug of established value in slowing disease progression for patients with ALS. The approval was based both on an initial study, which raised a number of questions about selective benefit for patients with bulbar onset, and a second much larger study which indicated equal benefit for patients with limb and bulbar onset. Both studies showed prolonged survival, albeit modest, for patients taking riluzole compared to placebo. There was concern that secondary outcome measures appeared to show no response. The Agency expressed no concern about safety issues. The drug was subsequently approved in many European countries, and most recently with a provisional approval in Canada. Cochrane reviews are rigorous, evidence-based, systematic reviews of available evidence from randomized controlled trials evaluating new therapies. Our initial Cochrane review of riluzole included only the first two trials because we had difficulty obtaining data from unpublished French and Japanese trials. A meta-analysis of the first two trials indicated a significant prolongation of survival in patients taking riluzole. There was also a functional benefit, as measured by the Norris bulbar and Norris limb scales, but no beneficial effect was found in muscle strength. Data from the French and Japanese trials later became available, and they had an impact upon these findings. When patients from the French study who had symptoms more than five years and age greater than 75 years, and who were ineligible for the second trial, were added to the meta-analysis, the results indicated an even more modest prolongation of survival (mean 1.5–2 months). The data from the Japanese trial were not added to the meta-analysis because of a different and more complex primary outcome measure in that trial. A systematic review carried out by The National Institute of Clinical Effectiveness (NICE) in the United Kingdom analyzing the data from all four trials concluded that the drug was effective and beneficial, although the benefit was modest. These studies had limitations. Secondary outcome measures including manual muscle testing and forced vital capacity were not rigorously standardized in this trial. Lack of standardization increases the variance and reduces the power of clinical trials. The Japanese data were difficult to analyze because of the complexity and difference of the primary outcome measure, which was time to failure of numerous functional end points. Utilizing similar primary outcome measures in different trials allows for meta-analysis and examination of all available evidence of a therapeutic intervention. The finding of differing survival in the placebo group when comparing data from the United States and Europe was surprising. Even though there were no statistical differences by region in the primary analysis, this led to some concern. There was no quality of life measure, and no measure of cost effectiveness in these trials. Future trials should include a quality of life measure, although there are still no widely accepted ALS-specific quality of life indicators. There is increasing concern about the cost effectiveness of medications for chronic disease and the burden of demonstrating cost effectiveness will increasingly fall both upon clinical investigators and the pharmaceutical industry. The pivotal study of riluzole was designed more than a decade ago. In the interim there have been tremendous advances in treating patients with ALS, particularly in the use of percutaneous endoscopic gastrostomy (PEG) for nutritional support, and the use of noninvasive mechanical ventilation for respiratory insufficiency. These interventions, which appear to improve quality of life and also to prolong survival, must be utilized in a standard, evidence-based and rigorous fashion in clinical trials in order to minimize the confounding impact of these standard therapies upon the results of therapeutic trials on survival. Although the neurologic community has been somewhat disappointed with the therapeutic effects of riluzole, there is a growing awareness that progress in slowing neurodegenerative diseases may well manifest itself in small increments. Even drugs which have a modest beneficial effect in slowing disease progression may prove to be useful when combined as a drug cocktail. Experience in AIDS and leukemia has tended to support this concept. Future trials should be designed and managed to detect relatively small effects which may still be clinically important.

Reduction of oxidative stress in amyotrophic lateral sclerosis following pramipexole treatment.

Abstract: Oxidative abnormalities have been identified both in familial amyotrophic lateral sclerosis (FALS) and the more prevalent sporadic ALS (SALS). Mitochondria dysfunction and toxic free radicals may play a role in this disease process, although the exact pathogenesis of both forms of ALS remains unknown. 2,3-DHBA is a hydroxylated salicylate by product that has been shown to be a reliable marker of increased free radical activity and is reliably assayed by HPLC. Following an oral salicylate load, we found elevated serum levels of 2, 3-dihydroxybenzoic acid (2,3-DHBA) and DHBA/salicylate in SALS subjects. Pramipexole has been shown to reduce oxidative stress and be neuroprotective in cell and animal models of neurodegeneration. We studied 12 SALS patients to determine the levels of 2,3-DHBA both before and after treatment with pramipexole. We found that pramipexole treatment up to 6 mg/day was well tolerated. The mean 2,3-DHBA serum levels were reduced by 45% and DHBA/salicylate ratios declined by 59% following treatment with pramipexole. SALS patients show apparent increases in systemic oxygen radical production that are reduced by pramipexole treatment at conventional doses, suggesting that pramipexole or related compounds may interrupt free radical production in SALS.

