The landscape of cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis

Although mutations in the superoxide dismutase 1 gene account for only a minority of total amyotrophic lateral sclerosis cases, the discovery of this gene has been crucial for amyotrophic lateral sclerosis research. Since the identification of superoxide dismutase 1 in 1993, the field of amyotrophic lateral sclerosis genetics has considerably widened, improving our understanding of the diverse pathogenic basis of amyotrophic lateral sclerosis. In this review, we focus on cognitive impairment in superoxide dismutase 1-amyotrophic lateral sclerosis patients. Literature has mostly reported that cognition remains intact in superoxide dismutase 1-amyotrophic lateral sclerosis patients, but recent reports highlight frontal lobe function frailty in patients carrying different superoxide dismutase 1-amyotrophic lateral sclerosis mutations. We thoroughly reviewed all the various mutations reported in the literature to contribute to a comprehensive database of superoxide dismutase 1-amyotrophic lateral sclerosis genotype-phenotype correlation. Such a resource could ultimately improve our mechanistic understanding of amyotrophic lateral sclerosis, enabling a more robust assessment of how the amyotrophic lateral sclerosis phenotype responds to different variants across genes, which is important for the therapeutic strategy targeting genetic mutations. Cognition in superoxide dismutase 1-amyotrophic lateral sclerosis deserves further longitudinal research since this peculiar frailty in patients with similar mutations can be conditioned by external factors, including environment and other unidentified agents including modifier genes

The risk to relatives of patients with sporadic amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a neurodegenerative disease of motor neurons with a median survival of 2 years. Most patients have no family history of amyotrophic lateral sclerosis, but current understanding of such diseases suggests there should be an increased risk to relatives. Furthermore, it is a common question to be asked by patients and relatives in clinic. We therefore set out to determine the risk of amyotrophic lateral sclerosis to first degree relatives of patients with sporadic amyotrophic lateral sclerosis attending a specialist clinic. Case records of patients with sporadic amyotrophic lateral sclerosis seen at a tertiary referral centre over a 16-year period were reviewed, and pedigree structures extracted. All individuals who had originally presented with sporadic amyotrophic lateral sclerosis, but who subsequently had an affected first degree relative, were identified. Calculations were age-adjusted using clinic population demographics. Probands (n = 1502), full siblings (n = 1622) and full offspring (n = 1545) were identified. Eight of the siblings and 18 offspring had developed amyotrophic lateral sclerosis. The unadjusted risk of amyotrophic lateral sclerosis over the observation period was 0.5% for siblings and 1.0% for offspring. Age information was available for 476 siblings and 824 offspring. For this subset, the crude incidence of amyotrophic lateral sclerosis was 0.11% per year (0.05–0.21%) in siblings and 0.11% per year (0.06–0.19%) in offspring, and the clinic age-adjusted incidence rate was 0.12% per year (0.04–0.21%) in siblings. By age 85, siblings were found to have an 8-fold increased risk of amyotrophic lateral sclerosis, in comparison to the background population. In practice, this means the risk of remaining unaffected by age 85 dropped from 99.7% to 97.6%. Relatives of people with sporadic amyotrophic lateral sclerosis have a small but definite increased risk of being affected

