Neurogenetics最新文献

Gaucher disease (GD) is a lysosomal storage disorder with an autosomal recessive inheritance pattern. The clinical manifestation of the GD arises from lack of appropriate metabolism of a fatty substance called glucocerebroside, predominantly within the lysosomes of monocyte and macrophage cells. Using whole exome sequencing, we found the genetic basis of GD in six Iranian patients. All cases had consanguineous parents. Developmental regression, hepatosplenomegaly and motor delay were the most common signs of these cases. The pathogenic p.L483P (c.1448T > C) variant was found in three patients. Other cases were found to be homozygote for p.D448H (c.1342G > C), p.S235P (c.703T > C) and p.N409S (c.1226 A > G) variants, respectively. This study demonstrates the prevalence of a pathogenic GBA variant among Iranian patients. This information can facilitate molecular diagnosis of GD with lower cost.

Neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), and intellectual disabilities (ID), have seen an increasing prevalence in recent years. Both genetic and environmental factors have been implicated in the pathogenesis of these conditions. One such gene, ZNRF3, plays a pivotal role in regulating neural cell growth and connectivity, with variations in this gene linked to disruptions in neural differentiation and communication. This review synthesizes genetic, molecular, and clinical research to examine the role of ZNRF3 in brain development. Furthermore, it explores the impact of prenatal environmental exposures and healthcare policies on diagnostic practices and treatment accessibility. The findings highlight the need for improved genetic screening, early intervention strategies, and policy reforms aimed at facilitating personalized care for individuals affected by ZNRF3-related NDDs.

Hunter syndrome, also known as Mucopolysaccharidosis type II (MPS II), is a rare X-linked lysosomal storage disorder caused by mutations in the IDS, which encodes the iduronate-2-sulfatase enzyme. The main aim of the current genetic study was to investigate a non-consanguineous Pakistani family segregating Hunter's syndrome. Clinical evaluation, biochemical assays, radiological imaging, and genetic sequencing were performed on the affected individuals. The Family was recruited from Khyber Pakhtunkhwa (KP) province of Pakistan and has two affected male individuals. Routine blood investigations showed low blood sugar (1/2), elevated SGPT (1/2), and increased RDW-CV levels (2/2). Both patients (2/2) presented with a severe phenotype, including cognitive impairment (2/2), coarse facial features (2/2), skeletal abnormalities (2/2), growth delay (2/2), hepatomegaly (2/2), hydrocephalus (2/2), macrocephaly (2/2), visual impairment (2/2), and restricted joint mobility (2/2). A previously reported hemizygous c.1122C>T mutation in exon 8 of the IDS. The identified mutation presumably creates an aberrant splicing and leads to the deletion of 20 amino acids in the open reading frame, which would distort the local folding of the polypeptide chain and lead to loss of its interacting sites. MRI analysis demonstrated typical MPS-II-related abnormalities, including enlarged perivascular spaces, ventriculomegaly, posterior fossa and sella turcica deformities, and spinal cord compression due to periodontoid thickening and spinal stenosis. Although the c.1122C>T (IDS) mutation is not novel, its identification in a Pakistani Pashtun family is reported here for the first time, contributing to the ethnic and geographic mapping of MPS II. This study underscores the importance of population-specific mutation data for effective genetic counseling, early diagnosis, and carrier screening.

We report the case of a Spanish female patient with progressive myopathy and severe muscle atrophy, intellectual delay, absence of expressive language development, overweight, and mitochondrial abnormalities. Whole-exome sequencing uncovered three heterozygous CHKB variants in the patient, one from the paternal allele and two from de maternal allele (NC_000022.11(NM_005198.5): c. [581G > A];[843 T > C;1031 + 3G > C]). This gene encodes the Choline/ethanolamine kinase (CHKB) protein, which catalyzes the first step of phosphatidylcholine biosynthesis. Pathogenic CHKB variants have been associated with megaconial congenital muscular dystrophy (MDCMC). In order to assess the pathogenicity of these variants, expression experiments of RNA for CHKB were carried out by RT-PCR from lymphocytes. The c.581G > A variant, instead to produce a missense change (p.Arg194Gln), induces an aberrant splicing event resulting in the deletion of exon 4 (V1 and V2: r.448_581del). On the other hand, the other two variants (c.843 T > C (p.Phe281 =) and c.1031 + 3G > C splice site variant) induces five alternative splicing events by altering the splice sites of exons 8 and 9 (V3: r.928_1031del, V4: r.970_1033del, V5: r.1026_1033del, V6: r.820_1032del and V7: r.819_927del). In all cases, the predicted codified proteins are truncated in carboxy-terminus, affecting to important domains of the protein or are likely to be degraded by NMD. In conclusion, we describe for the first time the pathological mechanism of the c.581G > A variant, show that c.843 T > C (synonymous variant) might be responsible for the exon 8 skipping, and confirm that c.1031 + 3G > C induces differential splicing as previously shown. Consequently, our findings provide additional functional evidences associated with CHKB variants.

