Afr J Paediatr Surg. 2022 Jul-Sep;19(3):189-191. doi: 10.4103/ajps.AJPS_63_21.

ABSTRACT

Children's schwannoma is a rare condition, generally occurring in a sporadic way. Its aetiology is still not fully understood. We report the case of a 10-year old girl who presented a left shoulder mass, along motility reduction of the left upper limb for 24 months before presentation at our service. A biopsy resection of the mass gave the diagnosis and 6 months after surgical resection, no complication occurred.

PMID:35775525 | DOI:10.4103/ajps.AJPS_63_21

Stud Health Technol Inform. 2022 Jun 29;295:422-425. doi: 10.3233/SHTI220755.

ABSTRACT

Automated coding of diseases can support hospitals in the billing of inpatient cases with the health insurance funds. This paper describes the implementation and evaluation of classification methods for two selected Rare Diseases. Different classifiers of an off-the-shelf system and an own application are applied in a supervised learning process and comparatively examined for their suitability and reliability. Using Natural Language Processing and Machine Learning, disease entities are recognized from unstructured historical patient records and new billing cases are coded automatically. The results of the performed classifications show that even with small datasets (≤ 200), high correctness (F1 score ∼0.8) can be achieved in predicting new cases.

PMID:35773901 | DOI:10.3233/SHTI220755

Stud Health Technol Inform. 2022 Jun 29;295:55-58. doi: 10.3233/SHTI220659.

ABSTRACT

The ERN-LUNG Population Registry is a new European-wide collection of patients with rare lung diseases, allowing patients to register online in the registry. Medical experts can recruit patients in the registry for disease-specific registries and care options. The Population Registry was implemented on the basis of the open source software OSSE and extended by functions for the self-registration of patients. Patients were invited through patient organizations between May and November 2022. 115 patients registered online in the registry, whereas 60 of them provided full data in the registry form. After first months of usage, further dissemination of the registry is necessary to reach more patients, e.g. by recruiting them via medical centres directly. Improvements of the registry should be conducted to achieve a higher number of fully completed forms.

PMID:35773805 | DOI:10.3233/SHTI220659

Eur Heart J. 2022 Jul 1:ehac339. doi: 10.1093/eurheartj/ehac339. Online ahead of print.

ABSTRACT

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is an orphan disease defined by extreme elevations in low-density lipoprotein cholesterol, cutaneous xanthomas, and pre-mature atherosclerotic cardiovascular disease. Survival has more than doubled over the past three decades. Aortic stenosis (AS) [supravalvular aortic stenosis (SVAS) or valvular aortic stenosis (VAS)] is commonly encountered. There are no medical treatments available and complex high-risk surgeries represent the only available option in severe cases. A systematic review was performed to summarize the current evidence on AS in HoFH and to determine whether pharmacological treatment (statins) have had an impact on clinical presentation, phenotype and clinical course over the past nine decades (PROSPERO CRD42021250565).

METHODS AND RESULTS: MEDLINE, Embase Classic + Embase, Cochrane Central Register of Controlled Trials, PubMed, AfricaWide, and Scopus were searched from inception to 10 November 2021. Searches identified 381 publications, of which 19 were retained; they were cross-sectional or retrospective studies. Separately, 108 individual case reports were described. Within the 424 HoFH cases, AS was identified in 57% of patients in the pre-statin era vs. 35% in patients reported more recently (>2000, long-term statin period). With an increase in longevity due to statins and lipoprotein apheresis, a change in the proportion of patients with SVAS and VAS with a SVAS:VAS ratio of 47:53 and 10:90 for HoFH patients not on statin and on long-term statin, respectively, was noted.

CONCLUSION: These data suggest that SVAS and VAS are frequent in HoFH and that the phenotype has shifted towards calcific VAS as statins and lipoprotein apheresis improve survival in these patients.

PMID:35776569 | DOI:10.1093/eurheartj/ehac339

Am J Med Genet A. 2022 Jul 1. doi: 10.1002/ajmg.a.62880. Online ahead of print.

