Publications by authors named "Daniele Galatolo"

Article Synopsis
  • * A specific case is presented of a 53-year-old male who experienced progressive myoclonus-ataxia and was found to have a new genetic variant (c.3835G > A) in the CACNA1G gene.
  • * The study suggests that this novel variant may affect calcium channel activity and emphasizes the significance of genetic testing for understanding myoclonus-ataxia disorders.
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Purpose: Spastic paraplegia, intellectual disability, nystagmus, and obesity syndrome (SINO) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising 8 with SINO and 4 with an autosomal recessive condition attributed to biallelic KIDINS220 variants.

Methods: In our international cohort, we have included 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form.

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Article Synopsis
  • ARSACS is a rare neurodegenerative disease caused by mutations in the sacsin gene that disrupts various cellular processes, and effective treatments are still being explored.
  • The study used untargeted proteomics to analyze protein differences in ARSACS fibroblasts compared to normal controls, revealing insights about biochemical pathways affected by sacsin loss.
  • The findings highlighted abnormal calcium levels and lipid profiles in ARSACS cells, specifically increased ceramides and decreased diacylglycerols, suggesting these factors are linked to the disease.
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  • CLN8 is a receptor involved in cellular processes, and its dysfunction leads to a neurodegenerative disorder known as neuronal ceroid lipofuscinosis, with no current therapies targeting the disease.
  • This study focuses on understanding the molecular pathways affected by CLN8 loss and aims to find potential treatments by using a new zebrafish model that mimics the disease's characteristics.
  • Researchers discovered that CLN8 dysfunction disrupts autophagy and found that compounds like trehalose and SG2 can help alleviate disease symptoms in zebrafish, suggesting new avenues for treatment.
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Tubulinopathies encompass neurodevelopmental disorders caused by mutations in genes encoding for different isotypes of α- and β-tubulins, the structural components of microtubules. Less frequently, mutations in tubulins may underlie neurodegenerative disorders. In the present study, we report two families, one with 11 affected individuals and the other with a single patient, carrying a novel, likely pathogenic, variant (p.

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The Ataxia Global Initiative (AGI) aims to serve as a platform to facilitate clinical trial readiness for the hereditary ataxias. Clinical trials for these diseases have been hampered by the lack of objective measures to study disease onset, progression, and treatment efficacy. While these issues are not unique to the genetic ataxias, the relative rarity of these diseases makes the need for such measures even more pressing to achieve statistical power in clinical trials.

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Hereditary spastic paraplegia (HSP) refers to a group of heterogeneous neurological disorders mainly characterized by corticospinal degeneration (pure forms), but sometimes associated with additional neurological and extrapyramidal features (complex HSP). The advent of next-generation sequencing (NGS) has led to huge improvements in knowledge of HSP genetics and made it possible to clarify the genetic etiology of hundreds of "cold cases," accelerating the process of reaching a molecular diagnosis. The different NGS-based strategies currently employed as first-tier approaches most commonly involve the use of targeted resequencing panels and exome sequencing, whereas genome sequencing remains a second-tier approach because of its high costs.

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The association of hypogonadism and cerebellar ataxia was first recognized in 1908 by Gordon Holmes. Since the seminal description, several heterogeneous phenotypes have been reported, differing for age at onset, associated features, and gonadotropins levels. In the last decade, the genetic bases of these disorders are being progressively uncovered.

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Article Synopsis
  • Advances in gene sequencing have highlighted the diverse clinical forms of RYR1-related myopathy (RYR1-RM), making diagnosis challenging.
  • Researchers developed a novel unsupervised cluster analysis method to better understand RYR1-RM by analyzing genetic, morphological, and clinical data from 600 patients, specifically focusing on 73 with genetic variants.
  • The analysis categorized 64 patients into four distinct clusters based on their clinical and morphological traits, revealing that many had mild or no symptoms and improving the understanding of genotype-phenotype correlations.
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Objective: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants.

Methods: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression.

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure.

