Typical Amyotrophic Lateral Sclerosis Research Articles

Phenotypic diversity in ALS and the role of poly-conformational protein misfolding.

In many types of familial amyotrophic lateral sclerosis (fALS), mutations cause proteins to gain toxic properties that mediate neurodegenerative processes. It is becoming increasingly clear that the proteins involved in ALS, and those responsible for a host of other neurodegenerative diseases, share many characteristics with a growing number of prion diseases. ALS is a heterogenous disease in which the majority of cases are sporadic in their etiology. Studies investigating the inherited forms of the disease are now beginning to provide evidence that some of this heterogeneity may be due to the existence of distinct conformations that ALS-linked proteins can adopt to produce the equivalent of prion strains. In this review, we discuss the in vitro and in vivo evidence that has been generated to better understand the characteristics of these proteins and how their tertiary structure may impact the disease phenotype.

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U.

SummarySkeletal muscle has the remarkable ability to modulate its mass in response to changes in nutritional input, functional utilization, systemic disease, and age. This is achieved by the coordination of transcriptional and post-transcriptional networks and the signaling cascades balancing anabolic and catabolic processes with energy and nutrient availability. The extent to which alternative splicing regulates these signaling networks is uncertain. Here we investigate the role of the RNA-binding protein hnRNP-U on the expression and splicing of genes and the signaling processes regulating skeletal muscle hypertrophic growth. Muscle-specific Hnrnpu knockout (mKO) mice develop an adult-onset myopathy characterized by the selective atrophy of glycolytic muscle, the constitutive activation of Akt, increases in cellular and metabolic stress gene expression, and changes in the expression and splicing of metabolic and signal transduction genes. These findings link Hnrnpu with the balance between anabolic signaling, cellular and metabolic stress, and physiological growth.

Tight expression regulation of senataxin, linked to motor neuron disease and ataxia, is required to avert cell-cycle block and nucleolus disassembly

The Senataxin (SETX) protein exhibits strong sequence conservation with the helicase domain of the yeast protein Sen1p, and recessive SETX mutations cause a severe ataxia, known as Ataxia with Oculomotor Apraxia type 2, while dominant SETX mutations cause Amyotrophic Lateral Sclerosis type 4. SETX is a very low abundance protein, and its expression is tightly regulated, such that large increases in mRNA levels fail to significantly increase protein levels. Despite this, transient transfection in cell culture can boost SETX protein levels on an individual cell basis. Here we found that over-expression of normal SETX, but not enzymatically-dead SETX, is associated with S-phase cell-cycle arrest in HEK293A cells. As SETX interacts with the nuclear exosome to ensure degradation of incomplete RNA transcripts, and SETX localizes to sites of collision between the DNA replication machinery and the RNAP II complex, altered dosage or aberrant function of SETX may impede this process to promote S-phase cell-cycle arrest. Because neurons are enriched for long transcripts with additional antisense regulatory transcription, collisions of RNAP II complexes may occur in such post-mitotic cells, underscoring a role for SETX in maintaining neuron homeostasis.

Chlorovirus Acceleration of Motor Neuron Disease in SOD1G93A Transgenic Mice may Clarify some of the Augmented anti-Chlorovirus Serology in Amyotrophic Lateral Sclerosis Patients

Abstract Infections and inflammatory responses may contribute to motor neuron diseases (MND), such as Amyotrophic Lateral Sclerosis (ALS). A portion of familial ALS is caused by polymorphic Superoxide Dismutase (SOD)1 gene (SOD1G93A). As chloroviruses (CV) infect macrophages inducing inflammatory cytokines, they may contribute to ALS. Moreover, ATCV-1 is one of several chlorovirus types that encodes its own SOD1. Thus we evaluated serum from human ALS patients compared with controls for antibody against ATCV-1. In addition, we i.c. injected saline or ATCV-1 into SOD1G93A-transgenic and C57Bl/6 control mice and assessed development of ALS-like MND. Sera from ALS patients and controls had antibody to ATCV-1. However, ALS patients had significantly greater IgG1 anti-ATCV-1 compared with controls. This was accompanied by elevated IL-6, IFN-γ, and anti-Tetanus toxin antibody, but not IL-17. SOD1G93A mice inoculated with ATCV-1 had significantly accelerated development of MND, including tail paralysis, hindlimb tucking, decreased righting reflex, and latency to fall in a hanging cage lid test, compared with saline injected SOD1G93A mice. Splenic T cells of SOD1G93A and control mice showed similar IFN-γ and IL-17 responses to anti-CD3/-CD28, while Foxp3 expression overall was significantly higher in T cells of SOD1G93A compared with control mice. Inoculation with ATCV-1 decreased Foxp3 expression in SOD1G93A T cells compared with mice not given ATCV-1. These results indicate that chloroviruses, ubiquitous in fresh waters worldwide, induce antibody responses in humans that are elevated in ALS and may accelerate MND in the SOD1G93A type of familial ALS. Funding was generously provided by the Stuart Nichols ALS Research Foundation.