ABSTRACT

Childhood-onset forms of hereditary spastic paraplegia are ultra-rare diseases and often present with complex features. Next-generation-sequencing allows for an accurate diagnosis in many cases but the interpretation of novel variants remains challenging, particularly for missense mutations. Where sufficient knowledge of the protein function and/or downstream pathways exists, functional studies in patient-derived cells can aid the interpretation of molecular findings. We here illustrate the case of a 13-year-old female who presented with global developmental delay and later mild intellectual disability, progressive spastic diplegia, spastic-ataxic gait, dysarthria, urinary urgency, and loss of deep tendon reflexes of the lower extremities. Exome sequencing showed a novel splice-site variant in trans with a novel missense variant in B4GALNT1 [NM_001478.5: c.532-1G>C/c.1556G>C (p.Arg519Pro)]. Functional studies in patient-derived fibroblasts and cell models of GM2 synthase deficiency confirmed a loss of B4GALNT1 function with no synthesis of GM2 and other downstream gangliosides. Collectively these results established the diagnosis of B4GALNT1-associated HSP (SPG26). Our approach illustrates the importance of careful phenotyping and functional characterization of novel gene variants, particularly in the setting of ultra-rare diseases, and expands the clinical and molecular spectrum of SPG26, a disorder of complex ganglioside biosynthesis.

PMID:35775650 | DOI:10.1002/ajmg.a.62880

Zhonghua Er Ke Za Zhi. 2022 Jul 2;60(7):731-734. doi: 10.3760/cma.j.cn112140-20211209-01032.

NO ABSTRACT

PMID:35768368 | DOI:10.3760/cma.j.cn112140-20211209-01032

Ann Biol Clin (Paris). 2022 Mar 1;80(2):203-204. doi: 10.1684/abc.2022.1721.

NO ABSTRACT

PMID:35766073 | DOI:10.1684/abc.2022.1721

Eur J Hum Genet. 2022 Jun 30. doi: 10.1038/s41431-022-01137-3. Online ahead of print.

ABSTRACT

Pathogenic variants in the SRCAP (SNF2-related CREBBP activator protein) gene, which encodes a chromatin-remodeling ATPase, cause neurodevelopmental disorders including Floating Harbor syndrome (FLHS). Here, we report the discovery of a de novo transposon insertion in SRCAP exon 13 from trio genome sequencing in a 28-year-old female with failure to thrive, developmental delay, mood disorder and seizure disorder. The insertion was a full-length (~2.8 kb), antisense-oriented SVA insertion relative to the SRCAP transcript, bearing a 5' transduction and hallmarks of target-primed reverse transcription. The 20-bp 5' transduction allowed us to trace the source SVA element to an intron of a long non-coding RNA on chromosome 12, which is highly expressed in testis. RNA sequencing and qRT-PCR confirmed significant depletion of SRCAP expression and low-level exon skipping in the proband. This case highlights a novel disease-causing structural variant and the importance of transposon analysis in a clinical diagnostic setting.

PMID:35768521 | DOI:10.1038/s41431-022-01137-3

BMJ Case Rep. 2022 Jun 28;15(6):e250177. doi: 10.1136/bcr-2022-250177.

ABSTRACT

Among the many potential causes and risk factors for acute portal venous thrombosis, viral hepatitis has been regarded as a rare associated condition. We present the first case in the literature of a 30-year-old previously healthy male who presented with acute portal venous thrombosis associated with acute hepatitis A virus (HAV) infection, describing the probable pathophysiology mechanism, work-up and treatment pursued. We encourage that hepatitis A serological markers should be routinely included in the investigation for acute portal venous thrombosis of unknown aetiology, in unvaccinated patients with risk factors of a recent HAV exposure.

PMID:35764336 | DOI:10.1136/bcr-2022-250177

Dis Model Mech. 2022 Jun 1;15(6):dmm049694. doi: 10.1242/dmm.049694. Epub 2022 Jun 28.

