CAG repeat length in androgen receptor gene is not associated with amyotrophic lateral sclerosis

Background: Epidemiological and clinical studies show higher prevalence of amyotrophic lateral sclerosis (ALS) in males than in females and more severe lesions in androgen receptor (AR)-expressing tissues. The AR gene contains a polymorphic CAG trinucleotide repeat, whose expansion over a certain threshold is toxic to motor neurons, causing spinal and bulbar muscular atrophy (SBMA). Purpose and methods: We tested the hypothesis that the AR CAG repeat linked to SBMA is a risk factor for ALS. We analyzed AR CAG expansions in 336 patients with ALS and 100 controls. Results: We found a negative association of AR CAG expansions with ALS susceptibility, clinical presentation, and survival. Conclusions: Our findings do not support a role of the AR CAG repeat length in ALS.     

Calendar of events

We compared serum creatine kinase (CK) levels between spinobulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis (ALS) and reviewed available histochemical studies of frozen sections of muscle biopsies. CK levels and the frequency of patients with elevated CK levels were significantly higher in the SBMA group when compared with the ALS group. CK levels occasionally approached values up to 8 times the upper limit of normal in the SBMA group. In addition to the chronic neurogenic changes in the muscle biopsy, all SBMA patients showed one or more myopathic changes. Increased numbers of markedly hypertrophic fibers were consistently seen in all patients. It is not clear whether the elevated CK level is directly related to the increased number of hypertrophic fibers or to other myopathic features. Based on these findings, we recommend genetic testing for SBMA in cases of male patients with motor neuron disease who present with a significantly elevated serum creatine kinase level, even when other characteristic clinical features of SBMA are absent. Muscle Nerve 40: 126–129, 2009     

Cardiomyopathy in motor neuron diseases

OBJECTIVE: Myocardial involvement in motor neuron diseases (MND) is an uncommon feature. In amyotrophic lateral sclerosis (ALS) abnormalities of the autonomic nervous system affecting cardiac function have been described, for the hereditary spastic paraplegias (HSP) comparable manifestations are unknown. This study observed ALS and HSP patients with coexisting cardiomyopathy without major cardial risk factors. METHODS: Four patients with definite ALS and two pHSP patients. In all patients detailed clinical, cardiological, electrophysiological and laboratory data were analysed. In two ALS patients skeletal muscle biopsy was performed. RESULTS: In all investigated MND patients cardiomyopathy was present. Beside hyperlipoproteinaemia and mild hypertension in one case, none of the patients showed major cardiovascular risk factors. There was no evidence for a secondary cause of cardiomyopathy like coronary heart disease, myocarditis, or mitochondrial damage mimicking MND. CONCLUSION: This report could not conclude that the occurrence of cardiomyopathy is rare logically. Although an underlying pathophysiological cause was not obvious, it is proposed that in all MND patients a routine cardiological evaluation should be performed.     

Prediction of response to IVIg treatment in patients with lower motor neurone disorders

The distinction between multifocal motor neuropathy, treatable by intravenous immunoglobulins (IVIg), and degenerative motor neurone disorders is often difficult. To find predictive factors for the response to IVIg treatment, 40 consecutive patients with pure lower motor neurone disorders (LMND) were prospectively examined. They all received at least two times IVIg (2 g/kg bodyweight). Prior to the first and before all the following treatments a standardized evaluation was performed including clinical examination, neurophysiological and laboratory evaluation. According to changes in the neurological examination and the Neuromuscular Symptom Score, the patients were divided into responders and non-responders after the second course of treatment. In our study, no single clinical, neurophysiological, or laboratory parameter was sensitive enough to predict response. The only single parameter that highly correlated with a positive response to treatment was an elevated GM1 antibody titre. Lack of response to IVIg treatment is likely in patients with generalization of electromyographic signs of denervation beyond the clinically involved site, proximal localization of the weakness, and an elevated level of the creatinekinase. Conduction blocks do not distinguish between both groups. We propose a scoring system combining clinical, serological and neurophysiological data in order to decide which patients with LMND may receive IVIg.     

