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Background To review the descriptive epidemiological data on neuronal ceroid lipofuscinoses (NCLs) in Italy, identify the spectrum of mutations in the causative genes, and analyze possible genotype-phenotype relations. Methods A cohort of NCL patients was recruited through CLNet, a nationwide network of child neurology units. Diagnosis was based on clinical and pathological criteria following ultrastructural investigation of peripheral tissues. Molecular confirmation was obtained during the diagnostic procedure or, when possible, retrospectively. Results One hundred eighty-three NCL patients from 156 families were recruited between 1966 and 2010; 124 of these patients (from 88 families) were tested for known NCL genes, with 9.7% of the patients in this sample having not a genetic diagnosis. Late infantile onset NCL (LINCL) accounted for 75.8% of molecularly confirmed cases, the most frequent form being secondary to mutations in CLN2 (23.5%). Juvenile onset NCL patients accounted for 17.7% of this cohort, a smaller proportion than found in other European countries. Gene mutations predicted severe protein alterations in 65.5% of the CLN2 and 78.6% of the CLN7 cases. An incidence rate of 0.98/100,000 live births was found in 69 NCL patients born between 1992 and 2004, predicting 5 new cases a year. Prevalence was 1.2/1,000,000. Conclusions Descriptive epidemiology data indicate a lower incidence of NCLs in Italy as compared to other European countries. A relatively high number of private mutations affecting all NCL genes might explain the genetic heterogeneity. Specific gene mutations were associated with severe clinical courses in selected NCL forms only.

Hereditary spastic paraplegia (HSP) groups rare, clinically and genetically heterogeneous neurodegenerative disorders, characterized by progressive lower-limb spasticity and weakness. Over the past decades, diagnostic strategies have evolved from pure clinical assessment to the integration of molecular tools, with next-generation and long-read sequencing (LRS) substantially increasing diagnostic yield and refining genotype–phenotype correlations. Neuroimaging provides complementary information, especially in specific subtypes such as SPG11 and SPG15, supporting diagnosis and guiding testing. Treatment has historically focused on symptomatic care, including physiotherapy, antispastic agents, and botulinum toxin, with dalfampridine explored for gait improvement in selected patients. More recently, research has expanded into disease-modifying avenues, such as drug repurposing (e.g., statins in SPG5, menatetrenone in ALS2) and early gene-based interventions in ultra-rare subtypes. At the same time, advances in technology, ranging from quantitative imaging and digital gait analysis to induced pluripotent stem cell models and artificial intelligence, are beginning to influence both clinical management and trial design. This review traces the trajectory of HSP care from its historical foundations to present standards and emerging innovations, outlining how technological progress is shaping realistic prospects for future therapeutic strategies. Research in HSP from today to tomorrow Hereditary spastic paraplegia (HSP) refers to a group of rare neurological conditions that mainly affect the legs, causing stiffness (spasticity), weakness, and difficulty walking. For many years, treatment options were limited, focusing mainly on easing symptoms through physical therapy or medications that reduce muscle stiffness. Genetic testing was not widely available, and many people went undiagnosed. In recent years, science and medicine have made major progress in understanding and managing HSP. Thanks to advanced genetic technologies, doctors can now identify the specific gene changes that cause the condition in many patients. This has opened the door to more targeted and personalized treatments. For example, gene therapy and antisense oligonucleotides – two forms of genetic medicine – are being tested in clinical trials and have already shown promising results in some rare forms of HSP. In parallel, researchers are finding new ways to repurpose existing drugs to treat HSP more quickly and effectively. Digital health tools like wearable sensors and smartphone apps are also helping patients and doctors to track symptoms and responses to treatment in real time, even from home. This article explains how treatment for HSP is moving from a “one-size-fits-all” approach to more personalized care, tailored to each person’s unique genetic and clinical profile. It also highlights how new technologies—like artificial intelligence—are helping scientists understand disease better and design more precise therapies. Although many treatments are still under development, the latest breakthroughs are offering new hope for individuals and families living with HSP.

