Charcot-Marie-Tooth type 1A (CMT1A), a prevalent progressive demyelinating peripheral neuropathy is caused by a duplication of the peripheral myelin protein (PMP22) gene. PMP22 is crucial for formation of compact myelin, but the mechanism by which PMP22 overexpression results in CMT1A pathogenesis remains elusive. Emerging evidence points to the role of PMP22 in lipid metabolism as a key modulator of disease progression. Here we show that C3 and C22 mouse models, carrying 5 and 10 additional copies of the human PMP22 gene, have PMP22 dose-dependent lipidomic and transcriptomic alterations. Both models show a decrease in membrane-associated lipids (e.g. phospholipids and sphingolipids) and an increase in neutral lipids (e.g. cholesteryl esters) from three weeks of age. Notably, while cholesteryl ester concentrations are elevated, particularly in C22 mice, total cholesterol levels were significantly reduced, accompanied by the downregulation of key genes involved in cholesterol biosynthesis. Significant decreases were also observed in phospholipids and sphingolipids, including ceramide and sphingomyelin, with a proportional shift towards shorter fatty acid chains in sphingomyelin due to altered ceramide synthase expression. Plasmalogen concentrations decreased with shifts in the proportion of specific plasmalogen species, aligning with impaired synthesis. These lipidomic changes, impacting myelin-associated lipids and fatty acid compositions, underscore their critical role in the dysmyelination observed in CMT1A. Our findings suggest potential avenues for dietary interventions, such as specific fatty acid and plasmalogen supplementation to improve myelination in CMT1A.

Background Neurovascular coupling is a fundamental aspect of brain function by regulating cerebral blood flow in response to regional neuronal activity. Increasing evidence suggest neurovascular decoupling occurs early in the progression of Alzheimer disease (AD), potentially reflecting early vascular damage. Therefore, understanding the relationship between neurovascular coupling and established vascular risk factors for AD is essential to gain deeper insights into the vascular mechanisms underlying AD. Methods This cross‐sectional observational study investigated the association between neurovascular coupling and vascular risk factors for AD, specifically small vessel disease magnetic resonance imaging markers, cardiovascular risk factors, and the apolipoprotein E genotype. The cohort included 119 participants diagnosed with subjective cognitive impairment, mild cognitive impairment, and AD‐related dementia, as well as individuals without cognitive complaints. Neurovascular coupling was measured by blood‐oxygen‐level‐dependent functional magnetic resonance imaging amplitude in response to visual stimulation. Results Our findings revealed that decreased neurovascular coupling is linked to structural brain changes typically seen in small vessel disease; specifically we found an association between neurovascular coupling and white matter hyperintensities load (β=−0.199, P=0.030) and presence of lobar intracerebral hemorrhage (β=−0.228, P=0.011). Conclusions This raises the suggestion that a decreased neurovascular coupling in the disease process of AD is related to comorbid small vessel disease.

Background and Objectives:The aim of this study was to investigate whether the considerable phenotypic variation in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) is due to additional pathogenic coding variants in severely affected patients, by screening a panel of neuropathy-related genes. Methods:In this cross-sectional study, the extremes of the spectrum of 742 patients with genetically confirmed CMT1A and HNPP were selected, based on disability as assessed using the Overall Neuropathy Limitation Scale (ONLS). The ONLS data of 183 patients with CMT1A and 102 with HNPP showed a Gaussian distribution. A next-generation sequencing panel containing 177 neuropathy-related genes was tested in a selected group of 20 patients with mild CMT1A, 24 with severe CMT1A, 25 with mild HNPP, and 25 with severe HNPP. Results:One additional autosomal dominant pathogenic variant in the MFN2 gene was identified in a severe CMT1A case. Heterozygous pathogenic variants in autosomal recessive neuropathy-related genes were found in 2 patients with severe CMT1A and in 2 with mild HNPP. Discussion:In our study, additional pathogenic coding variants in neuropathy-related genes did not contribute to variation in disease severity in most patients with CMT1A and HNPP. In cases with confirmed PMP22 copy-number alterations, further genetic screening for pathogenic variants in CMT-related genes is warranted only in severe cases.

