Motor Neuron Disease Group Research Articles

The prevalence of SMN gene deletion/duplication in spinal muscular atrophy families referred to neuro-genetic centers of Mashhad, Iran

BackgroundSpinal muscular atrophy (SMA) is a group of motor neuron diseases. In 95% of SMA patients, the telomeric copy of the SMN gene (SMN1) is homozygously deleted. Due to the autosomal recessive pattern of SMA inheritance, individuals with a family history of SMA are at risk of being carriers. A total of 622 individuals from SMA families, including parents, siblings, and first, second, and third-degree relatives, were recruited to the neuro-genetic clinic of Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. SMA cases and suspected carriers were referred to the genetic laboratory. Pregnant women underwent amniocentesis and chorionic villi sampling at 12–14 gestational weeks. RFLP-PCR and real-time PCR were performed for symptomatic and asymptomatic individuals (possible carriers), respectively. RFLP and real-time PCR were performed for amniotic fluid and chorionic villi samples.ResultsThe study enrolled 622 subjects from SMA-affected families, including 159 fetuses and 463 non-fetuses. Two samples were missing. A total of 268 individuals (43.2%) were healthy (wild type), 187 individuals (30.1%) were heterozygous for exon deletion of SMN1, and 143 individuals (23%) were homozygous for exon deletion of SMN1. Four individuals (0.6%) showed three copies of the SMN1 gene.ConclusionThe frequency of carriers with two SMN1 copies on a single chromosome (cis) was estimated at 2.9% (18/622), and the total rate of carriers was approximately 21.8%. Considering the high rate of SMA carriers in this study, genetic counseling and definitive prenatal diagnosis are of utmost importance for reducing the psychosocial burden of the SMA disease among Iranian families.

Clinicopathological correlates in the frontotemporal lobar degeneration-motor neuron disease spectrum.

Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease (MND) that shares a common clinical, genetic and pathologic spectrum with frontotemporal dementia (FTD). It is highly heterogeneous in its presentation and features. Up to 50% of patients with MND develop cognitive-behavioural symptoms during the course of the disease, meeting criteria for FTD in 10%-15% of cases. In the absence of a precise biomarker, neuropathology is still a valuable tool to understand disease nosology, reach a definite diagnostic confirmation and help define specific subgroups of patients with common phenotypic, genetic and biomarker profiles. However, few neuropathological series have been published, and the frequency of frontotemporal lobar degeneration (FTLD) in MND is difficult to estimate. In this work we describe a large clinicopathological series of MND patients, analysing the frequency of concurrent FTLD changes and trying to define specific subgroups of patients based on their clinical, genetic and pathological characteristics. We performed an observational, retrospective, multicentre case study. We included all cases meeting neuropathological criteria for MND from the Neurological Tissue Bank of the FRCB-IDIBAPS-Hospital Clínic Barcelona Biobank between 1994 and 2022, regardless of their last clinical diagnosis. While brain donation is encouraged in all patients, it is performed in very few, and representativeness of the cohort might not be precise for all patients with MND. We retrospectively reviewed clinical and neuropathological data and describe the main clinical, genetic and pathogenic features, comparing neuropathologic groups between MND with and without FTLD changes and aiming to define specific subgroups. We included brain samples from 124 patients, 44 of whom (35.5%) had FTLD neuropathologic features (i.e. FTLD-MND). Pathologic TDP-43 aggregates were present in 93.6% of the cohort and were more extensive (higher Brettschneider stage) in those with concurrent FTLD (P < 0.001). Motor symptom onset was more frequent in the bulbar region in FTLD-MND cases than in those with isolated MND (P = 0.023), with no differences in survival. We observed a better clinicopathological correlation in the MND group than in the FTLD-MND group (93.8% versus 61.4%; P < 0.001). Pathogenic genetic variants were more common in the FTLD-MND group, especially C9orf72. We describe a frequency of FTLD of 35.5% in our series of neuropathologically confirmed cases of MND. The FTLD-MND spectrum is highly heterogeneous in all aspects, especially in patients with FTLD, in whom it is particularly difficult to define specific subgroups. In the absence of definite biomarkers, neuropathology remains a valuable tool for a definite diagnosis, increasing our knowledge in disease nosology.