A rare Cu/Zn superoxide dismutase mutation causing familial amyotrophic lateral sclerosis with variable age of onset, incomplete penetrance and a sensory neuropathy.

Abstract: We present three members of a pedigree with familial amyotrophic lateral sclerosis (FALS) who have a rare mutation in exon 4 of Cu/Zn superoxide dismutase (SOD1) codon position 89, converting alanine to valine. This mutation was associated with incomplete penetrance and variable age of onset. The onset of the disease was late in two of our patients and early in the other. Two of our patients had symptoms and/or signs of an associated painful sensory neuropathy. The incomplete disease penetrance seen with this mutation (and others reported in the literature) emphasizes the potential value for obtaining an SOD1 genotype in patients with ALS, even if there is no apparent family history.

The genetics of motor neuron diseases.

Abstract: Motor neuron diseases may be divided into three categories: those with lower motor neuron involvement--spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA or Kennedy's disease); those with upper motor neuron involvement--primary lateral sclerosis (PLS) and the spastic paraplegias; and those with combined upper and lower motor neuron involvement--amyotrophic lateral sclerosis (ALS). Other familial motor neuron disorders include hereditary neuronopathies, GM2 gangliosidosis, and possibly the ALS/PD syndrome of Guam. The contribution of genetics to the etiopathogenesis of motor neuron considerably, accounting for a high percentage of spinal muscular atrophies, but only a small fraction of cases of ALS. The mode of inheritance also varies, with examples of autosomal dominant (AD), autosomal recessive (AR), or X-linked kindreds. (Tables 1 and 2).

Reduced p75NTR expression delays disease onset only in female mice of a transgenic model of familial amyotrophic lateral sclerosis.

Abstract: hSOD1 (G93A) transgenic mice develop pathological changes similar to those in patients with familial amyotrophic lateral sclerosis (FALS). In particular, the progressive degeneration of motoneurons is charactered in this mouse model. One feature of stressed motoneurons in ALS and the hSOD1 mice is the induction of the p75 neurotrophin receptor, which is thought, under certain circumstances, to be a death-signaling molecule. We have studied disease progression of hSOD1 (G93A) mice in the absence of the p75NTR receptor and we monitored histological changes in the ventral spinal cord. Whereas female double transgenics showed prolonged survival, this effect was not observed in males. Improved survival in female mice was not correlated with increased motoneuronal survival, but with less astrocytic activation in lumbar ventral spinal cord, as shown by glial fibrillary acidic protein immunohistochemistry. These data suggest that p75NTR is not directly involved in the mechanism leading to motoneuron degeneration. More likely, an indirect process, presumably via regulation of astrocytes, might be responsible for the increased survival responses of female double transgenic mice.

Neuroimaging in amyotrophic lateral sclerosis.

Abstract: Several neuroimaging modalities have been used with varying success to aid the clinical process of establishing the diagnosis of amyotrophic lateral sclerosis (ALS). By demonstrating evidence of oc...

Maximum Voluntary Isometric Contraction: Investigation of Reliability and Learning Effect

Abstract: Maximum Voluntary Isometric Contraction (MVIC) is a standardised, objective and sensitive tool for the measurement of muscle strength. The purpose of this study was to investigate different aspects of reliability of MVIC and to determine if a learning effect existed in a relatively new user of the system. Two clinical investigators participated in the study. The inter‐ and intra‐rater reliability of MVIC of 11 muscle groups was tested on healthy subjects (n=35). Intra‐class correlation co‐efficients (ICCs) were calculated and the statistical methods described by Bland and Altman were applied to the data. ICCs were higher for the more experienced investigator and a learning effect was demonstrated in a relatively new user of the system. Inter‐rater reliability was acceptable but lower than intra‐rater reliability. Upper limb tests generally yielded higher ICCs and lower ranges of error. The ICC was similar regardless of whether the maximum or average of the two values was taken in a single session. Utilisi...