Short tandem repeats (STRs) are recognized contributors to various neurodegenerative disorders, with evidence supporting genetic pleiotropy among these STRs. Multiple STRs have been associated with amyotrophic lateral sclerosis (ALS), although the strength of evidence supporting each association varies. To establish the role of disease-associated repeat expansions as pleiotropic risk factors in ALS susceptibility and progression, we genotyped a panel of 39 STRs, known to cause neurological diseases, within Project MinE in 6519 patients and 2412 controls, utilizing 100 and 150 bp short-read sequencing technology. Pathogenic allele frequencies were compared to those in a control cohort comprising 4930 Genome Aggregation Database (gnomAD) genomes. Repeat sizes and motif changes were detected using ExpansionHunter and ExpansionHunter Denovo. We developed a model to predict genotyping failures in STRs and established a best-practice protocol for assessing the accuracy of STR genotyping in short-read sequencing data. Following our genotyping assessment, 11 out of the 39 STRs exhibited insufficient genotyping accuracy, warranting caution in studying these STRs using these tools in combination with short-read sequencing. Furthermore, the observed differences in STR genotyping accuracy across studies applying different sequencing technologies and genotyping tools in control cohorts highlight the importance of a carefully designed experimental setup when interpreting potential disease-associated STR findings. Pathogenic C9orf72 and premutated ATXN2 expansions were confirmed to be significantly associated with ALS susceptibility. Additionally, pathogenic C9orf72 expansions were significantly associated with reduced mean ALS survival by 11.5 months and an earlier mean age at onset by 2.4 years. Premutation expansions in ATXN1 showed a nominally significant association with ALS susceptibility, while pathogenic expansions in NIPA1 displayed a nominally significant association with ALS survival. Previously reported ALS-associated pleiotropy in HTT and STMN2 could not be confirmed. Motif changes were identified in BEAN1, RFC1, ATXN8, C9orf72, DAB1, FXN and SAMD12; however, none of the motif changes were linked to ALS. Re-evaluation of clinical data from patients with ALS and a repeat expansion typically associated with another disease revealed that 7% of these patients' diagnoses had to be reclassified to the disease associated with the repeat expansion (e.g. Kennedy's disease or spinocerebellar ataxia). This underscores the value of broad STR screening in neurodegenerative cases. Pathogenic and premutation STRs were also found in controls in unexpected high frequencies, suggesting reduced penetrance or underdiagnosis, and highlighting the need for caution when interpreting genetic associations with disease without a proper control cohort.

The circadian rhythm of the central brain clock in the suprachiasmatic nucleus (SCN) is synchronized by light. White adipose tissue (WAT) is one of the metabolic endocrine organs containing a molecular clock, and it is synchronized by the SCN. Excess WAT is a risk factor for health issues including type 2 diabetes mellitus (DM2). We hypothesized that bright-light exposure would affect the human WAT transcriptome. Therefore, we analyzed WAT biopsies from two previously performed randomized cross-over trials (trial 1: n = 8 lean, healthy men, and trial 2: n = 8 men with obesity and DM2). From 7:30 h onwards, all the participants were exposed to either bright or dim light. Five hours later, we performed a subcutaneous abdominal WAT biopsy. RNA-sequencing results showed major group differences between men with obesity and DM2 and lean, healthy men as well as a differential effect of bright-light exposure. For example, gene sets encoding proteins involved in oxidative phosphorylation or respiratory chain complexes were down-regulated under bright-light conditions in lean, healthy men but up-regulated in men with obesity and DM2. In addition to evident group differences between men with obesity and DM2 and healthy lean subjects, autonomic or neuroendocrine signals resulting from bright-light exposure also differentially affect the WAT transcriptome.

Beta (β) thalassemia is an inherited disorder that occurs following mutations or deletions in the β globin gene. Rarely, it is caused by variants in genes coding for erythroid transcriptional factors or trans-acting factors. Here, we report three novel variants of SUPT5H revealed by next generation sequencing. This, gene has been progressively acknowledged as a mimicker of β thalassemia trait in two independent individuals and one family. These individuals have the same features, including hypochromic microcytic indices, increased Hb A2 levels, without mutations in the β globin gene. The three novel SUPT5H variants identified in this study (c.1168_1169del, c.2688del and c.307+1G>A) are frameshift variants leading to a premature stop codon or an intronic variant predicted to alter the splice site consensus sequence by in silico software. All three variants are characterized as Loss-of-Function variants either by generating a truncated protein or haplo-insufficiency due to nonsense-mediated decay. These findings confirm the general observation that most variants in SUPT5H associated with a β thalassemia trait phenotype are Loss-of-Function variants. This gene should be considered as a potential target gene in the genetic diagnosis of any unsolved cases of increased HbA2 and unexplained inconsistency of phenotype and genotype of β thalassemia intermedia.

