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Survey of Ophthalmology 2023Wolfram-like syndrome (WFLS) is a recently described autosomal dominant disorder with phenotypic similarities to autosomal recessive Wolfram syndrome (WS), including... (Review)
Review
Wolfram-like syndrome (WFLS) is a recently described autosomal dominant disorder with phenotypic similarities to autosomal recessive Wolfram syndrome (WS), including optic atrophy, hearing impairment, and diabetes mellitus. We summarize current literature, define the clinical characteristics, and investigate potential genotype phenotype correlations. A systematic literature search was conducted in electronic databases Pubmed/MEDLINE, EMBACE, and Cochrane Library. We included studies reporting patients with a clinical picture consisting at least 2 typical clinical manifestations of WSF1 disorders and heterozygous mutations in WFS1. In total, 86 patients from 35 studies were included. The most common phenotype consisted of the combination of optic atrophy (87%) and hearing impairment (94%). Diabetes mellitus was seen in 44% of the patients. Nineteen percent developed cataract. Patients with missense mutations in WFS1 had a lower number of clinical manifestations, less chance of developing diabetes insipidus, but a younger age at onset of hearing impairment compared to patients with nonsense mutations or deletions causing frameshift. There were no studies reporting decreased life expectancy. This review shows that, within the spectrum of WFS1-associated disorders or "wolframinopathies," autosomal dominantly inherited WFLS has a relatively mild phenotype compared to autosomal recessive WS. The clinical manifestations and their age at onset are associated with the specific underlying mutations in the WFS1 gene.
Topics: Humans; Hearing Loss; Mutation; Optic Atrophy; Tungsten; Wolfram Syndrome
PubMed: 36764396
DOI: 10.1016/j.survophthal.2023.01.012 -
Cell Reports. Medicine Nov 2023Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized,... (Randomized Controlled Trial)
Randomized Controlled Trial
Ketogenic dietary interventions (KDIs) are beneficial in animal models of autosomal-dominant polycystic kidney disease (ADPKD). KETO-ADPKD, an exploratory, randomized, controlled trial, is intended to provide clinical translation of these findings (NCT04680780). Sixty-six patients were randomized to a KDI arm (ketogenic diet [KD] or water fasting [WF]) or the control group. Both interventions induce significant ketogenesis on the basis of blood and breath acetone measurements. Ninety-five percent (KD) and 85% (WF) report the diet as feasible. KD leads to significant reductions in body fat and liver volume. Additionally, KD is associated with reduced kidney volume (not reaching statistical significance). Interestingly, the KD group exhibits improved kidney function at the end of treatment, while the control and WF groups show a progressive decline, as is typical in ADPKD. Safety-relevant events are largely mild, expected (initial flu-like symptoms associated with KD), and transient. Safety assessment is complemented by nuclear magnetic resonance (NMR) lipid profile analyses.
Topics: Humans; Polycystic Kidney, Autosomal Dominant; Diet, Ketogenic; Feasibility Studies; Liver; Magnetic Resonance Imaging
PubMed: 37935200
DOI: 10.1016/j.xcrm.2023.101283 -
Cell Dec 2023Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a...
Short tandem repeat (STR) instability causes transcriptional silencing in several repeat expansion disorders. In fragile X syndrome (FXS), mutation-length expansion of a CGG STR represses FMR1 via local DNA methylation. Here, we find megabase-scale H3K9me3 domains on autosomes and encompassing FMR1 on the X chromosome in FXS patient-derived iPSCs, iPSC-derived neural progenitors, EBV-transformed lymphoblasts, and brain tissue with mutation-length CGG expansion. H3K9me3 domains connect via inter-chromosomal interactions and demarcate severe misfolding of TADs and loops. They harbor long synaptic genes replicating at the end of S phase, replication-stress-induced double-strand breaks, and STRs prone to stepwise somatic instability. CRISPR engineering of the mutation-length CGG to premutation length reverses H3K9me3 on the X chromosome and multiple autosomes, refolds TADs, and restores gene expression. H3K9me3 domains can also arise in normal-length iPSCs created with perturbations linked to genome instability, suggesting their relevance beyond FXS. Our results reveal Mb-scale heterochromatinization and trans interactions among loci susceptible to instability.
Topics: Humans; Fragile X Syndrome; Trinucleotide Repeat Expansion; DNA Methylation; Mutation; Fragile X Mental Retardation Protein
PubMed: 38134876
DOI: 10.1016/j.cell.2023.11.019 -
Clinical Journal of the American... May 2024Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary... (Review)
Review
Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by kidney cyst formation and progressive kidney function loss. Dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet have recently emerged as potential strategies to induce metabolic reprogramming and slow ADPKD progression. We review the available evidence supporting the efficacy and safety of these interventions in ADPKD. Dietary interventions show promise in managing ADPKD by improving metabolic health and reducing oxidative stress. However, while preclinical studies have shown favorable outcomes, limited clinical evidence supports their effectiveness. In addition, the long-term consequences of these dietary interventions, including their effect on adverse events in patients with ADPKD, remain uncertain. To optimize ADPKD management, patients are advised to follow a dietary regimen that aims to achieve or maintain an ideal body weight and includes high fluid intake, low sodium, and limited concentrated sweets. Caloric restriction seems particularly beneficial for patients with overweight or obesity because it promotes weight loss and improves metabolic parameters. Supplementation with curcumin, ginkgolide B, saponins, vitamin E, niacinamide, or triptolide has demonstrated uncertain clinical benefit in patients with ADPKD. Notably, β -hydroxybutyrate supplements have shown promise in animal models; however, their safety and efficacy in ADPKD require further evaluation through well-designed clinical trials. Therefore, the use of these supplements is not currently recommended for patients with ADPKD. In summary, dietary interventions such as caloric restriction, intermittent fasting, and ketogenic diet hold promise in ADPKD management by enhancing metabolic health. However, extensive clinical research is necessary to establish their effectiveness and long-term effects. Adhering to personalized dietary guidelines, including weight management and specific nutritional restrictions, can contribute to optimal ADPKD management. Future research should prioritize well-designed clinical trials to determine the benefits and safety of dietary interventions and supplementation in ADPKD.
Topics: Humans; Polycystic Kidney, Autosomal Dominant; Caloric Restriction; Diet, Ketogenic; Fasting; Animals
PubMed: 37729939
DOI: 10.2215/CJN.0000000000000326