RNA processing defects associated with diseases of the motor neuron

Rapid progress in the discovery of motor neuron disease genes in amyotrophic lateral sclerosis, the spinal muscular atrophies, hereditary motor neuropathies, and lethal congenital contracture syndromes is providing new perspectives and insights into the molecular pathogenesis of the motor neuron. Motor neuron disease genes are often expressed throughout the body with essential functions in all cells. A survey of these functions indicates that motor neurons are uniquely sensitive to perturbations in RNA processing pathways dependent on the interaction of specific RNAs with specific RNA‐binding proteins, which presumably result in aberrant formation and function of ribonucleoprotein complexes. This review provides a summary of currently recognized RNA processing defects linked to human motor neuron diseases. Muscle Nerve, 2010     

Muscular fatigue and decremental response to repetitive nerve stimulation in X-linked spinobulbar muscular atrophy

Background and Purpose:  We report decremental responses to repetitive nerve stimulation (RNS) in 11 patients diagnosed with X-linked spinobulbar muscular atrophy (X-SBMA).
Methods:  The compound muscle action potential (CMAP) of the right abductor digiti minimi (ADM) and trapezius (TZ) in response to a 3-Hz stimulation of the ulnar nerve at the wrist and accessory nerve at the neck were recorded by surface electrodes.
Results:  A decremental response to RNS was observed in 90.9% of the TZ muscle and 27.2% in the ADM muscle of patients with X-SBMA.
Conclusion:  These electrophysiological features of X-SBMA are considered to be useful for diagnosis of X-SBMA. Furthermore, the waning phenomena that mostly appeared in the TZ muscle and increment of CMAP in RNS after the exercise also suggest a unique manifestation in X-SBMA.     

Cell therapy and stem cells in animal models of motor neuron disorders

Amyotrophic lateral sclerosis (ALS), spinal bulbar muscular atrophy (or Kennedy's disease), spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 are neurodegenerative disorders mainly affecting motor neurons and which currently lack effective therapies. Recent studies in animal models as well as primary and embryonic stem cell models of ALS, utilizing over-expression of mutated forms of Cu/Zn superoxide dismutase 1, have shown that motor neuron degeneration in these models is in part a non cell-autonomous event and that by providing genetically non-compromised supporting cells such as microglia or growth factor-excreting cells, onset can be delayed and survival increased. Using models of acute motor neuron injury it has been shown that embryonic stem cell-derived motor neurons implanted into the spinal cord can innervate muscle targets and improve functional recovery. Thus, a rationale exists for the development of cell therapies in motor neuron diseases aimed at either protecting and/or replacing lost motor neurons, interneurons as well as non-neuronal cells. This review evaluates approaches used in animal models of motor neuron disorders and their therapeutic relevance.     

Flaviviruses in motor neuron disease

Sporadic motor neuron disease (MND) causes a progressive loss of motor neurons. West Nile virus can attack motor neurons, so we examined whether flavivirus infection could be detected in MND cases. Spinal cord sections from 22 MND cases were stained immunohistochemically with a flavivirus-specific antibody. No staining for flavivirus was seen in any case. Sporadic MND does not appear to arise from a recent infection with a flavivirus.     

The risk of motor neurone disease and multiple sclerosis is different in Estonians and Russians. Data from South Estonia

Epidemiological studies were performed in South Estonia to establish the prevalence rate of multiple sclerosis (MS) and motor neurone disease (MND). The case finding method included information from the hospital records of the central hospital in the region-the University Hospital (for MS from 1942 to 1989), from all neurologists in the region, from the Estonian MS Society and Association of Muscular Disorders, and from nursing homes in the region. The prevalence day was 31 December 1989. MND incidence was established for the period of 1986-1995. The results demonstrated high prevalence rates of MS among native Estonians (55.3 per 100 000), somewhat lower prevalence among native-born representatives of other nationalities (43.6 per 100 000) and the lowest prevalence rate of MS among non-Estonian immigrants (26.6 per 100 000). The differences were not statistically significant. The results for MND demonstrated the opposite pattern. The mean annual incidence rate of MND for 10 years was statistically significantly higher among people of other nationalities (2.5 per 100 000) and Russians (2.6 per 100 000), and lower in native-born Estonians (1.1 per 100 000). No differences in health care or clinical picture were established. The reasons for the demonstrated differences in MND incidence remain unclear.     