FUS P525L mutation causing amyotrophic lateral sclerosis and movement disorders

BackgroundMutations in the fused in sarcoma (FUS) gene have been associated with amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration, and essential tremor. Among the FUS mutations, p.P525L as a hot spot variant has been reported in more than 20 patients with ALS. Apart from the typical ALS phenotype, patients with p.P525L mutation exhibit some atypical symptoms. However, movement disorders related to p.P525L mutation have not been emphasized currently.MethodsTwo unrelated patients with ALS were evaluated through a set of clinical and laboratory tests. The genetic screening was performed through next‐generation sequencing. Muscle biopsies were performed on the 2 patients. Muscle samples were stained according to standard histological and immunohistochemical procedures.ResultsThe first patient presented with juvenile‐onset neurogenic weakness and wasting and simultaneously had dropped head, ophthalmoplegia, tremor, involuntary movements, and cognitive impairments. The second patient showed a typical ALS phenotype and prominent adventitious movements. Genetic screening disclosed de novo p.P525L FUS mutation in the 2 patients by family cosegregation analysis. Muscle biopsy showed neurogenic patterns and numerous lipid droplets aggregating in the fibers.ConclusionApart from the typical ALS phenotype, patients with p.P525L mutation in the FUS gene can present with great clinical heterogeneity including multiple movement disorders. Numerous lipid droplets in muscle fibers indicate that skeletal muscle is likely an important therapeutic target for ALS.

Different gene expression profiles in iPSC-derived motor neurons from ALS8 patients with variable clinical courses suggest mitigating pathways for neurodegeneration.

Amyotrophic lateral sclerosis type 8 (ALS8) is an autosomal dominant form of ALS, which is caused by pathogenic variants in the VAPB gene. Here we investigated five ALS8 patients, classified as 'severe' and 'mild' from a gigantic Brazilian kindred, carrying the same VAPB mutation but displaying different clinical courses. Copy number variation and whole exome sequencing analyses in such individuals ruled out previously described genetic modifiers of pathogenicity. After deriving induced pluripotent stem cells (iPSCs) for each patient (N = 5) and controls (N = 3), motor neurons were differentiated, and high-throughput RNA-Seq gene expression measurements were performed. Functional cell death and oxidative metabolism assays were also carried out in patients' iPSC-derived motor neurons. The degree of cell death and mitochondrial oxidative metabolism were similar in iPSC-derived motor neurons from mild patients and controls and were distinct from those of severe patients. Similar findings were obtained when RNA-Seq from such cells was performed. Overall, 43 genes were upregulated and 66 downregulated in the two mild ALS8 patients when compared with severe ALS8 individuals and controls. Interestingly, significantly enriched pathways found among differentially expressed genes, such as protein translation and protein targeting to the endoplasmic reticulum (ER), are known to be associated with neurodegenerative processes. Taken together, the mitigating mechanisms here presented appear to maintain motor neuron survival by keeping translational activity and protein targeting to the ER in such cells. As ALS8 physiopathology has been associated with proteostasis mechanisms in ER-mitochondria contact sites, such differentially expressed genes appear to relate to the bypass of VAPB deficiency.