Zebrafish are one of the most used animal models in biological research and a cost-effective alternative to rodents. Despite this, nutritional requirements and standardized feeding protocols have not yet been established for this species. This is important to avoid nutritional effects on experimental outcomes, and especially when zebrafish models are used in preclinical studies, as many diseases have nutritional confounding factors. A key aspect of zebrafish nutrition is related to feed intake, the amount of feed ingested by each fish daily. With the goal of standardizing feeding protocols among the zebrafish community, this paper systematically reviews the available data from 73 studies on zebrafish feed intake, feeding regimes (levels), and diet composition. Great variability was observed regarding diet composition, especially regarding crude protein (mean 44.98 ± 9.87%) and lipid content (9.91 ± 5.40%). Interestingly, the gross energy levels of the zebrafish diets were similar across the reviewed studies (20.39 ± 2.10 kilojoules/g of feed). In most of the reviewed papers, fish received a predetermined quantity of feed (feed supplied). The authors fed the fish according to the voluntary intake and then calculated feed intake (FI) in only 17 papers. From a quantitative point of view, FI was higher than when a fixed quantity (pre-defined) of feed was supplied. Also, the literature showed that many biotic and abiotic factors may affect zebrafish FI. Finally, based on the FI data gathered from the literature, a new feeding protocol is proposed. In summary, a daily feeding rate of 9–10% of body weight is proposed for larvae, whereas these values are equal to 6–8% for juveniles and 5% for adults when a dry feed with a proper protein and energy content is used.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodevelopmental and neurodegenerative disorder characterized by ataxia, spasticity, and peripheral neuropathy. However, several studies have highlighted that some patients also experience cognitive, emotional and social deficits, suggesting a more complex clinical picture that extends beyond motor symptoms. Building on these findings, this study aimed to: (i) investigate locomotor, social and cognitive deficits in adult sacs -/- zebrafish versus wild-type (WT) controls through behavioural tests; (ii) identify molecular patterns associated with the adult disease phenotype using transcriptomic and proteomic analyses of sacs -/- and WT brains; (iii) evaluate the effectiveness of long-term treatment with tauroursodeoxycholic acid (TUDCA) on behavioural outcomes and omics profiles in the zebrafish sacs -/- model. Our findings indicate impairments in cognitive, social, and emotional behaviors in aged sacs -/- zebrafish, which resemble some deficits observed in human patients. Transcriptomic and proteomic analyses of adult brains identified alterations in genes related to circadian rhythms and neuroinflammation. Notably, disruptions in sleep and circadian rhythms are frequently reported in individuals with cerebellar ataxia and may contribute to cognitive and behavioral changes. Long-term treatment with TUDCA, a neuroprotective molecule, was associated with partial improvements in social and cognitive behaviors and modifications in omics profiles in the zebrafish model. These results support the potential of further exploring TUDCA in future preclinical and clinical studies, while also emphasizing the need for additional investigations to better understand its mechanisms of action.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurological disease caused by mutations in SACS , which encodes sacsin. The complex architecture of sacsin suggests that it could be a key player in cellular protein quality control system. Molecular chaperones that operate in protein folding/unfolding and assembly/disassembly patterns have been described as essential modulators of selectivity during the autophagy process. We performed RNA-sequencing analysis to generate a whole-genome molecular signature profile of sacsin knockout cells. Using data analysis of biological processes significantly disrupted due to loss of sacsin, we confirmed the presence of decreased mitochondrial function associated with increased oxidative stress, and also provided a demonstration of a defective autophagic pathway in sacsin-depleted cells. Western blotting assays revealed decreased expression of LC3 and increased levels of p62 even after treatment with the lysosomal inhibitor bafilomycin A1, indicating impairment of the autophagic flux. Moreover, we found reduced co-immunolocalization of the autophagosome marker LC3 with lysosomal and mitochondrial markers suggesting fusion inhibition of autophagic compartments and subsequent failed cargo degradation, in particular failed degradation of damaged mitochondria. Pharmacological up-regulation of autophagy restored correct autophagic flux in sacsin knockout cells. These results corroborate the hypothesis that sacsin may play a role in autophagy. Chemical manipulation of this pathway might represent a new target to alleviate clinical and pathological symptoms, delaying the processes of neurodegeneration in ARSACS.

Glucose is the brain’s main fuel source, used in both energy and molecular production. Impaired glucose metabolism is associated with adult and pediatric neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), GLUT1 deficiency syndrome, and progressive myoclonus epilepsies (PMEs). PMEs, a group of neurological disorders typical of childhood and adolescence, account for 1% of all epileptic diseases in this population worldwide. Diffuse glucose hypometabolism is observed in the brains of patients affected by PMEs such as Lafora disease (LD), dentatorubral-pallidoluysian (DRPLA) atrophy, Unverricht–Lundborg disease (ULD), and myoclonus epilepsy with ragged red fibers (MERRFs). PMEs also include neuronal ceroid lipofuscinoses (NCLs), a subgroup in which lysosomal and autophagy dysfunction leads to progressive loss of vision, brain atrophy, and cognitive decline. We examine the role of impaired glucose metabolism in neurodegenerative diseases, particularly in the NCLs. Our literature review, which includes findings from case reports and animal studies, reveals that glucose hypometabolism is still poorly characterized both in vitro and in vivo in the different NCLs. Better identification of the glucose metabolism pathway impaired in the NCLs may open new avenues for evaluating the therapeutic potential of anti-diabetic agents in this population and thus raise the prospect of a therapeutic approach able to delay or even halt disease progression.

