Science. 2021 Sep 24;373(6562):1468-1473. doi: 10.1126/science.abi8206. Epub 2021 Sep 23.

ABSTRACT

[Figure: see text].

PMID:34554790 | DOI:10.1126/science.abi8206

Science. 2021 Sep 24;373(6562):1460-1463. doi: 10.1126/science.acx9135. Epub 2021 Sep 23.

ABSTRACT

[Figure: see text].

PMID:34554775 | DOI:10.1126/science.acx9135

Science. 2021 Sep 24;373(6562):1442-1443. doi: 10.1126/science.abl5403. Epub 2021 Sep 23.

ABSTRACT

[Figure: see text].

PMID:34554771 | DOI:10.1126/science.abl5403

Clin Cancer Res. 2021 Sep 22:clincanres.1165.2021. doi: 10.1158/1078-0432.CCR-21-1165. Online ahead of print.

ABSTRACT

PURPOSE: The clinical phase II trial EORTC 90101 "CREATE" showed high anti-tumor activity of crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK)/ROS1, in patients with advanced inflammatory myofibroblastic tumor (IMFT). However, recent findings suggested that other molecular targets in addition to ALK/ROS1 might also contribute to the sensitivity of this kinase inhibitor. We therefore performed an in-depth molecular characterization of archival IMFT tissue, collected from patients enrolled in this trial, with the aim to identify other molecular alterations which could play a role in the response to crizotinib.

EXPERIMENTAL DESIGN: Twenty-four archival IMFT samples were used for histopathological assessment and DNA/RNA evaluation to identify gene fusions, copy number alterations (CNAs) and mutations in the tumor tissue. Results were correlated with clinical parameters to assess a potential association between molecular findings and clinical outcomes.

RESULTS: We found 12 ALK fusions with 11 different partners in ALK-positive IMFT cases by Archer analysis while we did not identify any ROS1-rearranged tumor. One ALK-negative patient responding to crizotinib was found to have an ETV6-NTRK fusion in the tumor specimen. The CNA profile and mutational landscape of IMFT revealed extensive molecular heterogeneity. Loss of chromosome 19 (25% of cases) and PIK3CA mutations (9% of cases) were associated with shorter progression-free survival in patients receiving crizotinib.

CONCLUSIONS: We identified multiple genetic alterations in archival IMFT material and provide further insight into the molecular profile of this ultra-rare, heterogeneous malignancy, which may potentially translate into novel treatment approaches for this orphan disease.

PMID:34551905 | DOI:10.1158/1078-0432.CCR-21-1165

Stud Health Technol Inform. 2021 Sep 21;283:78-85. doi: 10.3233/SHTI210544.

ABSTRACT

About 30 million people suffer from a rare disease in Europe. Those affected face a variety of problems. These include the lack of information and difficult access to scientific knowledge for physicians. For a higher visibility of rare diseases and high-quality research, effective documentation and use of data are essential. The aim of this work is to optimize the processing, use and accessibility of data on rare diseases and thus increase the added value from existing information. While dashboards are already being used to visualize clinical data, it is unclear what requirements are prevalent for rare diseases and how these can be implemented with available development tools so that a highly accepted dashboard can be designed. For this purpose, based on an analysis of the current situation and a requirements analysis, a prototype dashboard for the visualization of up-to-date key figures on rare diseases was developed at the University Hospital Carl Gustav Carus in Dresden. The development was based on the user-centered design process in order to achieve a high-level user-friendliness. The requirements analysis identified parameters that stakeholders wanted to see, focusing primarily on statistical analyses. The dashboard handles the automated calculation of statistics as well as their preparation and provision. The evaluations showed the prototypical dashboard would be considered valuable and used by potential users. This work demonstrates that stakeholders are interested in access to prepared information and exemplifies a way to implement it. The dashboard can increase the usage of existing information in terms of a higher accessibility and thus improve the knowledge about rare diseases.

PMID:34545822 | DOI:10.3233/SHTI210544

BMJ Case Rep. 2021 Sep 20;14(9):e244890. doi: 10.1136/bcr-2021-244890.

ABSTRACT

Restless legs syndrome (RLS) is a common neurological disorder characterised by an irresistible urge to move the lower limbs, often accompanied by unpleasant sensations in the legs, typically occurring in the evening and at night and improving with movement. Restless arms syndrome (RAS) predominantly affects the arms, while the legs are rarely affected. RAS appears to be very rare, with very few cases described to date, but the diagnosis of RAS is probably made too infrequently, especially for milder and transient forms. The patient reported here even had severe symptoms for years that could have indicated RAS. He observed an immediate improvement in all RAS-related symptoms after administration of 100 mg L-dopa +25 mg benserazide, which continues to this day. Clinicians should always be alert for RLS-like symptoms in one or both arms that worsen at rest and improve with movement, thinking of possible RAS.