Juvenile amyotrophic lateral sclerosis caused by a mutation in the SPTLC2 gene: case presentation

Juvenile amyotrophic lateral sclerosis (ALS) is a rare group of motor neuron diseases, with the age of onset up to 25 years. Juvenile ALS more commonly has genetic origin vs. sporadic forms of ALS that develop in adulthood. Genetic analysis of these cases with early onset makes it possible to identify the genes responsible for the disease. Here we present a case of a rare variant of juvenile ALS caused due to the SPTLC2 gene mutation.&#x0D; Cases with early disease onset are characterized by slow progression and variable phenotype, which often makes accurate diagnosis challenging. Therefore patients with combined upper and lower motor neuron disorders aged under 25 years should undergo comprehensive examination, in particular to identify gene mutations.

Extreme Sawtooth-Sign in Motor Neuron Disease (MND) suggests Laryngeal Resistance to Forced Expiratory Airflow.

The impact of laryngeal dysfunction on airflow has not been well characterized in motor neuron disease (MND). This study aimed to detect and characterize extreme airflow oscillations informally observed during volitional cough and forced vital capacity (FVC) tasks in individuals with MND who demonstrated neurolaryngeal impairments including reduced speed and extent of vocal fold abduction compared to healthy controls during volitional cough expulsion. The extreme airflow oscillations in the MND group, when viewed as a flow-volume loop, appeared similar to the "sawtooth-sign." If the airflow oscillations are periodic in a range similar to phonation, they may reflect reduced laryngeal patency. Volitional cough and FVC airflow data (3 trials each) from 12 participants with MND with bulbar/laryngeal involvement (3 F; ages 45-76) and 12 healthy controls (6 F; ages 41-68) were analyzed for periodicity. Percent and absolute durations of periodicity of the flow oscillations were calculated by an algorithm applied to the airflow signals. In addition, the frequency, magnitude, and kurtosis of the periodic airflow oscillations were described and compared between groups. In both volitional cough and FVC trials, the percent of airflow periodicity during forced expiration was significantly higher (z = 3.54) in individuals with MND, adjusted for age and sex. Periodic airflow accounted for on average 28% of the total time in participants with MND and was within a frequency range similar to phonation. Magnitude of the airflow oscillations was also larger for participants with MND (z = 3.46), and kurtosis of airflow was smaller (z = -4.70) during forced expiration, indicating persistent airflow oscillations throughout exhalation. The significantly larger-magnitude, lower-kurtosis, and more prominent presence of sawtooth-like airflow periodicity within a frequency range similar to phonation observed in individuals with MND with neurolaryngeal impairments suggests glottic airflow resistance during forced expiration.

Corneal confocal microscopy in the evaluation of immune-related motor neuron disease syndrome

BackgroundTo investigate the sensitivity and specificity of corneal confocal microscopy (CCM) in the diagnosis of immune-related motor neuron disease syndrome and evaluation of the response to immunosuppressive therapy.MethodsSeventy-two patients with clinical manifestations of motor neuron disease (MND) were analysed. According to whether they had concomitant rheumatic immune disease or rheumatic immune antibody abnormalities, they were divided into an MND group (33 patients) and an immune-related MND syndrome group (39 patients). Another 10 healthy adults were selected as the control group. All individuals were examined by CCM.ResultsFor Langerhans cell(LC) density, the area under the receiver operating characteristic(ROC)curve was 0.8, the best cut-off was 67.7 cells/mm2, the sensitivity was 79.5%, and the specificity was 72.7%. For inferior whorl length (IWL), the area under the ROC curve was 0.674, the best cut-off was 17.41 mm/mm2, the sensitivity was 69.2%, and the specificity was 66.7%. After immunosuppressive therapy in 5 patients with immune-related MND syndrome, the LCD was significantly reduced (P < 0.05), and there was no statistically significant change in the IWL (P > 0.05).ConclusionThe LC density and IWL are ideal for distinguishing MND from immune-related MND syndrome. The LC density reflects the immunotherapy response sensitively.