The serotonin precursor 5‐hydroxytryptophan delays neuromuscular disease in murine familial amyotrophic lateral sclerosis

Abstract: INTRODUCTION: Reduction in the levels of whole‐blood serotonin is a common feature of Down syndrome (DS) individuals and transgenic mice overexpressing wild‐type SOD1. Administration of the metabolic precursor 5‐hydroxytryptophan (5‐HTP) leads to reversal of both serotonin deficits and hypotonia in humans. The effect of 5‐HTP treatment on the progression of motor neuron disease in mutant SOD1 mice was examined.METHODS: Pre‐disease transgenic SOD1 G93A mice and wild‐type littermates were systemically administered 5‐HTP thrice weekly (0, 5 or 50 mg/kg). Animal weights, locomotor function and survival were recorded weekly. Plasma serotonin levels were measured post‐mortem.RESULTS: Treatment with 5‐HTP significantly delayed hindlimb weakness and mortality in SOD1 G93A mice in a dose‐dependent manner. Wild‐type mice were not adversely affected by 5‐HTP administration. Baseline serotonin levels did not differ between wild‐type and ALS mice. Blood platelet serotonin levels increased proportionally with dose.CONC...

Paradigms for the identification of new genes in motor neuron degeneration

Abstract: It is estimated that between 10-20% of amyotrophic lateral sclerosis (ALS) is familial and these cases encompass recessive and dominant modes of inheritance. So far, mutations in three genes, superoxide dismutase 1 (SOD1), the p150 subunit of dynactin (DCTN1), and alsin have been shown to be directly causal for motor neuron degeneration in humans. However, clearly the disorder is genetically heterogeneous and other causal genes remain to be found that explain the vast majority of familial ALS cases. Human genetics can be problematical in that it is difficult to detect linkage in disorders in which multiple loci give similar phenotypes and where families are often small. In addition, the vertical collection of generations is often not possible with late onset disorders. An excellent genetic model of humans is provided by the mouse. We can use mouse models of neurodegeneration to find new genes in the human population. These models are not exact replicas of the human condition, but are the mouse equivalent and are incredibly valuable resources for highlighting genes and biochemical pathways disrupted in ALS and other diseases. In addition mouse models give us access to both control and affected tissues, at all stages of development and disease, thus greatly facilitating our understanding of pathogenesis. They also provide us with model systems for testing new therapies. Here we describe the approach taken to the characterization of new models of motor neuron disease and illustrate this with examples, including a recently characterized mouse model, Legs at odd angles (Loa).

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.

Abstract: 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.

Expiratory muscle weakness and assisted cough in ALS

Abstract: Elimination of airway secretion is a major issue in the care of patients with ALS. Sufficient cough flows have to be generated by expiratory muscles to allow airway clearance. Bulbar and expiratory muscle weakness are often reasons for failure of non-invasive ventilation (NIV) and may lead to tracheostomy. Expiratory aids may help to overcome these problems, at least for some time. We report a patient with advanced ALS, receiving nocturnal NIV, who gained much benefit from regular use of a mechanical in-exsufflation device.

Amyotrophic lateral sclerosis associated with pregnancy: report of four new cases and review of the literature.

Abstract: Pregnancy in women with ALS is rare and is generally considered a potentially dangerous event. We describe four ALS cases associated with pregnancy, together with a review of the literature. Three of the four women described developed ALS during pregnancy. In three cases a normal delivery was performed, with a healthy child. One patient, with severe respiratory failure, underwent an interruption of pregnancy. Seven other cases are reported in the literature, featuring a total of 11 pregnancies. The association between pregnancy and ALS is quite rare, and a pathogenic relationship cannot be excluded. The pregnancy and the delivery may be normal, but respiratory function should be carefully monitored. Generally, ALS does not have deleterious effects on fetal development. However, pregnancy in a woman with severe respiratory failure may precipitate the disease.

