Severe Congenital Disease Research Articles

Role of DIP Diet in Managing Blood Transfusion-Dependent Thalassemia Major: A Case Study of Integrative Therapies”

Thalassemia Major, a severe genetic blood disorder, necessitates frequent blood transfusions to manage low hemoglobin levels. This case highlights the recovery journey of Dibyanshu Pani, a 4-year-old boy from Odisha, diagnosed with Blood Transfusion Dependent Thalassemia Major in April 2023. Initially treated at SCB Medical College, Cuttack, and subsequently in Mumbai, Dibyanshu underwent frequent transfusions every 20 days to maintain his hemoglobin levels, which fluctuated between 5 and 9. In July 2023, his family opted for an alternative approach under Dr. Namita’s guidance, incorporating integrative therapies such as the DIP Diet, Living Water Therapy, Sunlight Exposure, and HWI Therapy. Remarkably, Dibyanshu’s condition stabilized, reducing his dependence on transfusions. By October 2023, his hemoglobin levels were maintained between 6.8 and 7.5 without regular transfusions. His family’s adherence to integrative therapies transformed his prognosis, with the frequency of transfusions decreasing to once every eight months. In August 2024, a sudden episode of diarrhea necessitated a single transfusion. Today, Dibyanshu leads a healthy life, free from medications, following a holistic lifestyle. This case underscores the potential of integrative therapies in managing chronic conditions like Thalassemia Major, reducing medical dependence, and improving quality of life.

Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin-/-/Utrophin-/- Double-Knockout Mice.

Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease occurring due to mutations of the dystrophin gene. There is no cure for DMD. Using a dystrophin-/-utrophin-/- (DKO-Hom) mouse model, we investigated the PGE2/EP2 pathway in the pathogenesis of dystrophic muscle and its potential as a therapeutic target. We found that Ep2, Ep4, Cox-2, 15-Pgdh mRNA, and PGE2 were significantly increased in DKO-Hom mice compared to wild-type (WT) mice. The EP2 and EP4 receptors were mainly expressed in CD68+ macrophages and were significantly increased in the muscle tissues of both dystrophin-/- (mdx) and DKO-Hom mice compared to WT mice. Osteogenic and osteoclastogenic gene expression in skeletal muscle also increased in DKO-Hom mice, which correlates with severe muscle heterotopic ossification (HO). Treatment of DKO-Hom mice with the EP2 antagonist PF04418948 for 2 weeks increased body weight and reduced HO and muscle pathology by decreasing both total macrophages (CD68+) and senescent macrophages (CD68+P21+), while increasing endothelial cells (CD31+). PF04418948 also increased bone volume/total volume (BV/TV), the trabecular thickness (Tb.Th) of the tibia trabecular bone, and the cortical bone thickness of both the femur and tibia without affecting spine trabecular bone microarchitecture. In summary, our results indicate that targeting EP2 improves muscle pathology and improves bone mass in DKO mice.

Hydroxyapatite nanoparticle mediated delivery of full length dystrophin gene as a potential therapeutic for the treatment of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, primarily affecting young males. In this study, we investigated arginine-modified hydroxyapatite nanoparticles (R-HAp) as a novel non-viral vector for DMD gene therapy, particularly for delivering the large 18.8 kb dystrophin gene. Addressing the limitations of traditional adeno-associated viral vectors, R-HAp demonstrated efficient binding and delivery of the dystrophin plasmid to DMD patient-derived skeletal muscle cells. Using confocal imaging and RT-PCR analysis, our results showed effective gene delivery and expression in both mouse myotubes and patient-derived cells, with sustained expression evident up to 5 days post transfection. The patient-derived myotubes also showed dystrophin protein production 7 days post transfection. These findings suggest R-HAp nanoparticles as a promising and cost-effective alternative for DMD treatment, highlighting their potential for overcoming current gene therapy challenges.

