Neurogenetics最新文献

We describe a unique patient who had been diagnosed with inflammatory demyelinating polyneuropathy (CIDP) for 13 years with frequent clear responses to immunotherapies and was finally diagnosed with Charcot-Marie-Tooth disease (CMT) with a rare point mutation in PMP22 (c.320G > A, p.G107D). Some patients diagnosed with young-onset CIDP may have underlying CMT, and extensive genetic testing including point mutations of PMP22 gene is required not to miss the diagnosis.

Mutations in the DEPDC5 gene are inherited in an autosomal dominant manner and can lead to various clinical phenotypes, including focal seizures. While numerous case reports on DEPDC5 mutations exist, functional validation studies remain scarce. We analyzed seven cases of epilepsy or developmental disorders caused by DEPDC5 mutations, summarizing their clinical manifestations and conducting genetic analysis of the mutation sites. The age of onset in the seven patients ranged from 2 months to 4 years. Six mutation sites were identified, including three nonsense mutations: c.1443del (p.C481X), c.2512 C > T (p.R838X), and c.2620 C > T (p.R874X); one missense mutation: c.1140 C > A (p.F380L); and two splice-site mutations: c.2802-13 C > G (splicing) and c.4034-2 A > G (splicing). Among these, c.2512 C > T (p.R838X) and c.2620 C > T (p.R874X) had been previously reported, while the remaining mutations were novel. Minigene experiments confirmed that the c.4034-2 A > G mutation resulted in a slightly truncated protein.Focal seizures were the predominant symptom in six cases. Among the four patients with nonsense mutations, three (Cases 2, 4, and 5) exhibited drug-resistant epilepsy. Four out of seven patients responded effectively to lacosamide treatment. DEPDC5 mutations can cause focal seizures, with truncating mutations associated with more severe symptoms. Lacosamide may offer better therapeutic outcomes. The intronic mutation c.463 + 4 A > G (splicing) led to protein truncation and was determined to be pathogenic.

Metachromatic Leukodystrophy (MLD) is a rare autosomal recessive lysosomal disorder caused by ARSA gene variants, affecting central and peripheral nervous systems. While ARSA variants are reported globally, data from sub-Saharan Africa (SSA) are limited. We report the first SSA case, a Malian patient with a rare phenotype: predominant tonic seizures without typical peripheral neuropathy signs. The patient harbored a novel ARSA variant (c.191T > C; p.Phe64Ser), predicted deleterious by in silico tools. This case expands the genetic and phenotypic spectrum of MLD, underscoring the need for genetic studies in underrepresented regions.

Schizophrenia (SCZ) is a chronic and severe mental disorder with a complex molecular aetiology. Emerging evidence indicates a potential association between the gut microbiome and the development of SCZ. Considering the under-representation of African populations in SCZ research, this study aimed to explore the association between the gut microbiome and SCZ within a South African cohort. Gut microbial DNA was obtained from 89 participants (n = 41 SCZ cases; n = 48 controls) and underwent 16S rRNA (V4) sequencing. Data preparation and taxa classification were performed with the DADA2 pipeline in R studio followed by diversity analysis using QIIME2. Analysis of Compositions of Microbiomes with Bias Correction (ANCOM-BC) was utilised to identify differentially abundant taxa. No statistically significant differences were observed between SCZ patients and controls in terms of alpha-diversity (Shannon q = 0.09; Simpson q = 0.174) or beta-diversity (p = 0.547). Five taxa, namely Prevotella (p = 0.037), Faecalibacterium (p = 0.032), Phascolarctobacterium (p = 0.002), Dialister (p = 0.043), and SMB53 (p = 0.012), were differentially abundant in cases compared to controls, but this observation did not survive correction for multiple testing. This exploratory study suggests a potential association between the relative abundance of Prevotella, Faecalibacterium, Phascolarctobacterium, Dialister, and SMB53 with SCZ case-control status. Given the lack of significance after correcting for multiple testing, these results should be interpreted with caution. Mechanistic studies in larger samples are warranted to confirm these findings and better understand the association between the gut microbiome and SCZ.

