Progressive Ataxia Research Articles

Intragenic duplication disrupting the reading frame of MFSD8 in Small Swiss Hounds with neuronal ceroid lipofuscinosis.

Neuronal ceroid lipofuscinosis (NCL) represents a heterogenous group of lysosomal storage diseases resulting in progressive neurodegeneration. We investigated two Small Swiss Hound littermates that showed progressive ataxia and loss of cognitive functions and vision starting around the age of 12 months. Both dogs had to be euthanized a few months after the onset of disease owing to the severity of their clinical signs. Pathological investigation of one affected dog revealed cerebral and cerebellar atrophy with cytoplasmic accumulation of autofluorescent material in degenerating neurons. The clinical signs in combination with the characteristic histopathology led to a tentative diagnosis of NCL. In the subsequent genetic investigation, the genome of one affected dog was sequenced. This revealed a duplication of 18 819 bp within the MFSD8 gene. The duplication breakpoints were located in intron 3 and exon 12 of the gene and were predicted to disrupt the reading frame. Both affected dogs carried the duplication in a homozygous state and there was perfect cosegregation of the genotypes with the phenotype in a large pedigree, consistent with autosomal recessive inheritance. MFSD8 loss-of-function variants are a known cause of NCL7 in human patients, dogs and other mammalian species. The existing knowledge on MFSD8 together with the experimental data strongly suggests that the identified intragenic MFSD8 duplication caused the disease in the Small Swiss Hounds. These results allow their diagnosis to be refined to NCL7 and enable genetic testing in the breed to avoid further unintentional carrier × carrier matings.

Desmoid fibromatosis following surgery of an intradural spinal lipoma in a young cat

BackgroundIntradural lipomas have been previously reported in individuals with spinal dysraphism; however, they have not been reported in cats with an intact spinal canal. Desmoid tumors are a rare finding in veterinary medicine, and there is no prior description of these tumors invading the spinal cord. Furthermore, the etiopathogenesis remains debated, with trauma, such as surgical intervention of an intradural structure, potentially contributing to its development.Case descriptionA 10-month-old domestic shorthair cat was presented initially with progressive proprioceptive ataxia. The MRI identified an intradural compressive lesion at the cranio-cervical junction, confirmed as a lipoma by histopathology. Despite surgical removal, postoperative complications led to the cat's euthanasia. Postmortem examination revealed invasion of a desmoid tumor at the surgical site.ConclusionsThis case highlights the rarity of intradural lipomas in this location and the unusual complication of desmoid tumor invasion. It underscores the need for further research into the underlying mechanisms and potential diagnostic and therapeutic strategies for similar cases and suggests that these findings may be added to the list of potential post-surgical complications.

Clinical whole Exome Sequencing Reveals Novel Homozygous Missense Variant in the PMPCA Gene causing Autosomal Recessive Spinocerebellar Ataxia

Background & Objective: Autosomal recessive cerebellar ataxias (ARCA) are rare heterogenous neurodegenerative disorders characterized by degeneration of the cerebellum and spinal cord with an early onset before the age of 20 years. PMPCA (MIM: 613036), is a key enzyme in mitochondrial protein processing which is critical for cell survival and growth. Our objective was to investigate Peptidase, Mitochondrial Processing Subunit Alpha (PMPCA) mutations linked with Spinocerebellar ataxia, autosomal recessive 2 (SCAR2). Method: In the current study, Whole Exome Sequencing (WES) was done followed by Sanger sequencing for the validation of the WES results. Results: WES results identified a novel homozygous variant, NM_015160.2: c.802C>T p.(Arg268Trp) in PMPCA gene. Mutation in this gene leads to progressive cerebellar ataxia with fine motor skills difficulties, intentional tremors, slow slurred speech and learning difficulties in a 12-year-old Saudi patient. WES results were further validated by Sanger sequencing technique. Conclusions: Identified phenotype in our case was similar as previously described for SCAR2 related conditions. To our knowledge, this is the first reported mutation in PMPCA gene leading to SCAR2 in Saudi Arabia. These findings will enrich the scarce literature, further provide a new insight on the role of PMPCA gene-related disorders leading to SCAR2 and expand the disease concept. In addition, this will help to establish a database for the disease and its causative factors will further help in controlling diseases resulting from consanguinity in Saudi population. doi: https://doi.org/10.12669/pjms.40.10.10474 How to cite this: Bagabir HA, Abdulkareem AA, Muthaffar OY, Shirah BH, Naseer MI. Clinical whole Exome Sequencing Reveals Novel Homozygous Missense Variant in the PMPCA Gene causing Autosomal Recessive Spinocerebellar Ataxia. Pak J Med Sci. 2024;40(10):2243-2250. doi: https://doi.org/10.12669/pjms.40.10.10474 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Compound heterozygous mutation of AFG3L2 causes autosomal recessive spinocerebellar ataxia through mitochondrial impairment and MICU1 mediated Ca2+ overload.

