bioRxiv. 2023 Oct 20:2023.10.18.562924. doi: 10.1101/2023.10.18.562924. Preprint.

ABSTRACT

Inherited retinal diseases (IRDs) encompass a genetically diverse group of conditions in which mutations in genes critical to retinal function lead to progressive loss of photoreceptor cells and subsequent visual impairment. A handful of ribosome-associated genes have been implicated in retinal disorders alongside neurological phenotypes. This study focuses on the HBS1L gene, encoding HBS1 Like Translational GTPase which has been recognized as a critical ribosomal rescue factor. Previously, we have reported a female child carrying biallelic HBS1L mutations, manifesting growth restriction, developmental delay, and hypotonia. In this study, we describe her ophthalmologic findings, compare them with the Hbs1ltm1a/tm1a hypomorph mouse model, and evaluate the underlying microscopic and molecular perturbations. The patient was noted to have impaired visual function observed by electroretinogram (ERG), with dampened amplitudes of a- and b-waves in both rod- and cone-mediated responses. Hbs1ltm1a/tm1a mice exhibited profound retinal thinning of the entire retina, specifically of the outer retinal photoreceptor layer, detected using in vivo imaging of optical coherence tomography (OCT) and retinal cross sections. TUNEL assay revealed retinal degeneration due to extensive photoreceptor cell apoptosis. Loss of HBS1L resulted in comprehensive proteomic alterations in mass spectrometry analysis, with169 proteins increased and 480 proteins decreased including many critical IRD-related proteins. GO biological process and GSEA analyses reveal that these downregulated proteins are primarily involved in photoreceptor cell development, cilium assembly, phototransduction, and aerobic respiration. Furthermore, apart from the diminished level of PELO, a known partner protein, HBS1L depletion was accompanied by reduction in translation machinery associated 7 homolog (Tma7), and Endothelial differentiation-related factor 1(Edf1) proteins, the latter of which coordinates cellular responses to ribosome collisions. This novel connection between HBS1L and ribosome collision sensor (EDF1) further highlights the intricate mechanisms underpinning ribosomal rescue and quality control that are essential to maintain homeostasis of key proteins of retinal health, such as rhodopsin.

PMID:37905068 | PMC:PMC10614867 | DOI:10.1101/2023.10.18.562924

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Nov 10;40(11):1382-1386. doi: 10.3760/cma.j.cn511374-20220120-00048.

ABSTRACT

OBJECTIVE: To summarize the clinical features and biological characteristics of Helsmoortel Van der Aa syndrome (HVDAS) due to hotspot mutations of the ADNP gene in order to facilitate early diagnosis.

METHODS: Clinical data and result of genetic testing for a girl with HVDAS due to hotspot mutation of the ADNP gene was summarized. Related literature was also reviewed.

RESULTS: The patient, a 2-year-old girl, had presented with growth retardation, facial dysmorphism, psychomotor and language delay and recurrent respiratory infections. Whole exome sequencing revealed that she has harbored a heterozygous c.2496_2499delTAAA (p.Asn832Lysfs*81) variant of the ADNP gene, which was not found in either of her parents.

CONCLUSION: Although the typical features of the HVDAS have included intellectual disability and autism spectrum disorders, growth retardation and premature primary tooth eruption may also be present. In addition, the phenotypic difference among individuals carrying hot spot variants of the ADNP gene was not prominent.

PMID:37906146 | DOI:10.3760/cma.j.cn511374-20220120-00048

JMIR Public Health Surveill. 2023 Oct 31;9:e50147. doi: 10.2196/50147.

ABSTRACT

BACKGROUND: Rare diseases (RDs) affect millions of people worldwide, and these diseases can severely impact the health-related quality of life (HRQoL) of those affected. Despite this, there is a lack of research measuring HRQoL using the EQ-5D-5L, which is one of the most widely used generic preference-based instruments to measure HRQoL in populations living with RDs.