103 Atypical Progressive Bulbar Palsy presenting with Dropped Head

Typical amyotrophic lateral sclerosis (ALS) presents on neurological examination with specific signs of upper and lower motor neuron degeneration (Brooks et al, 1995), which can account for 85% of patients with ALS (Turner and Talbot, 2013). There are different types of clinical presentations, including progressive bulbar palsy (PBP), Limb-onset ALS, progressive muscular atrophy (PMA) and upper motor neuron (UMN) predominant ALS. PBP has mainly brainstem signs. There are a few case reports of dropped head syndrome in ALS, mainly in patients with the limb involvement variant. Case report. A 56 year old right-handed male, presented to the clinic with four months of dysphagia to liquids and solids, neck pain and progressive neck weakness causing constant drop head. No dysarthria or other neurological symptoms, no dyspnea. Neurological examination: Cranial Nerve (CN) CN XII: Nasal voice, bilateral atrophy of the tongue with tremor and fasciculations. Motor: Diffuse atrophy and decreased tone of the sternocleidomastoid and trapezii bilaterally, strength: 2/5 in neck flexors and extensors. Sensory: Hypoesthesia of the tongue. The rest of his neurological examination was normal. Labs: Routine blood work, thyroid function tests, collagen vascular work-up, and protein electrophoresis were normal. Creatine Phosphokinase (CPK) and Acetylcholine Receptor Antibodies (AChR Ab) were negative. Brain and Spinal Cord MRI: Showed mild brainstem, cerebellar and cervical spinal atrophy. Patients with ALS initially present with symptoms localized to the limbs or bulbar muscles. A very small percentage 1-2% of ALS patients had neck muscle weakness with head drop (Jokelainen et al, 1977; Gourie-Devi et al, 2003). However, in all the previously reported cases, the patients had limb involvement at the time of presentation which was absent in this case, and the head drop occurred after the onset of symptoms (Lange et al, 1986; Katz et al; 1996). Dropped head syndrome can be seen in inflammatory myopathies, myasthenia gravis, facioscapulohumeral muscular dystrophy, spinal muscular atrophy, nemaline myopathy and carnitine deficiency (Umapathy et al, 2003) but ALS should also be considered in patients with atypical presentations.

Characterization of the amyotrophic lateral sclerosis-linked P56S mutation of the VAPB gene in Southern Brazil

Objective: Amyotrophic lateral sclerosis (ALS) is a rare worldwide heterogeneous neurodegenerative disease with sporadic and familial (FALS) forms. A rare autosomal dominant subtype of FALS was identified in a Brazilian family, classified as ALS type 8 (ALS8) linked to the VAPB gene. The aim of our study was to analyze a series of ALS8 patients from unrelated families in order to further characterize the disease. Methods: We reviewed only patients with probable or definite ALS according to the Awaji criteria being managed at a single center between 2004 and 2018 and with DNA samples available for genetic analysis. A retrospective analysis of clinical, laboratory, and electrophysiological features was performed, relevant data were recorded and DNA was analyzed to detect VAPB gene mutation. Results: Thirty-one ALS patients were eligible for genetic screening for ALS8 and the mutation was detected in five patients from unrelated families. The mean age of onset was 45 ± 5.3 years for the ALS8 group and 47.6 ± 13.1 years for the non-ALS8 group and the time between symptom onset and last follow-up was longer for ALS8 patients. Three patients in the ALS8 group had tremor (60%), four had pain in affected limb (80%) and all had cramps and abdominal protrusion. Conclusions: This study presents the largest series of ALS8 patients in southern Brazil. Our findings demonstrate several clinical features that may be characteristic of ALS8 and confirm that clinicians should suspect ALS8 when the clinical manifestations include cramps, abdominal protrusion, pain, and tremor.

A comprehensive serum lipidome profiling of amyotrophic lateral sclerosis

Objective: To perform a comprehensive lipid profiling to evaluate potential lipid metabolic differences between patients with amyotrophic lateral sclerosis (ALS) and controls, and to provide a more profound understanding of the metabolic abnormalities in ALS. Methods: Twenty patients with ALS and 20 healthy controls were enrolled in a cross-sectional study. Untargeted lipidomics profiling in fasting serum samples were performed by optimized UPLC–MS platforms for broad lipidome coverage. Datasets were analyzed by univariate and a variety of multivariate procedures. Results: We provide the most comprehensive blood lipid profiling of ALS to date, with a total of 416 lipids measured. Univariate analysis showed that 28 individual lipid features and two lipid classes, triacylglycerides and oxidized fatty acids (FAs), were altered in patients with ALS, although none of these changes remained significant after multiple comparison adjustment. Most of these changes remained constant after removing from the analysis individuals treated with lipid-lowering drugs. The non-supervised principal component analysis did not identify any lipid clustering of patients with ALS and controls. Despite this, we performed a variety of linear and non-linear supervised multivariate models to select the most reliable features that discriminate the lipid profile of patients with ALS from controls. These were the monounsaturated FAs C24:1n-9 and C14:1, the triglyceride TG(51:4) and the sphingomyelin SM(36:2). Conclusions: Peripheral alterations of lipid metabolism are poorly defined in ALS, triacylglycerides and certain types of FAs could contribute to the different lipid profile of patients with ALS. These findings should be validated in an independent cohort.

