OBJECTIVE: To explore the clinical and genetic features of a child with Pontocerebellar hypoplasia type 2B (PCH2B) due to compound heterozygous variants of the TSEN2 gene. METHODS: A PCH2B patient presented at Department of Pediatric Neurology, Xiangya Hospital of Central South University in June 2023 was selected as the study subject. Clinical data of the patient were retrospectively analyzed. The patient and her parents were subjected to whole exome sequencing and bioinformatic analysis. Pathogenicity of the candidate variants were classified based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). A literature review was also conducted by searching the China National Knowledge Infrastructure (CNKI), Wanfang Data, and PubMed databases from their establishment to May 2025 using keywords "TSEN2 gene" "PCH2B" and "Pontocerebellar Hypoplasia 2B" to summarize the clinical and genotypic features of patients with PCH2B due to variants of the TSEN2 gene. This study was approved by the Medical Ethics Committee of the Hospital (No.: #202310892). RESULTS: The patient, a 6-year-5-month-old girl, had exhibited severe global developmental delay, developmental regression, autism spectrum disorder, myoclonus of eyelids, feeding difficulty, irritability, progressive microcephaly, esotropia, and hypotonia. MRI showed reduced volume of bilateral cerebellar hemispheres and vermis. Genetic testing revealed that she has harbored compound heterozygous variants of the TSEN2 gene (NM_025265.4), namely c.1054A>T (p.Lys352*) and c.899G>T (p.Ser300Ile), which were inherited from her father and mother, respectively. Both variants were classified as likely pathogenic based on the ACMG guidelines and were previously unreported. Literature review has identified six PCH2B patients with missense, nonsense, frameshift, and splice site variants of the TSEN2 gene. Their main clinical manifestations included global developmental delay, progressive microcephaly, feeding difficulties, irritability, and vermis hypoplasia. Cranial MRI and genetic testing are crucial for definite diagnosis. CONCLUSION The c.1054A>T (p.Lys352*) and c.899G>T (p.Ser300Ile) compound heterozygous variants of the TSEN2 gene probably underlay the pathogenesis in this patient. Above findings has expanded the genotypic and phenotypic spectra of TSEN2-related PCH2B, and offered guidance for genetic counseling for this family.
Child ; Female ; Humans ; Cerebellar Diseases/genetics* ; Exome Sequencing ; Heterozygote ; Mutation

OBJECTIVE: To explore the genetic etiology of Pontocerebellar Hypoplasia Type 2D (PCH2D) due to compound heterozygous variants of the SEPSECS gene and to conduct a literature review. METHODS: A child with PCH2D diagnosed at the Children's Hospital of Nanjing Medical University due to "motor and cognitive retardation" in June 2022 was selected as the study subject. Clinical and imaging data were collected. Genomic DNA was extracted from the peripheral blood samples of the child and her parents. Whole-exome sequencing (WES) was conducted using capture-based high-throughput sequencing technology. Candidate variants were confirmed by Sanger sequencing and bioinformatics analysis. The pathogenicity of variant was rated according to the Standards and Guidelines for the Interpretation of Sequence Variants released by American College of Medical Genetics and Genomics (ACMG). Additionally, relevant literature on PCH2D caused by SEPSECS gene variants was reviewed to assess the genotype-phenotype correlation. This study was approved by the Medical Ethics Committee of the hospital (Ethical No.: 202402022-1). RESULTS: The child, a 1-year-and-3-month-old girl, had presented with global developmental delay, progressive microcephaly, hypotonia, elevated blood lactic acid, feeding difficulties, and absent tendon reflexes. Cranial MRI indicated thinning of the splenium of the corpus callosum. Electromyography suggested peripheral neurogenic changes primarily affecting sensory nerves. WES revealed the she has harbored compound heterozygous variants of the SEPSECS gene, namely c.194A>G (p.N65S) and c.896_c.897insA (p.N299fs*2) (NM_016955), which were inherited from her father and mother, respectively. Neither of her parents had related clinical manifestations. According to the ACMG guidelines, the c.194A>G (p.N65S) variant was classified as pathogenic (PM1+PM2_Supporting+PM3+PP3), and the c.896_c.897insA (p.N299fs*2) variant was as likely pathogenic (PVS1+PM2_Supporting). A total of 18 relevant literature were retrieved, which have involved 32 patients (including this case). The p.N65S variant has been reported previously, while the p.N299fs*2 variant is novel. CONCLUSION Compound heterozygous variants in the SEPSECS gene probably underlay the pathogenesis of PCH2D in this child. Above finding has expanded the mutational and phenotypic spectrum of the SEPSECS gene.
Humans ; Female ; Infant ; Heterozygote ; Cerebellar Diseases/genetics* ; Membrane Proteins/genetics* ; Exome Sequencing ; Mutation