Corticomotoneuronal function and hyperexcitability in acquired neuromyotonia

Acquired neuromyotonia encompasses a group of inflammatory disorders characterized by symptoms reflecting peripheral nerve hyperexcitability, which may be clinically confused in the early stages with amyotrophic lateral sclerosis. Despite a clear peripheral nerve focus, it remains unclear whether the ectopic activity in acquired neuromyotonia receives a central contribution. To clarify whether cortical hyperexcitability contributes to development of clinical features of acquired neuromyotonia, the present study investigated whether threshold tracking transcranial magnetic stimulation could detect cortical hyperexcitability in acquired neuromyotonia, and whether this technique could differentiate acquired neuromyotonia from amyotrophic lateral sclerosis. Cortical excitability studies were undertaken in 18 patients with acquired neuromyotonia and 104 patients with amyotrophic lateral sclerosis, with results compared to 62 normal controls. Short-interval intracortical inhibition in patients with acquired neuromyotonia was significantly different when compared to patients with amyotrophic lateral sclerosis (averaged short interval intracortical inhibition acquired neuromyotonia 11.3 ± 1.9%; amyotrophic lateral sclerosis 2.6 ± 0.9%, P < 0.001). In addition, the motor evoked potential amplitudes (acquired neuromyotonia 21.0 ± 3.1%; amyotrophic lateral sclerosis 38.1 ± 2.2%, P < 0.0001), intracortical facilitation (acquired neuromyotonia −0.9 ± 1.3%; amyotrophic lateral sclerosis −2.3 ± 0.6%, P < 0.0001), resting motor thresholds (acquired neuromyotonia 62.2 ± 1.6%; amyotrophic lateral sclerosis 57.2 ± 0.9%, P < 0.05) and cortical silent period durations (acquired neuromyotonia 212.8 ± 6.9 ms; amyotrophic lateral sclerosis 181.1 ± 4.3 ms, P < 0.0001) were significantly different between patients with acquired neuromyotonia and amyotrophic lateral sclerosis. Threshold tracking transcranial magnetic stimulation established corticomotoneuronal integrity in acquired neuromyotonia, arguing against a contribution of central processes to the development of nerve hyperexcitability in acquired neuromyotonia

Amyotrophic Lateral Sclerosis

The word amyotrophic is derived from Greek, and means “without nourishment to muscles”, lateral means to the sides and sclerosis means hardened (“What is ALS?,” n.d.). First described by Jean-Martin Charcot in the 1800s, Amyotrophic Lateral Sclerosis (ALS) is a progressive degenerative motor neuron disease. Motor neurons are very important cells, and extremely unique since they can be very long with some motor neurons having a length of over a meter (“Disease Mechanisms,” n.d.). About 5-10% of the cases of ALS are inherited, which is known as familial ALS or fALS, and it is known as autosomal dominant in these patients (“Amyotrophic lateral sclerosis”, 2019; “ALS - amyotrophic lateral sclerosis,” n.d.). In the 1950s, there was an extraordinarily high rate of ALS diagnosis in Guam. There were about fifty cases of ALS in a group of 25,500 people, five of which were classified as familial cases. This was an indication to researchers that there may have been an unknown underlying cause. A few years later the researchers defined it as familial ALS with dominant inheritance (Mathis, Goizet, Soulages, & Vallat, 2018). In the other cases of this disease, known as sporadic ALS (sALS), the cause is unknown (“Amyotrophic lateral sclerosis (ALS)”, 2019). In the United States it is often referred to as Lou Gehrig’s disease, from the famous New York Yankee baseball player who had this disease in the 1940s. This specific type of motor neuron disease is the most common form of motor neuron disease in adults (“Amyotrophic lateral sclerosis”, 2015). Motor neurons are the neurons that control movements such as walking, talking, breathing, swallowing and others. These nerve cells expand from the brain to the spinal cord and then to muscles throughout the body that control voluntary muscle movement. When the motor neurons die, the brain can no longer initiate and control muscle movement due to lack of contact (“What is ALS?,” n.d.). This disease causes the motor neurons to slowly degenerate and, eventually, become hardened and die. Without neuronal stimulation to the muscles, the muscles begin to atrophy. ALS affects the motor neurons, cerebral cortex, brainstem and spinal cord (“ALS - amyotrophic lateral sclerosis,” n.d.)

