Genes (Basel). 2024 May 31;15(6):715. doi: 10.3390/genes15060715.

ABSTRACT

Genetic counseling and treatment options for rare developmental disabilities (DDs) have been revolutionized by the opportunities made possible by using massively parallel sequencing for diagnostic purposes [...].

PMID:38927651 | DOI:10.3390/genes15060715

Biomedicines. 2024 May 24;12(6):1162. doi: 10.3390/biomedicines12061162.

ABSTRACT

Spinal muscular atrophy (SMA) is an orphan disease characterized by the progressive degeneration of spinal alpha motor neurons. In recent years, nusinersen and several other drugs have been approved for the treatment of this disease. Transcutaneous spinal cord stimulation (tSCS) modulates spinal neuronal networks, resulting in changes in locomotion and posture in patients with severe spinal cord injury and stroke. We hypothesize that tSCS can activate motor neurons that are intact and restored by medication, slow the decline in motor activity, and contribute to the development of motor skills in SMA patients. Thirty-seven children and adults with SMA types 2 and 3 participated in this study. The median duration of drug treatment was over 20 months. The application of tSCS was performed during physical therapy for 20-40 min per day for ~12 days. Outcome measures were specific SMA motor scales, goniometry of contractured joints, and forced vital capacity. Significant increases in motor function, improved respiratory function, and decreased contracture were observed in both type 2 and 3 SMA participants. The magnitude of functional changes was not associated with participant age. Further studies are needed to elucidate the reasons for the beneficial effects of spinal cord electrical stimulation on SMA.

PMID:38927369 | DOI:10.3390/biomedicines12061162

Biomedicines. 2024 May 23;12(6):1157. doi: 10.3390/biomedicines12061157.

ABSTRACT

Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin, also known as SBP-101, has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in early pancreatic cancer clinical trials. We sought to determine if ivospemin was a viable treatment option for the under-served platinum-resistant ovarian cancer patient population by testing its efficacy in combination with commonly used chemotherapeutics. We treated four ovarian adenocarcinoma cell lines in vitro and found that each was sensitive to ivospemin regardless of cisplatin sensitivity. Next, we treated patients with ivospemin in combination with four commonly used chemotherapeutics and found that ivospemin increased the toxicity of each; however, only gemcitabine and topotecan combination treatments were more effective than ivospemin alone. Using the VDID8+ murine ovarian cancer model, we found that the addition of ivospemin to either topotecan or gemcitabine increased median survival over untreated animals alone, delayed tumor progression, and decreased the overall tumor burden. Our results indicate that the combination of ivospemin and chemotherapy is a worthwhile treatment option to further explore clinically in ovarian cancer.

PMID:38927364 | DOI:10.3390/biomedicines12061157

Biochim Biophys Acta Mol Basis Dis. 2024 Jun 24:167325. doi: 10.1016/j.bbadis.2024.167325. Online ahead of print.

ABSTRACT

The mechanism(s) underlying obesity-related postmenopausal (PM) breast cancer (BC) are not clearly understood. We hypothesized that the increased local presence of 'obese' mammary adipocytes within the BC microenvironment promotes the acquisition of an invasive and angiogenic BC cell phenotype and accelerates tumor proliferation and progression. BC cells, treated with primary mammary adipocyte secretome from premenopausal (Pre-M) and PM obese women (ObAdCM; obese adipocyte conditioned-media) upregulated the expression of several pro-tumorigenic factors including VEGF, lipocalin-2 and IL-6. Both Pre-M and PM ObAdCM stimulated endothelial cell recruitment and proliferation and significantly stimulated BC cell proliferation, migration and invasion. IL-6 and LCN2 induced STAT3/Akt signaling in BC cells and STAT3 inhibition abrogated the ObAdCM-stimulated BC cell proliferation and migration. Expression of proangiogenic regulators including VEGF, NRP1, NRP2, IL8RB, TGFβ2, and TSP-1 were found to be differentially regulated in mammary adipocytes from obese PM women. Comparative RNAseq indicated an upregulation of PI3K/Akt signaling, ECM-receptor interactions and lipid/fatty acid metabolism in PM versus Pre-M mammary adipocytes. Our results demonstrate that irrespective of menopausal status, cross-talk between obese mammary adipocytes and BC cells promotes tumor aggressiveness and suggest that targeting the LCN2/IL-6/STAT3 signaling axis may be a useful strategy in obesity-driven breast tumorigenesis.

