Exploiting the role of CSF NfL, CHIT1, and miR-181b as potential diagnostic and prognostic biomarkers for ALS.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers.

Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease.

Objective: Mitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.

Methods: Whole exome sequencing of the probands was performed to identify pathogenic variants.

Six-minute walk test as outcome measure of fatigability in adults with spinal muscular atrophy treated with nusinersen.

Introduction/aims: Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy (SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3.

Unleashing the potential of mRNA therapeutics for inherited neurological diseases.

Neurological monogenic loss-of-function diseases are hereditary disorders resulting from gene mutations that decrease or abolish the normal function of the encoded protein. These conditions pose significant therapeutic challenges, which may be resolved through the development of innovative therapeutic strategies. RNA-based technologies, such as mRNA replacement therapy, have emerged as promising and increasingly viable treatments.

Shaping the Neurovascular Unit Exploiting Human Brain Organoids.

Brain organoids, three-dimensional cell structures derived from pluripotent stem cells, closely mimic key aspects of the human brain in vitro, providing a powerful tool for studying neurodevelopment and disease. The neuroectodermal induction protocol employed for brain organoid generation primarily gives rise to the neural cellular component but lacks the vital vascular system, which is crucial for the brain functions by regulating differentiation, migration, and circuit formation, as well as delivering oxygen and nutrients. Many neurological diseases are caused by dysfunctions of cerebral microcirculation, making vascularization of human brain organoids an important tool for pathogenetic and translational research.

Lafora Disease: A Case Report and Evolving Treatment Advancements.

Lafora disease is a rare genetic disorder characterized by a disruption in glycogen metabolism. It manifests as progressive myoclonus epilepsy and cognitive decline during adolescence. Pathognomonic is the presence of abnormal glycogen aggregates that, over time, produce large inclusions (Lafora bodies) in various tissues.

Proposal of a new clinical protocol for evaluating fatigability in adult SMA patients.

Objective: Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disease affecting the lower motor neuron, carrying a significant burden on patients' general motor skills and quality of life, characterized by a great variability in phenotypic expression. As new therapeutic options make their appearance on the scene, sensitive clinical tools and outcome measures are needed, especially in adult patients undergoing treatment, in which the expected clinical response is a mild improvement or stabilization of disease progression.

Methods: Here, we describe a new functional motor scale specifically designed for evaluating the endurance dimension for the upper and lower limbs in adult SMA patients.

Unraveling the Neurological Complexity of Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, and Skin Changes Syndrome: A Report of a Challenging Case of a Young Woman and Cutting-Edge Advancements in the Field.

POEMS syndrome-characterized by polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes-is an uncommon and complex paraneoplastic disorder encompassing a diverse array of symptoms. Here we report the challenging case of a 34-year-old female who sought medical attention at the emergency department due to distal lower limb weakness. She was breastfeeding her first child at that time.

Respiratory function in a large cohort of treatment-naïve adult spinal muscular atrophy patients: a cross-sectional study.

Due to poor data in literature, we aimed to investigate the respiratory function in a large cohort of naïve Italian adult (≥18 years) SMA patients in a multi-centric cross-sectional study. The following respiratory parameters were considered: forced vital capacity (FVC), forced expiratory volume in one second (FEV1) and need for non-invasive ventilation (NIV). We included 145 treatment-naïve adult patients (SMA2=18, SMA3=125; SMA4=2), 58 females (40 %), with median age at evaluation of 37 years (range 18-72).

A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.

Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations. The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18 as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy. The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life.

Identification of Novel Biomarkers of Spinal Muscular Atrophy and Therapeutic Response by Proteomic and Metabolomic Profiling of Human Biological Fluid Samples.

Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations or deletions in that lead to progressive death of alpha motor neurons, ultimately leading to severe muscle weakness and atrophy, as well as premature death in the absence of treatment. Recent approval of SMN-increasing medications as SMA therapy has altered the natural course of the disease. Thus, accurate biomarkers are needed to predict SMA severity, prognosis, drug response, and overall treatment efficacy.