TP6.2.13 A PEG insertion pathway for Motor Neurone Disease patients improves efficiency and patient outcomes

Abstract Aims Patients with Motor Neurone Disease (MND) often require a Percutaneous Endoscopic Gastrostomy (PEG) as a palliative procedure during the later stages of their illness, due to swallowing difficulties. More recently these are being inserted earlier before the inevitable decrease in nutritional intake and subsequent fall in albumin levels. This allows patients to eat food they enjoy rather than concentrating on maintaining intake. Insertion has traditionally been done with local anaesthetic and OGD, which can be difficult and traumatic. We propose a method of insertion using TIVA (Totally Intravenous Anaesthetic) in theatre with no intubation, performed by the surgical team, with a pathway including pre-operative anaesthetic assessment. Methods Data was collected from all PEG insertions performed in theatre from 1/1/2011 to 1/9/2019. MND patients following our pathway were compared to all other indications for PEG insertions. Length of stay (LOS), 30-day re-admission rates, 30-day, 90-day and 1-year mortality were analysed. Results 98 patients were identified. Median LOS was 3 days (mean 12.2) with a 3% 30-day mortality, 12.2% 90-day mortality and 34.7% 1-year mortality. In the MND group there were 27 patients. Median LOS was 2 days (mean 8.6) with a 7.4% (2 patients) 30-day mortality, which remained 7.4% at 90 days. There were 13 re-admissions (13.3%) overall compared to 0% in the MND group (p = 0.04 (Chi-squaredtest)). Conclusions PEG insertion under TIVA for MND patients is safe. A set pathway for admission and pre/post-insertion care increases efficiency with reduced length of stay and improves patient outcomes with no re-admissions.

Motor neuron disease as an outcome of neurodegeneration, neuroinflammation or mercury poisoning?

Amyotrophic lateral sclerosis (ALS) is the main disease in the group of motor neuron diseases. It is fatal disease that affects lateral columns of spinal cord, leads to generalized muscular atrophy. Most severe damage to respiratory muscles resulting from degeneration of motor neurons ultimately leads to certain death approximately 5 months after first symptoms onset. Mercury intoxication (MI) in some cases makes significant contribution to neurodegenerative processes or aggravates existing symptoms of ALS and simultaneously immune deficiency.

Use of non-invasive ventilation in motor neuron disease – a retrospective cohort analysis

Motor neuron disease (MND) is a neurodegenerative disorder which leads to progressive muscle weakness including respiratory muscle decline. The introduction of non-invasive ventilation (NIV) has been shown to improve quality of life, survival and slow the rate of pulmonary function decline. A retrospective chart analysis of patients who attended the MND clinic from 2014 to 2019 at a tertiary-referral, academic, teaching hospital was carried out to evaluate if NIV and greater compliance with NIV was associated with improved survival. 111 patients were included. The mean age at diagnosis was 63.8 years and 61.3% were males. 66.7% of our cohort used NIV and of this 66.7%, 44.1% were compliant. There was a significantly longer survival in those who used NIV (p = 0.002) and in those who used NIV optimally (p = 0.02) when both groups were compared to those who did not use NIV. In the bulbar MND group those who were compliant with NIV survived longer than who those who did not use NIV (p = 0.001). We found a significantly longer survival with the use of NIV, the use of NIV optimally and with use of NIV in those with bulbar onset MND compared to those who did not use NIV.

Bone Mineral Density and Body Composition in Males with Motor Neuron Disease: A Study from Teaching Hospital in Southern Part of India.