Can we eliminate placebo in ALS clinical trials

Abstract: BACKGROUND: Previous studies concluded that the decline in strength in patients with amyotrophic lateral sclerosis (ALS) is a linear function. If so, a patient's natural history might serve as the control, instead of placebo, in a clinical trial.METHODS: A placebo‐controlled ALS clinical trial included a natural history phase, followed by a 6‐month treatment phase. Each patient's forced vital capacity (FVC) score and maximal voluntary isometric contraction (MVIC) raw scores were measured monthly, standardized, and averaged into megascores. For 138 patients, the arm, leg, FVC, arm+leg combination, and arm+leg+FVC combination megascore slopes during the natural history phase and during the placebo phase were compared.RESULTS: The mean slope of megascores during the natural history phase and the mean slope during the placebo phase were not different for the arm, leg, and arm+leg megascores, but were different for the FVC and arm+leg+FVC combination megascores.CONCLUSIONS: Natural history controls may be usef...

Stem therapy for ALS: hope and reality.

Abstract: All are agreed that there is pressing need for an effective treatment for Amyotrophic Lateral Sclerosis (ALS; MND). Such treatment may derive from a combination of therapeutic strategies aimed at different aspects of the disorder, and might include drugs directed at the initial, intermediate or terminal cascade of events leading to cell death, as well as the use of stem cells to replace dead motor neurons, or to protect those that remain. The attraction of cell implantation or transplantation is that it might help to overcome the inability of the CNS to replace lost neurons. It is also clear that neural implantation will yield little benefit if the donor cells fail to integrate functionally into the recipient CNS circuitry. In this respect, ALS poses an especially difficult problem. The recent breakthroughs in stem cell research might nevertheless provide possibilities for neural implantation and cell replacement therapy for patients with ALS. The potential impact of these new approaches to neurodegenerative diseases has been emphasised by the many experiments using human foetal cell grafts in patients affected by Parkinson's and Huntington's disease. Clinical benefits in Parkinson's disease seem to be associated with integration of the donor cells into the recipient brain. Despite promising results, however, significant constraints have hampered the use of foetal cells for neural implantation and transplantation. Besides ethical concerns, the viability, purity, and final destiny of the foetal tissue have not been completely defined. Foetal cells are, in addition, post-mitotic and cannot be expanded or stored for long periods, necessitating close synchronisation of tissue donation and neurosurgery.

An Italian dominant FALS Leu144Phe SOD1 mutation: genotype‐phenotype correlation

Abstract: INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disease. Mutations of the Cu/Zn superoxide dismutase gene (SOD1) are responsible for 20% of autosomal dominant familial ALS (FALS).RESULTS: We examined the clinical features of the first Italian FALS with the Leu144Phe SOD1 mutation. Seven affected members were identified in a six‐generation pedigree. A slowly progressive course (20.4±14.6 years) was observed in five patients. One patient died of cardiac failure two years after the onset of the disease. The propositus is still alive. Neurological manifestations began in the legs in all patients, while bulbar signs were absent or appeared late in the course of the disease.DISCUSSION: There is evidence of a correlation between this mutation and a slowly progressive phenotype of ALS. Moreover this rare mutation might derive from a common ancestor.

Molecular and cellular basis of spinal muscular atrophy.

Abstract: Autosomal recessive spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy combined with motor neuron degeneration. SMA is caused by homozygous mutation or loss of the telomeric copy of the survival of motor neuron gene (SMN). The SMN gene is localized as an inverted repeat on chromosome 5q13. Both gene copies (SMN1 and SMN2) are expressed, but they differ in the expression of full‐length protein. SMN2 gene preferentially gives rise to a truncated and less stable version of the SMN protein and thus can not compensate for SMN1 loss or mutations unless it is not present in multiple copies. The SMN protein is part of multiprotein complexes in the cytoplasm and the nucleus of all cell types. These complexes are involved in assembly of spliceosomal snRNPs. SMN interacts with RNA polymerase II and other binding proteins, indicating that the SMN protein is involved in messenger and ribosomal RNA transcription and processing. The analysis of animal models for SMA could help to i...