Autosomal recessive spinocerebellar ataxias (SCARs) are one of the most common neurodegenerative diseases characterized by progressive ataxia. Although SCARs are known to be caused by mutations in multiple genes, there are still many cases that go undiagnosed or are misdiagnosed. In this study, we presented a SCAR patient, and identified a probable novel pathogenic mutation (c.1A>G, p.M1V) in the AFG3L2 start codon. The proband's genotype included heterozygous mutations of the compound AFG3L2 (p.[M1V]; [R632X] (c.[1A>G]; [1894.C>T])), which were inherited from the father (c.1A>G, p.M1V) and mother (c.1894C>T, p.R632X). Functional studies performed on hiPSCs (human induced pluripotent stem cells) generated from the patients and HEK293T cells showed that the mutations impair mitochondrial function and the unbalanced expression of AFG3L2 mRNA and protein levels. Furthermore, this novel mutation resulted in the degradation of the protein and the reduction of the stability of the AFG3L2 protein, and MCU (mitochondrial calcium uniporter) complex mediated Ca2+ overload.

Pioglitazone as a Possible Treatment for Ataxia-Telangiectasia.

Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder characterized by immunodeficiency, progressive cerebellar ataxia, and an increased malignancy risk. Cells derived from individuals with AT show multiple defects, including high oxidant and ionizing radiation sensitivities, poor DNA repair, low iron-sulfur cluster levels, and low reduced glutathione. The clinical course of AT is progressive and unrelenting, with most individuals having a survival time of approximately twenty-five years. Presently, AT has no effective treatments, and most patients receive supportive care only. Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT. Here, I will discuss the possible molecular mechanisms of pioglitazone's favorable effects on the AT phenotype and why it may have utility in treating some aspects of AT.

Purkinje Cell-specific Deficiency in SEL1L-HRD1 Endoplasmic Reticulum-Associated Degradation Causes Progressive Cerebellar Ataxia in Mice.

Recent studies have identified multiple genetic variants of SEL1L-HRD1 ER-associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here we show that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell-specific deletion of SEL1L (Sel1LPcp2Cre) exhibit motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy (TEM) analysis reveals dilated ER and fragmented nuclei in Purkinje cells of adult Sel1LPcp2Cre mice, indicative of altered ER homeostasis and cell death. Lastly, loss of Purkinje cells is associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellum of Sel1LPcp2Cre mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.

Cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS): a family with five affected sibs from Turkey

BackgroundCerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS), a relatively common cause of late-onset progressive ataxia, is a genetic disease characterised by biallelic pentanucleotide AAGGG repeat expansion in intron 2 of the replication factor complex subunit 1 gene. Herein, we describe the first molecularly confirmed CANVAS family with five affected siblings from Turkey.Case presentationThe family comprised seven siblings born from healthy non-consanguineous parents. CANVAS phenotype was present in five of them; two were healthy and asymptomatic. Chronic cough was the first symptom reported in all five siblings, followed by the development of sensory symptoms, oscillopsia and imbalance. Clinical head impulse test (HIT) was positive in all cases and video HIT performed on three patients revealed very low vestibulo-ocular reflex gains bilaterally. Magnetic resonance imaging and nerve conduction studies revealed cerebellar atrophy and sensory neuronopathy, respectively. RP-PCR confirmed the homozygous presence of the AAGGG repeat expansion in all five cases.ConclusionGenetic screening for CANVAS should be considered in all patients with late-onset ataxia, sensory disturbances and vestibular involvement, especially in the presence of chronic cough.

Obsessive-compulsive disorder as a first manifestation of Ataxia with Oculomotor Apraxia type 2 due to a novel mutation of SETX gene.