OBJECTIVE: This study aimed to measure HRQoL using the EQ-5D-5L in a large number of patients with various types of RDs in China, and to examine the relationship between respondents' socioeconomic characteristics and preference-based health utility scores.

METHODS: The data used in this study were obtained from a web-based survey conducted in China. The survey aimed to explore and understand the health and socioeconomic status of patients with RDs in China. We recruited registered and eligible members, including patients or their primary caregivers, from 33 RD patient associations to complete the questionnaires via their internal social networks. HRQoL was measured using the EQ-5D-5L utility score, which was calculated based on an established Chinese value set. Utility scores have been presented based on demographics and disease-related information. Univariate linear regression analysis was used to assess the differences in the EQ-5D-5L utility scores between subgroups.

RESULTS: A total of 12,502 respondents completed the questionnaire and provided valid responses, including 6919 self-completed respondents and 5583 proxy-completed respondents. Data from 10,102 participants over the age of 12 years were elicited for analysis. Among patients with RDs, 65.3% (6599/10,102), 47.5% (4799/10,102), 47.0% (4746/10,102), 24.8% (2506/10,102), and 18.4% (1855/10,102) reported no problems for "self-care," "usual activities," "mobility," "pain/discomfort," and "anxiety/depression," respectively. A full health state was reported by 6.0% (413/6902) and 9.2% (295/3200) of self- and proxy-completed patients, respectively. Among self-completed patients, 69.9% (4826/6902) and 50.4% (3478/6902) reported no problems for "self-care" and "usual activities," respectively, whereas only 17.7% (1223/6902) reported problems for "anxiety/depression." Proxy-completed respondents showed a higher proportion of reporting extreme problems than self-completed respondents in all 5 dimensions. The mean utility scores reported by self- and proxy-completed respondents were 0.691 and 0.590, respectively. Different types of caregivers reported different utility scores, and among them, proxy-completed (mother) respondents reported the highest mean utility score.

CONCLUSIONS: The establishment of a normative profile for RD patients can facilitate patients' adaptation and assess the effectiveness of interventions to improve the HRQoL and well-being of this population. Differences between self- and proxy-completed HRQoL assessed by the EQ-5D-5L have been identified in this study. This finding highlights the importance of incorporating perspectives from both patients and their proxies in clinical practice. Further development of the patient cohort is necessary to assess long-term changes in HRQoL in the RD population.

PMID:37906229 | DOI:10.2196/50147

Medicina (Kaunas). 2023 Oct 4;59(10):1770. doi: 10.3390/medicina59101770.

ABSTRACT

Gastritis cystica profunda (GCP) has been defined as a rare submucosal benign gastric lesion with cystic gland growth. Due to its unclear etiopathogenesis, this lesion is often misdiagnosed and mistaken for other gastric masses. Currently, a standardized treatment for GCP lesions is still missing. Here, we illustrate a case of a patient admitted to our general surgery department for melena and general discomfort. No history of peptic ulcer or gastric surgery was present. Upper GI endoscopy was performed, showing a distal gastric lesion with a small ulceration on the top. CT-scan and endoscopic ultrasound confirmed the presence of the lesion, compatible with a gastric stromal tumor, without showing any eventual metastasis. Surgical gastric resection was performed. Histological findings were diagnostic for GCP, with cistically ectasic submucosal glands, chronic inflammation, eosinophilic infiltration and foveal hyperplasia. GCP is a very exceptional cause of upper-GI bleeding with specific histological features. Its diagnosis as well as its therapy are challenging, resulting in several pitfalls. Even though it is a rare entity, GCP should always be considered in the differential diagnosis of gastric submucosal lesions.

PMID:37893488 | DOI:10.3390/medicina59101770

Biomolecules. 2023 Sep 25;13(10):1441. doi: 10.3390/biom13101441.

ABSTRACT

Recent technical breakthroughs in genotyping and bioinformatics techniques have greatly facilitated the translation of genomics into clinical care [...].