Understanding the different types of ALS.

Amyotrophic lateral sclerosis (ALS) occurs in older adults, but it can show itself in many different ways. ALS mostly affects muscle strength. It can affect different muscles in our bodies, and because of this, does not always look the same from one person to another. For instance, some people will have a form of ALS that mostly affects their breathing (or respiratory) muscles. When this happens, they have shortness of breath, even after minor exercise. For others, ALS may affect their throat and mouth muscles first: this results in difficulty swallowing (often called bulbar ALS). With increasing study, scientists have also recognized that may people with ALS not only have muscle weakness, but may also have problems with thinking, or changes in their behavior.

Differences in nerve excitability properties between isolated bulbar palsy and bulbar-dominant amyotrophic lateral sclerosis

ABSTRACTObjectives: Isolated bulbar palsy (IBP) is a rare variant that can show a benign course, while progressive bulbar palsy (PBP) has been regarded as a bulbar-dominant type of classical amyotrophic lateral sclerosis (cALS). This study aimed to identify differences in the excitability properties between them.Methods: We consecutively collected data on 22 ALS patients: 13 with cALS, 5 with PBP, and 4 with IBP. An automated nerve excitability test (NET) was applied to measure the strength–duration time constant, threshold electrotonus (TE), current–threshold relationship, and recovery cycle. The axonal excitability properties were compared between the ALS groups and 25 controls.Results: Compared to controls, the cALS group showed a greater change in the depolarizing phase of TE of 90–100 ms after depolarizing current [TEd(90–100)] (53.3±1.3 [mean±SEM] for cALS and 49.0±0.7 for control, P<0.01) and lower S2 accommodation (19.6±0.8 and 22.6±0.7, respectively; P=0.01). There was a nonsignificant tendency for a high TEd(90–100) pattern to be less prominent in the IBP group than in the PBP group (51.5±4.22 and 48.8±1.5, respectively). In addition, all of the parameters of nerve excitability other than S2 accommodation in the PBP and IBP groups did not differ significantly from those in the controls.Conclusions: The excitability properties of IBP and PBP differ from those of cALS. The pattern of NET in PBP was more similar to that in cALS than that in IBP. These findings suggest that IBP is a different entity from bulbar-dominant ALS and PBP.

Autophagy and Motor Neuron Diseases.

Motor neuron diseases (MND) are a group of fatal progressive neurodegenerative diseases, which selectively affect the motor system in the anterior horn of spinal cord, brainstem, cortex and pyramidal tract. Motor neurons could be divided into two groups, which are upper groups in the motor cortex and lower groups in the brain stem and spinal cord. Loss of lower motor neurons leads to muscle weakness, wasting and cramps. Loss of upper motor neurons leads to brisk reflexes and functional limits. There are several types of motor neuron disease: amyotrophic lateral sclerosis (ALS), progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), primary lateral sclerosis (PLS). Now, the studies of autophagy in MND focus on the type of ALS, so this chapter will summarize the alteration of autophagy in motor neurons, and how that knowledge contributes to our understanding of the pathogenesis of ALS.

Behavioral manifestations in a Brazilian non-demented C9orf72-negative ALS population

Cognitive decline and behavioral changes are common features in amyotrophic lateral sclerosis (ALS) and imply worse prognosis as well as increased disease burden for patients and caregivers. Currently, there is a lack of studies regarding behavioral profile in Brazilian ALS cohorts. We assessed the prevalence and profile of behavioral impairment (ALSbi) in a Brazilian non-demented C9orf72-negative ALS cohort according to broad behavioral assessment and the latest consensus. Among 76 initially recruited consecutive ALS patients, 70 were included, including seven ALS type 8 (VAPB-related ALS) individuals. Patients with Frontotemporal Dementia (FTD) diagnosis were excluded. Sixteen ALS patients (23%) were diagnosed as ALSbi. Among ALS type 8 individuals, 2 (28.6%) were diagnosed as ALSbi. Neuropsychiatric Inventory Questionnaire (NPI) total scores did positively correlate with age, but not with other demographic or clinical data. Apathy was the most prevalent finding in the ALSbi subgroup, although the prevalence (20%) was smaller than reported in previous literature. Dysphoria and anxiety were also prevalent findings in the whole ALS cohort. Future studies with larger cohorts and validated ALS-specific tools are needed in order to expand our knowledge.