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disorder presenting with cerebellar ataxia, sensory-motor axonal neuropathy, oculomotor apraxia, cerebellar atrophy and high alpha-fetoprotein (AFP) serum level. AOA2 is due to coding mutations of the SETX gene, mapped to chromosome 9q34. Seldom noncoding mutations affecting RNA processing have been reported too. To date psychiatric symptoms have never been reported in AOA2. A 19 years-old man came to our attention for progressive gait ataxia debuted five years earlier. His past medical history was unremarkable, while his parents were consanguineous. On neurological examination, he had bilateral horizontal gaze-evoked nystagmus with hypometric saccades and saccadic horizontal smooth pursuit, appendicular ataxia, limbs and trunk myoclonic involuntary movements with hands' dystonic postures and dance of the tendons. Psychological evaluation described intrusive and obsessive thoughts experienced by the patient, then diagnosed as obsessive-compulsive disorder. Blood tests detected an elevated AFP level. Brain MRI showed cerebellar atrophy, while electroneuromyography revealed an axonal sensory-motor polyneuropathy. In the suspicion of a pathology belonging to the autosomal recessive cerebellar ataxias (ARCA) spectrum disorder, a direct search of point mutations by whole-exome sequencing was performed revealing a novel biallelic variant in SETX gene (c.6208+2dupT), which was classified as likely pathogenic. The present case expands the genotypic and phenotypic spectrum of AOA2, reporting a novel likely pathogenic SETX mutation (c.6208+2dupT) and highlighting an early psychiatric involvement in AOA2, suggesting the need for psychiatric assessment in these neurologic patients.

Clinical, Radiological and Pathological Features of a Large American Cohort of Spinocerebellar Ataxia (SCA27B).

Spinocerebellar ataxia 27B due to GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene has recently been recognized as a common cause of late-onset hereditary cerebellar ataxia. Here we present the first report of this disease in the US population, characterizing its clinical manifestations, disease progression, pathological abnormalities, and response to 4-aminopyridine in a cohort of 102 patients bearing GAA repeat expansions. We compiled a series of patients with SCA27B, recruited from 5 academic centers across the United States. Clinical manifestations and patient demographics were collected retrospectively from clinical records in an unblinded approach using a standardized form. Post-mortem analysis was done on 4 brains of patients with genetically confirmed SCA27B. In our cohort of 102 patients with SCA27B, we found that SCA27B was a late-onset (57 ± 12.5 years) slowly progressive ataxia with an episodic component in 51% of patients. Balance and gait impairment were almost always present at disease onset. The principal finding on post-mortem examination of 4 brain specimens was loss of Purkinje neurons that was most severe in the vermis most particularly in the anterior vermis. Similar to European populations, a high percent of patients 21/28 (75%) reported a positive treatment response with 4-aminopyridine. Our study further estimates prevalence and further expands the clinical, imaging and pathological features of SCA27B, while looking at treatment response, disease progression, and survival in patients with this disease. Testing for SCA27B should be considered in all undiagnosed ataxia patients, especially those with episodic onset. ANN NEUROL 2024.

CASE-CONTROL STUDY OF THE FREQUENCY AND ETIOLOGY OF ATAXIA IN ASIATIC LIONS (PANTHERA LEO PERSICA) BETWEEN 2002 AND 2020.

The Asiatic lion (Panthera leo persica) is an endangered species with a slowly increasing captive and wild population. Several zoos from within the European Association of Zoos and Aquaria Ex Situ Program reported Asiatic lions with neurological signs such as (progressive) ataxia, and stargazing. The aim of this study was to evaluate the frequency (prevalence and incidence) and etiology of these clinical signs within the captive Asiatic lion population. The medical history of 74 Asiatic lions (36 healthy and 38 affected) was retrieved and reviewed for blood tests (biochemical, hematological, and retinol), diagnostic imaging (MRI and CT scans) and postmortem examinations. The data of the affected lions was compared with those of healthy lions. Between 2002 and 2020, the prevalence of ataxia ranged from 0.6% in 2004 to 13.0% in 2020. The incidence of ataxia was variable per year between 2002 and 2020 and ranged between 0 and 40%. Besides ataxia, stiffness and lameness were the most described signs in this study. Blood results showed lower total protein, ALT and creatinine, and higher phosphate in lions with neurological signs. Moreover, neurologically affected lions showed a significant lower blood retinol than the control lions (0.59-0.81 µmol/L). The most important finding in diagnostic imaging and necropsy included caudal fossa hyperostosis and cerebellar herniation. These abnormalities are similar as found in African lions (Panthera leo) with calvarial hyperostosis syndrome associated with vitamin A deficiency. Leucomyelopathy, syringomyelia (in one case combined with cerebellar herniation) and incidental mineralization of the dura mater were also described. A possible congenital/hereditary component should not be excluded.

Compound Heterozygous WARS2 Variants Including a Hypomorphic Allele Cause a Milder Phenotype of Complex Dopa Responsive Dystonia: Case Report and Review of the Literature.