Unbiased metabolome screen leads to personalized medicine strategy for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a rapidly progressive neurodegenerative disease that affects 1/350 individuals in the United Kingdom. The cause of amyotrophic lateral sclerosis is unknown in the majority of cases. Two-sample Mendelian randomization enables causal inference between an exposure, such as the serum concentration of a specific metabolite, and disease risk. We obtained genome-wide association study summary statistics for serum concentrations of 566 metabolites which were population matched with a genome-wide association study of amyotrophic lateral sclerosis. For each metabolite, we performed Mendelian randomization using an inverse variance weighted estimate for significance testing. After stringent Bonferroni multiple testing correction, our unbiased screen revealed three metabolites that were significantly linked to the risk of amyotrophic lateral sclerosis: Estrone-3-sulphate and bradykinin were protective, which is consistent with literature describing a male preponderance of amyotrophic lateral sclerosis and a preventive effect of angiotensin-converting enzyme inhibitors which inhibit the breakdown of bradykinin. Serum isoleucine was positively associated with amyotrophic lateral sclerosis risk. All three metabolites were supported by robust Mendelian randomization measures and sensitivity analyses; estrone-3-sulphate and isoleucine were confirmed in a validation amyotrophic lateral sclerosis genome-wide association study. Estrone-3-sulphate is metabolized to the more active estradiol by the enzyme 17β-hydroxysteroid dehydrogenase 1; further, Mendelian randomization demonstrated a protective effect of estradiol and rare variant analysis showed that missense variants within HSD17B1, the gene encoding 17β-hydroxysteroid dehydrogenase 1, modify risk for amyotrophic lateral sclerosis. Finally, in a zebrafish model of C9ORF72-amyotrophic lateral sclerosis, we present evidence that estradiol is neuroprotective. Isoleucine is metabolized via methylmalonyl-CoA mutase encoded by the gene MMUT in a reaction that consumes vitamin B12. Multivariable Mendelian randomization revealed that the toxic effect of isoleucine is dependent on the depletion of vitamin B12; consistent with this, rare variants which reduce the function of MMUT are protective against amyotrophic lateral sclerosis. We propose that amyotrophic lateral sclerosis patients and family members with high serum isoleucine levels should be offered supplementation with vitamin B12

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72

A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for similar to 40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for similar to 60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis

Tackling clinical heterogeneity across the Amyotrophic Lateral Sclerosis-Frontotemporal Dementia spectrum using a transdiagnostic approach

The disease syndromes of amyotrophic lateral sclerosis and frontotemporal dementia display considerable clinical, genetic and pathological overlap, yet mounting evidence indicates substantial differences in progression and survival. To date, there has been limited examination of how profiles of brain atrophy might differ between clinical phenotypes. Here, we address this longstanding gap in the literature by assessing cortical and subcortical grey and white matter volumes on structural MRI in a large cohort of 209 participants. Cognitive and behavioural changes were assessed using the Addenbrooke’s Cognitive Examination and the Cambridge Behavioural Inventory. Relative to 58 controls, behavioural variant frontotemporal dementia (n = 58) and amyotrophic lateral sclerosis-frontotemporal dementia (n = 41) patients displayed extensive atrophy of frontoinsular, cingulate, temporal and motor cortices, with marked subcortical atrophy targeting the hippocampus, amygdala, thalamus, and striatum, with atrophy further extended to the brainstem, pons and cerebellum in the latter group. At the other end of the spectrum, pure-amyotrophic lateral sclerosis patients (n = 52) displayed considerable frontoparietal atrophy, including right insular and motor cortices and pons and brainstem regions. Subcortical regions included the bilateral pallidum and putamen, but to a lesser degree than in the amyotrophic lateral sclerosis-frontotemporal dementia and behavioural variant frontotemporal dementia groups. Across the spectrum the most affected region in all three groups was the insula, and specifically the anterior part (76-90% lower than controls). Direct comparison of the patient groups revealed disproportionate temporal atrophy and widespread subcortical involvement in amyotrophic lateral sclerosis-frontotemporal dementia relative to pure-amyotrophic lateral sclerosis. In contrast, pure-amyotrophic lateral sclerosis displayed significantly greater parietal atrophy. Both behavioural variant frontotemporal dementia and amyotrophic lateral sclerosis-frontotemporal dementia were characterised by volume decrease in the frontal lobes relative to pure-amyotrophic lateral sclerosis. The motor cortex and insula emerged as differentiating structures between clinical syndromes, with bilateral motor cortex atrophy more pronounced in amyotrophic lateral sclerosis-frontotemporal dementia compared to pure-amyotrophic lateral sclerosis, and greater left motor cortex and insula atrophy relative to behavioural variant frontotemporal dementia. Taking a transdiagnostic approach, we found significant associations between abnormal behaviour and volume loss in a predominantly frontoinsular network involving the amygdala, striatum and thalamus. Our findings demonstrate the presence of distinct atrophy profiles across the amyotrophic lateral sclerosis-frontotemporal dementia spectrum, with key structures including the motor cortex and insula, Notably, our results point to subcortical involvement in the origin of behavioural disturbances, potentially accounting for the marked phenotypic variability typically observed across the spectrum

