Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal dominant neurodegenerative disorder caused by CSF1R variants, which lead to microglial dysfunction and progressive white matter degeneration. This study identified CSF1R variants in three unrelated Chinese patients with HDLS. We identified heterozygous CSF1R variants (NM_001288705.3) in three unrelated Chinese patients with HDLS: c.2522A > C/p.(Tyr841Ser), c.2442 + 1G > A/p.?, and c.2546_2548del/p.(Phe849del). While the former two variants were categorized as likely pathogenic under the American College of Medical Genetics and Genomics framework, the latter (c.2546_2548del) was classified as a variant of uncertain significance due to insufficient evidence at the time of analysis. All patients exhibited cognitive decline, personality changes, and motor symptoms. Brain MRI showed characteristic diffuse white matter hyperintensities, restricted diffusion, corpus callosum atrophy, and brain atrophy. Symptoms progressed in Patient 1 (c.2522A > C p.(Tyr841Ser)) and Patient 3 (c.2546_2548del p.(Phe849del)) despite standard symptomatic treatments. Clinical status remained relatively stable in Patient 2 (c.2442 + 1G > A/p.?) following allogeneic hematopoietic stem cell transplantation (HSCT). These findings expand the molecular and clinical spectrum of CSF1R in Chinese populations and highlight the diagnostic value of genetic sequencing in adult-onset leukoencephalopathies. Establishing a precise molecular diagnosis is crucial, as allogeneic HSCT remains a potentially disease-modifying therapy for patients with CSF1R-related leukoencephalopathy. Further longitudinal studies are warranted to evaluate the long-term efficacy of HSCT and to explore emerging targeted therapeutic strategies.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unclear pathogenesis. This study aimed to investigate the possible molecular mechanisms of ALS by analyzing protein structure and dynamics in a rapidly progressing ALS patient carrying the N87D mutation. A patient with the N87D mutation experienced rapid disease progression and died within one year. We reviewed all known mutations at the 87th position of the superoxide dismutase (SOD1) gene and the clinical characteristics. To investigate the molecular basis of the severe phenotype, we performed protein structure modeling and molecular dynamics (MD) simulations, and compared wild type homodimers, mutant homodimers, and heterodimers in terms of energy, residue fluctuation, number of hydrogen bonds, radius of gyration (Rg), principal component analysis (PCA), free energy landscape (FEL), the contribution of dimer interface residues, solvent-accessible surface area, and metal ion coordination. Our analysis revealed that patients with mutations at the 87th position of the SOD1 gene typically exhibited rapid disease progression. Protein structure modeling and MD simulations demonstrated that the N87D mutation significantly increased the energy and RMSF of SOD1 heterodimers compared to homodimers. Furthermore, Rg, FEL and PCA analyses showed that the heterodimers had a broader and more unstable conformational energy distribution, along with a stronger tendency for aggregation. Additionally, the N87D mutation disrupted metal ion coordination, further destabilizing the heterodimer and promoting protein misfolding. These findings suggest a potential molecular mechanism underlying ALS and support a protein structure based approach for investigating the pathogenic mechanisms of disease causing mutations.

Allgrove syndrome, also known as Triple-A syndrome, is a rare autosomal recessive disorder characterized by the triad of alacrima, achalasia, and adrenal insufficiency, alongside a broad spectrum of neurological and autonomic dysfunctions. We present a compound heterozygosity for the pathogenic NM_015665.6:c.787T > C, p.(Ser263Pro) and the not previously described in the literature NM_015665.6:c.1442A > G, p.(His481Arg), as a possible cause for Allgrove syndrome. Exome sequencing was performed in a female patient with achalasia, alacrima, optic atrophy, asymmetrical axonal sensorimotor polyneuropathy, segmental demyelination, and chronic denervation, revealing the above-mentioned compound heterozygosity. Segregation analysis was performed in three siblings of the proband and in the mother. The affected brother of the proband (presenting with achalasia, alacrimia, motor neuropathy, autonomic dysfunction, optic atrophy and osteoporosis), was found to be compound heterozygotes for the same variants. Although the paternal genotype was not available, the absence of the p.(His481Arg) variant in the mother indicates paternal inheritance of this variant, providing indirect evidence that the two AAAS variants are located on different alleles (in trans). The proband and her affected sibling were found to carry compound heterozygosity for the known pathogenic AAAS variant p.(Ser263Pro) and the novel p.(His481Arg) variant. Segregation analysis in available family members supports a contributory role of p.(His481Arg) in the context of autosomal recessive inheritance, however, phase could not be directly confirmed due to the unavailability of the paternal sample. Functional validation and/or identification of the variant in unrelated affected individuals would be required to further clarify its pathogenic significance. We also provide a comprehensive review of reported Allgrove syndrome cases in the literature carrying compound heterozygosity for the NM_015665.6:c.787T > C, p.(Ser263Pro) variant and the respective wide spectrum of this syndrome.