A Hypothesis: Metabolic Contributions to 16p11.2 Deletion Syndrome

ABSTRACT16p11.2 deletion syndrome is a severe genetic disorder associated with the deletion of 27 genes from a Copy Number Variant region on human chromosome 16. Symptoms associated include cognitive impairment, language and motor delay, epilepsy or seizures, psychiatric disorders, autism spectrum disorder (ASD), changes in head size and body weight, and dysmorphic features, with a crucial need to define genes and mechanisms responsible for symptomatology. In this review, we analyze the clinical associations and biological pathways of 16p11.2 locus genes and identify that a majority of 16p11.2 genes relate to metabolic processes. We present a hypothesis in which changes in the dosage of 16p11.2 metabolic genes contribute to pathology through direct or indirect alterations in pathways that include amino acids or proteins, DNA, RNA, catabolism, lipid, energy (carbohydrate). This hypothesis suggests that research into the specific roles of each metabolic gene will help identify useful therapeutic targets.

Two Novel Mouse Models of Duchenne Muscular Dystrophy with Similar Dmd Exon 51 Frameshift Mutations and Varied Phenotype Severity

Duchenne muscular dystrophy (DMD) is a severe X-linked genetic disorder caused by an array of mutations in the dystrophin gene, with the most commonly mutated regions being exons 48–55. One of the several existing approaches to treat DMD is gene therapy, based on alternative splicing and mutant exon skipping. Testing of such therapy requires animal models that carry mutations homologous to those found in human patients. Here, we report the generation of two genetically modified mouse lines, named “insT” and “insG”, with distinct mutations at the same position in exon 51 that lead to a frameshift, presumably causing protein truncation. Hemizygous males of both lines exhibit classical signs of muscular dystrophy in all muscle tissues except for the cardiac tissue. However, pathological changes are more pronounced in one of the lines. Membrane localization of the protein is reduced to the point of absence in one of the lines. Moreover, an increase in full-length isoform mRNA was detected in diaphragms of insG line mice. Although further work is needed to qualify these mutations as sole origins of dissimilarity, both genetically modified mouse lines are suitable models of DMD and can be used to test gene therapy based on alternative splicing.

Severe congenital liver disease caused by FOCAD gene compound heterozygous variation in a child

Severe congenital liver disease caused by FOCAD gene compound heterozygous variation in a child

Uniparental disomy (UPD) exclusion in embryos following Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR).

Uniparental disomy (UPD) is a genetic condition which both copies of a chromosome are inherited from a single parent, potentially leading to imprinting disorders. This study aimed to assess the integration of Short Tandem Repeat (STR) analysis into Preimplantation Genetic Testing for Structural Rearrangements (PGT-SR) to assess UPD risk and its impact on selecting euploid embryos for embryo transfer in couples with chromosomal translocations involving imprinted chromosomes. This study evaluated three couples carrying balanced chromosomal translocations: 45,XX,der(13;14)(q10;q10), 46,XX,t(10;11)(q22;q13), and 45,XY,der(14;15)(q10;q10). STR analysis was performed on trophectoderm (TE) biopsies after Whole Genome Amplification (WGA) after PGT-SR analysis using parental blood samples to assess UPD risk in euploid embryos. Haplotyping was conducted with five to six STR markers specific to each rearranged chromosome to detect UPD in euploid embryos. Of the four embryos analyzed across the three families, two couples had euploid embryos that tested negative for UPD. These embryos were successfully transferred, resulting in the birth of two healthy children. In the third family, the euploid embryo also tested negative for UPD but failed to implant after transfer, resulting in no pregnancy. Despite its rarity, UPD involving imprinted chromosomes poses significant clinical risks, as seen in disorders such as Prader-Willi syndrome and Angelman syndrome. This study highlights the importance of integrating UPD screening into PGT-SR protocols, to detect both heterodisomic and isodisomic UPD events minimizing the risk of severe genetic disorders. Integrating STR-based UPD screening within PGT-SR workflows is a reliable and cost-effective strategy that enhances embryo selection and mitigates the risk of imprinting disorders. This approach improves reproductive outcomes for families with chromosomal rearrangements, offering a practical advancement in assisted reproduction.

Community-Sourced Reporting of Mortalities in Angelman Syndrome (1979-2022).

Angelman syndrome (AS) is a severe genetic neurodevelopmental disorder with an estimated prevalence of 1:20,000. Life expectancy appears to be normal, however, data regarding lifespan in AS are scarce. Until 2018, there was no unique diagnosis code for AS, thus true incidence, prevalence, mortality and morbidity rates are unknown. A social media effort was launched by caregivers of people with AS to gather community-sourced data to understand AS mortality risks. Information on 220 deaths was verified with obituaries and public postings. Respiratory illness was the primary cause of death among people with AS overall, followed by accidents and seizures. Surprisingly, sudden unexpected death in sleep (SUDS) was the fourth most common cause, which has not been reported previously. Approximately 91% of people with AS have epilepsy, thus some SUDS cases may represent sudden unexpected deaths in epilepsy (SUDEP). Causes of death vary by age, and differ from the general population. Though there are obvious limitations to data collected through social media, grass roots science is a starting point to amass preliminary data and inform future epidemiological research on AS.

Whole body vibration technique in rehabilitation of children with cystic fibrosis

BACKGROUND: Cystic fibrosis (or mucoviscidosis) is a severe genetic disease, which leads to disability and requires a permanent rehabilitation treatment aimed at improving the pulmonary function lung and the effort tolerance starting from childhood. The whole-body vibration (WBV) technique can potentially improve the effort tolerance and quality of life in patients with cystic fibrosis. AIM: To evaluate the efficacy and safety of the WBV technique in improving the effort tolerance in patients with cystic fibrosis. MATERIALS AND METHODS: Randomized controlled study enrolling 60 patients with pulmonary or mixed form of cystic fibrosis aged 8 to 17 years. Patients were randomized into three groups: the patients in the experimental Group 1 received a course of conventional kinesiotherapy combined with the WBV; in the experimental Group 2, the course of conventional kinesiotherapy combined with the WBV was enhanced with the aerobic exercises on an exercise bike; and the comparison group patients received only conventional kinesiotherapy. The study duration was consistent with the hospital stay time (12 days); the patients received a rehabilitation course of 10 exercises. The primary endpoint was the increased walking distance in the six-minute walk test. The methods of evaluation involved the pre-/post-treatment six-minute walk test results and the PedsQL 4.0 Generic Core Scales quality of life scores. RESULTS: The comparative analysis results demonstrate the statistically significantly increased six-minute walk test distance in the experimental Groups 1 and 2, which evidences the efficacy of the WBV technique aimed at improving the effort tolerance in patients with cystic fibrosis. The group that received kinesiotherapy combined with the WBV and aerobic exercises showed a more pronounced effect. In the comparison group, the six-minute walk test results did not significantly change. Based on the study results, no statistically significant change of the quality of life occurred in any group. CONCLUSION: Integrating the WBV into the individual rehabilitation programs for patients with cystic fibrosis can improve the effort tolerance. This technique can be used both combined with the aerobic exercises, and as an alternative training method, if a patient cannot perform aerobic exercises due to the severity of his or her condition or for epidemiological indications.

