Background: Amyotrophic lateral sclerosis (ALS) evolution is influenced by many dietary factors, biochemical and hormonal inter-relations and gut microbiota. This study focuses on dynamics by conducting a plasmatic quantitative analysis of six of the main short-chain fatty acids (SCFAs) for ALS patients and the shifts in circulating SCFA profiles during ALS progression as well as their potential responsiveness or change due to dietary modulation. Methods: A 12-month prospective study in parallel with control group determinations was conducted. The patients diagnosed with ALS were evaluated at the start of the study (T0) followed by a six-month observation time frame (T1) and after another six months of a Mediterranean diet intervention (T2). Plasma SCFAs were determined using liquid chromatography coupled to mass spectrometry to showcase the plasmatic profiles. Correlation between plasma levels of SCFAs and patients’ clinical characteristics next to correlations between plasma SCFA levels at T1 and T2 were performed. Results: A significant increase between control group and patients at T0 was observed for acetic, propionic, butyric and hydroxy-butyric acid. Hexanoic acid levels stagnated and 4-methyl-valeric acid concentrations decreased. Evolutions from T1 and T2 impacted acetate, propionate and 4-methyl-valerate. Conclusions: The study offers a better understanding regarding the differences in SCFA levels in ALS patients. The Mediterranean diet may impact the levels of acetic and propionic acid, indicating the modulation of SCFA production by gut microbiota.

Background: Developmental and epileptic encephalopathies (DEE) encompass a group of rare diseases with hereditary and genetic causes as well as acquired causes such as brain injuries or metabolic abnormalities. The phosphofurin acidic cluster sorting protein 2 (PACS2) is a multifunctional protein with nuclear gene expression. The first cases of the recurrent c.625G>A pathogenic variant of PACS2 gene were reported in 2018 by Olson et al. Since then, several case reports and case series have been published. Methods: We performed a systematic review of the PUBMED and SCOPUS databases using Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Our search parameters included DEE66 with a pathogenic PACS2 gene p.Glu209Lys mutation published cases to which we added our own clinical experience regarding this pathology. Results: A total of 11 articles and 29 patients were included in this review, to which we added our own experience for a total of 30 patients. There was not a significant difference between sexes regarding the incidence of this pathology (M/F: 16/14). The most common neurological and psychiatric symptoms presented by the patients were: early onset epileptic seizures, delayed global development (including motor and speech delays), behavioral disturbances, limited intellectual capacity, nystagmus, hypotonia, and a wide-based gait. Facial dysmorphism and other organs’ involvement were also frequently reported. Brain MRIs evidenced anomalies of the posterior cerebellar fossa, foliar distortion of the cerebellum, vermis hypoplasia, white matter reduction, and lateral ventricles enlargement. Genetic testing is more frequent in children. Only 4 cases have been reported in adults to date. Conclusions: It is important to maintain a high suspicion of new pathogenic gene variants in adult patients presenting with a characteristic clinical picture correlated with radiologic changes. The neurologist must gradually recognize the distinct evolving phenotype of DEE66 in adult patients, and genetic testing must become a scenario with which the neurologist attending adult patients should be familiar. Accurate diagnosis is required for adequate treatment, genetic counseling, and an improved long-term prognosis.

Background and Objectives: Traditionally regarded as a purely motor disorder, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. However, it is increasingly recognized as a condition with a broader clinical spectrum, encompassing a variety of non-motor symptoms (NMS) that significantly impact patients’ quality of life and may influence disease progression and prognosis. Materials and Methods: The study included 44 patients diagnosed with probable or definite ALS and 35 healthy controls (HC). Functional neurological status, non-motor manifestations, and cognitive and affective domains were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R), the Non-Motor Symptoms Questionnaire (NMSQuest), the Frontal Assessment Battery (FAB), and the Beck Depression Inventory (BDI), respectively. Results: A majority of ALS patients exhibited non-motor symptoms (NMS). Significant associations were identified between specific NMS domains and ALSFRS-R subdomains: sleep disturbances were associated with lower fine motor, respiratory, and total scores; digestive symptoms with lower bulbar, respiratory, and total scores; cardiovascular symptoms with lower total scores; urinary symptoms with higher bulbar subscores and a significantly slower progression rate (ΔPR); and sensory symptoms with higher gross motor subscores. BDI scores were negatively correlated with respiratory and bulbar functions, whereas FAB scores showed positive correlations with both bulbar and total ALSFRS-R scores. Conclusions: Non-motor symptoms are highly prevalent in this ALS cohort. These symptoms do not consistently correlate with greater motor impairment, as urinary and somatosensory involvement may occur independently of functional decline. Cognitive, affective, and behavioral alterations co-exist with motor symptoms and are associated with poorer overall functional performance.

Although the term of amyotrophic lateral sclerosis (ALS) is often used interchangeably with motor neuron disease, ALS is universally accepted as a multisystem disorder. Cognitive impairment is an acknowledged feature of ALS, affecting language, memory and behaviour, and apathy is considered to be the prevalent behavioural alteration in ALS. It can be divided in three subtypes: executive, emotional and initiation apathy. Out of the three subtypes, initiation apathy is common among patients with ALS. Even in patients that do not meet the criteria for ALS with frontotemporal dementia, low-key neuropsychiatric and cognitive changes can be observed. Apathy has also been found to be systematically associated with disruptions in medial frontal cortex and subcortical structures in several neuroimaging studies that confirm the pre-existing brain lesions in the early stages of this disease. Thus, there is a growing body of evidence that motor signs and symptoms are accompanied or even preceded by cognitive and behavioural alterations, and screening for non-motor signs and symptoms can be clinically relevant.

Background: Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder with highly variable progression and survival. Identifying early prognostic indicators is essential for patient stratification and management. Objectives: To evaluate clinical, respiratory, and functional predictors of survival in a prospective cohort of ALS patients over a three-year period. Methods: A cohort of 44 ALS patients was followed from 2022 to 2025. Demographic and anthropometric characteristics, clinical data including ALS subtypes and phenotypes, site of onset, revised ALS functional rating scale (ALSFRS-R) and subscores, ALSFRS-R progression rate, time to diffusion and generalization, spirometric parameters, and progression patterns were assessed. Survival analysis was performed using Kaplan–Meier estimates and univariate and multivariate Cox proportional hazard regression analysis. Results: The overall median survival time was 53 months. Univariate Cox regression revealed that older age at onset, shorter diagnostic delay, lower respiratory function, lower vitamin D levels, and rapid vertical progression were associated with reduced survival. Bulbar-onset phenotype and rapid disease progression rate (ΔPR) were significant predictors of mortality. Specific ALSFRS-R subscores also showed prognostic relevance. A longer time to diffusion as well as a longer time to generalization were significantly associated with prolonged survival. Multivariate analysis confirmed the independent prognostic value of ΔPR, time to diagnosis, and ALSFRS-R swallowing and handwriting subscores. Conclusions: This study supports the prognostic value of previously studied clinical and paraclinical markers in ALS and proposes novel predictors, ALSFRS-R handwriting, and time to diffusion, which require further validation in larger prospective cohorts.