Background:Osteoporosis and sarcopenia are important aspects of motor neuron disease (MND). Individuals with amyotrophic lateral sclerosis (MND-ALS) have an increased risk of falls and fractures. Currently, the standard of care does not involve a routine assessment of bone mineral density (BMD) and body composition in these patients. We aimed to assess BMD, bone mineral parameters and body composition in men with MND and compared them with healthy controls.Methods:Consecutive males between 50 and 80 years of age diagnosed as MND-ALS by revised El Escorial criteria and able to walk unassisted attending Neurology outpatient clinic were recruited into the study. Age, gender and body mass index (BMI) matched healthy controls were recruited from the local community. BMD and body composition were assessed by dual-energy x-ray absorptiometry (DXA). Bone mineral parameters and bone turnover markers (BTMs) were also assessed in them.Results:A total of 30 subjects with MND-ALS and 33 controls were recruited. The mean age (years) was 59.2 in cases and 61.2 in controls. The mean BMD (g/cm2) between the two groups was similar; however, BTMs were significantly higher in the MND group (P < 0.05). Subjects with MND-ALS had significantly lower mean appendicular lean mass (ALM) (19.9 versus 22.4 kg; P = 0.007) and ALM corrected for BMI than the healthy control group (0.858 versus 0.934 kg/kg/m2; P = 0.034). Sarcopenic obesity (Percentage fat mass >27% + ALM/BMI <0.786 kg/kg/m2) was more prevalent in MND-ALS compared to controls (44.5% versus 16.7%; P = 0.03).Conclusion:Although BMD was not significantly different between subjects with MND-ALS and healthy controls, BTMs were significantly higher in the MND group indicating a high bone turnover state. Sarcopenia and sarcopenic obesity were also more in MND-ALS group than controls. Routine assessment for bone health parameters and body composition indices may be included in management of the patients with MND.

Spinal and bulbar muscular atrophy as a multisystem disease with motor neuron and muscle involvement: literature review and a case report

The spinal and bulbar muscular atrophy is a slowly progressive X-linked polysystemic disease associated with polyglutamine expansion in the androgen receptor gene. The mutant protein exhibits toxic properties towards neurons and myocytes. The main motor manifestations of the spinal and bulbar muscular atrophy are weakness, atrophy and fasciculation of the muscles of the limbs and bulbar group. Traditionally spinal and bulbar muscular atrophy belongs to the group of motor neuron diseases, but in recent years there is increasing evidence of a significant role of primary muscle pathology in the pathogenesis and clinical picture of this disease. This article provides a review of the literature on the pathogenesis, clinical manifestations and diagnosis of the spinal and bulbar muscular atrophy. We present a case report of the spinal and bulbar muscular atrophy with a clinical findings resembling metabolic myopathy.

Ventilatory Support and Management of Secretions in Amyotrophic Lateral Sclerosis

The term amyotrophic lateral sclerosis (ALS) comprises a group of motor neuron diseases which are characterized by rapid disease progression and poor prognosis which is mostly due to severe respiratory muscle weakness and its sequelae. Since causative treatment options are limited it is crucial to offer comprehensive symptomatic therapies to affect patients. Symptoms of respiratory muscle weakness, sleep-disordered breathing and, subsequently, chronic hypercapnic respiratory failure are known to severely affect health-related quality of life and social functioning of patients with ALS. This review article delineates the clinical presentation of respiratory muscle weakness, diagnostic procedures to assess diaphragmatic function, and practical aspects of both mechanical ventilation and cough assistance, respectively. Various technical and electrophysiological methods allow for detection of diaphragmatic weakness and nocturnal hypoventilation. These include spiro-manometric tests of respiratory muscle strength, cardiorespiratory polygraphy and polysomnography, transcutaneous capnography, and blood gas analysis. Once the diagnosis of respiratory muscle weakness is established, non-invasive ventilation, tracheostomy-invasive ventilation (if the patient agrees to it), and management of secretions all become increasingly important in the course of the disease.

Non-Motor Symptoms in Patients Suffering from Motor Neuron Diseases.