Distribution of values of indicators of minimum suppressive concentrations of antibiotics in relation to gram-negative bacterial strains isolated from cystic fibrosis

Introduction. Cystic fibrosis is a severe chronic genetic disease, in which the microbiological status of the patient plays an important role, because it will determine the severity of the respiratory infection. In recent years, representatives of non-fermenting gram-negative bacteria (NFGNB) - P. aeruginosa, B. cenocepacia, Axylosoxidans; as well as representatives of the order Flavobacteriales - have become of great clinical importance in patients with cystic fibrosis. A feature of some representatives of NFGNB is the formation of resistance to antibacterial drugs, due to prolonged antimicrobial therapy. In addition to the acquired, there is a high level of natural resistance, and therefore the possibilities of using antibacterial drugs are significantly limited.Aim. To estimate the distribution of the values of the minimum suppressive concentrations (MSC) of cefepim / sulbactam, piperacillin / tazobactam, biapenem in relation to 100 strains of Gram-negative bacteria isolated from respiratory samples from patients with cystic fibrosis.Materials and methods. To date, new compounds have appeared with potential activity against the strains under consideration - cefepim / sulbactam, piperacillin / tazobactam, biapenem. We selected 100 bacterial strains isolated from respiratory samples from patients with cystic fibrosis from various regions of the Russian Federation. Among them, 69 strains are Pseudomonas aeruginosa, 6 - Achromobacter xylosoxidans, 14 - Burkholderia cenocepacia, 10 - Chryseobacterium spp., 1 - Elizabethkingia miricola. MSC values were determined for 3 antimicrobial drugs: cefepim / sulbactam, piperacillin / tazobactam, biapenem.Results and discussions. According to the data obtained, it was found that most strains of Pseudomonas aeruginosa, Achromobacter xylosoxidans have a high level of sensitivity to cefepim/sulbactam, piperacillin/tazobactam. The criteria for evaluating the MSC indicators of the studied drugs in relation to Burkholderia cenocepacia and representatives of the order Flavobacteriales have not been determined, however, it is worth noting that most isolates have demonstrated an achievable value of MSC indicators. This suggests the possibility of practical application of antimicrobial drugs under test.Conclusions. The data obtained indicate the microbiological efficacy of the drugs: cefepim/sulbactam, piperacillin/tazobactam, biapenem relative to NFGNB isolated from patients with cystic fibrosis.

Genome-based newborn screening for severe childhood genetic diseases has high positive predictive value and sensitivity in a NICU pilot trial

Large prospective clinical trials are underway or planned that examine the clinical utility and cost effectiveness of genome-based newborn screening (gNBS). One gNBS platform, BeginNGS, currently screens 53,575 variants for 412 severe childhood genetic diseases with 1,603 efficacious therapies. Retrospective evaluation of BeginNGS in 618,290 subjects suggests adequate sensitivity and positive predictive value (PPV) to proceed to prospective studies. To inform pivotal clinical trial design, we undertook a pilot clinical trial. We enrolled 120 infants in a regional neonatal intensive care unit (NICU) who were not under consideration for rapid diagnostic genome sequencing (RDGS). Each enrollee received BeginNGS and two index tests (California state NBS and RDGS). California NBS identified 4 of 4 true positive (TP) findings (TP rate 3.6%, sensitivity 100%) and 11 false positive (FP) findings (PPV 27%). RDGS identified 41 diagnostic findings in 36 neonates (diagnostic rate 30%). BeginNGS identified 5 of 6 on-target TP disorders (TP rate 4.2%, 95% confidence interval 1%-8%, sensitivity 83%) and no FPs (PPV 100%). Changes in management were anticipated following the return of 27 RDGS results in 25 enrollees (clinical utility [CU] 21%), 3 of 4 NBS TPs (CU 2.7%), and all BeginNGS TPs (CU 4.2%). The incidence of actionable genetic diseases in NICU infants not being considered for RDGS suggests (1) performance of RDGS in ∼20% of admissions misses many genetic diagnoses, (2) NICU enrollment in gNBS trials will greatly increase power to test endpoints, and (3) NICUs may be attractive for early implementation of consented BeginNGS screening.

Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection

Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P)or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.

Evaluating the Cost-Effectiveness of Etranacogene Dezaparvovec Gene Therapy for Hemophilia B Treatment in the USA.