ABSTRACT

Monkol Lek, Assistant Professor at Yale University School of Medicine, and Associate Editor at Disease Models & Mechanisms, dedicates his research to finding a genetic diagnosis and improving treatments for rare disease patients. As he originally studied computer engineering at the University of New South Wales in Sydney, Australia, he now utilises computational methods to optimise large-scale genetic studies, provide globally accessible resources for genetic research communities and, importantly, resolve diagnostic odysseys for rare disease patients. Monkol completed his PhD in Prof. Kathryn North's lab at the University of Sydney, studying the genetics of muscle strength and performance, and then continued his investigation of muscle disease in Prof. Daniel MacArthur's lab at Massachusetts General Hospital and the Broad Institute. During his postdoc, he led several large-scale studies aimed at distinguishing pathogenic from benign variants, including the Exome Aggregation Consortium (ExAC) project ( Lek et al., 2016). Monkol established his own lab at Yale University School of Medicine, which continues to improve the diagnosis and treatment of rare muscle disease, and also focuses on underserved populations, whose genetic mutations are not as well characterised as those of European ancestry. In this interview, Monkol discusses how his own diagnosis with limb girdle muscular dystrophy has shaped his career and what he envisions for the future of genetic research in rare disease.

PMID:35762399 | DOI:10.1242/dmm.049694

J Pharmacol Exp Ther. 2022 Jun 28:JPET-AR-2022-001208. doi: 10.1124/jpet.122.001208. Online ahead of print.

ABSTRACT

Background: X-linked adrenoleukodystrophy (ALD) is a severe orphan disease caused by mutations in the peroxisomal ABCD1 transporter gene, leading to toxic accumulation of Very Long-Chain Fatty Acids (VLCFA - in particular C26:0) resulting in inflammation, mitochondrial dysfunction and demyelination. AMP-activated protein kinase (AMPK) is downregulated in ALD, and its activation is implicated as a therapeutic target. PXL770 is the first direct allosteric AMPK activator with established clinical efficacy and tolerability. Methods: We investigated its effects in ALD patient-derived fibroblasts/lymphocytes and Abcd1 KO mouse glial cells. Readouts included VLCFA levels, mitochondrial function and mRNA levels of proinflammatory genes and compensatory transporters (ABCD2-3). Following PXL770 treatment in Abcd1 KO mice, we assessed VLCFA levels in tissues, sciatic nerve axonal morphology by electronic microscopy and locomotor function by open-field/balance-beam tests. Results: In patients' cells and Abcd1 KO glial cells, PXL770 substantially decreased C26:0 levels (by ~90%), improved mitochondrial respiration, reduced expression of multiple inflammatory genes and induced expression of ABCD2-3 In Abcd1 KO mice, PXL770 treatment normalized VLCFA in plasma and significantly reduced elevated levels in brain (-25%) and spinal cord (-32%) vs. untreated (p<0.001). Abnormal sciatic nerve axonal morphology was also improved along with amelioration of locomotor function. Conclusion: Direct AMPK activation exerts beneficial effects on several hallmarks of pathology in multiple ALD models in vitro and in vivo, supporting clinical development of PXL770 for this disease. Further studies would be needed to overcome limitations including small sample size for some parameters, lack of additional in vivo biomarkers and incomplete pharmacokinetic characterization. Significance Statement Adrenoleukodystrophy is a rare and debilitating condition with no approved therapies, caused by accumulation of very long-chain fatty acids. AMPK is downregulated in the disease and has been implicated as a potential therapeutic target. PXL770 is a novel clinical stage direct AMPK activator. In these studies, we used PXL770 to achieve preclinical validation of direct AMPK activation for this disease - based on correction of key biochemical and functional readouts in vitro and in vivo, thus supporting clinical development.

PMID:35764327 | DOI:10.1124/jpet.122.001208

Front Endocrinol (Lausanne). 2022 Jun 9;13:928667. doi: 10.3389/fendo.2022.928667. eCollection 2022.

NO ABSTRACT

PMID:35757420 | PMC:PMC9219599 | DOI:10.3389/fendo.2022.928667

Zh Nevrol Psikhiatr Im S S Korsakova. 2022;122(6):30-39. doi: 10.17116/jnevro202212206130.

