Search Results (114)

Hereditary ataxias are a highly heterogenous group of diseases characterized by loss of coordination. In this study, we investigated a family of random-bred dogs, in which two siblings were affected by a slowly progressive ataxia. They presented with clinical signs of progressive cerebellar ataxia, hypermetria, and absent menace response. The MRI revealed generalized brain atrophy, reduced cortical demarcation, hypoplastic corpus callosum, and cerebellar folia thinning, highly suggestive of a neurodegenerative disorder. We sequenced the genomes of the two affected dogs and their unaffected parents. Filtering for protein-changing variants that had homozygous alternate genotypes in the affected dogs, heterozygous genotypes in the parents, and homozygous reference genotypes in 1576 control genomes yielded a single missense variant in the RAB24 gene, XM_038534663.1:c.239G>T or XP_038390591.1:p.(Gly80Val). Genotypes at this variant showed the expected co-segregation with the ataxia phenotype in the investigated family. The predicted amino acid affects the conserved RabF4 motif. Glycine-80 resides at the protein surface and the introduction of a hydrophobic isopropyl side chain of the mutant valine might impede solvent accessibility. Another missense variant in RAB24, p.Glu38Pro, was previously reported to cause a clinically similar form of cerebellar ataxia in Gordon Setters and Old English Sheepdogs. Taken together, the available data suggest that RAB24:p.Gly80Val represents the causal variant in the studied dogs. To the best of our knowledge, this is only the second report of a potentially pathogenic RAB24 variant in any species and further supports that RAB24 should be considered a candidate gene in human ataxia patients with unclear molecular etiology. Full article

Introduction: Cerebellar transcranial magnetic stimulation (TMS) has emerged as a promising neuromodulatory intervention for addressing motor, cognitive, and socio-affective deficits across a range of clinical populations. Materials and Methods: This systematic review aimed to synthesize recent evidence (2015–2025) on the efficacy, safety, and methodological characteristics of multi-session cerebellar TMS protocols used in rehabilitation settings. Following PRISMA guidelines, a comprehensive search of PubMed and Scopus was conducted to identify peer-reviewed studies applying multi-session cerebellar TMS in clinical populations for motor, cognitive, or affective rehabilitation. A total of 1750 records were screened, and 46 studies met the inclusion criteria. Data extraction included sample characteristics, study design, TMS protocol, targeted symptoms, outcomes, and risk of bias. Results: The results show that repeated sessions of cerebellar TMS are safe, well-tolerated, and associated with functional improvements primarily in motor disorders—such as spinocerebellar ataxia, Parkinson’s disease, multiple system atrophy, essential tremor, and post-stroke deficits—as well as in psychiatric populations, particularly patients with schizophrenia. Discussion: Evidence regarding the effects of cerebellar TMS on cognitive functions remains limited, though promising. Despite overall positive findings, the literature is limited by variability in stimulation parameters, protocol designs, and outcome measures, small sample sizes and potential publication bias. Conclusions: The review highlights the need for further large-scale and well-controlled trials to refine stimulation protocols, explore long-term effects, and clarify the underlying mechanisms of cerebellar TMS across motor, cognitive, and affective domains. This systematic review has been registered on PROSPERO (registration number: CRD420251067308). Full article

Phosphomannomutase 2 (PMM2) catalyzes the interconversion of mannose-6-phosphate and mannose-1-phosphate, a key step in the biosynthesis of GDP-mannose for N-glycosylation. Its deficiency is the most common cause of congenital disorders of glycosylation (CDGs), accounting for the subtype known as PMM2-CDG. PMM2-CDG is a rare autosomal recessive disease characterized by multisystemic dysfunction, including cerebellar atrophy, peripheral neuropathy, developmental delay, and coagulation abnormalities. The disease is associated with a spectrum of pathogenic missense mutations, particularly at residues involved in dimerization and catalytic function (i.e., p.Phe119Leu and p.Arg141His). The dimerization of PMM2 is considered essential for enzymatic activity, although it remains unclear whether this supports structural stability alone, or whether both subunits are catalytically active—a distinction that may affect how mutations in each monomer contribute to overall enzyme function and disease phenotype. PMM2 has a paralog, phosphomannomutase 1 (PMM1), which shares substantial structural similarity—including obligate dimerization—and displays mutase activity in vitro, but does not compensate for PMM2 deficiency in vivo. To investigate potential heterodimerization between PMM1 and PMM2 and the effect of interface mutations over PMM2 dimer stability, we first assessed the likelihood of their co-expression using data from GTEx and the Human Protein Atlas. Building on this expression evidence, we modeled all possible dimeric combinations between the two paralogs using AlphaFold3. Models of the PMM2 and PMM1 homodimers were used as internal controls and aligned closely with their respective reference biological assemblies (RMSD < 1 Å). In contrast, the PMM2/PMM1 heterodimer model, the primary result of interest, showed high overall confidence (pLDDT > 90), a low inter-chain predicted alignment error (PAE∼1 Å), and robust interface confidence scores (iPTM = 0.80). Then, we applied PISA, PRODIGY, and mmCSM-PPI to assess interface energetics and evaluate the impact of missense variants specifically at the dimerization interface. Structural modeling suggested that PMM2/PMM1 heterodimers were energetically viable, although slightly less stable than PMM2 homodimers. Interface mutations were predicted to reduce dimer stability, potentially contributing to the destabilizing effects of disease-associated variants. These findings offer a structural framework for understanding PMM2 dimerization, highlighting the role of interface stability, paralogs co-expression, and sensitivity to disease-associated mutations. Full article

Pontocerebellar hypoplasia (PCH) encompasses a group of autosomal recessive neurodegenerative disorders marked by cerebellar and pontine atrophy. Multiple subtypes of PCH have been identified, among which the rare subtype PCH type 16 is caused by MINPP1 genetic variants. MINPPI encodes an enzyme essential for inositol polyphosphate dephosphorylation, regulating calcium and iron homeostasis. We conducted genome sequencing on a proband from the consanguineous family, who presented with a severe neurodegenerative disorder, to identify the underlying cause of disease. A comprehensive clinical assessment in addition to neuroradiological findings are described. We performed the functional validation of the identified variant and conducted untargeted metabolomic analyses. The clinical and radiological assessment of the patient showed a congenital brain anomaly and neurodegenerative symptoms. Further genetic analysis identified a homozygous loss-of-function variant (c.1401del, p.Ser468Valfs10*) in MINPP1, providing molecular confirmation of a clinical PCH diagnosis. While real-time quantitative PCR (RT-qPCR) showed that MINPP1 gene expression was unaffected in the proband, Western blot analysis demonstrated reduced protein abundance, supporting a pathogenic role of the variant. Metabolomic profiling revealed elevated lipid levels and disrupted inositol metabolism, providing further insights into the disease mechanism. These findings establish the pathogenicity of the p.Ser468Valfs10* variant in MINPP1 and highlight inositol metabolism as a potential pathway involved in PCH16, advancing the understanding of the pathophysiology of the disease. Full article

Ataxia-telangiectasia is a rare autosomal recessive disorder that is difficult to diagnose due to its unpredictable presentation. It is characterized by cerebellar degeneration, telangiectasias, immunodeficiency, frequent pulmonary infections, and tumors. Immune system abnormalities manifest as disruptions in both cellular and humoral immunity. The most common findings include decreased levels of immunoglobulin classes (IgA, IgM, IgG, and IgG subclasses) and a reduced number of T and B lymphocytes. A four-year-old girl was initially evaluated and treated for skin lesions that presented as crusts spreading across her body. She was monitored by a pulmonologist due to frequent bronchial obstructions. Over time, she developed bilateral scleral telangiectasia, saccadic eye movements, and impaired convergence. Her gait was wide-based and unstable, with truncal ataxia and a positive Romberg sign. Laboratory tests revealed decreased immunoglobulin G levels, subclass IgG4 levels, elevated alpha-fetoprotein, and a reduced number of T and B lymphocytes. Brain magnetic resonance imaging showed cerebellar atrophy. Whole-exome sequencing identified heterozygous variants c.1564-165del, p.(Glu5221lefsTer43), and c.7630-2A>C in the serine/threonine-protein kinase ATM (ataxia-telangiectasia mutated) gene, confirming the diagnosis of ataxia-telangiectasia. Following diagnosis, treatment with intravenous immunoglobulin replacement was initiated along with infection prevention and management. The goal of this case report is to raise awareness of the atypical initial presentation that may lead to a diagnostic delay. We emphasize the importance of considering ataxia-telangiectasia in the differential diagnosis, even when classical neurological signs are not yet evident. Full article

Pontocerebellar hypoplasia is a rare neurodegenerative syndrome characterized by severe hypoplasia or atrophy of pons and cerebellum that may be associated with other brain malformations, microcephaly, optic nerve atrophy, dystonia, ataxia and neuromuscular disorders. At this time, there are 17 variants of PCH distinguished by clinical presentation and distinctive radiological and biochemical features in addition to pontine and cerebellar hypoplasia. PCH1 is defined as PCH variant associated with anterior horn degeneration in the spinal cord with muscle weakness and hypotonia, and is associated with recessive variants in genes VRK1, EXOSC3, EXOSC8, EXOSC9 and SLC25A46. Neuromuscular manifestations may clinically present as amyotrophic lateral sclerosis (ALS), motor neuropathy (HMN) or neuronopathy (non-5q spinal muscular atrophy; SMA) or sensorimotor polyneuropathy (HMSN). Physiologic functions of PCH1-associated genes include regulation of RNA metabolism, mitochondrial fission and neuronal migration. Overall, complex phenotypes associated with PCH1 gene variants ranging from PCH and related neurodevelopmental disorders combined with neuromuscular disorders to isolated neuromuscular disorders have variable outcomes with isolated neuromuscular disorders typically having later onset with better outcomes. Improved understanding of pathogenesis of pontocerebellar hypoplasia and its association with motor neuronopathies and peripheral neuropathies may provide us with valuable insights and lead to potential new therapeutic targets for neurodegenerative disorders. Full article

Background/Objectives: Pediatric multiple sclerosis (MS) is a rare and complex neuroinflammatory disease characterized by demyelination and neurological dysfunction in individuals under 18 years of age. This systematic review and activation likelihood estimation (ALE) meta-analysis aimed to synthesize the existing literature on functional and structural brain alterations in pediatric MS patients. Methods: Following the PRISMA guidelines, we analyzed 21 studies involving 917 pediatric MS patients and 320 healthy controls, assessing brain structure and function using MRI and fMRI techniques. Results: The results reveal consistent alterations in brain regions critical for cognitive and motor functions, including reduced brain volume, increased lesion load, and disrupted functional connectivity, particularly in the thalamus, cerebellum, and hippocampus. The ALE meta-analysis identified significant activation clusters in the dorsal anterior cingulate cortex, angular gyrus, and superior parietal lobes, regions associated with cognition, attention, and working memory. Conclusions: These findings suggest that pediatric MS uniquely affects brain development, contributing to cognitive impairments that differ from those observed in adult MS. Our study underscores the importance of early diagnosis and tailored therapeutic interventions to mitigate neurodevelopmental disruptions and improve long-term outcomes in pediatric MS patients. Full article

C-terminal-binding proteins (CtBPs) dimerize and function predominantly as transcriptional corepressors by recruiting various chromatin-modifying factors to promoter-bound repressors. Hypotonia, ataxia, developmental delay, and tooth enamel defects syndrome (HADDTS) is a recently discovered neurodevelopmental disorder resulting from a heterozygous missense mutation in CTBP1. It is often associated with the early onset of profound cerebellar atrophy in patients. Allen Institute’s Allen Brain Cell (ABC) atlas of human brain data was used to localize CTBP1 expression in the brain to elucidate the etiology of HADDTS. Based on the ABC atlas, CTBP1 is highly expressed in the upper rhombic lip supercluster, which gives rise to cerebellar cells and provides insights into the cerebellar pathophysiology observed in HADDTS patients. Full article

Introduction: Neurodegenerative diseases like progressive supranuclear palsy (PSP) present challenges concerning their diagnosis. Neuroimaging using magnetic resonance (MRI) may add diagnostic value. However, modern techniques such as volumetric assessment using Voxel-Based Morphometry (VBM), although proven to be more accurate and superior compared to MRI, have not gained popularity among scientists in the investigation of neurological disorders due to their higher cost and time-consuming applications. Conventional brain MRI methods may present a quick, practical, and easy-to-use imaging rating tool for the differential diagnosis of PSP. The purpose of this study is to evaluate a string of existing visual MRI rating scales and signs regarding their impact for the diagnosis of PSP. Materials and Methods: The population study consisted of 30 patients suffering from PSP and 72 healthy controls. Each study participant underwent a brain MRI, which was subsequently examined by two independent researchers in a double-blinded fashion. Fifteen visual rating scales and signs were evaluated, including pontine atrophy, cerebellar atrophy, midbrain atrophy, aqueduct of Sylvius enlargement, cerebellar peduncle hyperintensities, enlargement of the fourth ventricle (100% sensitivity and 71% specificity) and left temporal lobe atrophy (97% sensitivity and 78% specificity). Conclusions: Enlargement of the Sylvius aqueduct, enlargement of the fourth ventricle and atrophy of both temporal lobes together with the presence of morning glory and hummingbird signs can be easily and quickly distinguished and identified by an experienced radiologist without involving any complex analysis, making them useful tools for PSP diagnosis. MRI visual scale measurements could be added to the diagnostic criteria of PSP and may serve as an alternative to highly technical and more sophisticated quantification methods. Full article

Background: Fatigue is a prevalent and debilitating symptom in people with multiple sclerosis (pwMS), significantly impairing quality of life. While the cerebellum is traditionally associated with motor control, emerging evidence suggests its involvement in cognitive, emotional, and integrative functions. This study aimed to explore the relationship between fatigue components (physical, cognitive, and psychosocial), clinical disability, and cerebellar structural changes in pwMS acquired via magnetic resonance imaging (MRI). Methods: Participants of this cross-sectional study underwent clinical assessments for fatigue (Modified Fatigue Impact Scale) and disability (Expanded Disability Status Scale). Cerebellar volumes were measured using high-resolution MRI and voxel-based morphometry (VBM) to identify correlations between fatigue subdomains and specific cerebellar subregions. Statistical analyses included group comparisons and correlation tests. Results: Forty-four pwMS were included. Fatigued MS patients exhibited reduced sensorimotor cerebellar volumes compared to non-fatigued counterparts. Physical fatigue correlated negatively with sensorimotor cerebellum volume, while cognitive fatigue showed an inverse relationship with limbic cerebellum regions. Interestingly, psychosocial fatigue was positively associated with limbic cerebellum volume, contrary to initial hypotheses. Higher disability scores were linked to atrophy in cognitive and limbic cerebellar regions. Conclusions: The findings highlight the cerebellum’s multifaceted role in MS-related fatigue, with distinct subregions contributing to physical, cognitive, and psychosocial fatigue components. These results underscore the cerebellum’s critical function as a hub for motor, cognitive, and emotional integration. Future longitudinal studies incorporating objective measures and advanced imaging are essential to elucidate these relationships further and inform targeted therapeutic strategies for pwMS. Full article

Multiple System Atrophy (MSA) is a rare, rapidly progressive neurodegenerative disorder marked by autonomic dysfunction, parkinsonism, and cerebellar ataxia. While predominantly affecting individuals in their fifth or sixth decade, advancements in assisted reproductive technologies (ART) have created new clinical scenarios involving pregnancies in women within MSA’s typical onset range. Given the scarcity of documented MSA pregnancies, this review leverages insights from related Parkinson’s spectrum mechanisms to explore hypothetical scenarios for how pregnancy-induced physiological changes might influence MSA progression. Pregnancy-induced hormonal fluctuations, including elevated estrogen and progesterone levels, may modulate α-synuclein aggregation and neuroinflammatory pathways. Immune adaptations, such as fetal microchimerism and Th2-biased immune profiles, introduce additional complexities, particularly in donor embryo pregnancies involving complex microchimerism. Metabolic demands and oxidative stress further intersect with these mechanisms, potentially accelerating disease progression. We analyze existing literature and theoretical models, emphasizing the need for interdisciplinary research. Clinical implications are discussed to propose evidence-based strategies for optimizing maternal-fetal outcomes. This paper identifies critical knowledge gaps and proposes avenues for future investigation to optimize maternal-fetal outcomes in this unique and underexplored clinical intersection. Full article

This study investigates age-related neurodegeneration in the cerebellar cortex, emphasizing the role of IL-6 deficiency in preserving Purkinje cells. We found that apoptosis plays a minimal role in Purkinje cell loss by using 4-month- and 24-month-old wild-type (WT) and IL-6 knockout (IL-6KO) mice. At 24 months, WT mice exhibited severe Purkinje cell degeneration, including atrophic cell bodies, eosinophilic cytoplasm, pyknotic nuclei, mitochondrial disruption, and increased levels of lipofuscin-rich lysosomes. In contrast, IL-6KO mice showed fewer lysosomes, reduced mitochondrial damage, and less neuronal atrophy, indicating a neuroprotective effect. Lower p53 expression and decreased levels of its downstream effectors (p21, and Bax) in IL-6KO mice correlated with reduced cellular stress. Minimal changes in apoptotic markers (Bax and caspase-3) further reinforce the limited role of apoptosis. Neuroinflammation, marked by elevated GFAP, was prominent in aged WT mice but attenuated in IL-6KO mice. Reduced p53 accumulation, less severe neuroinflammation, and preserved metabolic homeostasis in IL-6KO mice correlated with improved Purkinje cell survival. These findings suggest that IL-6 accelerates neurodegeneration via p53-associated stress and inflammation, while IL-6 deficiency mitigates these effects. Targeting IL-6 signaling through anti-inflammatory strategies or IL-6 inhibition may offer a therapeutic approach for age-related neurodegenerative disorders. Full article

Background/Objectives: Cerebral folate transporter deficiency is characterized by pauses and regression in general development stages, with ataxia, choreoathetoid movements, and myoclonic epilepsy generally resistant to treatment. The aim of this study was to comprehensively evaluate cases followed up in two centres in Türkiye for a diagnosis of folate receptor-α deficiency. Methods: The study included nine cases from six different families. Results: The patients comprised 22.2% males and there was parental consanguinity in 88.9% of cases. The mean age at which complaints were first noticed was 3.7 years, and the age of definitive diagnosis was 10.4 years. The most frequently seen first complaints were febrile convulsions and attention deficit-hyperactivity-learning difficulties. The diagnosis most commonly made before the definitive diagnosis was epilepsy, and the first seizure occurred at a mean of 5.2 years. On cranial imaging, white matter involvement, cerebellar atrophy and cerebral atrophy were determined most often. Definitive diagnosis was established solely through clinical findings and genetic analysis. Three different variants in the FOLR1 gene were determined. Treatment with folinic acid at a dose of 5.2 mg/kg/day of PO was started at the age of 9.8 years on average, and intravenous folinate was started at different doses. Conclusions: This study stands out as one of the largest case series in the literature and identifies a previously unreported novel variant. Our study suggests that FOLR1-related CFD should be considered in cases with febrile convulsions, developmental delay, ataxia, autism spectrum disorder, acquired microcephaly, and MRI findings of white matter involvement and cerebellar atrophy. Due to an asymptomatic early period, CFD diagnosis may be delayed, and treatment after symptom onset may be less effective. Incorporating FOLR1 gene analysis into newborn screening programmes could facilitate early diagnosis and treatment. It is thought that the application of vagus nerve stimulation, in addition to folinic acid and anticonvulsant drug treatment, could be effective in seizure control. Full article