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Article Synopsis
  • * Researchers found that this mouse model exhibited symptoms similar to human patients, identifying vitamin B2 and other compounds as potential biomarkers for diagnosis and monitoring the disease.
  • * The study suggested that deficiencies in the CYP2U1 enzyme disrupts mitochondrial function and neurodevelopment but may be mitigated by folate supplementation, highlighting possible avenues for therapeutic intervention.
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The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests.

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a multisystem hereditary ataxia associated with mutations in , which encodes sacsin, a protein of still only partially understood function. Although mouse models of ARSACS mimic largely the disease progression seen in humans, their use in the validation of effective therapies has not yet been proposed. Recently, the teleost has attracted increasing attention as a vertebrate model that allows rapid and economical screening, of candidate molecules, and thus combines the advantages of whole-organism phenotypic assays and in vitro high-throughput screening assays.

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Introduction: Spinocerebellar ataxia type 14 (SCA14) is a dominantly inherited neurological disorder characterized by slowly progressive cerebellar ataxia. SCA14 is caused by mutations in PRKCG, a gene encoding protein kinase C gamma (PKCγ), a master regulator of Purkinje cells development.

Methods: We performed next-generation sequencing targeted resequencing panel encompassing 273 ataxia genes in 358 patients with genetically undiagnosed ataxia.

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Background And Purpose: Spinocerebellar ataxia 21 (SCA21) is a rare autosomal dominant neurodegenerative disorder caused by TMEM240 gene mutations. To date, SCA21 has been reported only in a limited number of families worldwide. Here, we describe clinical and molecular findings in five additional SCA21 patients from four unrelated families, diagnosed through a multicentre next generation sequencing-based molecular screening project on a large cohort of patients with degenerative and congenital ataxias.

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COQ4 is a component of an enzyme complex involved in the biosynthesis of coenzyme Q (CoQ), a molecule with primary importance in cell metabolism. Mutations in the COQ4 gene are responsible for mitochondrial diseases showing heterogeneous age at onset, clinical presentations and association with CoQ deficiency. We herein expand the phenotypic and genetic spectrum of COQ4-related diseases, by reporting two patients harboring bi-allelic variants but not showing CoQ deficiency.

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Neuroacanthocytosis (NA) syndromes are a group of genetically defined diseases characterized by the association of red blood cell acanthocytosis, progressive degeneration of the basal ganglia and neuromuscular features with characteristic persistent hyperCKemia. The main NA syndromes include autosomal recessive chorea-acanthocytosis (ChAc) and X-linked McLeod syndrome (MLS). A series of Italian patients selected through a multicenter study for these specific neurological phenotypes underwent DNA sequencing of the and genes to search for causative mutations.

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Although the genetic basis of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) has been uncovered, our poor understanding of disease mechanisms requires new light on functional pathways and modifying factors to improve early diagnostic strategies and offer alternative treatment options in a rare condition with no cure. Investigation of the pathologic state combining disease models and quantitative omic approach might improve biomarkers discovery with possible implications in patients' diagnoses. In this study, we analyzed proteomics data obtained using the SomaLogic technology, comparing cell lysates from ARSACS patients and from a KO SH-SY5Y neuroblastoma cell model.

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Introduction: Biallelic mutations in STUB1, which encodes the E3 ubiquitin ligase CHIP, were originally described in association with SCAR16, a rare autosomal recessive spinocerebellar ataxia, so far reported in 16 kindreds. In the last 2 years, a new form of spinocerebellar ataxia (SCA48), associated with heterozygous mutations in the same gene, has been described in 12 kindreds with autosomal dominant inheritance.

Methods: We reviewed molecular and clinical findings of both SCAR16 and SCA48 described patients.

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Mutations in histidyl-tRNA synthetase (HARS1), an enzyme that charges transfer RNA with the amino acid histidine in the cytoplasm, have only been associated to date with autosomal recessive Usher syndrome type III and autosomal dominant Charcot-Marie-Tooth disease type 2W. Using massive parallel sequencing, we identified bi-allelic HARS1 variants in a child (c.616G>T, p.

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