ABSTRACT

Orphan diseases have a prevalence ranging one patient per 10.000 population in the Russian Federation to one per 1500-2000 individuals in Australia and the USA. Many orphan diseases lead to a severe decrease in quality of life and high mortality. In this article, we discuss the problem of early diagnosis in orphan diseases in the Russian Federation, which has lagged behind global trends towards improved recognition and treatment of orphan diseases. We identify the need for improved focus at the level of national healthcare, while discussing relevant issues arising from the international experience. We review national and regional health programs and healthcare practices of Australia, Germany, Denmark, China, Norway, Slovenia, UK, and the United States, with a focus on screening and diagnosis of orphan disease. We also present a review on the state of affairs in the Russian Federation. Orphan diseases are amenable to current molecular-genetic and other diagnostic technologies, including targeted, whole exome and whole genome sequencing (targeted NGS, WES, WGS) using next generation sequencing technologies (next generation sequencing, NGS) and tandem mass spectrometry (TMS, MS/MS). We conclude with a call for major measures aimed at improving the diagnosis of orphan diseases, in particular through the expansion of the neonatal screening program, the creation of a network of orphan disease referral centers, and centralized management of patients registers.

PMID:35758945 | DOI:10.17116/jnevro202212206130

Orphanet J Rare Dis. 2022 Jun 25;17(1):247. doi: 10.1186/s13023-022-02380-z.

ABSTRACT

BACKGROUND: X-linked early-onset osteoporosis, caused by mutations in plastin3 (PLS3), is an extremely rare disease characterized by low bone mineral density (BMD) and recurrent osteoporotic fractures. There is limited information on genetic and phenotypic spectrum, as well as genotype-phenotype correlations of the disease. Moreover, whether decreased PLS3 levels were also involved in osteoporosis among subjects without PLS3 pathogenic mutations remains unknown.

METHODS: Whole-exome sequencing and bidirectional Sanger sequencing were performed for screening and validation of pathogenic mutations. Serum biochemical parameters and clinical information of the subjects were retrospectively collected. ELISA and online datasets were utilized to investigate the association between PLS3 expression and BMD.

RESULTS: We identified a novel splicing mutation (c.892-2A > G) which led to the skipping of exon 9 in a family with X-linked early-onset osteoporosis. Scoliosis represents a potential new phenotype in the patients harboring PLS3 mutations, which may be corrected by brace treatment. Genotype-phenotype analysis reveals that there was no significant difference in BMD z-scores between different types of reported mutations including this study (p = 0.5). There is a marginally significant negative correlation between age and BMD z-score (p = 0.059, r = - 0.30). The conditions of osteoporosis in all patients were improved after bisphosphonates therapy, with mean BMD z-score increased from - 2.9 to - 0.57 (p < 0.0001). Serum PLS3 levels in adolescents and adults without PLS3 pathogenic mutations but representing osteoporosis were also evaluated, while no association was found between bone mineral density and PLS3 levels (p > 0.05).

CONCLUSIONS: Our findings expanded the mutation and phenotype spectrum of the rare disease and highlights the importance of early diagnosis and early treatment with bisphosphonates. More reports of cases with PLS3 mutation and function studies of the gene are warranted to understand genotype-phenotype correlations.

PMID:35752817 | PMC:PMC9233774 | DOI:10.1186/s13023-022-02380-z

Expert Rev Hematol. 2022 May;15(sup1):1-18. doi: 10.1080/17474086.2022.2074395. Epub 2022 Jun 24.

ABSTRACT

Hemophilia, von Willebrand disease (VWD), and thrombotic thrombocytopenic purpura (TTP) are rare diseases affecting normal hemostasis. Although they differ in their pathogenesis and clinical manifestation, if left undiagnosed and untreated, all these conditions can result in severe long-term consequences and can be potentially life-threatening. This article summarizes a poster series funded by Takeda and presented virtually at the 29th annual congress of the International Society on Thrombosis and Haemostasis (ISTH) in 2021: Data from real-world evidence highlight the importance of joint health and personalized prophylaxis to prevent bleeding for patients with hemophilia, the need to further raise disease awareness in support of timely diagnosis and access to treatment in general practice settings for patients with VWD, and describe the clinical burden for patients with TTP and the importance to advance treatment options for these patients.

PMID:35748691 | DOI:10.1080/17474086.2022.2074395

Actas Dermosifiliogr. 2022 Jun;113(6):T543-T549. doi: 10.1016/j.ad.2022.04.012. Epub 2022 Apr 27.

ABSTRACT

BACKGROUND: Cutaneous manifestations are complicated to treat in rare diseases. The main aim of this study was to analyze the impact of compounded drugs prepared by hospital pharmacists on the quality of life of patients with genodermatoses.