The recently postulated "disease spreading hypothesis" has gained much attention, especially for Parkinson's disease (PD). The various non-motor symptoms (NMS) in neurodegenerative diseases would be much better explained by this hypothesis than by the degeneration of disease-specific cell populations. Motor neuron disease (MND) is primarily known as a group of diseases with a selective loss of motor function. However, recent evidence suggests disease spreading into non-motor brain regions also in MND. The aim of this study was to comprehensively detect NMS in patients suffering from MND. We used a self-rating questionnaire including 30 different items of gastrointestinal, autonomic, neuropsychiatric, and sleep complaints [NMS questionnaire (NMSQuest)], which is an established tool in PD patients. 90 MND patients were included and compared to 96 controls. In total, MND patients reported significantly higher NMS scores (median: 7 points) in comparison to controls (median: 4 points). Dribbling, impaired taste/smelling, impaired swallowing, weight loss, loss of interest, sad/blues, falling, and insomnia were significantly more prevalent in MND patients compared to controls. Interestingly, excessive sweating was more reported in the MND group. Correlation analysis revealed an increase of total NMS score with disease progression. NMS in MND patients seemed to increase with disease progression, which would fit with the recently postulated "disease spreading hypothesis." The total NMS score in the MND group significantly exceeded the score for the control group, but only 8 of the 30 single complaints of the NMSQuest were significantly more often reported by MND patients. Dribbling, impaired swallowing, weight loss, and falling could primarily be connected to motor neuron degeneration and declared as motor symptoms in MND.

Network analyses reveal novel aspects of ALS pathogenesis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons, muscle atrophy and paralysis. Mutations in the human VAMP-associated protein B (hVAPB) cause a heterogeneous group of motor neuron diseases including ALS8. Despite extensive research, the molecular mechanisms underlying ALS pathogenesis remain largely unknown. Genetic screens for key interactors of hVAPB activity in the intact nervous system, however, represent a fundamental approach towards understanding the in vivo function of hVAPB and its role in ALS pathogenesis. Targeted expression of the disease-causing allele leads to neurodegeneration and progressive decline in motor performance when expressed in the adult Drosophila, eye or in its entire nervous system, respectively. By using these two phenotypic readouts, we carried out a systematic survey of the Drosophila genome to identify modifiers of hVAPB-induced neurotoxicity. Modifiers cluster in a diverse array of biological functions including processes and genes that have been previously linked to hVAPB function, such as proteolysis and vesicular trafficking. In addition to established mechanisms, the screen identified endocytic trafficking and genes controlling proliferation and apoptosis as potent modifiers of ALS8-mediated defects. Surprisingly, the list of modifiers was mostly enriched for proteins linked to lipid droplet biogenesis and dynamics. Computational analysis reveals that most modifiers can be linked into a complex network of interacting genes, and that the human genes homologous to the Drosophila modifiers can be assembled into an interacting network largely overlapping with that in flies. Identity markers of the endocytic process were also found to abnormally accumulate in ALS patients, further supporting the relevance of the fly data for human biology. Collectively, these results not only lead to a better understanding of hVAPB function but also point to potentially relevant targets for therapeutic intervention.

What is unique about quality of life in motor neurone disease? A qualitative query

Background: Quality of Life (QoL) is an important consequence in neurological clinical care. The debate about generic and disease specific measures of quality of life reflects uncertainty about whether there are unique aspects to understanding QoL in different diseases. If there are commonalities to different disabling neurological diseases, it may be credible to extrapolate from more common and better-studied conditions, like multiple sclerosis (MS) to rarer diseases like motor neurone disease (MND). Distinctions across neurological conditions would suggest that strategies to maximise QoL must be disease specific. Objectives: In this analysis our aim was to explore psychosocial factors affecting QoL in MND in comparison with MS. Methods: The study employed both semi-structured interviews and focus groups. Each focus group was consisted of either MND or MS. All interviews and group discussions were audio recorded and transcribed verbatim for a thematic analysis. Themes were inductively developed within a condition before they were compared across the two conditions for cross-sectional exploration. Results: Data was collected from 40 people with MND: 26 interviews (male=14; mean age= 64yrs; mean illness duration=1.6yrs); 14 in focus groups (male=9; mean age=62yrs; mean illness duration=3.5yrs); and from 61 people with MS: 43 interviews (male=16; mean age=52yrs; mean illness duration=15yrs); 18 in focus groups (male=6; mean age=47yrs; mean illness duration=9yrs). A codebook for each condition was developed for the analysis and saturation was achieved in both MND and MS. Whilst the analysis identified the same psychosocial domains to be important for QoL irrespective of disease, there was an aspect unique to MND of it being a terminal condition. Both MS and MND patients valued their lives, but MND patients recognised their shorter life expectancy and differed from MS patients because thoughts of imminent death adversely impacted QoL. Participant’s concerns about their death were not restricted to themselves, but extended to impact on significant others. The differences between MND and MS were further observed with regard to factors that were beneficial to QoL. Although the positive influence of environmental factors and spirituality were found in both conditions, additional implications of these factors were found amongst the MND group: it was found that the importance of environment included the place of death, and spirituality was described to provide hope even beyond death. Discussion and conclusions: The current study reveals complexity in ascertaining QoL across neurological diseases. Despite distinct illness trajectories, the same psychosocial factors were identified to be important for QoL in MND and MS. Nevertheless, MND as a terminal condition was found to further challenge patient’s QoL. The findings confirm the importance of addressing this aspect of the condition in addition to commonly investigated psychosocial factors.