Ischemic optic neuropathy as first presentation in patient with m.3243 A > G MELAS classic mutation.

Background: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a systemic disorder in which multi-organ dysfunction may occur from mitochondrial metabolism failure. Maternally inherited mutations in the MT-TL1 gene are the most frequent causes for this disorder. Clinical manifestations may include stroke-like episodes, epilepsy, dementia, headache and myopathy.

Regional spreading pattern is associated with clinical phenotype in amyotrophic lateral sclerosis.

Increasing evidence shows that disease spreading in amyotrophic lateral sclerosis (ALS) follows a preferential pattern with more frequent involvement of contiguous regions from the site of symptom onset. The aim of our study was to assess if: (i) the burden of upper (UMN) and lower motor neuron (LMN) involvement influences directionality of disease spreading; (ii) specific patterns of disease progression are associated with motor and neuropsychological features of different ALS subtypes (classic, bulbar, primary lateral sclerosis, UMN-predominant, progressive muscular atrophy, flail arm, flail leg); and (iii) specific clinical features may help identify ALS subtypes, which remain localized to the site of onset for a prolonged time (regionally entrenching ALS). A single-centre, retrospective cohort of 913 Italian ALS patients was evaluated to assess correlations between directionality of the disease process after symptom onset and motor/neuropsychological phenotype.

Advancing Stroke Research on Cerebral Thrombi with Omic Technologies.

Cerebrovascular diseases represent a leading cause of disability, morbidity, and death worldwide. In the last decade, the advances in endovascular procedures have not only improved acute ischemic stroke care but also conceded a thorough analysis of patients' thrombi. Although early anatomopathological and immunohistochemical analyses have provided valuable insights into thrombus composition and its correlation with radiological features, response to reperfusion therapies, and stroke etiology, these results have been inconclusive so far.

NOTCH2NLC GGC repeats are not expanded in Italian amyotrophic lateral sclerosis patients.

Repeat expansions in genes other than C9orf72 and ATXN2 have been recently associated with Amyotrophic Lateral Sclerosis (ALS). Indeed, an abnormal number of GGC repeats in NOTCH2NLC has been recently reported in 0.7% of sporadic ALS patients from mainland China.

Analysis of miRNA rare variants in amyotrophic lateral sclerosis and prediction of their biological effects.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and/or lower motor neurons and characterized by complex etiology. Familial cases show high genetic heterogeneity and sporadic cases (90%) are associated with several genetic and environmental risk factors. Among the genetic risk factors, the contribution of non-coding elements, such as microRNAs (miRNAs), to ALS disease susceptibility remains largely unexplored.

Adults with spinal muscular atrophy: a large-scale natural history study shows gender effect on disease.

Background: Natural history of spinal muscular atrophy (SMA) in adult age has not been fully elucidated yet, including factors predicting disease progression and response to treatments. Aim of this retrospective, cross-sectional study, is to investigate motor function across different ages, disease patterns and gender in adult SMA untreated patients.

Methods: Inclusion criteria were as follows: (1) clinical and molecular diagnosis of SMA2, SMA3 or SMA4 and (2) clinical assessments performed in adult age (>18 years).

Correlation between clinical phenotype and electromyographic parameters in amyotrophic lateral sclerosis.

Introduction: Even if electromyography (EMG) is routinely used to confirm the diagnosis of amyotrophic lateral sclerosis (ALS), few studies have analysed the correlation between electrophysiological parameters and clinical characteristics of ALS. We assessed if the quantification of active denervation (AD) and chronic denervation (CD) provides clinicians with information about phenotype, disease progression and survival in ALS patients.

Methods: We studied a cohort of 689 ALS patients recording the following parameters: age and site of onset, survival, MRC scale for muscle strength evaluation, burden of upper and lower motor signs as measured with specific scales (PUMNS and LMNS, respectively), ALSFRS-R, progression rate (ΔFS), MITOS and King's Staging systems (KSS).

Primary mitochondrial myopathy: 12-month follow-up results of an Italian cohort.

Objectives: To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).

Methods: Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures.