Search Results (283)

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

Background: Cerebrotendinous Xanthomatosis (CTX) is a rare, inherited metabolic disease caused by pathogenic variants in CYP27A1. The clinical presentation of this progressive disease includes cognitive deficits, ataxia, peripheral neuropathy, and pyramidal signs, as well as bilateral cataracts and tendon xanthomas. In some cases, CTX also includes parkinsonism. The goals of this study are to develop a data source that provides improved characterization and awareness of parkinsonism in CTX. Methods: We conducted a systematic review of the literature according to PRISMA guidelines to identify all published individuals diagnosed with CTX and parkinsonism. Clinical signs, imaging findings and treatment response to both chenodeoxycholic acid and dopaminergic medications were examined for 72 subjects. Results: The average age of onset of parkinsonism in these CTX patients was 42 years, illustrating the early onset nature of parkinsonism in CTX. Functional dopaminergic imaging revealed the loss of presynaptic dopaminergic neurons in the substantia nigra which points to neurodegeneration of the dopaminergic system as the underlying pathophysiology for parkinsonism in CTX. Brain MRI showed abnormalities in the basal ganglia in 38% of subjects. MRI also showed abnormalities in the cerebellum in 88% of subjects which is typical for CTX and can be utilized to distinguish subjects with CTX and parkinsonism from individuals with other forms of atypical parkinsonism. Dopaminergic medication mitigated parkinsonism signs in most individuals with CTX. Conclusion: CTX is a neurometabolic disease that can result in levodopa-responsive parkinsonism that should be included in the differential for atypical parkinsonism. Full article

Background: Riboflavin transporter deficiency type 2 is an ultra-rare, yet treatable, inborn error of metabolism. This autosomal recessive disorder is caused by pathogenic mutations in the SLC52A2 gene leading to progressive ataxia, polyneuropathy, and hearing and visual impairment. The early initiation of riboflavin therapy can prevent or mitigate the complications. To date, only 200 cases have been reported, mostly in consanguineous populations. The p.Gly306Arg founder mutation, identified in patients of Lebanese descent, is the most frequently reported worldwide. It was described in a homozygous state in a total of 21 patients. Therefore, studies characterizing the phenotypic spectrum of this mutation remain scarce. Methods: A retrospective review of charts of patients diagnosed with riboflavin transporter deficiency type 2 at a tertiary-care reference center in Lebanon was performed. Clinical, biochemical, and molecular profiles were analyzed and compared to reported cases in the literature. Results: A total of six patients from three unrelated families were diagnosed between 2018 and 2023. All patients exhibited the homozygous founder mutation, p.Gly306Arg, with variable phenotypes, even among family members. The median age of onset was 3 years. Diagnosis was achieved by exome sequencing at a median age of 5 years, as clinical and biochemical profiles were inconsistently suggestive. The response to riboflavin was variable. One patient treated with high-dose riboflavin recovered his motor function, while the others were stabilized. Conclusions: This study expands the current knowledge of the phenotypic spectrum associated with the p.Gly306Arg mutation in the SLC52A2 gene. Increased awareness among physicians of the common manifestations of this rare disorder is crucial for early diagnosis and treatment. In the absence of a consistent clinical or biochemical phenotype, the use of next-generation sequencing as a first-tier diagnostic test may be considered. Full article

Cerebellar ataxias are a group of disorders characterized by clumsy movements because of defective muscle control. In affected individuals, muscular impairment might have an impact on activities like walking, balance, hand coordination, speech, and feeding, as well as eye movements. The development of symptoms typically takes place during the span of adolescence, and it has the potential to cause distress for individuals in many areas of their lives, including professional and interpersonal relationships. Although skeletal muscle is understudied in ataxias, its examination may provide hitherto unexplored details in this family of disorders. Observing muscle involvement can assist in diagnosing conditions where genetic tests alone are inconclusive. Furthermore, it helps determine the stage of progression of a pathology that might otherwise be challenging to assess. In this study, we reviewed the main scientific literature reporting on skeletal muscle examination in autosomal recessive cerebellar ataxias (ARCAs), with a focus on the rare Marinesco–Sjögren syndrome. (MSS). Our aim was to highlight the similarities in muscle alterations observed in ARCA patients while also considering data gathered from preclinical models. Analyzing the similarities among these disorders could enhance our understanding of the unidentified mechanisms underlying the phenotypic evolution of some less common conditions. Full article

Introduction: There are no validated clinical diagnostic criteria for chronic traumatic encephalopathy or traumatic encephalopathy syndrome (TES). To understand the historical clinical condition, its applicability to modern day athletes, and the pathogenesis of clinical problems, we examined the literature describing boxers from the 20th century, with specific attention paid to neurological findings and characteristics of clinical disease progression. Methods: Data were extracted for 243 boxers included in 45 articles published between 1928 and 1999, including cases from articles originally published in German. The presence or absence of 22 neurological signs and features were extracted. Results: The most common neurological problems were slurring dysarthria (49%), gait disturbances (44%), and memory loss (36%), with several other problems that were less frequent, including hyperreflexia (25%), ataxia (22%), increased tone (19%), and extensor Babinski sign (16%). Frank dementia appeared in some cases (17%). There were significantly fewer neurological deficits reported in boxers who fought in the latter part of the 20th century compared to boxers who fought earlier in the century. For more than half of the cases, there were no comments about whether the neurological problems were progressive (145, 60%). A progressive condition was described in 71 cases (29%) and a stationary or improving condition was described in 27 cases (11%). Canonical neurodegenerative disease-like progression was described in 15 cases (6%). Discussion: Neurological problems associated with boxing-related neurotrauma during the 20th century are the foundation for present-day TES. However, the clinical signs and features in the 20th century differ in most ways from the modern criteria for TES. Full article

Rare genetic movement disorders usually manifest early in life with dystonia, parkinsonism, chorea, or a combination thereof. These are often associated with neurodevelopmental delay, intellectual disability, speech problems, retinal abnormalities, seizures, ataxia, spasticity, or systemic features. Due to their vast number and pheno–genotypic heterogeneity, the diagnosis of these disorders can be challenging. However, recognising their core motor phenomenology as well as clinical, laboratory, and neuroradiological clues can expedite appropriate diagnostic workup, molecular diagnosis, and adequate treatment. In this review, we outline diagnostic clues to rare movement disorders (RMDs), focusing on those that present mainly with dystonia, parkinsonism, or paroxysmal dyskinesia due to genetic causes. Additionally, we provide a decision tree approach linking clinical, genetic, and imaging testing. Finally, we highlight selected RMDs that should not be missed, as they possess established treatments that can hinder their progression, prevent irreversible or life-threatening sequelae and, in certain cases, lead to complete symptom remission. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach. Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks. In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy. Full article

Background: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder due to mutations in the ATM gene. Given the residual kinase activity and the type of ATM mutation, its clinical spectrum varies from a severe classic phenotype to a variant atypical form. Material and methods: This study included 28 patients belonging to four big Bulgarian Muslim pedigrees with tremor and dystonia. Whole-exome sequencing was performed in seven affected individuals from two unrelated pedigrees, followed by Sanger sequencing of the coding sequences and exon–intron borders of the ATM gene. Results: Twenty-four of the affected individuals were homozygous for c.8147T>C (p.Val2716Ala) in ATM, while four of the affected individuals were compound heterozygous. The targeted Sanger sequencing along the ATM gene revealed as a second mutation in three of the patients the splice-site variant c.4909+1G>A and in one patient a synonymous pathogenic variant with a splicing effect, c.3576G>A, p.Lys1192. The age at onset in our group varied between 14 days and 40 years. The main symptoms were dystonia and tremor, more prominent in the upper limbs and the neck, and dystonic dysarthria and dysphagia. The clinical course was very slowly progressive. Brain imaging was normal in the majority of the patients. Conclusion: Clinical features due to mutations in the ATM gene can be very broad. The disease may appear as dystonia, especially of early onset, without frank cerebellar involvement and also normal cerebral imaging. A-T should be considered in all patients with unexplained, even mild movement disorders and elevated α fetoprotein. Full article

Spinocerebellar ataxia type 7 (SCA7), a rare form of ataxia, possesses a wide phenotypic spectrum ranging from classic ataxic symptoms to blindness, multiorgan failure, cardiomyopathy, and early death among younger age groups. Biomarkers associated with disease progression and severity could aid in disease prognostication. We evaluated the utility of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in distinguishing patients with SCA7 from healthy controls and estimating patient prognosis. GFAP and NfL levels were measured in 23 plasma and 20 cerebrospinal fluid (CSF) samples from asymptomatic (N = 3) and symptomatic SCA7 participants (N = 10) and from healthy controls (N = 8). GFAP concentrations were elevated in the plasma (82.7 pg/mL) and CSF (9318 pg/mL) of patients with SCA7 compared to controls (plasma: 48.0 pg/mL; CSF: 89,056 pg/mL). Similarly, NfL plasma (21.6 pg/mL) and CSF (2615.0 pg/mL) levels were also significantly upregulated in SCA7 compared to controls (plasma: 8.2 pg/mL; CSF: 414.6 pg/mL). Higher levels of NfL, but not of GFAP, significantly discriminated symptomatic SCA7 patients from controls (area under de curve, AUC: 0.898, p = 0.0059, in plasma, and AUC: 1.0, p = 0.0012, in CSF). The levels of both biomarkers increased overtime, with plasma NfL levels strongly associated with a worse score in the scale for the assessment and rating of ataxia (SARA) (Spearman r: 0.8354, p = 0.0007; regression analysis: β: 0.021, 95% CI: 0.008–0.035, p = 0.0048). These findings suggest that NfL could serve as a valuable biomarker for monitoring disease progression and prognosis in SCA7 patients. Full article

Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant neurodegenerative disorder marked by cerebellar dysfunction, ataxic gait, and progressive motor impairments. SCA2 is caused by the pathologic expansion of CAG repeats in the ataxin-2 (ATXN2) gene, leading to a toxic gain-of-function mutation of the ataxin-2 protein. Currently, SCA2 therapeutic efforts are expanding beyond symptomatic relief to include disease-modifying approaches such as antisense oligonucleotides (ASOs), high-throughput screening (HTS) for small molecule inhibitors, and gene therapy aimed at reducing ATXN2 expression. In the present study, data mining and machine learning techniques were employed to analyze HTS data and identify robust molecular properties of potential inhibitors of ATXN2. Three HTS datasets were selected for analysis: ATXN2 gene expression, CMV promoter expression, and biochemical control (luciferase) gene expression. Compounds displaying significant ATXN2 inhibition with minimal impact on control assays were deciphered based on effectiveness (E) values (n = 1321). Molecular descriptors associated with these compounds were calculated using MarvinSketch (n = 82). The molecular descriptor data (MD model) was analyzed separately from the experimentally determined screening data (S model) as well as together (MD-S model). Compounds were clustered based on structural similarity independently for the three models using the SimpleKMeans algorithm into the optimal number of clusters (n = 26). For each model, the maximum response assay values were analyzed, and E values and total rank values were applied. The S clusters were further subclustered, and the molecular properties of compounds in the top candidate subcluster were compared to those from the bottom candidate subcluster. Six compounds with high ATXN2 inhibiting potential and 16 molecular descriptors were identified as significantly unique to those compounds (p < 0.05). These results are consistent with a quantitative HTS study that identified and validated similar small-molecule compounds, like cardiac glycosides, that reduce endogenous ATXN2 in a dose-dependent manner. Overall, these findings demonstrate that the integration of HTS analysis with data mining and machine learning is a promising approach for discovering chemical properties of candidate drugs for SCA2. Full article

Feline healthcare phobia is a major challenge in veterinary practice, limiting medical care and increasing stress for cats, owners, and veterinarians. Traditional desensitization–counter-conditioning (DS-CC) protocols aim to reduce fear responses, but their success is limited in sensitized cats. This study evaluates whether gabapentin can improve the efficiency of DS-CC training in healthcare phobia in cats. Forty-two sensitized cats participated in a claw-trimming learning protocol. Using a double-blind, placebo-controlled crossover trial, the cats followed 10 training sessions: the first 5 under one product and the last 5 under the other one. Their progression through the learning steps was monitored. The results indicate that gabapentin significantly accelerated the cats’ ability to complete DS-CC steps, suggesting a positive effect on the learning process. While some side effects, such as mild sedation and ataxia, were observed in 42% of the cats, they were transient and did not hinder participation. These findings suggest that gabapentin should be added when engaging patients in DS-CC protocols in order to lower the time needed to achieve therapy, which will improve the overall welfare of our patients. Further studies are needed to confirm these results in other types of therapies and in a clinical setting. Full article

Susceptibility-weighted imaging (SWI) is a magnetic resonance imaging (MRI) sequence sensitive to substances that alter the local magnetic field, such as calcium and iron, allowing phase information to distinguish between them. SWI is a 3D gradient–echo sequence with high spatial resolution that leverages both phase and magnitude effects. The interaction of paramagnetic (such as hemosiderin and deoxyhemoglobin), diamagnetic (including calcifications and minerals), and ferromagnetic substances with the local magnetic field distorts it, leading to signal changes. Neurodegenerative diseases are typically characterized by the progressive loss of neurons and their supporting cells within the neurovascular unit. This cellular decline is associated with a corresponding deterioration of both cognitive and motor abilities. Many neurodegenerative disorders are associated with increased iron accumulation or microhemorrhages in various brain regions, making SWI a valuable diagnostic tool in clinical practice. Suggestive SWI findings are known in Parkinson’s disease, Lewy body dementia, atypical parkinsonian syndromes, multiple sclerosis, cerebral amyloid angiopathy, amyotrophic lateral sclerosis, hereditary ataxias, Huntington’s disease, neurodegeneration with brain iron accumulation, and chronic traumatic encephalopathy. This review will assist radiologists in understanding the technical framework of SWI sequences for a correct interpretation of currently established MRI findings and for its potential future clinical applications. Full article

Case summary: A 2-year-old male neutered domestic shorthair cat was presented with a progressive history of tetraparesis, ataxia, and inappetence over 4 days. A physical exam revealed mucopurulent nasal discharge and stertor. A neurologic exam revealed a multifocal neurolocalization. The cat was non-ambulatory tetraparetic and developed seizures while in hospital. Hematologic assessment revealed anemia, hypoalbuminemia and hyperglobulinemia. Magnetic resonance imaging (MRI) of the brain revealed multifocal meningeal contrast enhancement in the brainstem and cervical spine, as well as mandibular and retropharyngeal lymphadenopathy. Cerebrospinal fluid revealed marked neutrophilic pleocytosis; no infectious organisms were seen. Toxoplasma IgG/IgM and Cryptococcus antigen latex agglutination were negative. Mandibular and abdominal lymph nodes were aspirated, and cytology revealed mixed inflammation. The cat was suspected to have feline infectious peritonitis, and to aid in clinical diagnosis he was enrolled in research study—with targeted Nanopore-based sequencing specifically identifying and characterizing FCoV-1 RNA in spinal fluid and anal swab, but not in urine. The cat was treated with anticonvulsants (phenobarbital and levetiracetam), an antibiotic (ampicillin/clavulanic acid), and GS-441524. Neurologic signs did not improve on an antibiotic alone but improved significantly after two subcutaneous injections of GS-441524. The cat received an 84-day course of GS-441524 and, at the time of manuscript preparation (over 12 months after diagnosis), remains ambulatory and seizure-free without recurrence of neurologic signs and no detectable viral shedding in feces. Full article

Brain stem cavernomas are exceedingly rare in pediatric populations, with limited literature addressing their natural history, treatment guidelines, and counseling. We report the case of a 5-year-old girl presenting with acute neurological symptoms, including diplopia, gait ataxia, headache, and altered consciousness. Initial imaging revealed obstructive hydrocephalus caused by a hemorrhagic lesion near the pineal region. After emergency external ventricular drainage (EVD), most symptoms resolved except for diplopia. A subsequent MRI suggested a space-occupying hemorrhagic cyst in the tectal lamina, leading to endoscopic third ventriculostomy (ETV). During ETV, a large hemorrhagic mass at the aqueduct entrance was identified but not removed due to its fragility. Following ETV, the patient improved rapidly and was discharged. However, she was readmitted with recurrent symptoms and altered consciousness. An emergency MRI indicated a progressive hemorrhagic mass lesion compressing the midbrain, necessitating surgical intervention. The patient underwent suboccipital craniotomy using a telovelar approach. The intraoperative findings included cavernoma-like tissue within the aqueduct, which was successfully resected. Histopathology confirmed hemorrhagic and angiomatous tissue, excluding a primary brain tumor. Postoperatively, the patient showed significant, progressive neurological improvement, with mild internuclear strabism, trunk ataxia, and fatigue at the last follow-up. Six months later, a follow-up MRI and cerebral angiography showed no cavernoma remnants but identified a midbrain deep venous anomaly. This case underscores the feasibility of the microsurgical resection of midbrain cavernomas in symptomatic pediatric patients, highlighting the importance of the thorough assessment of atypical hemorrhagic midbrain lesions to exclude rare vascular malformations from differential diagnoses. Full article

Background/Objectives: This study investigated the prognostic and predictive significance of Ataxia–Telangiectasia Mutated (ATM) expression in patients with metastatic non-small-cell lung cancer (NSCLC) who were treated with pembrolizumab. Methods: A retrospective analysis was conducted on 49 patients with metastatic NSCLC who received first-line pembrolizumab, either as a single agent or in combination with chemotherapy. ATM expression in archival pathology specimens was assessed using immunohistochemistry, where nuclear staining was considered to be positive. ATM expression was categorized into low- and high-expression groups based on staining intensity and the percentage of positive cells. Subsequently, the prognostic and predictive value of ATM expression was evaluated. Results: In terms of demographics, the mean age was 62.7 ± 9.5, most patients (91.8%) were male, and the majority (75.5%) had adenocarcinoma. The objective response rate (ORR) was 69.4%, and ATM expression was high in 75.5% of patients. Patients with low ATM expression had significantly longer progression-free survival (PFS) compared to those with high expression (51 vs. 5.7 months, p = 0.004). In multivariate analysis, ATM expression was the only independent prognostic factor for PFS, showing that patients with high ATM expression had a shorter overall survival (OS) compared to those with low expression (51 vs. 8.9 months, p = 0.013), which was statistically significant (HR 2.41, p = 0.034). Logistic regression analysis showed that ATM expression, as well as the presence of bone metastasis and the absence of liver metastasis, was significantly associated with a response to treatment (p = 0.006; OR: 0.06; 95% CI: 0.008–0.45). Conclusions: The findings of this study concerning ATM expression as a biomarker should be interpreted cautiously due to inherent limitations, including its retrospective design, the semi-quantitative nature of immunohistochemistry for ATM assessment, the small sample size with uneven clinical characteristics, and the relatively short follow-up period, which collectively impact generalizability. Despite these limitations, lower ATM expression was associated with better prognosis and pembrolizumab treatment response, suggesting that it may be a valuable biomarker for predicting these factors. Full article