The differential diagnosis of dizziness is broad and can include both vestibular and autonomic pathology. Vestibular dizziness is typically described as a sensation of movement (e.g. the world is spinning) while dizziness related to autonomic dysfunction is typically described as symptoms of orthostatic intolerance (e.g. postural lightheadedness). It is important to differentiate the type of dizziness to guide proper diagnostic and therapeutic workup. We describe the case of a young patient evaluated in the autonomic clinic for dizziness, ultimately found to have a rare cerebellar neurodegenerative disorder. A 23-year-old female with a past medical history of migraine without aura presented in autonomic clinic with a four-month history of slow, progressive onset of vestibular dizziness. Neurological exam was notable for downbeat nystagmus, but no appendicular or truncal ataxia was appreciated. Subsequent vestibular evaluation was consistent with central vestibular dysfunction. Magnetic resonance imaging (MRI) of the brain with and without contrast was notable for severe cerebellar atrophy. The patient subsequently underwent genetic testing which demonstrated a pathogenic and likely pathogenic variant in the Anoctamin 10 (ANO10) gene, which is seen in Autosomal Recessive Spinocerebellar Ataxia, Autosomal Recessive Type 10 (SCAR10). To our knowledge, this case represents the first reported instance of SCAR10 presenting with the sole neurologic exam finding of downbeat nystagmus without cerebellar ataxia. Additionally, the finding of severe cerebellar atrophy seen on MRI, without gait or limb ataxia on exam is an interesting clinicoradiological dissociation. This case suggests that nystagmus may represent an early disease marker, even in the absence of clinical ataxia in patients with SCAR10.
Nonconvulsive status epilepticus (NCSE) is defined as a condition of prolonged epileptiform activity on electroencephalography (EEG) accompanied by altered mental status without prominent motor manifestations. It is frequently underdiagnosed, particularly in patients with pre-existing cognitive impairment or neurodegenerative disorders [1, 2]. Reports describing NCSE in patients with AARS2-related leukoencephalopathy remain extremely limited. This case identifies NCSE as a potential cause of clinical deterioration in AARS2-related leukoencephalopathy and highlights the importance of considering NCSE in patients presenting with subacute neurological deterioration. A 41-year-old woman was admitted with progressive cognitive decline and social withdrawal that had markedly worsened over the preceding month. The patient initially developed slowly progressive memory impairment approximately 18 months before admission followed by gradual cognitive decline and increasing dependence in daily activities. During the month before hospitalization, her condition deteriorated more rapidly, with marked reduction in speech, impaired responsiveness, and behavioral changes. Because of this abrupt deterioration, EEG was performed and showed rhythmic frontal delta activity with superimposed sharp waves. These EEG findings, together with her altered mental status and the subsequent clinical and EEG response to antiseizure treatment, supported a diagnosis of NCSE. Following treatment, her consciousness and interaction improved markedly, with regression of the previously observed EEG abnormalities on follow-up recording. She had experienced a single generalized tonic-clonic seizure several months before admission. Antiseizure medication was prescribed following the seizure, but subsequently did not continue with the treatment. Her medical history revealed premature menopause at the age of 21 years and she was born to consanguineous parents. Brain magnetic resonance imaging showed bilateral patchy T2/FLAIR hyperintense lesions predominantly affecting the frontal and temporal white matter, together with corpus callosum thinning and cerebellar atrophy. Next-generation sequencing identified compound heterozygous variants in the AARS2 gene, and gynecological evaluation confirmed premature ovarian failure.
Missense mutations in NOTCH3, especially cysteine-altering pathogenic variants, are the cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. The NOTCH3 p.Arg1231Cys variant, located in EGFr domain 31, is classified as low-risk under the three-tiered EGFr domain risk stratification system. We report two cases of p.Arg1231Cys heterozygosity presenting with early-onset dementia, strokes, and extensive leukoencephalopathy. These cases highlight the potential contributing factors to increasing penetrance of p.Arg1231Cys variant, and the need for functional evaluation to improve the clinical utility of genetic testing in hereditary small vessel disease.
Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions resulting in abnormal movements and postures. DYT-THAP1 is one of the most frequent genetic causes of generalized dystonia and may present with characteristic clinical features that help guide diagnostic suspicion before molecular confirmation. We report a 58-year-old man who developed dysphagia and dysarthria at 22 years of age, followed by progressive dystonic posturing involving the upper limbs, face, neck, and lower limbs. Family history revealed a similar condition in his father. Neurological examination demonstrated generalized dystonia with marked cranio-cervical and bulbar involvement. Brain magnetic resonance imaging and extensive metabolic and autoimmune investigations were unremarkable. Given the clinical presentation and family history, a genetic etiology was suspected. A dystonia gene panel identified a variant in the THAP1 gene, NM_018105.3:c.108G > T (p.Trp36Cys), establishing the diagnosis. Cranio-cervical involvement and prominent bulbar symptoms may represent important clinical clues suggesting DYT-THAP1 in patients with generalized dystonia, highlighting the importance of careful phenotypic characterization.
The LRRK2 c.6055G>A (p.Gly2019Ser) mutation represents one of the most frequent genetic causes of autosomal dominant Parkinson’s disease (PD) worldwide. Morocco exhibits the highest documented global prevalence of this variant, with carrier rates approaching 38.8
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder caused by pathogenic variants in the SACS gene. While traditionally defined by a motor triad, emerging evidence suggests a broader phenotypic spectrum that includes significant cognitive involvement. We describe a 16-year-old Sicilian female, born to consanguineous parents, and homozygous for missense variant c.815G > A (p.Arg272His). Alongside the classical triad of progressive cerebellar ataxia, pyramidal spasticity, and demyelinating sensorimotor polyneuropathy, the patient exhibited mild intellectual disability (ID) with a Full-Scale Intelligence Quotient (IQ) of 60. Additional clinical markers included early-onset axial hypotonia and marked retinal nerve fiber layer thickening on optical coherence tomography. Longitudinal neuroimaging over 13 years documented progressive cerebellar vermis atrophy and the emergence of pontine transverse fiber hyperintensity. Comparison with previously published patients carrying the identical homozygous variant strongly supports p.Arg272His as a recurrent mutational hotspot involving a highly conserved functional residue within the SIRPT1 domain of sacsin, likely critical for mitochondrial homeostasis and neuronal cytoskeletal organization. Importantly, comparison with previously reported patients suggests that cognitive impairment and intellectual disability may represent recurrent and potentially under-recognized features among individuals carrying the p.Arg272His variant, although the limited number of reported cases precludes definitive genotype–phenotype conclusions. This case adds longitudinal clinical, neuroimaging, ophthalmological, and neuropsychological data to the limited literature on patients carrying the p.Arg272His variant, supporting further investigation of genotype–phenotype relationships in ARSACS. We advocate for the integration of standardized neuropsychological assessments into the routine diagnostic workup for ARSACS to ensure comprehensive patient management.
Pathogenic variants of PMP22 cause Charcot-Marie-Tooth disease type 1 A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP). As CMT1A is the most common inherited neuropathy and the most common pathogenic PMP22 variants are duplications and deletions, focused analysis of this gene remains relevant in the era of large gene panels and exome studies. We investigated the use and findings of PMP22 gene analyses carried out at Turku University Hospital (TUH; Turku, Finland) in 2005–2020. Using the electronic medical record system at TUH, we identified all patients who underwent PMP22 genetic diagnostic testing in 2005–2020. Data on testing indication, clinical features, relevant family history, genetic testing results, and final neurological diagnoses were collected. Out of total 244 tests, 64 (26
Drug-resistant epilepsy (DRE) in children is linked to poor developmental outcomes and increased mortality. Genetic factors are increasingly recognized in its pathogenesis, and whole- exome sequencing (WES) offers a promising diagnostic tool for early intervention, especially in cases with unclear etiology. However, data on the genetic causes of pediatric DRE remain scarce in Indonesia, a low-resource setting with limited access to advanced genetic testing. We conducted a retrospective review at the Neuropediatric Clinic of Sardjito Hospital, Yogyakarta, Indonesia, from January to December 2024. Children aged 0–18 years at the time of epilepsy diagnosis or genetic testing were included. WES was performed for all patients, and in cases with positive findings, Sanger sequencing was used to confirm variants in parents and siblings. WES identified pathogenic or likely pathogenic variants in 3 of 10 patients, with one patient harboring three variants. In total, three pathogenic or likely pathogenic variants were identified in TSC2, CC2D2A, and WDFY3, and two variants of uncertain significance were identified in CC2D2A and ATP6V1A. Among the five variants, two were missense mutations, two were nonsense mutations, and one was a frameshift mutation. WES can yield a definitive genetic diagnosis in a subset of patients, enabling individualized management, facilitating genetic counseling, and reducing the need for further diagnostic investigations.