Mitochondrial Complex V (ATP synthase) deficiency nuclear type 6 (MC5DN6) is a progressive neurodegenerative disorder characterized by autosomal recessive inheritance and developmental regression, particularly in gross motor skills, which manifests in early childhood. This study aims to present the discovery of a novel variant in four male siblings aged 13 years 9 months to 25 years, making this the fourth family reported globally, while also raising awareness of rare mitochondrial diseases. Four individuals from the same family were retrospectively evaluated based on their demographic, clinical, laboratory, and molecular genetic data. The mutation in the ATP5MK gene was analyzed using the exome sequencing (ES) method. The detected variation was classified according to the criteria American College of Medical Genetics. Four cases, aged between 13 years 9 months and 25 years, were analyzed. All individuals were male. While all four cases had a history of neurodegenerative disease, they also exhibited intellectual disability, muscle weakness, increased deep tendon reflexes in the lower extremities, spasticity, scoliosis, pes cavus deformity, positive Babinski reflex, abnormal gait patterns due to foot deformities, and normal cerebellar tests. Additional findings included geographic tongue (n = 2), strabismus (n = 2), nystagmus (n = 1), ophthalmoplegia (n = 2), hypertrophic upper extremity muscle body build (n = 2), keloid tissue (n = 1), and short stature (n = 3). ES of the first case identified a homozygous splice donor variant (c.87 + 1G > A) in the ATP5MK gene as a novel variant, and family screening revealed the same variant in a biallelic state in the other three siblings. The parents were confirmed as heterozygous carriers, consistent with autosomal recessive inheritance. Mitochondrial diseases can mimic a wide range of neurological disorders. They should be considered as a potential underlying cause when treatment for suspected differential diagnoses proves ineffective.

ADNP-Related Disorder [previously known as Helsmoortel-Van der Aa syndrome (HVDAS)] is a rare genetic condition resulting from mutations in the activity-dependent neuroprotector homeobox (ADNP) gene. The ADNP protein has multiple functions, including serving as an essential transcription factor for brain development. In addition, pathogenic variants in ADNP have been recognized as one of the most frequent monogenic causes of autism spectrum disorder (ASD) and intellectual disability. Clinical features include craniofacial dysmorphisms, congenital heart defects, gastrointestinal problems such as feeding difficulties, gastroesophageal reflux and frequent vomiting, vision problems, recurrent infections and seizures. Here we describe the novel case of a girl who came to our attention in infancy because of poor and stereotyped motor repertoire, repetitive purposeless movements, and intellectual disability. Whole exome sequencing revealed a de novo heterozygous variant in the ADNP gene, leading to the diagnosis of HVDAS at age 5 years. At the age of 12, nerve conduction velocity testing showed severe four-limb axonal motor polyneuropathy. In this article, we would like to focus on the presence of peripheral nervous system involvement associated with the pathogenic ADNP de novo variant, which may contribute to the clinical characterization of ADNP-Related Disorder.

The SMARCB1 gene codes for a key element of the SWI/SNF chromatin-modifying complex, which plays a vital role in controlling gene expression by modifying chromatin architecture. Alterations in SMARCB1 have been linked to several neurological disabilities, including schwannomatosis, a condition marked by the formation of numerous benign tumors affecting the nerve sheaths. Present study explore the effects of nonsynonymous single nucleotide polymorphisms (nsSNPs) within the SMARCB1 gene on its protein structure and functionality. We utilized both sequence-based and structure-oriented predictive models, followed by molecular dynamics simulations to examine their influence on the stability of protein and dynamic behaviour. The study focused on three key mutations: R60S, R190W, and I237M. The R190W mutation emerged as particularly significant, leading to increased protein compactness and stability due to enhanced hydrophobic interactions, although conformational flexibility was reduced. The R60S mutation was associated with destabilization of the protein structure, increasing solvent exposure and reducing hydrogen bond stability, potentially impairing the protein's function. The I237M mutation had a relatively mild impact, with only subtle changes observed in protein dynamics. These findings highlight the diverse impacts of different nsSNPs on SMARCB1, with the potential to contribute to various pathologies, including Schwannomatosis and other related disorders. This study highlights the necessity for additional experimental testing to confirm these computational findings and gain a deeper understanding of the molecular processes through which these mutations contribute to disease. The present comprehensive approach provides significant knowledge regarding the connection between SMARCB1 structure and function, providing the groundwork for potential therapeutic strategies targeting these key mutations.