Biomarkers in Different Types of Amyotrophic Lateral Sclerosis (ALS) Patients Being Treated With Edaravone

Biomarkers in Different Types of Amyotrophic Lateral Sclerosis (ALS) Patients Being Treated With Edaravone

Consideration of gravity as a possible etiological factor in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with an unknown mechanism of onset that predominantly impairs the upper and lower motor neurons. Components of the sensory and autonomic nervous system were once thought to be spared in the disease, but more recently they have been identified to be impaired at various levels. However, some of the motor neurons such as oculomotor, abducens, or pudendal nerves are spared even in the later stages of ALS. The mechanism of such complex and heterogeneous neuronal loss in typical ALS is still unknown. In this study, the characteristics of the nervous system involved in the pathogenesis of ALS were comprehensively reviewed. As a result, the direction of the axon in the anatomical position, rather than the functional type or length of the axon, was suggested to contribute the most to the onset of ALS. This finding suggested that downward directed axons, represented by motor neurons, require extra energy to move waste or unnecessary substances from the synapse side to the neural cell body with retrograde fast axonal transport. Based on this theory, the extra energy that is required in vertically directed axons due to the effect of gravity was mathematically estimated. As a result, several percent more adenosine triphosphate molecules were suggested to be consumed in vertical axonal transport by gravity, compared to those consumed in transverse axonal transport. Because most of the motor neurons project downward in the anatomical position, unretrieved waste will gradually sediment in axon terminals by gravity, which could eventually result in motor neuron-dominant neuronal loss. Although the theory that gravity is one of the mechanisms responsible for ALS is still hypothetical, it is theoretically reasonable and compatible with the clinical manifestations of the disease. Further basic research studies with cultured neurons or animal models are necessary to confirm the association between gravity and the onset of ALS.

Aproximación genética en la esclerosis lateral amiotrófica.

The superoxide dismutase type 1 (SOD1) gene is the first responsible gene mapped in amyotrophic lateral sclerosis type 1 (ALS1), and it codes for the enzyme SOD1, the function of which is to protect against damage mediated by free radicals deriving from oxygen. Its pathophysiological mechanism in ALS1 is related to ischemia. Several molecular studies of the SOD1 gene show that point mutations are the most frequent. The most common mutations in familial cases are p.A4V, p.I113Y, p.G37R, p.D90A and p.E100G, which account for more than 80% of cases, although intronic mutations have also been described as responsible for ALS1. Sporadic cases are explained by mutations in other genes such as SETX and C9orf72. ALS1 is a complex disease with genetic heterogeneity. On the other hand, familial and sporadic cases have a different etiology, which is explained by molecular heterogeneity and multiple pathogenic mechanisms that lead to ALS1; oxidative stress and ischemia are not the only cause. In Mexico, ALS molecular genetics studies are scarce. Clinical studies show an increase in cytokines such as adipsin in cerebrospinal fluid.

High BMI is associated with low ALS risk: A population-based study.

To investigate the temporal relationship among prediagnostic body mass index (BMI), weight change, and risk of amyotrophic lateral sclerosis (ALS). From the compulsory Norwegian tuberculosis screening program, we collected objectively measured BMI from 85% of all citizens (near 1.5 million) between 20 and 70 years of age living in 18 of 19 Norwegian counties between 1963 and 1975. For those who participated in later health surveys, we collected further information on weight change, lifestyle, and health. We identified ALS cases until September 2017 through national registries of diagnoses at death and at encounters with the specialist health service. Both Cox hazard models and flexible parametric survival models were fitted to address our research question. We identified 2,968 ALS cases during a mean of 33 (maximum 54) years follow-up. High prediagnostic BMI was associated with low subsequent ALS risk across the typical ALS ages in both sexes. Overall, hazard ratio (HR) for ALS per 5-unit increase in prediagnostic BMI was 0.83 (95% confidence interval [CI] 0.79-0.88). After an initial increase during the first 10 years, it decreased almost linearly throughout the observation period and was 0.69 (95% CI 0.62-0.77) after 50 years. Those in the quartile with highest weight gain had lower ALS risk than those in the lowest quartile (HR 0.63, 95% CI 0.44-0.89). High BMI and weight gain are associated with low ALS risk several decades later. The strength of the association between BMI and ALS risk increases up to 50 years after BMI measurement.