Hereditary neurodegenerative disorders comprise a heterogeneous group of genetic conditions that affect the central and/or peripheral nervous system, often presenting with hallmark clinical features including ataxia, spasticity, dystonia and neuropathy. Our study aims to investigate the underlying cause of rare and overlapping phenotypes of inherited neurodegenerative disorders in the four familial cases of the Pakistani population. Four Pakistani families with a wide range of spastic-ataxic features were evaluated using exome sequencing, homozygosity mapping, and Sanger sequencing. These molecular studies identified four known pathogenic variants: CYP2U1:c.604G > A (p.Glu202Lys), ATXN1 expansion: [(CAG)46/(CAG)27], ATM:c.103 C > T (p.Arg35*), and COQ4:c.577 C > T (p.Pro193Ser). All these phenotypes were correlated with the literature-based reported cases of rare neurological disorders. We present previously reported pathogenic variants in our enrolled 13 affected individuals from four unrelated families. Our findings underscore the pathogenic relevance of the identified variants and pinpoint their importance for regional diagnostic and genetic counseling strategies.
Myotonia congenita is a skeletal muscle channelopathy caused by pathogenic variants in CLCN1, encoding the ClC-1 chloride channel. We report two sisters with clinical features consistent with recessive myotonia congenita and compound heterozygous variants in CLCN1 identified through short-read genome sequencing: a paternally inherited pathogenic missense variant c.871G > A (p.Glu291Lys) and a novel maternally inherited deep intronic variant, c.697-620 T > G. RNA sequencing of a muscle biopsy revealed that the deep intronic variant activates a cryptic splice donor site, resulting in inclusion of an out-of-frame cryptic exon, multiple aberrant splice junctions and partial nonsense mediated decay. Allele-specific expression analysis showed a 70:30 skew favouring the paternal allele, supporting degradation of the maternally-derived transcript. These findings confirm the likely pathogenicity of c.697-620 T > G as a novel loss-of-function variant in CLCN1 and expand the spectrum of CLCN1-related autosomal recessive myotonia congenita.
We analyzed the clinical features of a patient with amyotrophic lateral sclerosis (ALS) carrying a novel variant in the sequestosome 1 (SQSTM1) gene and explored the genotype-phenotype association of SQSTM1 gene variants in combination with previous literature. Clinical data and genetic testing results of an ALS patient treated at our hospital were collected. Whole-exome sequencing was used to screen for ALS-related genes, and candidate variants were validated by Sanger sequencing and family analysis. A systematic search was conducted in the PubMed database using the keywords (“amyotrophic lateral sclerosis”) OR (“motor neuron disease”) AND (“SQSTM1”) to summarize the clinical and genetic characteristics of previously reported ALS patients with SQSTM1 variants. The patient was a 49-year-old male with progressive weakness in both lower limbs for one year and weakness in the left upper limb for the past three months. Electromyography showed extensive neurogenic damage. Genetic testing identified a novel heterozygous missense variant, c.355 C > T (p.Arg119Cys), in the SQSTM1 gene. Family verification revealed that his phenotypically normal mother carried the same variant. The literature search identified 58 cases of ALS associated with SQSTM1 variants. Missense variants were the most common type. We identified a novel SQSTM1 variant, c.355 C > T (p.Arg119Cys), in a ALS patient. Although this finding expands the variant spectrum, its pathogenicity remains uncertain and requires further functional validation and pedigree confirmation. Our literature review further shows that SQSTM1-associated ALS predominantly presents with limb onset, with a subset of patients exhibiting frontotemporal dementia or Paget’s disease.