PMID:38925485 | DOI:10.1016/j.bbadis.2024.167325

Child Care Health Dev. 2024 Jul;50(4):e13294. doi: 10.1111/cch.13294.

ABSTRACT

BACKGROUND: Rare diseases encompass a diverse group of debilitating and sometimes life-threatening conditions that affect a small percentage of the population, posing a significant public health challenge. Despite their rarity, around 70% of these diseases afflict children, yet limited research has focused on their experiences. This study aimed to gain insights into the day-to-day challenges children living with rare diseases face.

METHODS: We conducted semistructured one-to-one interviews with 11 children and young people (7-16 years) diagnosed with a range of rare diseases, purposively sampled from a tertiary pediatric healthcare setting in Ireland. We analyzed the interview transcripts, and themes were devised inductively.

RESULTS: Two themes were identified: "Knowledge and Understanding of Rare Diseases" and "Fitting in Versus Feeling Different." These themes emerged across various settings-the home, hospital, school, and social environments-to illustrate the impact of rare diseases on the participants' daily lives. A conceptual framework was developed to illustrate how the children's knowledge, experiences, and emotions shape their identity in a rare disease context.

CONCLUSIONS: Our analysis revealed a complex interplay between the participants' sense of belonging and their awareness of being different, influenced by the manifestations and demands of their rare conditions or illnesses. This duality in their identity was most pronounced in social settings, where the participants felt the most significant impact of their rare diseases. Understanding this interplay sheds light on the unique social challenges children with rare medical conditions face. Raising awareness about these conditions could mitigate these children's social challenges, fostering a more inclusive society for those with rare diseases.

PMID:38924454 | DOI:10.1111/cch.13294

Dis Model Mech. 2024 Jun 1;17(6):dmm050715. doi: 10.1242/dmm.050715. Epub 2024 Jun 26.

ABSTRACT

Founder mutations are disease-causing variants that occur frequently in geographically or culturally isolated groups whose shared ancestor(s) carried the pathogenic variant. While some disease alleles may vanish from the genetic pool due to natural selection, variants with weaker effects may survive for a long time, thereby enhancing the prevalence of some rare diseases. These are predominantly autosomal recessive diseases but can also be autosomal dominant traits with late-onset or mild phenotypes. Cultural practices, such as endogamy and consanguinity, in these isolated groups lead to higher prevalence of such rare diseases compared to the rest of the population and worldwide. In this Perspective, we define population isolates and the underlying genetic mechanisms for accumulating founder mutations. We also discuss the current and potential scientific, clinical and public-health implications of studying founder mutations in population isolates around the world, with a particular focus on the Arab population.

PMID:38922202 | DOI:10.1242/dmm.050715

Ann Ist Super Sanita. 2024 Jan-Mar;60(1):29-36. doi: 10.4415/ANN_24_01_05.

ABSTRACT

Originally established to evaluate the ethical aspects of clinical trials, Ethics Committees (ECs) are now requested to review different types of projects, including, among others, observational studies and disease registries. In Italy, clinical trials on medicinal products for human use and on medical devices are regulated by EU Regulation 536/2014, EU Regulation 2017/745, and 2017/746 while pharmacological observational studies are regulated by the Italian Medicines Agency guidelines of 2008 and by Ministerial Decree of November 30th, 2021. The other types of studies are not strictly regulated, causing discrepancies in their definition and assessment by the ECs, and slowdowns in the start of projects. The present contribution aims to propose definitions and distinctions between non-pharmacological observational studies and disease registries, which constitute different entities but are often assimilated by ECs, and to formulate suggestions for the evaluation of rare disease registries, which are an expanding research area of interest.

PMID:38920256 | DOI:10.4415/ANN_24_01_05

Ann Acad Med Singap. 2023 Nov 29;52(11):625-634. doi: 10.47102/annals-acadmedsg.202323.

ABSTRACT

INTRODUCTION: Rare paediatric eye diseases (RPEDs) threaten both vision and life. Recently, rare diseases were recognised as a global public health agenda, with children specified as a priority in the World Health Organization's VISION 2020 against avoidable visual loss.

METHOD: We conducted a review through a query of online databases (PubMed, Embase and Cochrane Library). Articles related to RPEDs were selected based on relevance by 2 authors, with any disagreements adjudicated by the third author.

RESULTS: We synthesise the current state of knowledge regarding RPEDs, barriers to their care, and recommendations for the future. RPEDs often result in significant visual loss, profoundly impacting the way children comprehend and participate in the world. These diseases may also reduce life expectancy and even be life-threatening. Barriers to the care of RPEDs include an unclear definition of "rare diseases", missed or delayed diagnosis, inadequate knowledge and expertise in management, and challenging research environments.