Monozygotic twins and triplets discordant for amyotrophic lateral sclerosis display differential methylation and gene expression

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of upper and lower motor neurons. ALS exhibits high phenotypic variability including age and site of onset, and disease duration. To uncover epigenetic and transcriptomic factors that may modify an ALS phenotype, we used a cohort of Australian monozygotic twins (n = 3 pairs) and triplets (n = 1 set) that are discordant for ALS and represent sporadic ALS and the two most common types of familial ALS, linked to C9orf72 and SOD1. Illumina Infinium HumanMethylation450K BeadChip, EpiTYPER and RNA-Seq analyses in these ALS-discordant twins/triplets and control twins (n = 2 pairs), implicated genes with consistent longitudinal differential DNA methylation and/or gene expression. Two identified genes, RAD9B and C8orf46, showed significant differential methylation in an extended cohort of >1000 ALS cases and controls. Combined longitudinal methylation-transcription analysis within a single twin set implicated CCNF, DPP6, RAMP3, and CCS, which have been previously associated with ALS. Longitudinal transcriptome data showed an 8-fold enrichment of immune function genes and under-representation of transcription and protein modification genes in ALS. Examination of these changes in a large Australian sporadic ALS cohort suggest a broader role in ALS. Furthermore, we observe that increased methylation age is a signature of ALS in older patients.

P44-T Axonal excitability properties of bulbar-dominant amyotrophic lateral sclerosis

Background Isolated bulbar palsy (IBP) is a rare regional variant that can show a relatively benign course, while progressive bulbar palsy (PBP) has recently been regarded as a bulbar-dominant type of classical amyotrophic lateral sclerosis (cALS). This study aimed to identify differences in the excitability properties between IBP and PBP. Material and methods We consecutively collected both clinical and electrophysiological data of 22 ALS patients for 9 years at two university-based hospitals. An automated nerve excitability test (NET) utilizing the threshold-tracking technique was applied to measure the strength–duration time constant, parameters of threshold electrotonus (TE), the current–threshold relationship, and the recovery cycle. The axonal excitability properties were compared in 13cALS, 5PBP, and 4IBP patients to those in 25 normal controls. Results Compared to controls, the cALS group showed a more change in the depolarizing phase of TE (90–100 ms) (53.3 ± 1.3 [mean ± SEM] for the ALS group and 49.0 ± 0.7 for the control group, P Conclusions This study identified that the excitability properties of IBP and PBP differ from those of cALS. The pattern of NET in PBP was more similar to that in cALS than IBP. These findings suggest that IBP is a different entity to bulbar-dominant ALS or PBP.

Amyotrophic lateral sclerosis type 8 is not a pure motor disease: evidence from a neuropsychological and behavioural study.

Amyotrophic lateral sclerosis type 8 (ALS8) is a familial form of motor neuron disease, with predominance of lower motor neuron degeneration, and is caused by mutation of the vesicle-associated membrane protein-associated protein B (VAPB). We aimed to compare the cognitive profile of patients with ALS8 and healthy controls (HC), and to screen for behavioural features in ALS8 patients. The sample was composed of ALS8 patients (n = 22; 14 men; median age 48years old; median disease duration 6.5years) and HC (n = 33; 19 men; median age 48years old). Patients and HC were matched for sex, age and educational level. Participants underwent behavioural, psychiatric (Hospital Anxiety and Depression Scale and Cambridge Behavioural Inventory-Revised) and neuropsychological assessments, focused on executive functions, visual memory, and facial emotion recognition. ALS8 patients exhibited subtle deficits in executive functions. Compared to controls, ALS8 patients were significantly impaired in measures of flexibility and inhibitory control. ALS8 patients and HC did not differ in scores of facial emotion recognition. There was clinically relevant anxiety and depression in 36% and 27% of ALS8 patients, respectively. Behavioural disorders such as stereotypic and motor behaviours were present in more than 30% of patients. ALS8 patients present mild executive dysfunction and behavioural changes such as mood disorders, apathy and stereotypic behaviour. Our findings suggest that ALS8 is not a pure motor disorder and it is associated with subtle cognitive and behavioural impairments.