A patient with amyotrophic lateral sclerosis and atypical clinical and electrodiagnostic features: a case report

INTRODUCTION: Amyotrophic lateral sclerosis is a rapidly progressive, fatal neurodegenerative disorder for which there is no effective treatment. The diagnosis is dependent on the clinical presentation and consistent electrodiagnostic studies. Typically, there is a combination of upper and lower motor neuron signs as well as electrodiagnostic studies indicative of diffuse motor axonal injury. The presentation of amyotrophic lateral sclerosis, however, may be variable. At the same time, the diagnosis is essential for patient prognosis and management. It is therefore important to appreciate the range of possible presentations of amyotrophic lateral sclerosis. CASE PRESENTATION: We present the case of a 57-year-old Caucasian man with pathological findings on postmortem examination consistent with amyotrophic lateral sclerosis but atypical clinical and electrodiagnostic features. He died after a rapid course of progressive weakness. The patient did not respond to immunosuppressive therapy. CONCLUSION: Amyotrophic lateral sclerosis should be considered in patients with a rapidly progressive, unexplained neuropathic process. This should be true even if there are atypical clinical and electrodiagnostic findings. Absence of response to therapy and the development of upper motor neuron signs should reinforce the possibility that amyotrophic lateral sclerosis may be present. Since amyotrophic lateral sclerosis is a fatal illness, however, the possibility of this disease in patients with atypical clinical features should not diminish the need for a thorough diagnostic evaluation and treatment trials

ATXN1 repeat expansions confer risk for amyotrophic lateral sclerosis and contribute to TDP-43 mislocalization

Increasingly, repeat expansions are being identified as part of the complex genetic architecture of amyotrophic lateral sclerosis. To date, several repeat expansions have been genetically associated with the disease: intronic repeat expansions in C9orf72, polyglutamine expansions in ATXN2 and polyalanine expansions in NIPA1. Together with previously published data, the identification of an amyotrophic lateral sclerosis patient with a family history of spinocerebellar ataxia type 1, caused by polyglutamine expansions in ATXN1, suggested a similar disease association for the repeat expansion in ATXN1. We, therefore, performed a large-scale international study in 11,700 individuals, in which we showed a significant association between intermediate ATXN1 repeat expansions and amyotrophic lateral sclerosis (P = 3.33 x 10−7). Subsequent functional experiments have shown that ATXN1 reduces the nucleocytoplasmic ratio of TDP-43 and enhances amyotrophic lateral sclerosis phenotypes in Drosophila, further emphasizing the role of polyglutamine repeat expansions in the pathophysiology of amyotrophic lateral sclerosis

Higher Risk Of Complications In Odynophagiaassociated Dysphagia In Amyotrophic Lateral Sclerosis [disfagia Associada á Odinofagia Na Esclerose Lateral Amiotrófica Pode Sugerir Maior Risco Para Complicaçes Pulmonares E Nutricionais]