CONCLUSION: Our findings provide an update on the diagnosis and management of RPEDs, which is of relevance to ophthalmologists, paediatricians, healthcare policymakers and social workers. We propose supportive policies and adequate resource allocation to these diseases, comprehensive and patient-centred care, alongside improved education and training, enhanced research capabilities and continued collaboration across institutions.

PMID:38920150 | DOI:10.47102/annals-acadmedsg.202323

Nat Rev Drug Discov. 2024 Aug;23(8):574-576. doi: 10.1038/d41573-024-00109-0.

NO ABSTRACT

PMID:38918582 | DOI:10.1038/d41573-024-00109-0

Eur J Paediatr Neurol. 2024 Jul;51:110-117. doi: 10.1016/j.ejpn.2024.06.007. Epub 2024 Jun 19.

ABSTRACT

BACKGROUND: NKX2-1-related disorder (NKX2-1-RD) is a rare disease characterized by a triad of primary hypothyroidism, neonatal respiratory distress, and neurological features, including chorea.

OBJECTIVE: This study aimed to identify discrepancies in the management of NKX2-1-RD among European Union (EU) specialists.

METHODS: The ERN-RND Chorea & Huntington disease group designed a survey to conduct a cross-sectional multicenter study on the management of NKX2-1-RD. Descriptive analysis was performed, and total responses are presented for each item.

RESULTS: The study involved 23 experts from 13 EU countries with experience in evaluating hyperkinetic patients with NKX2-1-RD: 11 were adult specialists, and 12 were pediatric specialists. NKX2-1-RD diagnosis was made at different ages, with the most common initial symptoms being hypotonia and/or motor developmental delay (reported by 11 experts) and chorea (reported by 8 experts). Chorea involved various body parts and showed improvement as reported by 9 experts, stabilization by 12 experts, and worsening by 2 experts with age. The pharmacological treatment of chorea varied widely among the experts. Misdiagnosis was reported by 14 experts. NKX2-1 pathogenic variants or deletions were confirmed in >75 % of patients (reported by 12 experts). Pulmonary and endocrinology evaluations were requested by 7 and 12 experts, respectively. The management of psychiatric comorbidities also varied among the different experts.

CONCLUSIONS: This study highlights the need for a clinical practice guideline for the management of NKX2-1-RD to ensure that patients across the EU receive consistent and appropriate care. Such a guideline would benefit both doctors and healthcare practitioners.

PMID:38917695 | DOI:10.1016/j.ejpn.2024.06.007

Med. 2024 Jun 14:S2666-6340(24)00222-8. doi: 10.1016/j.medj.2024.05.018. Online ahead of print.

ABSTRACT

BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome based on the results of the phase 3, randomized, placebo-controlled, 12-week LAVENDER study. Rett syndrome is a chronic disorder requiring long-term treatment. We report the efficacy and safety results of LILAC, a 40-week, open-label extension study of LAVENDER.

METHODS: Females with Rett syndrome aged 5-21 years received open-label treatment with trofinetide for 40 weeks. The primary endpoint was long-term safety of trofinetide; secondary endpoints included the change from baseline at week 40 in the Rett Syndrome Behaviour Questionnaire score and the Clinical Global Impression-Improvement score at week 40.

FINDINGS: Overall, 154 participants were enrolled and treated with trofinetide in LILAC. The most common adverse events in LILAC were diarrhea (74.7%), vomiting (28.6%), and COVID-19 (11.0%). Diarrhea was the most common adverse event leading to treatment withdrawal (21.4%). The Rett Syndrome Behaviour Questionnaire mean score (standard error) improvement from the LAVENDER baseline to week 40 in LILAC was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean Clinical Global Impression-Improvement scores (standard error) at week 40 rated from the LILAC baseline were 3.1 (0.11) and 3.2 (0.14) for participants treated with trofinetide and placebo in LAVENDER, respectively.

CONCLUSIONS: Treatment with trofinetide for ≤40 weeks continued to improve symptoms of Rett syndrome. Trofinetide had a similar safety profile in LILAC as in LAVENDER.

FUNDING: The study was supported by Acadia Pharmaceuticals Inc. (San Diego, CA, USA). This trial was registered at ClinicalTrials.gov (NCT04279314).

PMID:38917793 | DOI:10.1016/j.medj.2024.05.018

Lab Anim (NY). 2024 Jul;53(7):161-165. doi: 10.1038/s41684-024-01395-2.