PPP1R21-related neurodevelopmental disorder (PPP1R21-NDD) is an ultra-rare autosomal-recessive encephalopathy caused by dysfunction of the Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY (FERRY) complex. To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD and outline diagnostic and research priorities. Targeted searches of PubMed, EMBASE, Scopus, Web of Science, and Google Scholar through January 2026 were performed. Eligible reports included molecularly confirmed biallelic PPP1R21 cases and related functional studies. Two researchers independently extracted individual-level data following narrative review quality criteria. Twenty-five individuals from 21 families harbored 17 distinct variants (15 loss-of-function, 2 missense), all homozygous, reflecting high consanguinity. Profound global developmental delay/intellectual disability was universal; hypotonia near-universal (22/25, 88
Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4
Objective the study investigated the association of rs57095329 polymorphism with Parkinson’s disease (PD) susceptibility, clinical features, and miR-146a expression. Methods in this case-control study (204 PD patients, 218 controls), rs57095329 genotype was performed using TaqMan assays. Serum miR-146a expression levels were detected via RT-qPCR. Statistical evaluation included ROC analysis to assess the diagnostic value of miR-146a, Pearson correlation analysis to examine its association with clinical scores (UPDRS-III, H-Y stage, and MoCA), and logistic regression to identify risk factors associated with PD. Results the dominant model genotypes (AG/GG) and the G allele conferred a reduced risk of PD compared to the AA genotype. This protective relevance was more pronounced in individuals aged ≥ 60 years and those with diabetes. Carriers of the AG/GG genotype presented with lower UPDRS-III scores and H-Y staging, together with higher MoCA scores and upregulated miR-146a levels.Serum miR-146a demonstrated outstanding diagnostic accuracy and correlated inversely with PD severity, and was identified as an independent protective factor for PD. Conclusion the miR-146a rs57095329 polymorphism confers reduced susceptibility to PD, with the G allele exerting a protective effect. Reduced serum miR-146a expression was an independent protective marker and shown promising diagnostic value for PD.
Huntington's disease (HD) and Friedreich's ataxia (FRDA) are progressive inherited neurodegenerative disorders caused by trinucleotide repeat expansions but characterized by distinct pathogenic mechanisms. HD arises from a coding-region CAG expansion in the HTT gene that produces toxic gain-of-function effects of mutant huntingtin (mHTT), whereas FRDA results primarily from intronic GAA repeat expansion in FXN, leading to epigenetic repression and frataxin deficiency. The emergence of CRISPR-based genome engineering has created new opportunities to address these diseases at their genetic origin. This review examines current CRISPR therapeutic strategies for HD and FRDA, including allele-specific editing, transcriptional suppression, repeat excision, epigenetic reactivation, and emerging precision editing approaches such as base editing and prime editing. We compare the molecular rationale, preclinical outcomes, and translational limitations associated with each approach while highlighting how disease architecture influences therapeutic design. Although preclinical studies demonstrate promising restoration of cellular phenotypes and functional improvement, significant barriers remain. Efficient delivery to the central nervous system and cardiac tissue, control of editing duration, immune responses, off-target activity, and emerging concerns regarding on-target genomic instability continue to limit clinical translation. Recent advances in delivery engineering, non-viral systems, and programmable editing platforms suggest that future therapeutic success will depend on integrating disease-specific biology with increasingly precise and controllable genome engineering technologies. Ethical and regulatory concerns remain substantial, particularly regarding informed consent in the context of cognitive decline and the irreversibility of genomic modification.
The genetics of dystonia have been extensively investigated in population-based and multicenter cohorts. In this study, we analyzed a consecutively recruited, single-center German dystonia cohort using whole-exome sequencing (n = 153 affected individuals [n = 152 index cases from 152 dystonia families], n = 10 unaffected family members). Pathogenic or likely pathogenic variants were identified in established (n = 7) and less-established (n = 4) dystonia-associated genes, resulting in a diagnostic yield of 7.2
BACKGROUND AND OBJECTIVE:Charcot-Marie-Tooth disease type 4 C (CMT4C) is a hereditary neuropathy caused by recessive mutations in the SH3TC2 gene. Due to overlapping symptoms with acquired conditions like chronic inflammatory demyelinating polyneuropathy (CIDP), misdiagnosis is common. This study examines the clinical and electrophysiological profiles of five patients initially misdiagnosed with CIDP but later confirmed to have CMT4C. METHODS:Data were collected on demographics, clinical features, nerve conduction studies, and ultrasonographic findings. Patients underwent genetic testing to identify pathogenic SH3TC2 variants. RESULTS:All patients exhibited early-onset symptoms, including progressive muscle weakness, pes cavus, and spinal deformities; some had a positive family history of neuropathy, while others appeared to be sporadic cases. Nerve conduction studies revealed diminished motor and sensory amplitudes and conduction velocities, with conduction block or temporal dispersion, subsequently reappraised as temporal dispersion-related pseudo-block in the tibial nerves. Genetic testing confirmed SH3TC2 mutations in all cases. Nerve ultrasonography showed an increase in cross-sectional area (CSA), indicating nerve hypertrophy, a characteristic observed in both Charcot-Marie-Tooth disease (CMT) and Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). CONCLUSION:Accurate distinction between CMT4C and CIDP is critical to avoid ineffective treatments. Genetic testing should be considered in refractory or atypical cases of presumed immune-mediated neuropathy. This study highlights that the initial misdiagnosis was driven by electrodiagnostic findings rather than the clinical picture, and identifies specific clues (early onset, parental consanguinity, scoliosis, and poor response to immunotherapy) that should prompt clinicians to pursue genetic testing before attributing NCS findings to an acquired inflammatory process.