PMID:37892123 | PMC:PMC10604584 | DOI:10.3390/biom13101441

Healthc Pap. 2023 Jul;21(3):70-71. doi: 10.12927/hcpap.2023.27198.

ABSTRACT

Rawson and Adams (2023) are certainly entitled to express their views about the lead and response articles by Sirrs et al. (2023a; 2023b). Their entitlement comes with a responsibility to accurately and comprehensively state their conflicts of interest (COI) so that readers can assess whether their arguments may be influenced by other interests.

PMID:37887173 | DOI:10.12927/hcpap.2023.27198

S Afr Med J. 2023 Aug 3;113(8):8. doi: 10.7196/SAMJ.2023.v113i8.1142.

NO ABSTRACT

PMID:37882112 | DOI:10.7196/SAMJ.2023.v113i8.1142

BMC Health Serv Res. 2023 Oct 25;23(1):1153. doi: 10.1186/s12913-023-10155-w.

ABSTRACT

We developed an algorithm to explore unexpected growth in the usage and costs of health technologies. We exploit data from the expenditures on technologies funded by the Colombian government under the compulsory insurance system, where all prescriptions for technologies not included in an explicit list must be registered in a centralized information system, covering the period from 2017 to 2022. The algorithm consists of two steps: an outlier detection method based on the density of the expenditures for selecting a first set of technologies to consider (39 technologies out of 106,957), and two anomaly detection models for time series to determine which insurance companies, health providers, and regions have the most notorious increases. We have found that most medicines associated with atypical behavior and significant monetary growth could be linked to the use of recently introduced drugs in the market. These drugs have valid patents and very specific clinical indications, often involving high-cost pharmacological treatments. The most relevant case is the Burosumab, approved in 2018 to treat a rare genetic disorder affecting skeletal growth. Secondly, there is clear evidence of anomalous increasing trend evolutions in the identified enteral nutritional support supplements or Food for Special Medical Purposes. The health system did not purchase these products before July 2021, but in 2022 they represented more than 500,000 USD per month.

PMID:37880691 | PMC:PMC10601102 | DOI:10.1186/s12913-023-10155-w

medRxiv. 2023 Oct 5:2023.10.05.23296595. doi: 10.1101/2023.10.05.23296595. Preprint.

ABSTRACT

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and with new innovative methods can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the GREGoR consortium. Each family's CNV data was analyzed using the seqr platform and candidate CNVs classified using the 2020 ACMG/ClinGen CNV interpretation standards. We developed additional evidence criteria to address situations not covered by the current standards. The addition of CNV calling to exome analysis identified causal CNVs for 173 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb with estimates that 44% would not have been detected by standard chromosomal microarrays. The causal CNVs consisted of 141 deletions, 15 duplications, 4 suspected complex structural variants (SVs), 3 insertions and 10 complex SVs, the latter two groups being identified by orthogonal validation methods. We interpreted 153 CNVs as likely pathogenic/pathogenic and 20 CNVs as high interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

PMID:37873196 | PMC:PMC10593084 | DOI:10.1101/2023.10.05.23296595

Nat Rev Drug Discov. 2023 Dec;22(12):937-938. doi: 10.1038/d41573-023-00168-9.

NO ABSTRACT

PMID:37872324 | DOI:10.1038/d41573-023-00168-9

Soc Sci Med. 2023 Dec;338:116332. doi: 10.1016/j.socscimed.2023.116332. Epub 2023 Oct 17.

ABSTRACT

Patient organisations play an increasingly crucial role in the pharmaceutical sector, yet their impact on innovation remains unexplored. We estimate the impact of patient organisations on R&D activity in the context of rare diseases in Europe using a proprietary dataset that maps clinical trials from discovery to phase III across 29 countries, 1893 indications, and 30 years (1990-2019). By applying difference-in-differences and event study methodologies to a panel of 1,646,910 unique R&D observations, we find that country-indication pairs with at least one operating patient organisation have a higher rate of R&D activity compared to those without, with stronger effect in more prevalent rare diseases compared to ultra-rare conditions. We observe a lag in effects from patient organisation introduction, suggesting it takes approximately five years for these organisations to affect R&D activity. Overall, our work suggests that patient organisations play an important role in steering R&D efforts in rare diseases. Further research is needed to better understand mechanisms driving this effect and the potential impact of patient organisations on existing health inequities.