Biallelic hypomorphic variants in PRORP cause the rare autosomal recessive disorder combined oxidative phosphorylation deficiency type 54 (COXPD54). COXPD54 encompasses a clinical spectrum of sensorineural hearing loss and ovarian insufficiency (Perrault syndrome) to leukodystrophy with developmental delay and epilepsy. Here, we report two new affected individuals with biallelic PRORP variants with clinical features consistent with COXPD54. One individual was homozygous for c.1505G > A p.Arg502Gln, whereas the other was compound heterozygous for c.1510C > T, p.His504Tyr and c.893C > A, p.Ser298Ter (NM_014672.4). In vitro tRNA processing assays revealed decreased mitochondrial 5′ tRNA leader cleavage by human RNase P complex with the two novel missense PRORP metallonuclease domain variants. These data provide further evidence that biallelic PRORP variants disrupt 5’ tRNA leader cleavage and are associated with a pleiotropic phenotype of COXPD54.

De novo KCNA3 variants cause a Developmental and Epileptic Encephalopathy (DEE). We describe a 14-year-old boy presenting with DEE and carrying a heterozygous de novo KCNA3 (NM_002232.4) variant (c.1433T>A, p.Val478Glu) and an inherited KCNQ3 (NM_004519.3) variant (c.1720C>T, p.Pro574Ser). Human dermal fibroblasts (HDFs) were isolated from the patient and an age-matched control. KCNA3 and KCNQ3 transcript levels were quantified by qRT-PCR, showing in patient-HDFs a reduction of 77% and 40%, respectively (p < 0.0001; p = 0.0002). Western blot confirmed decreased KCNA3 and KCNQ3 protein levels by 50% and 35%, respectively (p < 0.05). The contributing role of both variants supports the rationale for a channel-targeted treatment strategy.

MYCBP2-associated neurodevelopmental disorder is an autosomal dominant genetic disorder, previously described with de novo variants. We present the case of a two-generation review of a proband with a maternally inherited heterozygous pathogenic variant in MYCBP2, c.4409dup (p.Leu1470Phefs*7). Neuropsychology assessment indicated developmental delays with proband’s scores falling well below age-level expectations, while proband’s mother demonstrated generally intact cognition with evidence of subtle executive inefficiency. Assessment of parental genotype and phenotype can help to anticipate child’s developmental trajectory, especially in genetic disorders associated with highly variable expressivity. However information gaps on familial impact of inherited neurodevelopmental disorders across generations remain.

This study aims to investigate the clinical baseline characteristics and HbA1c variability in elderly patients with mild cognitive impairment (MCI) associated with type 2 diabetes mellitus (T2DM), as well as the synergistic relationship between these factors and dementia progression.A total of 186 elderly patients with T2DM with MCI were enrolled and stratified into 94 with normolipidemia and 92 with dyslipidemia. The patients' demographics, baseline characteristics, lipid levels, baseline HbA1c, and Montreal cognitive assessment scale scores were recorded. Patients were followed up for at least 36 months, with a maximum follow-up period of 48 months.Patients in the dyslipidemia group had a longer duration of DM and had significantly higher total cholesterol, triglycerides, and low-density lipoprotein cholesterol than those in the normolipidemia group. Thirty-five patients progressed to dementia, with 25% (23/92) in the dyslipidemia group compared to 12.77% (12/94) in the normolipidemia group. Patients in the dyslipidemia group had significantly higher HbA1c variability than those in the normolipidemia group. Furthermore, the group progressing to dementia exhibited advanced age, prolonged DM duration, shorter years of education, and abnormal lipid levels, as well as greater HbA1c variability. Dyslipidemia under the association with the glycemic variability profile (HbA1c variability ≥ 10.49%) was also strongly associated with the degree of MCI in patients with dementia. Multivariable logistic regression confirmed that both dyslipidemia (OR = 2.05, P = 0.015) and high HbA1c variability (OR = 3.56, P = 0.010) were independent risk factors, with a significant interaction between them (OR = 3.15, P = 0.046).Dyslipidemia and glycemic variability are not only correlates of cognitive decline in patients with T2DM, but may also act synergistically to accelerate the process of MCI to dementia. The stratification by lipid status effectively identifies patient subgroups at differential risk, highlighting the combined impact of these metabolic factors.

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%.