Childhood apraxia of speech (CAS) is a genetically heterogeneous pediatric motor speech disorder. The advent of whole exome sequencing (WES) and whole genome sequencing techniques has led to increased identification of pathogenic variants in CAS genes. In an as yet uncharacterized Italian cohort, we aimed both to identify new pathogenic gene variants associated with CAS, and to confirm the disease-related role of genes already reported by others. We also set out to refine the clinical and neurodevelopmental characterization of affected children, with the aim of identifying specific, gene-related phenotypes. In a single-center study aiming to explore the genetic etiology of CAS in a cohort of 69 Italian children, WES was performed in the families of the 34 children found to have no copy number variants. Each of these families had only one child affected by CAS. High-confidence (HC) gene variants were identified in 7/34 probands, in two of whom they affected and , thus confirming the involvement of these genes in speech impairment. The other probands carried variants in low-confidence (LC) genes, and 20 of these variants occurred in genes not previously reported as associated with CAS. , and genes were found to be more enriched in the CAS cohort compared to control individuals. Our results also showed that most HC genes are involved in epigenetic mechanisms and are expressed in brain regions linked to language acquisition processes. Our findings confirm a relatively high diagnostic yield in Italian patients.

Early diagnosis is critical for the effective management of neurodegenerative disorders, and retinal alterations have emerged as promising early biomarkers due to the retina’s close developmental and functional link to the brain. The zebrafish (Danio rerio), with its rapid development, transparent embryos, and evolutionarily conserved visual system, represents a powerful and versatile model for studying retinal degeneration. This review discusses a range of behavioral assays—including visual adaptation, motion detection, and color discrimination—that are employed to evaluate retinal function in zebrafish. These methods enable the detection of subtle visual deficits that may precede overt anatomical damage, providing a non-invasive, efficient strategy for early diagnosis and high-throughput drug screening. Importantly, these behavioral tests also serve as sensitive functional readouts to evaluate the efficacy of pharmacological treatments over time. Compared to traditional murine models, zebrafish offer advantages such as lower maintenance costs, faster development, optical transparency for live imaging, and ethical benefits due to reduced use of higher vertebrates. However, variability in experimental protocols highlights the need for standardization to ensure reliability and reproducibility.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social skills and the presence of repetitive and restricted behaviors and interests. The social behavior of the zebrafish (Danio rerio) makes this organism a valuable tool for modeling ASD in order to explore the social impairment typical of this disorder. In addition to transgenic models, exposure of zebrafish embryos to valproic acid (VPA) has been found to produce ASD-like symptoms. This review first sets out to examine the existing literature on adult social behavior in the zebrafish VPA-induced model of autism, and the authors also aim to identify the ideal VPA dosage able to induce a persistent and long-lasting ASD-like phenotype while minimizing the suffering and distress of research animals in compliance with the principles of replacement, refinement, and reduction (3Rs).

Hereditary spastic paraplegia (HSP) and hereditary ataxias (HA) are clinically and genetically heterogeneous neurodegenerative disorders that primarily affect motor coordination and neural integrity. Despite distinct pathological features, such as pyramidal tract degeneration in HSP and spinocerebellar pathway involvement in HA, these conditions share overlapping genetic pathways and mechanisms. The fruit fly Drosophila melanogaster has emerged as a powerful model organism for investigating the molecular basis of rare diseases, including HSP and HA. Its genetic tractability, rapid life cycle, and high degree of gene conservation with humans make it a cost-effective and ethically viable platform for disease modelling. In this review, we provide a comprehensive overview of Drosophila-based models for HSP and HA. We highlight the use of advanced genetic tools, including RNA interference, CRISPR/Cas9, and the GAL4/UAS system, as well as behavioral and neuroanatomical assays to model disease features. Furthermore, we discuss the application of genetic “avatars” and high-throughput drug screening platforms to test therapeutic candidates. Collectively, these models have deepened our understanding of the pathophysiology of HSP and HA, offering valuable insights for the development of targeted therapies and approaches to personalized medicine.