Hemophilia B, a severe genetic disorder, involves substantial treatment costs and frequent interventions. Etranacogene dezaparvovec (EDZ) is a recently approved gene therapy for hemophilia B. This study evaluates the cost-effectiveness of EDZ compared with conventional factor IX (FIX) prophylaxis. A semi-Markov model simulated a cohort of adult males with severe hemophilia B to assess the economic impact of EDZ versus FIX prophylaxis over a lifetime horizon from a health system perspective in the USA. Inputs derived from clinical trials included therapy durability and transition probabilities based on Pettersson Scores. Scenario analyses incorporated frameworks suggested by the Institute for Clinical and Economic Review for single or short-term transformative therapies. Base-case analysis showed that at a cost of US$3.5 million, EDZ led to lifetime cost savings of US$11 million and an additional 0.64 quality-adjusted life years (QALYs) compared with FIX. However, FIX has extremely high annual costs. When annual cost offsets attributed to EDZ were capped at US$150,000, EDZ was found to have a threshold price of US$3.1 million at a willingness-to-pay of US$150,000 per QALY. EDZ proved to be a dominant strategy over FIX prophylaxis in the base-case scenario, providing large cost savings and slightly better outcomes. The substantial costs associated with FIX are a primary driver behind these results. The introduction of cost-offset caps significantly affects the value-based price of EDZ. Using caps on cost offsets in considering price can help to balance affordability and value in the health system.

Infections in sickle cell disease.

Sickle cell disease (SCD) is one of the commonest severe inherited disorders in the world. Infection accounts for a significant amount of the morbidity and mortality, particularly in sub- Saharan Africa, but is relatively poorly studied and characterized. Patients with SCD have significant immunodeficiency and are more likely to suffer severe and life-threatening complications of infection, and additionally infections can trigger complications of SCD itself. Those with more severe forms of SCD have functional asplenia from a very early age, which accounts for much of the morbidity in young children, particularly invasive infections from encapsulated bacteria including Streptococcus Pneumoniae, Haemophilus Influenzae, Salmonella Typhi and meningococcal disease. Additionally, there are other defects in immune function in SCD, associated with anemia, tissue infarction and impaired adaptive immunity. Complications of infections in SCD include acute chest syndrome (ACS), acute painful episodes, osteomyelitis, meningitis, urinary tract infections, overwhelming sepsis and death. Viral infections cause significant morbidity, particularly severe anemia associated with Parvovirus, and to a lesser extent other infections such as influenza and COVID19. The relationship between malaria and SCD is complicated and discussed in this review. Unlike many of the genetic risk factors for poor outcomes in SCD, it is theoretically possible to modify the risks associated with infections with established public health measures. These include the provision of vaccinations, prophylactic antibiotics and access to clean water and mosquito avoidance, although current financial restraints and political priorities have made this difficult.

Efficient suppression of premature termination codons with alanine by engineered chimeric pyrrolysine tRNAs.

Mutations that introduce premature termination codons (PTCs) within protein-coding genes are associated with incurable and severe genetic diseases. Many PTC-associated disorders are life-threatening and have no approved medical treatment options. Suppressor transfer RNAs (sup-tRNAs) with the capacity to translate PTCs represent a promising therapeutic strategy to treat these conditions; however, developing novel sup-tRNAs with high efficiency and specificity often requires extensive engineering and screening. Moreover, these efforts are not always successful at producing more efficient sup-tRNAs. Here we show that a pyrrolysine (Pyl) tRNA (tRNAPyl), which naturally translates the UAG stop codon, offers a favorable scaffold for developing sup-tRNAs that restore protein synthesis from PTC-containing genes. We created a series of rationally designed Pyl tRNAScaffold Suppressor-tRNAs (PASS-tRNAs) that are substrates of bacterial and human alanyl-tRNA synthetase. Using a PTC-containing fluorescent reporter gene, PASS-tRNAs restore protein synthesis to wild-type levels in bacterial cells. In human cells, PASS-tRNAs display robust and consistent PTC suppression in multiple reporter genes, including pathogenic mutations in the tumor suppressor gene BRCA1 associated with breast and ovarian cancer. Moreover, PTC suppression occurred with high codon specificity and no observed cellular dysregulation. Collectively, these results unveil a new class of sup-tRNAs with encouraging potential for tRNA-based therapeutic applications.