OBJECTIVE: To analyze the clinical characteristics and genotypic changes of six children with RARS2 gene variants. METHODS: The clinical data of 6 children with RARS2 gene variants diagnosed at the Third Affiliated Hospital of Zhengzhou University from January 2017 to August 2024 were collected. Genetic variants were detected using trio-whole exome sequencing. Genomic DNA was extracted from samples and subjected to high-throughput sequencing. Variants were detected and analyzed using relevant databases and software. Pathogenic variants were validated by Sanger sequencing. The protein structure encoded by a previously unreported variant was predicted using a SWISS-MODEL online server. This study was approved by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethics No.: 2024-373-01). RESULTS: Among the six children, four were males and two were females, with the most recent follow-up age ranging from 1-year-and-1-month to 7 years old. The age of onset was under 1 year in all cases. All six children exhibited seizures, including infantile spasms in three, spasms and tonic spasms in one, and focal seizures in two. One child became seizure-free for 4 ~ 5 years following Valproic acid combined with topiramate and adrenocorticotropic hormone (ACTH) pulse therapy, but subsequently experienced a relapse. Another child has remained seizure-free for nearly one year with oral sodium valproate, levetiracetam, and a "cocktail" therapy. Seizures were not controlled in the remaining four children. Pontocerebellar hypoplasia was observed on neuroimaging in two children. All six patients exhibited severe psychomotor retardation. A total of 10 RARS2 gene variants were identified, three of which were previously unreported. CONCLUSION The predominant clinical features of Pontocerebellar hypoplasia associated with RARS2 gene variants include infantile onset, severe psychomotor retardation or regression, drug-resistant epilepsy, and feeding difficulties. The characteristic neuroimaging finding is pontocerebellar hypoplasia. However, its appearance may vary widely with time. The majority of affected children have a poor prognosis.
Humans ; Male ; Female ; Child, Preschool ; Infant ; Child ; Olivopontocerebellar Atrophies/genetics* ; Arginine-tRNA Ligase/genetics* ; Mutation ; Cerebellar Diseases

Abnormal eye movements are commonly observed in movement disorders. Ocular motility examination should include bedside evaluation and laboratory recording of ocular misalignment, involuntary eye movements, including nystagmus and saccadic intrusions/oscillations, triggered nystagmus, saccades, smooth pursuit (SP), and the vestibulo-ocular reflex. Patients with Parkinson's disease (PD) mostly show hypometric saccades, especially for the self-paced saccades, and impaired SP. Early vertical saccadic palsy is characteristic of progressive supranuclear palsy-Richardson's syndrome. Patients with cortico-basal syndrome typically show a delayed onset of saccades. Downbeat and gaze-evoked nystagmus and hypermetric saccades are characteristic ocular motor findings in ataxic disorders due to cerebellar dysfunction. In this review, we discuss various ocular motor findings in movement disorders, including PD and related disorders, ataxic syndromes, and hyperkinetic movement disorders. Systemic evaluation of the ocular motor functions may provide valuable information for early detection and monitoring of movement disorders, despite an overlap in the abnormal eye movements among different movement disorders.
Ataxia ; Cerebellar Diseases ; Eye Movements ; Humans ; Hyperkinesis ; Movement Disorders ; Paralysis ; Parkinson Disease ; Parkinsonian Disorders ; Pursuit, Smooth ; Reflex, Vestibulo-Ocular ; Saccades

