Aim: Barth syndrome (BTHS; OMIM 302060) is an ultra-rare, complex, multi-system X-linked disorder that arises from pathogenic mutations in the gene TAFAZZIN. BTHS is characterized by cardiomyopathy, skeletal myopathy, muscle weakness, and neutropenia. To better understand the natural history and lived experience of affected individuals, the Barth Syndrome Foundation maintains the patient-inputted Barth Syndrome Registry and Repository (BRR).
Methods: Available cross-sectional and longitudinal participant data (n = 115) were analyzed to illustrate the diagnostic odyssey, manifestations, and healthcare utilization across a broad range of affected individual age groups.
Results: Individuals who experienced cardiomyopathy or heart failure as the first manifestation had the shortest times to diagnosis compared to less appreciated manifestations (e.g., frequent infections, poor muscle tone, growth delay). The most frequently reported manifestations across all ages were due to cardiac disorders (80.7%), gastrointestinal (GI) disorders (68.7%), neutropenia or frequent infections (67.2%), and fatigue (60.9%), with 47.1% of participants scoring in the moderate-to-severe range of the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 8A survey. Participants saw, on average, 3.6 specialists in the previous year, with cardiologists (97.9%) and hematologists (58.2%) being the most commonly seen specialists.
Conclusion: The data suggest that cardiac disorders are the most common manifestations of BTHS, but also reveal a high frequency of feeding and GI-related issues that previous reports have not captured. Physician-targeted education on the lesser-known symptoms and population-based screening for BTHS may aid in timely diagnosis and improved clinical management.
Fabry disease, a rare X-linked lysosomal storage disorder, is marked by a deficiency in the activity of the enzyme
Chronic inflammation and its role in driving cellular plasticity have recently been documented as a significant risk factor for prostate cancer. The progression of prostate cancer has been linked to stages of inflammation-driven changes, ranging from simple atrophy to prostatic intraepithelial neoplasia and eventually to low- and high-grade neoplastic forms. Long-term oxidative stress and the genetic damage caused by chronic inflammation are among the well-characterized risk factors in the development of prostate cancer. Both uncontrollable and controllable factors contribute to this transition process. Non-modifiable risk factors for prostate cancer include age, race, ethnicity, family history of obesity, and certain genetic predispositions. Modifiable risk factors, such as a sedentary lifestyle, poor diet, obesogenic habits, and microbial dysbiosis, may further elevate the risk of neoplastic transformation. Additionally, environmental pollutants, like chlordecone and nitrates, can interact with biological factors, potentially influencing cellular plasticity. These factors collectively contribute to an increased risk of prostate cancer and may facilitate neoplastic progression. Certain molecular markers have also been implicated in promoting chronic inflammation, enhancing cellular proliferation, and inhibiting apoptosis, thereby aiding in this transition. This review provides a comprehensive summary of the known modifiable and non-modifiable risk factors that contribute to the neoplastic transition in the prostate and elevate the risk of prostate cancer.
Breast cancer (BC) remains the most common cause of death in women worldwide, but advances in science have allowed earlier diagnosis and more comprehensive treatment. This review highlights the impact of extensive molecular genetic testing in assessing the risk of BC susceptibility, as well as possible responses to chemotherapy and radiotherapy. Studies in the literature show that several Single Nucleotide Polymorphisms (SNPs) of genes involved in molecular pathways may become predictors of the risk of developing BC. For example, SNPs in genes such as RAD51 and XRCC3, already known to be linked with high BC susceptibility, were also correlated with a different response to radiotherapy and related adverse effects. In addition, the SNP ESR1 PvuII (rs2234693), on the ESR1 gene, has been associated with a poor prognosis in advanced BC, but can be a good predictor of the therapeutic effect of hormonal treatment. Therefore, SNPs can be considered as possible new biomarkers for BC risk and prognosis. In this view, it is important to evaluate Polygenic Risk Score, an essential component for accurate BC risk prediction, which may potentially improve screening and prevention strategies. Bioinformatics tools are available to calculate polygenic risk by assessing the presence of SNPs and patients’ family and personal history. This represents an important step forward in the era of personalized medicine for BC.