Advances and Challenges in Microdystrophin gene therapy for Duchenne Muscular Dystrophy: progress and future directions

Duchenne muscular dystrophy (DMD) is a severe degenerative genetic muscle disease affecting mainly young boys, characterized by a significant alteration or absence of dystrophin expression. Significant strides have been made in comprehending and treating DMD, particularly with the recent approval of the first gene therapy using a recombinant adeno-associated vector (rAAV) to deliver a shortened form of dystrophin (microdystrophin). Nevertheless, major challenges remain in improving therapeutic outcomes. The use of rAAV vectors is hindered by major limitations, notably the risks of immunotoxicity and hepatotoxicity, linked to high-dose administration. Additionally, microdystrophin exhibits inherent functional limitations and immunological risks. This article examines these challenges and explores the avenues for enhancing gene therapy for DMD.

Polysaccharide, Conjugate, and mRNA-based Vaccines are Immunogenic in Patients with Netherton Syndrome

BackgroundNetherton syndrome (NS) is a rare, severe genetic skin disorder, currently classified as an inborn error of immunity (IEI) due to previously reported immune dysregulation. We recently reported the results of an immunological evaluation showing no evidence for a relevant B- and/or T-cell mediated immunodeficiency, but immune responses after vaccination were not evaluated in that study. Therefore, we evaluated immune responses to three vaccine platforms in adult NS patients to further investigate the presence of a clinically relevant B- and/or T-cell immunodeficiency.MethodsVaccination responses in eight adult NS patients were assessed in a cross-sectional study performed between January and August 2022. Clinical patient data were retrospectively retrieved from electronic patient files. Immune responses to a polysaccharide Streptococcus pneumoniae vaccine (PPV23) and conjugate Haemophilus influenzae type b vaccine (ActHiB) were measured. SARS-CoV-2-specific (functional) antibody and T-cell responses following booster vaccination with an mRNA-based COVID-19 vaccine were compared to controls.ResultsNone of the included patients suffered from recurrent and/or severe infections that could be attributed to a B- and/or T-cell immunodeficiency. ActHiB induced immune responses were normal in 7/7 NS patients. PPV23 induced responses were absent in 1/7, diminished in 2/7, and normal in 4/7 patients. Levels of SARS-CoV-2-specific binding and neutralizing antibodies after mRNA-based COVID-19 booster vaccination in NS patients were comparable to controls. SARS-CoV-2-specific CD4 + T-cell responses were detectable in all NS patients. In contrast, SARS-CoV-2-specific CD8 + T-cell responses were detectable in only 2/6 NS patients. T-cell responses to a positive control antigen pool were comparable to controls.ConclusionsVaccine-induced immune responses were detectable after polysaccharide, conjugate and mRNA-based vaccination in our cohort of NS patients. A spectrum of responsiveness to vaccine challenges was found, with the ranges of vaccine responses overlapping those demonstrated in healthy control populations.

Health-related quality of life and associated factors among children with Transfusion-dependent β-thalassaemia: a cross-sectional study in Guangxi Province