NO ABSTRACT

PMID:38914824 | DOI:10.1038/s41684-024-01395-2

Ital J Pediatr. 2024 Jun 24;50(1):121. doi: 10.1186/s13052-024-01691-0.

ABSTRACT

BACKGROUND: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterized by imperforate anus, dysplastic ears, thumb malformations, and other abnormalities. Previous studies have revealed that mutations in the SALL1 gene can disrupt normal development, resulting in the characteristic features of Townes-Brocks syndrome. Spalt-like transcription factors (SALLs) are highly conserved proteins that play important roles in various cellular processes, including embryonic development, cell differentiation, and cell survival. Over 400 different variants or mutations have been reported in the SALL1 gene in individuals with TBS. Most of these variants lead to the formation of premature termination codons (PTCs), also known as nonsense mutations. The majority of these PTCs occur in a specific region of the SALL1 gene called the "hotspot region", which is particularly susceptible to mutation.

METHODS: In this study, we conducted whole-exome sequencing on a three-generation Chinese family with anorectal malformations.

RESULTS: We identified a novel heterozygous mutation (chr16:51175376:c.757 C > T p.Gln253*) in the SALL1 gene. Molecular analysis revealed a heterozygous C to T transition at nucleotide position 757 in exon 2 of the SALL1 (NM_002968) gene. This mutation is predicted to result in the substitution of the Gln253 codon with a premature stop codon (p.Gln253*). The glutamine-rich domain forms a long alpha helix, enabling the mutant protein to interact with the wild-type SALL1 protein. This interaction may result in steric hindrance effects on the wild-type SALL1 protein.

CONCLUSIONS: Our findings have expanded the mutation database of the SALL1 gene, which is significant for genetic counseling and clinical surveillance in the affected family. Furthermore, our study enhances the understanding of Townes-Brocks syndrome and has the potential to improve its diagnosis and treatment.

PMID:38915054 | DOI:10.1186/s13052-024-01691-0

Dev Med Child Neurol. 2024 Aug;66(8):e163. doi: 10.1111/dmcn.16008. Epub 2024 Jun 19.

NO ABSTRACT

PMID:38898751 | DOI:10.1111/dmcn.16008

Br J Gen Pract. 2024 Jun 20;74(suppl 1):bjgp24X738105. doi: 10.3399/bjgp24X738105.

ABSTRACT

BACKGROUND: Rare diseases affect millions of people globally, with a lifetime incidence of 1 in 17. They are complex, multisystem, severe disease, and patients experience a diagnostic delay averaging 5.6 years with associated misdiagnoses, inappropriate treatments, and anxiety. MendelScan is a digital case-finding tool that uses structured primary care data to identify patients at risk of being affected by one of a series of rare diseases. This qualitative study explored primary healthcare professionals' experiences of implementing this technology.

AIM: To develop an understanding of primary healthcare professionals' experiences of implementing MendelScan with a focus on their perception of the technology and its implementation, challenges and opportunities.

METHOD: A qualitative appraisal of implementing MendelScan using descriptive analysis of surveys and semi-structured interviews with professionals.

RESULTS: A total of 11 professionals from the two project areas participated. Participants included GPs, nurses, a genetic counsellor, and healthcare managers.Participants reported that they received adequate support, the project increased confidence in integrating genetics in primary care, and that it may improve inequity in rare disease diagnosis. Professionals' reservations were related to knowledge, time commitments, primary care pressures, contacting patients, data sharing and confidentiality, and overcoming clinical resistance in sharing data with a non-NHS external body.

CONCLUSION: This study provides a valuable insight into the experiences of primary care professionals using a novel tool to identify rare diseases. The potential of this tool is promising with benefits for skill development. Large-scale implementation faces challenges related to primary care capacity, data, and funding.

PMID:38902040 | DOI:10.3399/bjgp24X738105

Nat Med. 2024 Jul;30(7):1823-1825. doi: 10.1038/s41591-024-03055-x.

NO ABSTRACT

PMID:38898121 | DOI:10.1038/s41591-024-03055-x

Dig Dis Sci. 2024 Jun 19. doi: 10.1007/s10620-024-08497-4. Online ahead of print.