Fabry disease is a rare genetic disorder classified as a lysosomal storage disease. It is an X-linked disease, caused by the mutation of the GLA gene, leading to the deficit or absence of function of the enzyme α-galactosidase A. It is a multi-organ and progressive disease characterized by systemic involvement primarily affecting the cardiac, renal and neurological systems. Current treatment options include established therapies such as two enzyme replacement therapies (agalsidase α, agalsidase β), one chaperone treatment (migalastat), and a recently approved enzyme replacement therapy targeting pegunigalsidase α. New drugs are being developed, including substrate reduction therapy, mRNA therapy, and genetic therapy. These emerging treatments have the potential to address the limitations of current therapies and ensure more effective and personalized treatment. This review explores and analyzes the diverse therapeutic strategies available for treating this complex and intriguing disease.
Steatotic liver disease (SLD), particularly metabolic dysfunction-associated SLD, represents a significant public health concern worldwide. Among the various factors implicated in the development and progression of this condition, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene has emerged as a critical player. Variants of PNPLA3 are associated with altered lipid metabolism, leading to increased hepatic fat accumulation and subsequent inflammation and fibrosis. Understanding the role of PNPLA3 not only enhances our comprehension of the pathomechanisms driving SLD but also informs potential therapeutic strategies. The molecular mechanisms through which PNPLA3 variants contribute to lipid dysregulation and hepatocyte injury in SLD are critically discussed in the present review article. We extensively analyze clinical cohorts and population-based studies underpinning the association between PNPLA3 polymorphisms and the risk of developing SLD, and its liver-related and protean extrahepatic outcomes, in concert with other risk modifiers, notably including age, sex, and ethnicity in adults and children. We also discuss the increasingly recognized role played by the PNPLA3 gene in liver transplantation, autoimmune hepatitis, and acquired immunodeficiency syndrome. Finally, we examine the clinical implications of PNPLA3 diagnostics regarding risk stratification and targeted therapies for patients affected by SLD in the context of precision medicine approaches.
Objective: To enhance the safety, simplicity, and efficacy of non-invasive prenatal paternity testing, we developed a method based on multiplex PCR targeted capture sequencing technology utilizing single nucleotide polymorphisms (SNPs) as genetic markers.
Method: We screened 627 SNPs from public databases and literature based on specific criteria and population genetic data from 100 unrelated individuals. A total of 15 peripheral blood samples were collected from pregnant women and the suspected father. Paternal alleles were detected and analyzed in the plasma cell-free DNA (cfDNA) of pregnant women, fetal SNP genotypes were obtained, and the combined paternity index (CPI) was calculated for paternity testing.
Results: Biological fathers were accurately determined in all cases, with CPI values ranging from 1.05 × 1014 to
Conclusion: This novel approach demonstrates significant improvements by reducing the number of SNPs, streamlining the research procedure, and lowering costs, yielding substantial advancements in non-invasive prenatal paternity testing.
Aim: Progressive kidney deterioration can occur in females with Fabry disease. Despite this, many females go undiagnosed or are labeled “carriers”. Our study aimed to review biopsy findings of adult female Fabry patients with creatinine values within the “normal reference ranges” and minimal proteinuria.
Methods: This study was a single-center retrospective analysis of female patients presenting to the University of Alabama at Birmingham. Kidney biopsies and clinical characteristics were reviewed. Kidney biopsies were scored using the Fogo scoring system.
Results: All of the 13 participants had classic mutations (11 nonsense, 2 missense). The mean age was 31.7 years. The median serum creatinine was 0.7 mg/dL (0.5-1.2), and estimated glomerular filtration rate (eGFR) values calculated using the chronic kidney disease epidemiology collaboration (CKD-EPI) equation ranged from 56 to 130 ml/min/1.73m2. The serologic biomarkers were not elevated in any of the patients - plasma globotriaosylsphingosine (Lyso GL-3) was < 5.1 ng/mL and globotriaosylceramide (GL-3) was < 3 µg/mL. The average score for the biopsies per the International Study Group of Fabry Nephropathy (ISGFN) was 2.43. Thirty-eight percent of patients had greater than 50% foot process effacement despite normal creatinine and minimal proteinuria.
Conclusion: Females with Fabry disease, despite having normal reference range creatinine, minimal proteinuria, and low plasma Lyso GL-3, had significant histologic evidence of the disease. When possible, histologic assessment should be performed in females to assess tissue involvement. Longitudinal follow-up is needed to determine if histologic findings on presentation predict long-term outcomes.