BackgroundTransfusion-dependent β-thalassemia (TDT) is a severe inherited disorder. Without regular treatment, patients with TDT experience complications that can significantly shorten life expectancy and severely impact both their quality of life and that of their families. The condition has attracted significant attention in global health discussions. Due to the challenges of blood supply shortages, the high costs of iron chelation therapy, and hematopoietic stem cell transplantation (HSCT), TDT presents a serious health risk to patients and imposes a substantial burden on families and society. However, research on the health-related quality of life (HRQoL) of thalassemia patients in China remains limited. This study evaluated the factors affecting the HRQoL of these patients, with the goal of developing strategies to improve their quality of life.MethodsIn this cross-sectional study, children with TDT were recruited from five treatment centers in Guangxi, a province with a high prevalence of thalassemia in China. Structured questionnaires were employed to gather relevant data on sociodemographic variables, disease characteristics, treatments, and associated costs. The HRQoL was assessed using the Transfusion-Dependent Quality of Life (TranQoL) questionnaire, with a proxy version for patients aged 0–11 years and a child version for those aged 12–18 years.ResultsThe study included 418 participants, yielding an overall TranQoL score of 60.6 ± 16.3 among thalassemia patients. Multiple linear regression analysis revealed a negative correlation (P < 0.05) between overall TranQoL scores and several factors: increasing patient age, the presence of multiple thalassemia patients within a family, and undergoing HSCT. Conversely, adherence to regular treatment was positively correlated with higher TranQoL scores (P < 0.05).ConclusionThe study demonstrates that HRQoL among Chinese patients with TDT is at a low level. Age, treatment adherence, family support, and socioeconomic status were identified as key determinants influencing HRQoL. It is essential to further enhance and optimize health insurance policies and medical services to support comprehensive treatment strategies for these patients.

Unveiling homozygous familial hypercholesterolemia in Greece: a comprehensive analysis of baseline traits and LDL goal achievement in adults from the HELLAS-FH Registry

Abstract Background Homozygous familial hypercholesterolemia (HoFH) is a severe genetic disorder characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels. This study aimed to analyze demographic characteristics, lipid profile, and rate in achieving LDL-C targets in adult HoFH patients in Greece. Methods This is a cross-sectional analysis of the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH). Adults with genetically or clinically diagnosed HoFH were included. Median LDL-C levels were assessed during HoFH diagnosis and enrollment. Results Seventeen HoFH adults (mean age 41 years and mean age at diagnosis 31 years, men 58.8%). Genetic confirmation of HoFH was available in 10 patients, while the remaining were diagnosed based on clinical criteria. Family history of atherosclerotic cardiovascular disease was documented in 70.5% of patients. Clinical presentations varied, with 47.0% exhibiting tendon xanthomas, 17.6% xanthelasmas, 23.5% corneal arcus, and 52.9% premature coronary artery disease (CAD). Predominant treatment involved statins (88.2%), ezetimibe (58.8%),PCSK9i (23.5%), lomitapide (29.4%), while LDL apheresis was utilized in 23.5%. Median LDL-C levels were 407 mg/dL (10.53 mmol/L) at diagnosis and 226 mg/dL (5.84 mmol/L) at enrollment. None of the patients achieved the LDL-C target set by the 2019 EAS/ESC Guidelines. Conclusion The challenges of delayed diagnosis, undertreatment, and unattained LDL-C targets persist in HoFH management in Greece, emphasizing the critical need for effective lipid-lowering interventions to mitigate cardiovascular risk.

Regulation of HTT mRNA Biogenesis: The Norm and Pathology.

Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the HTT gene, leading to the formation of a toxic variant of the huntingtin protein. It is a rare but severe hereditary disease for which no effective treatment method has been found yet. The primary therapeutic targets include the mutant protein and the mutant mRNA of HTT. Current clinical trial approaches in gene therapy involve the application of splice modulation, siRNA, or antisense oligonucleotides for RNA-targeted knockdown of HTT. However, these approaches do not take into account the diversity of HTT transcript isoforms in the normal conditions and in HD. In this review, we discuss the features of transcriptional regulation and processing that lead to the formation of various HTT mRNA variants, each of which may uniquely contribute to the progression of the disease. Furthermore, understanding the role of known transcription factors of HTT in pathology may aid in the development of potentially new therapeutic tools based on endogenous regulators.