Associations between laryngeal and cough dysfunction in motor neuron disease with bulbar involvement.

True vocal fold (TVF) dysfunction may lead to cough ineffectiveness. In individuals with motor neuron disease (MND), cough impairment in the context of dysphagia increases risk for aspiration and respiratory failure. This study characterizes differences and associations between TVF kinematics and airflow during cough in individuals with bulbar MND. Sequential glottal angles associated with TVF movements during volitional cough were analyzed from laryngeal video endoscopy examinations of adults with bulbar MND (n = 12) and healthy controls (n = 12) and compared with simultaneously collected cough-related airflow measures. Significant group differences were observed with airflow and TVF measures: volume acceleration (p ≤ 0.001) and post-compression abduction TVF angle average velocity (p = 0.002) were lower and expiratory phase rise time (p = 0.001) was higher in the MND group. Reductions in maximum TVF angle during post-compression abduction in the MND group approached significance (p = 0.09). All subjects demonstrated complete TVF and supraglottic closure during the compression phase of cough, except for incomplete supraglottic closure in 2/12 MND participants. A strong positive relationship between post-compression maximum TVF abduction angle and peak expiratory cough flow was observed in the MND group, though it was not statistically significant (r = 0.55; p = 0.098). Reductions in the speed and extent of TVF abduction are seen during the expulsion phase of cough in individuals with MND. This may contribute to cough impairment and morbidity.

Histone Acetylation as a Potential Therapeutic Target in Motor Neuron Degenerative Diseases

Among hereditary diseases, the group of motor neuron diseases (MNDs) includes some of the most devastating and rapidly progressive lethal conditions. Although degeneration of motor neurons is common to all of them, the phenotypic spectrum of MNDs is relatively broad and ranges from perinatal conditions like spinal muscular atrophy (SMA) to adult-onset diseases such as amyotrophic lateral sclerosis (ALS). While the understanding of the pathology of the diseases is constantly growing, the development of therapeutic approaches lags behind. In fact, there is no approved therapy for MNDs available at the moment. Recent findings demonstrated the existence of some patterns that are shared by several MNDs such as transcriptional dysregulation. In addition, conditions like SMA or certain types of Charcot-Marie-Tooth disease provide some defined targets which may be amenable to therapeutic approaches. Consequently, counteracting this dysregulation may be a valuable therapeutic option and ameliorate disease progression in MND patients. The feasibility of such an approach has been proven during the past years by the epigenetic treatment of various neoplastic entities with histone deacetylase inhibitors (HDACi). On these grounds, also epigenetic therapy of MNDs has become a promising option. So far, several HDACi have been tested in vitro and in animal models and some proceeded further and were evaluated in clinical trials. This review will summarize the advances of HDACi in MNDs and will give a perspective where the road will lead us.