Oculopharyngeal muscular dystrophy (OPMD) is a rare, adult-onset, autosomal dominant myopathy characterized by variability in the age of onset and disease progression. However, its pathogenesis and phenotypic variability remain poorly understood. The disorder is caused by an expansion of a short polyalanine tract in the poly(A) binding protein nuclear 1 (PABPN1) gene. This study presents data from 23 patients across 19 Greek families with pathogenic PABPN1 expansions, including demographic and laboratory data, as well as molecular and electron microscopy findings. Eight distinct trinucleotide expansion genotypes were identified. Electron microscopy consistently demonstrated mitochondrial abnormalities, including swelling, disrupted cristae and atypical lipid inclusions. Clinical heterogeneity was observed at both inter- and intrafamilial levels, and milder phenotypes were generally linked to smaller alleles. Notably, maternally inherited expansions were associated with an earlier disease onset and more severe progression in affected offspring. Given the genetic variability observed in the cohort, the presence of a founder effect could not be supported. A significant degree of underdiagnosis or diagnostic delay was noted, largely attributable to the rarity and clinical heterogeneity of the disease. The observed intrafamilial heterogeneity - particularly in maternally inherited expansions - supports previous reports suggesting that mitochondrial dysfunction may contribute to transgenerational disease progression in the context of a dominant, causative nuclear variant.

Alzheimer's disease (AD) is a progressive illness that can cause behavioural abnormalities, personality changes, and memory loss. Early detection helps with future planning for both the affected person and caregivers. Thus, an innovative hybrid Deep Learning (DL) method is introduced for the segmentation and classification of AD. The classification is performed by a Fuzzy Res-LeNet model. At first, an input Magnetic Resonance Imaging (MRI) image is attained from the database. Image preprocessing is then performed by a Bilateral Filter (BF) to enhance the quality of image by denoising. Then segmentation is carried out by the proposed O-SegUNet. This method integrates the O-SegNet and U-Net model using Pearson correlation coefficient-based fusion. After the segmentation, augmentation is carried out by utilizing Synthetic Minority Oversampling Technique (SMOTE) to address class imbalance. After that, feature extraction is carried out. Finally, AD classification is performed by the Fuzzy Res-LeNet. The stages are classified as Mild Cognitive Impairment (MCI), AD, Cognitive Normal (CN), Early Mild Cognitive Impairment (EMCI), and Late Mild Cognitive Impairment (LMCI). Here, Fuzzy Res-LeNet is devised by integrating Fuzzy logic, ResNeXt, and LeNet. Furthermore, the proposed Fuzzy Res-LeNet obtained the maximum performance with an accuracy of 93.887%, sensitivity of 94.587%, and specificity of 94.008%.

Pyridoxine-dependent epilepsy (PDE) is a rare genetic metabolic disorder characterized by seizures that are often resistant to conventional antiseizure medication but responsive to pyridoxine. Although its early diagnosis and treatment are crucial for achieving optimal neurodevelopmental outcomes, resource-limited settings often present considerable challenges in recognizing and managing this complex condition. This case report describes the diagnostic and management experience of the first genetically confirmed case of PDE in an Indonesian neonate, highlighting the critical need to improve access to specialized care and resources in this setting. Our data may provide valuable insights into the unique hurdles and potential solutions for managing PDE in similar settings.

Huntington's disease (HD) is a progressive, autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive decline, and psychiatric disturbances. It is caused by CAG repeat expansions in the HTT gene, resulting in the formation of mutant huntingtin protein that aggregates and disrupts neuronal function. This review outlines the pathogenesis of HD, including genetic, molecular, and environmental factors. Additionally, current management approaches and emerging therapeutic strategies-such as RNA interference, antisense oligonucleotides (ASOs), peptide inhibitors, and CRISPR/Cas9 gene editing-are discussed. Advancements in these novel therapies highlight a shift towards disease-modifying interventions. However, continued clinical and translational research is essential to develop a definitive cure.

The detection of complex structural variants in patients with familial cerebral cavernous malformations (FCCM) remains challenging. Short-read whole genome sequencing was performed for a patient with strong clinical evidence of FCCM but negative results from previous genetic tests. The analysis revealed a large insertion of an intronic KRIT1 fragment into a coding exon of KRIT1. This novel structural variant results in a frameshift and was classified as pathogenic. Predictive testing can now be offered to asymptomatic family members. This case expands the known mutation spectrum in FCCM and suggests that, after negative whole exome or gene panel sequencing, whole genome sequencing should be offered as a second-line diagnostic test.

Schinzel-Giedion Syndrome (SGS) is a rare neurodevelopmental disorder caused by pathogenic SETBP1 gain-of-function variants. SGS medical features have been well described. Associated skills critical to quality of life have such as communication, feeding, and motor skills are yet to be characterised. Here we used standardised caregiver report tools to characterise these skills as well as the medical features, in 16 children with SGS (median = 5 years, 7 months, range 6 months to 12.5 years). Vineland-3 scores reflected severe impairment in communication, daily living, socialisation and motor skills. Average receptive and expressive language skills were equivalent to a 0-to-1-month-old. Average motor skills were slightly stronger with age equivalents of 2-months-old for gross motor skills and 4-months for fine motor skills. 13/16 (81%) children could attend to someone's voice, and 15/16 (94%) could make happy vocalisations. One individual (6%) could follow basic instructions. Despite a relatively homogenous phenotype, some children presented with relative strengths when compared to the rest of the cohort. Our expanded phenotype of SGS allows better targeted therapies and supports, highlighting the importance of early feeding intervention and augmentative and alternative communication (e.g., assistive technology for communication). Given the severity of the SGS profile, our data highlight the need for sensitive measurement tools for detecting subtle skill changes in SGS in response to precision medicine interventions.