X-linked Intellectual Disability (XLID) is one of the heterogenous neurodevelopmental disorders caused by a gene defect on the X chromosome. Clinical symptoms of ID are comprised of the disability of adapting to social environments and cognitive dysfunction which is often defined by having an IQ of less than 70. Whole exome sequencing revealed a hemizygous variant c.2680G > A (p.Asp894Asn) in IQSEC2 in the proband, further validated by Sanger sequencing. Subsequently, the three-dimensional structures of the wild and mutated type (Asp894Asn) IQSEC2 were deduced by structural bioinformatics approaches in order to compare the structural changes in both the structures. Molecular dynamics simulations revealed that the D894N mutation significantly destabilizes the protein structure, as reflected by increased backbone RMSD, elevated residue-level fluctuations (RMSF), and altered intramolecular interactions, collectively leading to enhanced conformational variability in the mutant protein compared with the wild type. The results obtained from this study will pave the way for early diagnosis, genetic counseling, and better therapeutic interventions.
NEK1 variants are recognized genetic contributors to amyotrophic lateral sclerosis (ALS) and have occasionally been reported within the ALS–frontotemporal dementia (FTD) spectrum. However, their association with isolated behavioral variant frontotemporal dementia (bvFTD) remains unclear. Here, we describe a 69-year-old man who developed progressive behavioral symptoms beginning in his early 60s. Cognitive evaluation demonstrated reduced verbal fluency with relative preservation of memory functions. Structural and functional neuroimaging demonstrated right-predominant frontotemporal atrophy and hypometabolism. Genetic testing for common FTD-associated genes (MAPT, GRN, and C9orf72) was negative. Whole-exome sequencing identified a heterozygous NEK1 c.899T > C (p.Ile300Thr) missense variant, currently classified as a variant of uncertain significance. This observation raises the possibility that NEK1-associated disease may extend beyond ALS or ALS–FTD phenotypes and may include isolated bvFTD presentations. However, further genetic and functional studies are required to clarify the clinical significance of this variant.
The CHD8 gene encodes a chromatin-remodeling protein critical for neural development and transcriptional regulation. Although CHD8 mutations are classically associated with autism spectrum disorder, macrocephaly, and intellectual disability, recent reports suggest that dystonia may also be part of this spectrum. Two unrelated female patients presenting with progressive dystonia were evaluated through detailed clinical, neurological, and neuroimaging assessments. Whole exome sequencing (WES) was performed using the Twist Human Core Exome capture kit and variants were classified following American College of Medical Genetics and Genomics (ACMG) and Clingen SVI guidelines. A literature review was conducted to identify previously published CHD8 related dystonia cases. Patient 1 exhibited adult-onset segmental dystonia beginning at age 27, associated with macrocephaly and mild facial dysmorphism. Patient 2 developed generalized dystonia from adolescence, without cognitive or behavioral abnormalities. Pallidal deep brain stimulation produced marked motor improvement in Patient 1. Whole exome sequencing analyses revealed two heterozygous nonsense variants in the CHD8 gene NM_001170629.2:c.1444C>T (p.Arg482Ter) and NM_001170629.2:c.727C>T (p.Arg243Ter), respectively. Both variants were classified as likely pathogenic according to the current ACMG/ClinGen recommendations. These cases reinforce the evidence in the literature that CHD8 mutations are not only associated with neurodevelopmental disorders but may also cause isolated, adult-onset dystonia that is resistant to conventional pharmacological treatment, particularly in female patients.