Hereditary pure lower motor neuron disease with adult onset and rapid progression

We describe three members each of two families presenting with a hereditary form of lower motor neuron disease with adult onset and rapid progression and compare their pathological and clinical features with hereditary lower motor neuron disease with adult onset, as described in the literature. No involvement of upper motor neurons was found either clinically or pathologically. Disease progression was rapid, and the majority of patients died from respiratory failure within 1–5 years after onset of disease. On pathological examination of the spinal cord we found ballooned neurons, neuronophagia and gliosis in family A, which have been regarded as characteristic pathological features of infantile-onset spinal muscular atrophy (SMA). In family B specific neuronal changes were observed that also occur in patients with amyotrophic lateral sclerosis (ALS). An autosomal dominant mode of inheritance would seem likely in both families. In family A the pathological findings and the clinical presentation with symmetrical proximal limb weakness show similarities with autosomal dominant SMA. Based on the finding of pathological features in family B that also occur in ALS, together with the distal asymmetrical muscle weakness and bulbar signs and a high age at onset we hypothesize that the members of family B suffered from familial ALS. The disease forms in both families in our opinion further broaden the spectrum of motor neuron disease Received: 2 June 2000, Received in revised form: 1 September 2000, Accepted: 23 October 2000     

Protein aggregation,misfolding and consequential human neurodegenerative diseases

Proteins are major components of the biological functions in a cell. Biology demands that a protein must fold into its stable three-dimensional structure to become functional. In an unfavorable cellular environment, protein may get misfolded resulting in its aggregation. These conformational disorders are directly related to the tissue damage resulting in cellular dysfunction giving rise to different diseases. This way, several neurodegenerative diseases such as Alzheimer, Parkinson Huntington diseases and amyotrophic lateral sclerosis are caused. Misfolding of the protein is prevented by innate molecular chaperones of different classes. It is envisaged that work on this line is likely to translate the knowledge into the development of possible strategies for early diagnosis and efficient management of such related human diseases. The present review deals with the human neurodegenerative diseases caused due to the protein misfolding highlighting pathomechanisms and therapeutic intervention.     

Reduced reactivation rate in mutant CuZnSOD and progression rate of amyotrophic lateral sclerosis

Mutations in the SOD1 gene are associated with familial amyotrophic lateral sclerosis (fALS). The mechanisms by which these mutations lead to anterior horn cell loss are unknown, however, increased binding of Hsps on the demetallated mutant SOD1 has been described which would make the HSPs unavailable for other purposes, and reduce the SOD1 concentration in mitochondria, thereby creating a proapoptotic situation finally leading to motor neuron death. Here we report the recombinant expression of four human copper/zinc superoxide dismutase (CuZnSOD) variants, including the wild-type enzyme and mutant proteins associated with familial ALS. The bacterial expression level of soluble mutated proteins was influenced by the mutations leading to drastically reduced levels of soluble CuZnSOD. Simultaneously, increasing levels of insoluble and probably aggregated mutated CuZnSOD were identified in bacterial cell pellets. In addition, altered reactivation kinetics of the purified mutant apoproteins after expression in bacterial culture was shown. Biophysical and biochemical analysis showed that zinc incorporation is severely reduced in the CuZnSOD proteins associated with the most severely forms of fALS (A4V, G93A). These data indicate that a reduced holoenzyme formation rate of mutant enzymes may be a critical factor in the etiopathology of fALS.     