PMID:37866173 | DOI:10.1016/j.socscimed.2023.116332

Reumatol Clin (Engl Ed). 2023 Nov;19(9):527-529. doi: 10.1016/j.reumae.2023.10.001. Epub 2023 Oct 17.

ABSTRACT

Hajdu-Cheney syndrome or acro-dento-osteo-dysplasia syndrome is a rare disease characterized by band osteolysis of distal phalanges and facial dysmorphia, among other manifestations. We present the case of a 45-year-old male who consulted for mechanical joint pain of both hands, facial dysmorphism, cranio-facial alterations, and digital telescoping with acroosteolysis.

PMID:37858457 | DOI:10.1016/j.reumae.2023.10.001

Inn Med (Heidelb). 2023 Nov;64(11):1033-1040. doi: 10.1007/s00108-023-01599-7. Epub 2023 Oct 20.

ABSTRACT

BACKGROUND: Approximately 300 million people worldwide suffer from a rare disease. An optimal treatment requires a successful diagnosis. This takes a particularly long time, especially for rare diseases. Digital diagnosis support systems could be important aids in accelerating a successful diagnosis in the future.

OBJECTIVE: The current possibilities of digital diagnostic support systems in the diagnosis of rare diseases and questions that still need to be clarified are presented in relation to the parameters of ethics, economy and quality of life.

MATERIAL AND METHODS: Current research results of the authors were compiled and discussed in the context of the current literature. A case study is used to illustrate the potential of digital diagnostic support systems.

RESULTS: Digital diagnostic support systems and experts together can accelerate the successful diagnosis in patients with rare diseases. This could have a positive impact on patients' quality of life and lead to potential savings in direct and indirect costs in the healthcare system.

CONCLUSION: Ensuring data security, legal certainty and functionality in the use of digital diagnostic support systems is of great importance in order to create trust among experts and patients. Continuous further development of the systems by means of artificial intelligence (AI) could also enable patients to accelerate diagnosis in the future.

PMID:37861723 | DOI:10.1007/s00108-023-01599-7

Inn Med (Heidelb). 2023 Nov;64(11):1041-1043. doi: 10.1007/s00108-023-01616-9. Epub 2023 Oct 19.

NO ABSTRACT

PMID:37855883 | DOI:10.1007/s00108-023-01616-9

BMJ Open. 2023 Oct 18;13(10):e064811. doi: 10.1136/bmjopen-2022-064811.

ABSTRACT

OBJECTIVE: To evaluate the impacts of the 2017 adjustment of National Reimbursement Drug List (NRDL) on orphan drugs hospital procurement volumes and spending in China.

DESIGN: We used an interrupted time series design covering the period from 2016 to 2018 to analyse changes in hospital procurement volumes and spending of orphan drugs for which were included in the 2017 NRDL.

SETTING AND DATA: The study was conducted in China. Orphan drug procurement data of 789 public hospitals (594 tertiary hospitals and 195 secondary hospitals) were derived from the Chinese Medical Economic Information (CMEI).

OUTCOME MEASURES: Monthly orphan drugs hospital procurement volumes and spending.

RESULTS: Nine orphan drugs were included in the 2017 NRDL (seven were directly included, and two were included after price negotiation). Comparing to orphan drugs not included in the NRDL, hospital procurement volumes ([Formula: see text] =43 312, p<0.001) and spending ([Formula: see text] =6 48 927, p<0.001) of the nine included drugs showed significant upward trends after implementation of the 2017 NRDL adjustment.

CONCLUSIONS: Our results suggest that the 2017 adjustment of NRDL significantly changed the usage and spending on certain orphan drugs. The increase in orphan drug hospital procurement volumes should improve rare disease patients' access to these orphan drugs.