Biallelic WARS2 pathogenic variants responsible for partial defect in aminoacylation, have recently been reported in subjects presenting with late-onset phenotypes combining dopa-responsive early-onset dystonia parkinsonism with altered DaTSCAN and progressive myoclonus ataxia. Here, we present the case of a 39-year-old male with childhood-onset progressive dopa-responsive dystonia parkinsonism, prominent psychiatric features and ataxia whose genome sequencing identified a p.(Arg36Ter) nonsense variant and a hypomorphic p.(Trp13Gly) missense variant, allowing the diagnosis of WARS2-related disease. The p.(Trp13Gly) missense variant has previously been reported in individuals with less severe phenotypes than those carrying biallelic WARS2 loss-of-function variants. Among these individuals, two subjects had similar genetic backgrounds and almost identical clinical history to our patient. Our report brings additional proof that the p.(Trp13Gly) variant acts as a hypomorphic allele, offering insight on a genotype-phenotype correlation in WARS2-related disorders.

Clinical, magnetic resonance imaging and histopathological findings of a congenital hypomyelinating leukodystrophy in a Holstein Friesian calf

AbstractA 12‐day‐old, male Holstein Friesian calf was presented to the hospital due to progressive ataxia and tremors since birth. A diffuse central nervous system disorder primarily affecting white matter was suspected based on clinical neurological examination. Blood tests were unremarkable, except for positive serology for Schmallenberg virus. Magnetic resonance imaging of the brain demonstrated severe, diffuse abnormalities primarily affecting the white matter regions of the encephalon and cranial cervical spinal cord, consistent with leukoencephalomyelopathy. Euthanasia was performed at 8 weeks of age after no clinical improvement. A postmortem examination was performed. Histopathological examination of the central nervous system revealed changes compatible with hypomyelinating leukodystrophy, with no signs of infectious agents observed. The disorder was considered most likely to be hereditary, as Schmallenberg virus infections during pregnancy in cattle have not been reported to result in such clinical, magnetic resonance imaging or histopathological findings, and no viral genomic material was identified with polymerase chain reaction.

Loss of Elp1 in cerebellar granule cell progenitors models ataxia phenotype of Familial Dysautonomia

Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.

Post-gastric sleeve gastrectomy mixed Wernicke's and Hashimoto's encephalopathies with brain atrophy: A case-report from Qatar

We present a case of a 21-year-old male patient who presented with progressive dizziness, gait instability, and ataxia of 1-week duration. Three months prior to presentation, the patient underwent Laparoscopic Sleeve Gastrectomy (LSG). His workup showed a very low level of thiamine, high thyroid-stimulating hormone (TSH) level, and very low free thyroxine (T4). The patient was diagnosed with Wernicke Encephalopathy (WE) post LSG, exacerbated by Hashimoto Encephalopathy (HE), given the history of an underlying uncontrolled Hashimoto's thyroiditis (HT).

Exploring the diverse phenotypes of anti-GAD 65 encephalitis, diagnosis and treatment challenges

Objectives. To present two cases of anti-glutamic acid decarboxylase 65 (anti-GAD65) antibody encephalitis with different clinical phenotypes. Introduction. Anti-glutamic acid decarboxylase 65 antibody encephalitis (GAD-65 AE) is a rare pathology with a high potential for severity, having multiple forms of presentation and multiple differential diagnoses. This presentation aims to exemplify the strong clinical heterogeneity that is associated with this clinical entity by putting forth two cases that were treated in our clinic, each representing a separate clinical phenotype of this pathology. Material and methods. We analyzed two cases from our clinic of autoimmune encephalitis with positive anti-GAD65 antibodies and compared the cases with the data from the literature regarding clinical presentation, differential diagnosis, treatment, and evolution. Content. The first case presented is a woman aged 71 (66 at onset) presenting with progressive cerebellar ataxia. She was diagnosed with GAD-65 AE based on clinical presentation and positive anti-GAD65 antibodies titer. She was initially treated with methylprednisolone pulse therapy and received four such courses in the first year after diagnosis, resulting in a slowing of the progression of the neurological deficit. During the COVID19 pandemic, treatment was paused and her neurological status resumed its decline, and she also developed insulin-dependent diabetes mellitus. Starting in 2021, treatment was continued, having received one course of IVIg and one course of plasma exchange in our clinic. Eventually, the treatment was switched to Mycophenolate mofetil but her status continues to decline. The second case is about a 32 years old woman, with a history of recurrent seizures and progressive memory decline that started at 28 years. She was diagnosed 11 months after the onset with limbic encephalitis with anti-GAD65 antibodies, left temporal focal epilepsy with nocturnal seizures and mild cognitive decline. She was treated with corticotherapy and IgG. She was discharged home with antiepileptic treatment with no recurring seizures, but a slow cognitive decline. She had two relapses at distance from the onset, the first one with status epilepticus and the second one with focal seizures and a generalized seizure. She developed type I diabetes with positive anti-pancreatic islet antibodies. After the first relapse, immunosuppressive therapy with Mycophenolate mofetil was initiated. The evolution was good and under immunosuppression she had only one episode of seizures in the context of a COVID-19 infection. Conclusions. Autoimmune encephalitis with positive GAD antibodies presents a very diverse clinical picture, as we can see in the presented cases.

Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency.

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

Whole Exome Sequencing Indicating GGCCTG Hexanucleotide Repeat in Patients with Spinocerebellar Ataxia Type 36

Introduction: Spinocerebellar ataxia type 36 (SCA36) is caused by large GGCCTG repeat expansion in the NOP56 gene. The genetic diagnosis based on Southern blot is expensive and time-consuming. This study aimed to evaluate the reliability and effectiveness of whole exome sequencing (WES) for routine genetic diagnosis of suspected SCA36 patients. Methods: Pathogenic repeat expansions for SCAs including SCA36 were first analyzed based on WES data using ExpansionHunter in five probands from SCA families, then the results were confirmed by triplet repeat primed polymerase chain reaction (TP-PCR) and Southern blot. Results: GGCCTG repeat expansion in NOP56 was indicated in all five probands by WES, then it was found in 11 SCA patients and three asymptomatic individuals by TP-PCR. The sizes of GGCCTG repeat expansions were confirmed to be 1,390–1,556 by Southern blot. The mean age at onset of the patients was 51.0 ± 9.3 (ranging from 41 to 71), and they presented slowly progressive cerebellar ataxia, atrophy and fasciculation in tongue or limb muscles. Conclusion: The patients were clinically and genetically diagnosed as SCA36. This study proposed that WES could be a rapid, reliable, and cost-effective routine test for the preliminarily detection of SCA36 and other ataxia diseases.

Progressive degeneration in a new Drosophila model of spinocerebellar ataxia type 7

Spinocerebellar ataxia type 7 (SCA7) is a progressive neurodegenerative disorder resulting from abnormal expansion of an uninterrupted polyglutamine (polyQ) repeat in its disease protein, ataxin-7 (ATXN7). ATXN7 is part of Spt-Ada-Gcn5 acetyltransferase (SAGA), an evolutionarily conserved transcriptional coactivation complex with critical roles in chromatin remodeling, cell signaling, neurodifferentiation, mitochondrial health and autophagy. SCA7 is dominantly inherited and characterized by genetic anticipation and high repeat-length instability. Patients with SCA7 experience progressive ataxia, atrophy, spasticity, and blindness. There is currently no cure for SCA7, and therapies are aimed at alleviating symptoms to increase quality of life. Here, we report novel Drosophila lines of SCA7 with polyQ repeats in wild-type and human disease patient range. We find that ATXN7 expression has age- and polyQ repeat length-dependent reduction in fruit fly survival and retinal instability, concomitant with increased ATXN7 protein aggregation. These new lines will provide important insight on disease progression that can be used in the future to identify therapeutic targets for SCA7 patients.

Case report: Cerebrotendinous xanthomatosis treatment follow-up.

Xanthomatosis is a genetic disease inherited in an autosomal recessive manner. The specific phenotypic features are associated with patient's genetic profile. The result of the mutation is disorder of cholesterol synthesis and the accumulation of its precursors in tissues. The characteristic symptoms are progressive cerebellar ataxia, cataract, diarrhea, and the deposition of cholesterol in the tendons. Our objective is to follow-up information to treatment efficacy of 22-year-old patient diagnosed with cerebrotendinous xanthomatosis through 1.5 year observation. In 2012, an 11-year-old patient with a long history of deformed feet and frequent yellowing of the skin, was admitted to the Department of Neurology due to seizures. In 2013, the patient began to suffer from diarrhea, and its frequency was correlated with the concentration of bilirubin in the blood. In the same year cataract was diagnosed. Gradually, the patient starts to complain about progressive difficulties in moving. In 2019, genetic tests confirmed the diagnosis of cerebrotendinous xanthomatosis. Since July 2021, the patient has been treated with chenodeoxycholic acid. The deterioration of patient's mobility has been significantly inhibited, consequently his quality of life has improved. The presented case report underscores the efficacy of CDCA supplementation in halting the progression of CTX, resulting in marked improvements in the patient's quality of life.

Spinocerebellar ataxia 27B: a frequent and slowly progressive autosomal-dominant cerebellar ataxia-experience from an Italian cohort.

Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.