Factors which predict physical and mental health status in patients with amyotrophic lateral sclerosis over time.

Abstract: OBJECTIVES: To determine which factors are predictive of physical and mental health one year after a first measurement of health status in amyotrophic lateral sclerosis (ALS) patientsMETHODS: The Physical Component Summary (PCS) score and the Mental Component Summary (MCS) score of the SF‐36 were used as the main outcome measures in patients enrolled in the European ALS Health Profile Study (ALS‐HPS) Correlation and stepwise regression procedures were used to determine the relationship between patients' physical and mental health status at follow‐up with baseline measuresRESULTS: A total of 1118 patients were recruited into the ALS‐HPS, of which 918 (8211%) returned fully or partially completed baseline and follow‐up surveys PCS scores declined over time No significant changes were reported for the MCS scores over time for patients with ALS Baseline scores were found to be significant predictors of patients' health status over timeCONCLUSIONS: Overall, patients' physical health status at the time

Spastin and paraplegin gene analysis in selected cases of motor neurone disease (MND)

Abstract: Mutations in both the spastin and paraplegin genes have been associated with upper motor neurone degeneration in hereditary spastic paraparesis. The aim of this study was to investigate if mutation in these genes is associated with upper motor neurone degeneration in primary lateral sclerosis (PLS) or selected motor neurone disease (MND) cases. DNA was extracted from whole blood and screened using single stranded conformation polymorphism and heteroduplex analysis. No mutation in the spastin or paraplegin genes was identified in the PLS or MND cases. Polymorphism was identified in the paraplegin gene but no association was shown with PLS or MND. We therefore conclude that mutation in spastin and paraplegin genes does not appear to cause PLS or MND.

Psychosocial factors and cognition in amyotrophic lateral sclerosis.

Abstract: (2003). Psychosocial factors and cognition in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders: Vol. 4, No. 4, pp. 217-224.

Health-related locus of control: does it change in motor neurone disease (MND)?

Abstract: ObjectivesPrevious studies have attempted to describe locus of control beliefs in people with MND. This exploratory, longitudinal study set out to examine some of the possible correlations of health‐related locus of control beliefs and the stability of these beliefs.Method32 people with Motor Neurone Disease completed the Multi‐dimensional Health Locus of Control (MHLC) scale, initially on average 10.3 months after diagnosis, and again on average 16.4 months after diagnosis. Physical symptoms were assessed at both times.ResultsInitially there were no correlations between MHLC beliefs or disease duration and physical symptomatology, although longer disease duration was associated with greater beliefs in the role of powerful others in health control. At the second assessment, belief in the role of powerful others controlling health had increased, with this increase relating significantly to a worsening in physical symptoms. At this second assessment, neither duration of symptoms nor time since diagnosis cor...

Rehabilitation care for patients with ALS in the Netherlands

Abstract: BACKGROUND: In the Netherlands, rehabilitation medicine plays an important role in the symptomatic and palliative treatment of ALS patients. Detailed information about the actual care of ALS patients in the Netherlands and about the attitude of consultants in rehabilitation medicine towards the management of this disease was lacking.OBJECTIVE: To obtain detailed information about the rehabilitation care for patients with ALS in the Netherlands.METHODS: We have performed a survey among all consultants in rehabilitation medicine in the Netherlands, using a questionnaire about the organisation of care and the care management of ALS patients.RESULTS: Two hundred eighty one questionnaires were gathered with a response rate of 98%. There were 14 specialised ALS centres spread throughout the country, except in the northwest and southwest. Most consultants worked with an ALS multidisciplinary team and most patients were treated in an outpatient rehabilitation clinic. Follow up visits were performed in most cases ...