PMID:37852769 | DOI:10.1136/bmjopen-2022-064811

Orphanet J Rare Dis. 2023 Oct 17;18(1):328. doi: 10.1186/s13023-023-02907-y.

ABSTRACT

BACKGROUND: Progressive ataxias are rare and complex neurological disorders that represent a challenge for the clinicians to diagnose and manage them. This study explored the patient pathways of individuals attending specialist ataxia centres (SAC) compared with non-specialist settings. We investigated specifically how diagnosis was reached, the access to healthcare services, treatments, and care satisfaction. The focus of this study was on early intervention, coordination of treatment to understand the care provision in different countries.

METHODS: A patient survey was done in the UK, Germany and Italy to gather information about diagnosis and management of the ataxias in specialist (SAC) and non-specialist settings, utilisation of other primary and secondary health care services, and patients' satisfaction of received treatment.

RESULTS: Patients gave positive feedback about the role of SAC in understanding their condition, ways to manage their ataxia (p < 0.001; UK) and delivering care adapted to their needs (p < 0.001; UK), in coordinating referrals to other healthcare specialists, and in offering opportunities to take part in research studies. Similar barriers for patients were identified in accessing the SACs among the selected countries, UK, Germany, and Italy.

CONCLUSIONS: This study provides crucial information about the ataxia patients care pathways in three European countries. Overall, the results showed a trend in patients' satisfaction being better in SAC compared to non-SAC. The outcomes can be used now for policy recommendations on how to improve treatment and care for people with these very rare and complex neurological diseases across Europe.

PMID:37848998 | PMC:PMC10583310 | DOI:10.1186/s13023-023-02907-y

Orphanet J Rare Dis. 2023 Oct 17;18(1):327. doi: 10.1186/s13023-023-02935-8.

ABSTRACT

BACKGROUND: The purpose of this study was twofold: (i) To assess the parents' experiences and perception of participating in a "Parental Intervention Program for Preschool children with Rare Diseases" (PIPP-RDs). (ii) To evaluate which elements of the PIPP-RDs that the parents emphasized as important for improving their health literacy related to facilitating the transition of their children from kindergarten to school.

METHOD: A mixed methods evaluation study was conducted ten and eleven months post-intervention, integrating an online quantitative survey combined with individual semi-structured interviews. Twenty-two parents participated in individual interviews, of these 18 also responded to the online questionnaire survey.

RESULTS: All parents that participated in this study reported that the information conveyed at the program was of great value and utility, 88% reported significantly alleviated stress associated to their child`s school-start, 84% indicated had improved the school-home collaboration and 84% reported that it had encouraged them to establish contact with the school prior to school commencement. From the qualitative data five main themes emerged: (i) Competence and Knowledge Acquisition, (ii) Becoming more Prepared and Relaxed, (iii) Achieved Realistic Expectations, (iv) Enhanced Communication Skills, (v) Increased Health Literacy and Self-Efficacy. The evaluative findings suggest that this invention program has notably improved the parents' aptitude for school interaction, enhanced the adaptions according to children`s needs for accommodations, and has provided reassurance in the school-home collaboration. Parents also described increased self-confidence and self-efficacy in managing the school start for children with RDs.

CONCLUSION: The highly positive response of participating in PIPP-RDs may not only reflect the merits of the program`s content, but also underscore the significant needs for such support during the transition to school for parents of children with RDs. Comparable initiatives, oriented towards enhancing the health literacy and empowering the parents, are anticipated to yield similarly favourable results. We argue that intervention program amalgamate pertinent information, group discourse, and workshops on school-related issues, alongside opportunities for parents to meet other parents in similar situations.

PMID:37848938 | PMC:PMC10583464 | DOI:10.1186/s13023-023-02935-8

Clin Nucl Med. 2023 Dec 1;48(12):1102-1104. doi: 10.1097/RLU.0000000000004910. Epub 2023 Oct 16.