Objective: This investigation aimed to identify associated factors with dysphagia severity in amyotrophic lateral sclerosis (ALS). Method: We performed a cross-sectional study of 49 patients with ALS. All patients underwent fiberoptic endoscopy evaluation of swallowing and answered a verbal questionnaire about swallowing complaints. The patients were divided into groups according to dysphagia severity. Results: Among the factors analyzed, only odynophagia was associated with moderate or severe dysphagia. Conclusion: Odynophagia was associated with moderate and severe dysphagia in ALS and suggests a high risk of pulmonary and nutritional complications.723203207Fattori, B., Grosso, M., Bongioanni, P., Assessment of swallowing by oropharyngoesophageal scintilography in patients with amyotrophic lateral sclerosis (2006) Dysphagia, 21, pp. 280-286Janzen, V.D., Hae, R., Hudson, A.J., Otolaryngologic manifestations of amyotrophic lateral sclerosis (1996) J Otolaryngol, 17, pp. 41-42Hadjikoutis, S., Wiles, C.M., Respiratory complications related to bulbar dysfunction in motor neuron disease (2001) Acta Neurol Scand, 103, pp. 207-213Oliveira, A.S.B., Pereira, R.D.B., Amyotrophic lateral sclerosis (ALS): Three letters that change the people's life (2009) Arq Neuropsiquiatr, 67, pp. 750-782O'toole, O., Traynor, B.J., Brennan, P., Epidemiology and clinical features of amyotrophic lateral sclerosis in Ireland between 1995 and 2004 (2008) J Neurol Neurosurg Psychiatry, 79, pp. 30-32Zoccolella, S., Beghi, E., Palagano, G., Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: A population based study (2008) J Neurol Neurosurg Psychiatry, 79, pp. 33-37Ganzini, L., Johnston, W.S., Hoffman, W.F., Correlates of suffering in amyotrophic lateral sclerosis (1999) Neurology, 52, pp. 1434-1440Oliver, D., The quality of care and symptom control-the effects on the terminal phase of ALS/MND (1996) J Neurol Sci, 139 (SUPPL.), pp. S134-S136Chiò, A., Canosa, A., Gallo, S., Pain in amyotrophic lateral sclerosis: A population-based controlled study (2012) Eur J Neurol, 19, pp. 551-555Wilson, J.D., (1991) Harrison's Principles of Internal Medicine, p. 417. , 12th edition. New York: McGraw-HillVaiman, M., Eviatar, E., Surface electromyography as a screening method for evaluation of dysphagia and odynophagia (2009) Head Face Med, 5, pp. 1-11Brooks, B.R., El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors (1994) J Neurol Sci, 124 (SUPPL.), pp. S96-S107McEdo Filho, E.D., Gomes, G.F., Furkim, A.M., (2000) Manual de cuidados do paciente com disfagia, , São Paulo: LovisePontes, R.T., Orsini, M., Freitas, M.R.G., Antonioli, R.S., Nascimento, O.F.M., Alterações da fonação e deglutição na esclerose lateral amiotrófica: Revisão de literatura (2010) Rev Neurocienc, 18, pp. 69-73Thomas, C.K., Zijdewind, I., Fatigue of muscles weakened by death of motoneurons (2006) Muscle Nerve, 33, pp. 21-41Handy, C.R., Krudy, C., Boulis, N., Federici, T., Pain in amyotrophic lateral sclerosis: A neglected aspect of disease (2011) Neurol Res Int, 1, pp. 1-8Brettschneider, J., Kurent, J., Ludolph, A., Mitchell, J.D., Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease (2008) Cochrane Database Syst Rev, 3, pp. CD005226Ertekin, C., Aydogdu, I., Yüceyar, N., Kiylioglu, N., Tarlaci, S., Uludag, B., Pathophysiological mechanisms of oropharyngeal dysphagia in amyotrophic lateral sclerosis (2000) Brain, 123, pp. 125-140Simmons, Z., Management strategies for patients with amyotrophic lateral sclerosis from diagnosis through death (2005) Neurologist, 11, pp. 257-270Garon, B.R., Engle, M., Ormiston, C., Reliability of the 3-oz water swallow test utilizing cough reflex as sole indicator of aspiration (1995) J Neurol Rehab, 9, pp. 139-143Pagnini, F., Lunetta, C., Banfi, P., Pain in amyotrophic lateral sclerosis: A psychological perspective (2012) Neurol Sci, 33, pp. 1193-1196Maessen, M., Veldink, J.H., van den Berg, L.H., Schouten, H.J., van der Wal Onwuteaka-Philipsen, B.D., Requests for euthanasia: Origin of suffering in ALS, heart failure, and cancer patients (2010) J Neurol, 257, pp. 1192-119