Secreted VAPB/ALS8 Major Sperm Protein Domains Modulate Mitochondrial Localization and Morphology via Growth Cone Guidance Receptors

The VAPB/ALS8 major sperm protein domain (vMSP) is implicated in amyotrophic lateral sclerosis and spinal muscular atrophy, yet its function in the nervous system is not well understood. In Caenorhabditis elegans and Drosophila, the vMSP is cleaved from its transmembrane anchor and secreted in a cell type-specific fashion. We show that vMSPs secreted by neurons act on Lar-like protein-tyrosine phosphatase and Roundabout growth cone guidance receptors expressed in striated muscle. This signaling pathway promotes Arp2/3-dependent actin remodeling and mitochondrial localization to actin-rich muscle I-bands. C. elegans VAPB mutants have mitochondrial localization, morphology, mobility, and fission/fusion defects that are suppressed by Lar-like receptor or Arp2/3 inactivation. Hence, growth cone guidance receptor pathways that remodel the actin cytoskeleton have unanticipated effects on mitochondrial dynamics. We propose that neurons secrete vMSPs to promote striated muscle energy production and metabolism, in part through the regulation of mitochondrial localization and function.

Cognitive impairment in motor neuron disease.

A systematic investigation of the cognitive functions of 22 patients affected with motor neuron disease (MND) compared to 36 controls matched for age and education was performed. The MND group showed cognitive performances slightly but significantly lower than the control group; 6 MND patients, however, had decidedly pathological values. Cognitive impairment was stereotyped and global, with sparing of memory. There was no significant difference between patients with isolated involvement of the lower motor neuron and those with associated pyramidal involvement. Our neuropsychological findings are in agreement with previous clinical, neuroradiological and pathological reports indicating extra-motor cerebral involvement in MND.

HVAPB, the causative gene of a heterogeneous group of motor neuron diseases in humans, is functionally interchangeable with its Drosophila homologue DVAP-33A at the neuromuscular junction

Motor neuron diseases (MNDs) are progressive neurodegenerative disorders characterized by selective death of motor neurons leading to spasticity, muscle wasting and paralysis. Human VAMP-associated protein B (hVAPB) is the causative gene of a clinically diverse group of MNDs including amyotrophic lateral sclerosis (ALS), atypical ALS and late-onset spinal muscular atrophy. The pathogenic mutation is inherited in a dominant manner. Drosophila VAMP-associated protein of 33 kDa A (DVAP-33A) is the structural homologue of hVAPB and regulates synaptic remodeling by affecting the size and number of boutons at neuromuscular junctions. Associated with these structural alterations are compensatory changes in the physiology and ultrastructure of synapses, which maintain evoked responses within normal boundaries. DVAP-33A and hVAPB are functionally interchangeable and transgenic expression of mutant DVAP-33A in neurons recapitulates major hallmarks of the human diseases including locomotion defects, neuronal death and aggregate formation. Aggregate accumulation is accompanied by a depletion of the endogenous protein from its normal localization. These findings pinpoint to a possible role of hVAPB in synaptic homeostasis and emphasize the relevance of our fly model in elucidating the patho-physiology underlying motor neuron degeneration in humans.

Geographic distribution of amyotrophic lateral sclerosis through motor neuron disease mortality data

Amyotrophic lateral sclerosis (ALS) is a rare and devastating neurological disorder of the adult age with a prognosis of about 2-3 years from the onset of the disease. No clear cause has been identified but it seems to be a multifactorial disease with genetic and environmental components involved. Increments of mortality rates were observed since 1980 both in Italy and in many other countries. The objective of the present study is to describe the distribution of ALS mortality in Italy in the period 1980-2001 detecting single municipalities or clusters with high mortality levels for motor neuron disease (MND). ALS represents the main part (85%) of the MND group which is globally identified by the IX ICD (International Classification of Diseases and Causes of Death) 335.2 code. Death numbers and standardized mortality ratios (SMR) for MND were calculated for all Italian municipalities through the ENEA mortality database system (data source: National Institute of Statistics-ISTAT), using national mortality rates as reference. Subsequently, in order to detect municipal clusters, spatial analysis was performed. Out of the 8,099 Italian municipalities, 132 where characterized by SMR values higher than expected. Moreover 16 clusters with significant high relative risk values (RR) were identified, 12 out of them including only a single municipality. Only 22 of the municipalities with high SMR were included in the clusters. In conclusion, the two different epidemiological methodologies demonstrated to be widely complementary in detecting the geographical distribution of the disease in terms of risk for populations. A first selection of the priority areas where analytical studies should be carried on, in order to identify risk factors associated to ALS, is tentatively suggested.