ABSTRACT

Thoracic SMARCA4-deficient undifferentiated tumor (SMARCA4-UT) is a rare malignant disease. We present the case of a 56-year-old woman with thoracic SMARCA4-UT presenting as a mediastinal mass who underwent 68 Ga-DOTA-FAPI-04 PET/CT imaging. Intense 68 Ga-DOTA-FAPI-04 uptake was observed in the primary tumor and lymph node metastases. After 7 cycles of immune checkpoint inhibitor plus chemotherapy, the patient underwent mediastinal mass resection, and postoperative pathology confirmed a complete pathologic response. This case may provide valuable insights into the diagnosis and monitoring of the treatment response of thoracic SMARCA4-UT.

PMID:37846457 | DOI:10.1097/RLU.0000000000004910

J Clin Endocrinol Metab. 2023 Oct 17:dgad610. doi: 10.1210/clinem/dgad610. Online ahead of print.

ABSTRACT

CONTEXT: Clinical endocrinology encompasses many diseases requiring long-term drug therapy. Prohibitive pricing of some endocrine drugs classified as essential by the World Health Organisation has created sub-optimal care of patients with endocrine disorders.

EVIDENCE ACQUISITION: This review is based on evidence obtained from several databases and search engines including PubMed, Google and Google Scholar, reference searches, manual searching for web pages of international regulatory bodies and the authors' experience from different healthcare settings.

EVIDENCE SYNTHESIS: After the expiry of a patent, generic versions with the opportunity for increased availability and a price reduction are expected. There are access barriers worldwide for many off-patent endocrine drugs. The high price is the main issue for several medicines including insulin, hydrocortisone, testosterone, and gonadotropins. This is contributed to by several factors including the market monopoly due to the lack of registered generics or suppliers limiting the benefit of competition and a complex supply chain. Additionally, the lack of some medicines had been concerning due to market factors such as the relatively small number of patients making it less attractive for the manufacturers. Commissioning of non-profit manufacturers and state manufacturing as well as strict price control measures could alleviate this situation.

CONCLUSIONS: Lack of availability and disproportionate price inflation affecting essential off-patent endocrine therapies is common due to several interrelated factors. Global collaboration among healthcare organisations with the support of policy-making bodies might be needed to mitigate this.

PMID:37846800 | DOI:10.1210/clinem/dgad610

Eur J Med Genet. 2023 Nov;66(11):104866. doi: 10.1016/j.ejmg.2023.104866. Epub 2023 Oct 13.

ABSTRACT

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disorder caused by pathogenic loss-of-function variants in the ALPL gene, encoding the tissue-nonspecific isoenzym of alkaline phosphatase (ALP; TNSALP). Low serum ALP is the biochemical hallmark of HPP, but it is unknown whether ALP levels can increase due to concurring liver disease, which may lead to a missed diagnose of HPP. We present a patient with genetically confirmed HPP, who showed a transient increase of serum ALP levels due to alcohol-induced hepatitis.

CLINICAL REPORT: A 71-year old man was seen at our Bone Center for surveillance of HPP. Serum ALP was always low (23 U/L; reference value: <115 U/L). During follow-up, his serum ALP increased (156 U/L, further rising to 204 U/L), with concomitantly elevated serum gamma-glutamyl transferase and transaminases, and a rise in bone specific ALP (18.7 μg/L; reference value: 5.7-32.9 μg/L). This was attributed to alcohol-induced hepatitis. After refraining from alcohol intake, both serum ALP and bone specific ALP levels returned to initial low levels (30 U/L and 4.3 μg/L respectively).

CONCLUSIONS: We demonstrated the history of a 71-year old patient with HPP, presenting during routine follow-up with an elevated serum ALP level up to 204 U/L due to alcohol-induced hepatitis. This case illustrates that the diagnosis of HPP can potentially be missed when ALP levels are normal or elevated due to a concomitant liver disease.

PMID:37839783 | DOI:10.1016/j.ejmg.2023.104866