Gene-based treatment of motor neuron diseases

Motor neuron diseases (MND), such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), are progressive neurodegenerative diseases that share the common characteristic of upper and/or lower motor neuron degeneration. Therapeutic strategies for MND are designed to confer neuroprotection, using trophic factors, anti-apoptotic proteins, as well as antioxidants and anti-excitotoxicity agents. Although a large number of therapeutic clinical trials have been attempted, none has been shown satisfactory for MND at this time. A variety of strategies have emerged for motor neuron gene transfer. Application of these approaches has yielded therapeutic results in cell culture and animal models, including the SOD1 models of ALS. In this study we describe the gene-based treatment of MND in general, examining the potential viral vector candidates, gene delivery strategies, and main therapeutic approaches currently attempted. Finally, we discuss future directions and potential strategies for more effective motor neuron gene delivery and clinical translation.     

Maximal and minimal motor nerve conduction velocities in patients with motor neuron diseases: correlation with age of onset and duration of illness.

We measured the maximal and minimal motor nerve conduction velocities of the ulnar nerve in 17 patients with spinal muscular atrophy (SMA), 27 patients with amyotrophic lateral sclerosis (ALS), and 40 age-matched control subjects. Crude values of the maximal and minimal motor nerve conduction velocities were reduced in both patient groups, but their difference in each patient was not statistically different from that of a control subject. The conduction velocities adjusted according to each patient's age were faster in SMA patients than in ALS patients. Among patients with either ALS or SMA, the age-adjusted conduction velocities were larger in those who had developed the disease at younger ages and suffered from it for shorter periods of time. These findings suggest that the motor nerve fibers regenerate more in younger patients in the early stages of the disease, particularly in SMA.     

Genetically confirmed Huntington's disease masquerading as motor neuron disease

We describe a patient with Huntington's disease (HD) who showed asymmetrical upper limb amyotrophy as a main manifestation. Chorea and psychiatric symptoms were not prominent. Electromyography revealed generalized active and chronic denervation and fasciculations. A genetic test showed 46 CAG repeats in the huntingtin gene. Asymmetrical amyotrophy restricted to the upper limb has been reported in some patients with progressive chorea and amyotrophy without acanthocytosis, but genetically proven cases of HD have rarely been reported. It is not known why only a few HD patients show the motor neuronal loss; however, certain as‐yet‐unidentified genetic factors combined with some environment factors and the underlying cellular dysfunctions by polyglutamine aggregation could be responsible for the motor neuronal loss similar to that in amyotrophic lateral sclerosis. © 2008 Movement Disorder Society     

Prevalence of depression in amyotrophic lateral sclerosis and other motor disorders

Background: Research suggests the prevalence of severe depression in ALS is <20%. In contrast, studies have reported that severe depression affects 40–50% of patients with other neurodegenerative motor conditions (e.g. multiple sclerosis, Parkinson’s disease and Huntington’s disease). The comparison with such disorders has generated a clinical impression that patients with ALS have surprisingly low rates of depression. However, comparisons with such disorders do not take into account the markedly different pathological, physical and behavioural profiles associated with these disorders. To assess further the extent to which ALS is associated with a low prevalence of depression, we compared the prevalence of depression in patients with ALS to that in patients with neuromuscular disorders with more comparable disease profiles. Methods: The Beck Depression Inventory‐II (BDI‐II), the Major Depression Inventory (MDI), the Hospital Anxiety and Depression Scale (HADS) and the ALS Functional Rating Scale‐Revised were sent to 212 patients from a tertiary referral Motor Nerve Clinic in London, UK. Results: Data were obtained from 51 people with ALS and 39 with other neuromuscular disorders. The non‐ALS group included patients diagnosed with disorders that are characterized by motor neurone dysfunction and/or a decline in everyday function. Analyses revealed no between‐group differences on severity and prevalence rates of depression according to the BDI‐II, HADS Depression Subscale and MDI. Conclusions: Our findings do not support the impression that patients with ALS have lower rates of depression than patients with other varied neuromuscular disorders.