Background: The clinical profiles of MNDs are dominated by inexorable motor decline, but subclinical proprioceptive, nociceptive and somatosensory deficits may also exacerbate mobility, dexterity, and bulbar function. While extra-motor pathology and frontotemporal involvement are widely recognised in motor neuron diseases (MNDs), reports of sensory involvement are conflicting. The potential contribution of sensory deficits to clinical disability is not firmly established and the spectrum of sensory manifestations is poorly characterised. Methods: A systematic review was conducted to examine the clinical, neuroimaging, electrophysiology and neuropathology evidence for sensory dysfunction in MND phenotypes. Results: In ALS, paraesthesia, pain, proprioceptive deficits and taste alterations are sporadically reported and there is also compelling electrophysiological, histological and imaging evidence of sensory network alterations. Gait impairment, impaired dexterity, and poor balance in ALS are likely to be multifactorial, with extrapyramidal, cerebellar, proprioceptive and vestibular deficits at play. Human imaging studies and animal models also confirm dorsal column-medial lemniscus pathway involvement as part of the disease process. Sensory symptoms are relatively common in spinal and bulbar muscular atrophy (SBMA) and Hereditary Spastic Paraplegia (HSP), but are inconsistently reported in primary lateral sclerosis (PLS) and in post-poliomyelitis syndrome (PPS). Conclusions: Establishing the prevalence and nature of sensory dysfunction across the spectrum of MNDs has a dual clinical and academic relevance. From a clinical perspective, subtle sensory deficits are likely to impact the disability profile and care needs of patients with MND. From an academic standpoint, sensory networks may be ideally suited to evaluate propagation patterns and the involvement of subcortical grey matter structures. Our review suggests that sensory dysfunction is an important albeit under-recognised facet of MND. Full article

Background: Childhood-onset progressive ataxias are rare neurodegenerative disorders characterized by cerebellar signs, sometimes associated with other neurological or extra-neurological features. The autosomal dominant forms, known as spinocerebellar ataxias (SCAs), linked to trinucleotide (i.e., CAG) repeat disorders, are ultra-rare in children. We describe three patients from two unrelated families affected by spinocerebellar ataxia type 2 (SCA2) and present a literature review of pediatric cases. Methods: The patients’ clinical and genetic data were collected retrospectively. Results: The first case was a 9.5-year-old boy, affected by ataxia with oculomotor apraxia and cerebellar atrophy, subcortical myoclonus, and peripheral axonal sensitive polyneuropathy caused by a pathologic expansion in ATXN2, inherited from his asymptomatic father. Two brothers with familial SCA2 presented neurodegeneration leading to early death in one case and progressive ataxia, parkinsonism, and epilepsy with preserved ambulation at age 18 years in the second. To date, 19 pediatric patients affected by SCA2 have been reported, 3 of whom had a phenotype consistent with progressive ataxia with shorter CAG repeats, while 16 had more severe early-onset encephalopathy, with longer alleles. Conclusions: Although they are ultra-rare, trinucleotide repeat disorders must be considered in differential diagnosis of hereditary progressive ataxias in children, especially considering that they require targeted genetic testing and can manifest even before a parental carrier becomes symptomatic. Thus, they must also be taken into account with negative family history and when Next-Generation Sequencing (NGS) results are inconclusive. Notably, the association between cerebellar ataxia and other movement disorders should raise suspicion of SCA2 among differential diagnoses. Full article