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), which is caused by mutations in SACS gene, is a very rare neurodegenerative disorder characterized by the clinical triad of early onset cerebellar ataxia, pyramidal tract features, and sensorimotor polyneuropathy. Herein, we report a 35-year-old Korean male who presented with gait disturbance and lower extremity weakness. Neuroimaging and ophthalmologic evaluation revealed features consistent with ARSACS. Mutation in SACS gene was demonstrated in clinical exome sequence analysis and the patient was finally diagnosed as ARSACS.
Adult ; Ataxia ; Cerebellar Ataxia ; Exome ; Gait ; Humans ; Lower Extremity ; Male ; Muscle Spasticity ; Neurodegenerative Diseases ; Neuroimaging ; Polyneuropathies ; Pyramidal Tracts ; Sequence Analysis ; Spinocerebellar Degenerations

Genetic prion diseases account for about 10-15% of all cases of human prion disease and are caused by mutations in the prion protein gene. Gerstmann-Sträussler-Scheinker (GSS) disease is a rare genetic prion disease, which is characterized by slowly progressive cerebellar ataxia and the occurrence of cognitive decline in the later stage. P102L is the most common mutation in GSS. We report a patient with a P102L mutation that initially manifested as rapidly progressive dementia without cerebellar symptoms.
Cerebellar Ataxia ; Creutzfeldt-Jakob Syndrome ; Dementia ; Gerstmann-Straussler-Scheinker Disease ; Humans ; Prion Diseases ; Prions

There have been several reports of patients with isolated lesions of the cerebellar vermis presenting with clinical features similar to those of peripheral vestibulopathy. We report a case of small, isolated hematoma in the cerebellar vermis in a patient who presented with vertigo, ipsilesional nystagmus, and body lateropulsion to the contralesional side without the usual signs or symptoms of cerebellar dysfunction. Although they present with symptoms that mimic those of peripheral vestibulopathy, and brain computed tomography shows no abnormality, as there may be a small, isolated hematoma or infarction in the cerebellar vermis. Thus, brain magnetic resonance imaging should be performed in elderly patients with vascular risk factors.
Aged ; Brain ; Cerebellar Diseases ; Cerebellar Vermis ; Hematoma ; Hemorrhage ; Humans ; Infarction ; Magnetic Resonance Imaging ; Risk Factors ; Vertigo

BACKGROUND: Cerebellum has an important role in sensorimotor control including speech. Multiple system atrophy (MSA) is a sporadic and rapidly progressive neurodegenerative disorder that presents with autonomic failure in combination with Parkinsonism or cerebellar ataxia. CASE REPORT: We report a case of MSA-cerebellum subtype associated with emergence of irreversible explosive speech following olanzapine therapy. CONCLUSIONS: Further investigation into speech problems in MSA according to subtype and disease severity is needed, and side effects of olanzapine therapy should also be considered.
Antipsychotic Agents ; Cerebellar Ataxia ; Cerebellum ; Humans ; Multiple System Atrophy* ; Neurodegenerative Diseases ; Parkinsonian Disorders

Dentatorubropallidoluysian atrophy (DRPLA) is a neurodegenerative disease caused by an expansion of a cytosine-adenine-guanine (CAG) repeat encoding a polyglutamine tract in the atrophin-1 protein. Unlike other CAG repeat diseases, sleep related problems have not been reported in patients with DRPLA. There was a 65-year-old man and his family with DRPLA. They suffered from seizure, gait disturbance, and cognitive decline. The patients commonly showed dream enacting sleep disorder, insomnia. The results from overnight polysomnography showed rapid eye movement (REM) without atonia in patients with DRPLA. The man died 2 years after diagnosis and was subjected for brain autopsy. We report REM sleep behavior disorders in patients with DRPLA confirmed with polysomnography with pathological description of the patient.
Aged ; Atrophy* ; Autopsy ; Brain ; Cerebellar Ataxia ; Diagnosis ; Dreams ; Gait ; Humans ; Mental Disorders ; Neurodegenerative Diseases ; Polysomnography ; Seizures ; Sleep Initiation and Maintenance Disorders ; Sleep Wake Disorders ; Sleep, REM

BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan. METHODS: Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases. CONCLUSIONS: This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.
Alleles ; Apraxias* ; Ataxia Telangiectasia ; Ataxia* ; Cerebellar Ataxia ; DNA ; Exome ; Genome ; Humans ; Magnetic Resonance Imaging ; Movement Disorders ; Mutation, Missense ; Neurodegenerative Diseases ; Pakistan ; Phenotype ; Population Characteristics ; Spinocerebellar Ataxias ; Vertebrates