Precision medicine has the potential to provide more accurate diagnosis, appropriate treatment and timely prevention strategies by considering patients' biological makeup. However, this cannot be realized without integrating clinical and omics data in a data-sharing framework that achieves large sample sizes. Systems that integrate clinical and genetic data from multiple sources are scarce due to their distinct data types, interoperability, security and data ownership issues. Here we present a secure framework that allows immutable storage, querying and analysis of clinical and genetic data using blockchain technology. Our platform allows clinical and genetic data to be harmonized by combining them under a unified framework. It supports combined genotype-phenotype queries and analysis, gives institutions control of their data and provides immutable user access logs, improving transparency into how and when health information is used. We demonstrate the value of our framework for precision medicine by creating genotype-phenotype cohorts and examining relationships within them. We show that combining data across institutions using our secure platform increases statistical power for rare disease analysis. By offering an integrated, secure and decentralized framework, we aim to enhance reproducibility and encourage broader participation from communities and patients in data sharing.

It is well known that modifiers play a role in ameliorating or exacerbating disease phenotypes in patients and carriers of recessively inherited disorders such as sickle cell disease and thalassemia. Here, we give an overview of the literature concerning a recently described association in carriers of SUPT5H Loss-of-Function variants with a beta-thalassemia-like phenotype including the characteristic elevated levels of HbA2. That SUPT5H acts as modifier in beta-thalassemia carriers became evident from three reported cases in whom combined heterozygosity of SUPT5H and HBB gene variants was observed to resemble a mild beta-thalassemia intermedia phenotype. The different SUPT5H variants and hematologic parameters reported are collected and reviewed to provide insight into the possible effects on hematologic expression, as well as potential disease mechanisms in carriers and patients.

Purpose: To describe a recessively inherited cerebral small vessel disease, caused by loss-of-function variants in Nitrilase1 (NIT1). Methods: We performed exome sequencing, brain magnetic resonance imaging, neuropathology, electron microscopy, western blotting, and transcriptomic and metabolic analyses in 7 NIT1-small vessel disease patients from 5 unrelated pedigrees. Results: The first identified patients were 3 siblings, compound heterozygous for the NIT1 c.727C>T; (p.Arg243Trp) variant and the NIT1 c.198_199del; p.(Ala68*) variant. The 4 additional patients were single cases from 4 unrelated pedigrees and were all homozygous for the NIT1 c.727C>T; p.(Arg243Trp) variant. Patients presented in mid-adulthood with movement disorders. All patients had striking abnormalities on brain magnetic resonance imaging, with numerous and massively dilated basal ganglia perivascular spaces. Three patients had non-lobar intracerebral hemorrhage between age 45 and 60, which was fatal in 2 cases. Western blotting on patient fibroblasts showed absence of NIT1 protein, and metabolic analysis in urine confirmed loss of NIT1 enzymatic function. Brain autopsy revealed large electron-dense deposits in the vessel walls of small and medium sized cerebral arteries. Conclusion: NIT1-small vessel disease is a novel, autosomal recessively inherited cerebral small vessel disease characterized by a triad of movement disorders, massively dilated basal ganglia perivascular spaces, and intracerebral hemorrhage. (c) 2024 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited peripheral neuropathy caused by a 1.5 Mb tandem duplication of chromosome 17 harbouring the PMP22 gene. This dose-dependent overexpression of PMP22 results in disrupted Schwann cell myelination of peripheral nerves. To obtain better insights into the underlying pathogenic mechanisms in CMT1A, we investigated the role of PMP22 duplication in cellular homeostasis in CMT1A mouse models and in patient-derived induced pluripotent stem cells differentiated into Schwann cell precursors (iPSC-SCPs).We performed lipidomic profiling and bulk RNA sequencing (RNA-seq) on sciatic nerves of two developing CMT1A mouse models and on CMT1A patient-derived iPSC-SCPs. For the sciatic nerves of the CMT1A mice, cholesterol and lipid metabolism was downregulated in a dose-dependent manner throughout development. For the CMT1A iPSC-SCPs, transcriptional analysis unveiled a strong suppression of genes related to autophagy and lipid metabolism. Gene ontology enrichment analysis identified disturbances in pathways related to plasma membrane components and cell receptor signalling. Lipidomic analysis confirmed the severe dysregulation in plasma membrane lipids, particularly sphingolipids, in CMT1A iPSC-SCPs. Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs. Importantly, this phenotype could be rescued by stimulating autophagy and lipolysis.We conclude that PMP22 duplication disturbs intracellular lipid storage and leads to a more disordered plasma membrane owing to an alteration in the lipid composition, which might ultimately lead to impaired axo-glial interactions. Moreover, targeting lipid handling and metabolism could hold promise for the treatment of patients with CMT1A. Peripheral nerve insulation requires an intricate relationship between neurons and Schwann cells which is highly dependent on lipids. Prior et al. show how an excess of the PMP22 protein dysregulates the storage of lipids and their incorporation into the plasma membrane of Schwann cells, giving rise to Charcot-Marie-Tooth disease type 1A.