ABSTRACT

Decision-making in clinical medicine ideally is based upon evidence from randomized, placebo-controlled trials (RCTs) and subsequent systematic reviews and meta-analyses. However, for orphan diseases, the expectation of having one or multiple RCTs that inform clinical guidelines or justify specific treatments can be unrealistic and subsequent therapeutic nihilism can be detrimental to patients. This article discusses the benefits of therapeutic decision-making in the context of orphan diseases, focusing on primary sclerosing cholangitis (PSC) as an example of an orphan disease with poor clinical outcomes. PSC is a rare disorder characterized by inflammation and progressive fibrosis of the bile ducts. It carries a high risk of liver failure, malignancies, and debilitating symptoms that impair quality of life. Liver transplantation is currently the only life-prolonging intervention for PSC, but it is not a curative option. The article highlights the potential benefits of treating PSC patients with oral vancomycin (OV), which has shown significant clinical responses and improved quality of life in some cases. However, access to OV therapy is limited due to the lack of RCTs supporting its use. The standard requirement of having evidence from RCTs may result in withholding potentially life-altering and/or life-saving treatments for patients with orphan diseases. Conducting RCTs is challenging in these patient populations due to difficulties in recruiting the required patient cohorts and limited commercial returns. A standardized 'adaptive treatment strategy' is proposed to address this. This approach leverages the best available evidence for specific treatments, considers individual clinical responses, and adjusts treatment over time.

PMID:38896361 | DOI:10.1007/s10620-024-08497-4

Sensors (Basel). 2024 Jun 3;24(11):3613. doi: 10.3390/s24113613.

ABSTRACT

The interpretability of gait analysis studies in people with rare diseases, such as those with primary hereditary cerebellar ataxia (pwCA), is frequently limited by the small sample sizes and unbalanced datasets. The purpose of this study was to assess the effectiveness of data balancing and generative artificial intelligence (AI) algorithms in generating synthetic data reflecting the actual gait abnormalities of pwCA. Gait data of 30 pwCA (age: 51.6 ± 12.2 years; 13 females, 17 males) and 100 healthy subjects (age: 57.1 ± 10.4; 60 females, 40 males) were collected at the lumbar level with an inertial measurement unit. Subsampling, oversampling, synthetic minority oversampling, generative adversarial networks, and conditional tabular generative adversarial networks (ctGAN) were applied to generate datasets to be input to a random forest classifier. Consistency and explainability metrics were also calculated to assess the coherence of the generated dataset with known gait abnormalities of pwCA. ctGAN significantly improved the classification performance compared with the original dataset and traditional data augmentation methods. ctGAN are effective methods for balancing tabular datasets from populations with rare diseases, owing to their ability to improve diagnostic models with consistent explainability.

PMID:38894404 | DOI:10.3390/s24113613

Sensors (Basel). 2024 May 22;24(11):3294. doi: 10.3390/s24113294.

ABSTRACT

Cerebrospinal fluid (CSF) is a body fluid that can be used for the diagnosis of various diseases. However, CSF collection requires an invasive and painful procedure called a lumbar puncture (LP). This procedure is applied to any patient with a known risk of central nervous system (CNS) damage or neurodegenerative disease, regardless of their age range. Hence, this can be a very painful procedure, especially in infants and elderly patients. On the other hand, the detection of disease biomarkers in CSF makes diagnoses as accurate as possible. This review aims to explore novel electrochemical biosensing platforms that have impacted biomedical science. Biosensors have emerged as techniques to accelerate the detection of known biomarkers in body fluids such as CSF. Biosensors can be designed and modified in various ways and shapes according to their ultimate applications to detect and quantify biomarkers of interest. This process can also significantly influence the detection and diagnosis of CSF. Hence, it is important to understand the role of this technology in the rapidly progressing field of biomedical science.

PMID:38894085 | DOI:10.3390/s24113294

Cells. 2024 May 29;13(11):934. doi: 10.3390/cells13110934.

ABSTRACT

Sickle cell disease is an orphan disease affecting ethnic minorities and characterized by profound systemic manifestations. Although around 100,000 individuals with SCD are living in the US, the exact number of individuals is unknown, and it is considered an orphan disease. This single-gene disorder leads to red blood cell sickling and the deoxygenation of hemoglobin, resulting in hemolysis. SCD is associated with acute complications such as vaso-occlusive crisis, infections, and chronic target organ complications such as pulmonary disease and renal failure. While genetic therapy holds promise to alter the fundamental disease process, the major challenge in the field remains the target end organ damage and ways to mitigate or reverse it. Here, we provide an overview of the clinical manifestations and pathogenesis with a focus on end-organ damage and current therapeutic options, including recent FDA-approved stem cell and gene editing therapies.

PMID:38891066 | DOI:10.3390/cells13110934