MATERIAL AND METHODS: We undertook a cross-sectional study of patients with genodermatoses treated with topical medications compounded and dispensed by the pharmacy at Complejo Hospitalario Universitario in Pontevedra, Spain. We collected demographic data and answers to questionnaires examining generic and disease-specific quality of life, treatment satisfaction, and treatment adherence.

RESULTS: Nine patients were included. We observed a significant improvement in health-related quality of life following treatment with compounded drugs. Satisfaction with the topical medications was 2.8 on a scale of 0 (greatest satisfaction) to 25. Treatment adherence was greater than 89%.

CONCLUSIONS: Drug compounding facilitates access to orphan drugs that are not available for many rare diseases. Few studies, however, have analyzed impact on quality of life in this setting. In this series of patients with genodermatoses, topical medications compounded and dispensed by a hospital pharmacy improved health-related quality of life. This preliminary study has given rise to a multicenter study of compounding for ichthyosis. We expect that analysis of a larger sample will confirm our findings.

PMID:35747999 | DOI:10.1016/j.ad.2022.04.012

Int J Mol Sci. 2022 Jun 18;23(12):6792. doi: 10.3390/ijms23126792.

ABSTRACT

Rare diseases impact the lives of 300 million people in the world. Rapid advances in bioinformatics and genomic technologies have enabled the discovery of causes of 20-30% of rare diseases. However, most rare diseases have remained as unsolved enigmas to date. Newer tools and availability of high throughput sequencing data have enabled the reanalysis of previously undiagnosed patients. In this review, we have systematically compiled the latest developments in the discovery of the genetic causes of rare diseases using machine learning methods. Importantly, we have detailed methods available to reanalyze existing whole exome sequencing data of unsolved rare diseases. We have identified different reanalysis methodologies to solve problems associated with sequence alterations/mutations, variation re-annotation, protein stability, splice isoform malfunctions and oligogenic analysis. In addition, we give an overview of new developments in the field of rare disease research using whole genome sequencing data and other omics.

PMID:35743235 | PMC:PMC9224427 | DOI:10.3390/ijms23126792

Int J Mol Sci. 2022 Jun 10;23(12):6525. doi: 10.3390/ijms23126525.

ABSTRACT

A rare disease is defined by its low prevalence in the general population [...].

PMID:35742964 | PMC:PMC9223693 | DOI:10.3390/ijms23126525

Int J Environ Res Public Health. 2022 Jun 18;19(12):7489. doi: 10.3390/ijerph19127489.

ABSTRACT

Hajdu-Cheney syndrome is a rare genetic disease. Its main features include phenotypic variability, age-dependent progression and the presence of acroosteolysis of the distal phalanges and generalized osteoporosis, which have significant disabling potential. Currently, there is no effective curative treatment, so nursing care is essential to ensure the maintenance of the quality of life of these patients. The main objective of this study was to establish a specific standardized nursing care plan using the NANDA-NIC-NOC taxonomy. The application of a care plan as such would improve the quality of life of patients affected by this rare disease, will contribute to increasing healthcare professionals' knowledge on this matter and will support future studies on this disease.

PMID:35742738 | PMC:PMC9223558 | DOI:10.3390/ijerph19127489

J Perinatol. 2022 Jun 24. doi: 10.1038/s41372-022-01428-z. Online ahead of print.

ABSTRACT

Rapid genomic sequencing has been shown to have a high diagnostic yield for critically ill infants, with multiple research studies demonstrating both diagnostic and clinical utility. However, clinical implementation of rapid sequencing in the neonatal intensive care unit (NICU), as well as other aspects of genomic medicine such as precision therapy, may be challenging. We describe the Neonatal Genomics Program, developed at our institution as a multidisciplinary approach to improve clinical genetic diagnosis and outcomes for infants in our NICU through genomic medicine. The creation of a dedicated program implementing genomic medicine to improve care in the NICU allows not only for improved access to genomic sequencing for rapid diagnosis, but also advancement of rare disease research and precision therapeutics. Ongoing efforts will help to define an optimal approach to genomic medicine in the NICU context.

PMID:35750755 | DOI:10.1038/s41372-022-01428-z