ROBO3 is a member of the Roundabout (ROBO) gene family of evolutionarily conserved guidance receptors, which plays crucial roles in axon crossing of the CNS midline. In 2004, pathogenic variants in ROBO3 were first linked to Horizontal Gaze Palsy with Progressive Scoliosis type 1 [HGPPS1 (OMIM # 607313)], an autosomal recessive disorder that is characterized by failure of the corticospinal and somatosensory axon tracts to decussate in the medulla. Hitherto, over 60 ROBO3 pathogenic (or likely pathogenic) variants associated with HGPPS1 have been described in almost 100 patients. With the 20-year milestone, this minireview underscores the growing opportunities to improve the current understanding of the spectrum of HGPPS1 phenotype and ROBO3 genotypes. The increasing need for translational studies that can pave the way for improved clinical management of ROBO3-related disorders is also highlighted.

Epilepsy is among the most prevalent serious neurological disorders, affecting over 70 million people worldwide, in Algeria, the prevalence of epilepsy was estimated to be eight times more common. Carbamazepine is frequently the first-line treatment, making early prediction of patient response essential for personalized care. This approach helps reduce adverse effects and healthcare costs, while enhancing patient outcomes. This study aims to explore the link between the ABCB1 c.3435C > T genetic variation and Carbamazepine resistance and toxicity in Algerian patients with epilepsy, with a focus on the impact of genetic variations on Carbamazepine plasma concentrations and treatment outcomes. Ninety-eight Algerian patients with epilepsy were recruited and categorized as either drug-responsive or drug-resistant based on their clinical response to CBZ treatment. Genotyping of the ABCB1 c.3435 C > T polymorphism was performed using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method, and CBZ plasma levels were measured to assess its effect on metabolism. Clinical data, including drug response, therapy type, and adverse drug reactions (ADRs), were collected and analyzed. For the statistical analysis we used chi-squared tests and Exact Fisher's for corrections. Our findings show no significant association between the ABCB1 c.3435C > T genotypes with carbamazepine resistance (p = 0,1) nor incidence of adverse reactions. This polymorphism also indicated no statistically significant link with Carbamazepine plasma levels. The sample size in this study might be limitation; therefore, expanded investigations on Algerian population are needed. Although this study indicates no significant correlation of the ABCB1 c.3435C > T polymorphism with influencing CBZ Pharmacoresistance and therapeutic outcomes, larger-scale-studies are required to confirm these results and assess their reliability.

Parkinson's disease (PD) is a multifaceted neurodegenerative disorder with both non-motor and motor symptoms. Variants in the glucosylceramidase beta 1 (GBA1) gene are the strongest genetic risk factor for PD, while homozygous or compound heterozygous variants in this gene classically cause Gaucher disease (GD). This study presents an early-onset PD patient with a homozygous GBA1 deletion. Whole-exome sequencing (WES) was performed, and the identified variant was validated via Sanger sequencing. The variant was classified according to ACMG guidelines and ClinGen updates. The patient, a Brazilian female of mixed ethnicity, exhibited the full spectrum of classical motor and non-motor PD symptoms without evident hallmarks of GD. The identified homozygous GBA1 variant (NM_000157.4:c.222_224del; p.T75del; rs761621516) has a very low global allele frequency (0.00003284) and is associated with reduced enzymatic activity. This variant exhibits a founder effect among individuals of African descent. This case highlights an intricate genotype-phenotype landscape for GBA1 variants, underscoring the role of homozygous GBA1 variants in PD pathogenesis.