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most prevalent hereditary demyelinating neuropathy. This autosomal, dominantly inherited disease is caused by a duplication on chromosome 17p which includes the peripheral myelin protein 22 (PMP22) gene. There is clinical evidence that the disability in CMT1A is to a large extend due to axonal damage rather than demyelination. Over-expression of PMP22 is recently thought to impede cholesterol trafficking causing a total shutdown of local cholesterol and lipid synthesis in the Schwann cells, thus disturbing their ability to remyelinate. But there is a large variety in disease burden between CMT1A patients with the same genetic defect, indicating the presence of modifying factors that affect disease severity. One of these potential factors is the immune system. Several reports have described patients with co-occurrence of CMT1A with chronic inflammatory demyelinating disease or Guillain-Barré syndrome. We have previously shown in multiple animal models that the innate immune system and specifically the terminal complement system is a driver of inflammatory demyelination. To test the contribution of the terminal complement system to neuroinflammation and disease progression in CMT1A, we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3-PMP22 and C3-PMP22 c-JunP0Cre models. Both models over-express human PMP22, and one (C3-PMP22 c-JunP0Cre) also has a Schwann cell-specific knockout of c-Jun, a crucial regulator of myelination controlling autophagy. We found that systemic inhibition of C6 using antisense oligonucleotides affects the neuroinflammation, Rho GTPase and ERK/MAPK signalling pathways in the CMT1A mouse models. The cholesterol synthesis pathway remained unaffected. Analysis of motor function during treatment with C6 antisense oligonucleotides did not reveal any significant improvement in the CMT1A mouse models. This study shows that the contribution of the terminal complement system to progressive loss of motor function in the CMT1A mouse models tested is limited.

Supplementary Figures S1-S4 from Molecular Risk Stratification of Medulloblastoma Patients Based on Immunohistochemical Analysis of MYC, LDHB, and CCNB1 Expression

Highly penetrant monogenic causes of intracerebral haemorrhage are rare, and are almost exclusively hereditary cerebral amyloid angiopathies caused by heterozygous pathogenic variants in the APP gene. Here, we identified a novel genetic cause of mid-adult onset non-lobar ICH, caused by bi-allelic pathogenic variants in the NIT1 gene. The seven identified patients from five unrelated pedigrees presented with movement disorders, slowly progressive cognitive decline, ischemic strokes and psychiatric disturbances. All patients shared a striking neuroimaging phenotype with a honeycomb appearance of the basal ganglia due to an extremely high burden of enlarged perivascular spaces. Two patients were deceased, due to mid-adult massive non-lobar intracerebral haemorrhage. Small cerebral arteries showed strongly abnormal morphology, with thickening of the media and numerous large electron dense deposits located between the media and adventitia. Patients were homozygous for the NIT1 c.727C>T; p.Arg243Trp variant or compound heterozygous for the NIT1 c.727C>T; p.Arg243Trp and c.198_199del, p.Ala68* variant. Urine analysis showed increased levels of deaminated gluthatione, consistent with loss of NIT1 function in both homozygous and compound heterozygous patients. Based on NIT1 carrier frequencies in UK Biobank and gnomAD, an estimated minimum of 4500 individuals worldwide are affected with this novel, autosomal recessively inherited cause of intracerebral haemorrhage, which we term NIT1-small vessel disease.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study was funded by the Netherlands Organisation for Health Research and Development (ZonMW grant no 91717325 and 09150161910010)### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This study has been approved by the Medical Ethics Committee Leiden The Hague Delft (P21.013)I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

COPYRIGHT © 2023 Michailidou, Fluiter, Boziki, Grigoriadis and Baas. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial: Complement in nervous system disease