PMID:34544716 | DOI:10.1136/bcr-2021-244890

Adv Skin Wound Care. 2021 Oct 1;34(10):539-541. doi: 10.1097/01.ASW.0000790476.13111.5f.

ABSTRACT

OBJECTIVE: Leg ulcers affect 15% of people with sickle cell disease. However, wound centers typically treat few people with this condition, which makes it difficult to concentrate clinical expertise or support the scientific study of this orphan disease. This article describes an initiative to increase engagement in care through a partnership between wound healing and hematology leadership that led to colocating wound services within a sickle cell clinic.

METHODS: Via a retrospective chart review, the authors collected records of all adult patients with sickle cell disease who received wound care in the last decade, including 7 years of wound center data and 3 years of data from the colocated services. Patient and visit characteristics were analyzed using descriptive analytics.

RESULTS: The general wound center had previously treated 35 patients with sickle cell ulcers over 7 years. In contrast, colocated services engaged 56 patients within 3 years, including 20 who transferred care and 36 new patients. The majority of patients at the colocated site were women, unlike at the wound center (58% vs 47%, P = .07). Results indicated that 36% of patients healed initial wounds, and 45% had new wound occurrences.

CONCLUSIONS: Colocation successfully increases the number of patients with sickle cell ulcers who will engage in wound care at a single site, laying the foundation for clinical studies to improve the evidence base for this difficult-to-treat condition.

PMID:34546205 | DOI:10.1097/01.ASW.0000790476.13111.5f

Neurology. 2021 Sep 20:10.1212/WNL.0000000000012836. doi: 10.1212/WNL.0000000000012836. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: AP-4-associated hereditary spastic paraplegia (AP-4-HSP: SPG47, SPG50, SPG51, SPG52) is an emerging cause of childhood-onset hereditary spastic paraplegia and mimic of cerebral palsy. This study aims to define the spectrum of brain MRI findings in AP-4-HSP and to investigate radio-clinical correlations.

METHODS: A systematic qualitative and quantitative analysis of 107 brain MRI studies from 76 individuals with genetically-confirmed AP-4-HSP and correlation with clinical findings including surrogates of disease severity.

RESULTS: We define AP-4-HSP as a disorder of gray and white matter and demonstrate that abnormal myelination is common and that metrics of reduced white matter volume correlate with severity of motor symptoms. We identify a common diagnostic imaging signature consisting of (1) a thin splenium of the corpus callosum, (2) an absent or thin anterior commissure, (3) characteristic signal abnormalities of the forceps minor ("ears of the grizzly sign"), and (4) periventricular white matter abnormalities. The presence of two or more of these findings has a sensitivity of ∼99% for detecting AP-4-HSP, while the combination of all four is found in ∼45% of cases. Compared to other HSP with a thin corpus callosum, the absent anterior commissure appears to be specific to AP-4-HSP. Our analysis further identified a subset of AP-4-HSP patients with polymicrogyria, underscoring the role of AP-4 in early brain development. Of clinical importance, these patients displayed a higher prevalence of seizures and status epilepticus, many at a young age.

DISCUSSION: Our findings define the MRI spectrum of AP-4-HSP providing opportunities for early diagnosis, identification of individuals at risk for complications, and a window into the role of the AP-4 complex in brain development and neurodegeneration.

PMID:34544818 | DOI:10.1212/WNL.0000000000012836

J Investig Med High Impact Case Rep. 2021 Jan-Dec;9:23247096211045254. doi: 10.1177/23247096211045254.

ABSTRACT

While diverticulosis is a common phenomenon in the large intestine, it is a rare disease found in the small intestine accounting for only 0.06% to 1.3% of cases. Although most cases are asymptomatic, roughly 30% to 40%, it is crucial that it is on the differential of acute abdominal pain as it can be life-threatening and potentially require surgical management. Here, we describe a case of a 61-year-old Hispanic man who was found to have a perforated jejunal diverticula after initially presenting with left upper quadrant abdominal pain.

PMID:34538107 | PMC:PMC8450547 | DOI:10.1177/23247096211045254

Z Rheumatol. 2021 Oct;80(8):707-715. doi: 10.1007/s00393-021-01074-4. Epub 2021 Sep 17.

ABSTRACT

For some rare rheumatic diseases the data situation on fertility and pregnancy is still scant. This article attempts to present the data known so far and to derive and supplement some treatment recommendations from the data. A stable disease situation before the pregnancy drastically reduces the risk of complications for mother and child; therefore, an appropriate and timely adjustment of treatment in consultation with patients and gynecologists is important.

PMID:34535819 | DOI:10.1007/s00393-021-01074-4

BMJ Case Rep. 2021 Sep 17;14(9):e245353. doi: 10.1136/bcr-2021-245353.

ABSTRACT

Primary lymphoedema is a rare disorder. Often presents at a young age with asymptomatic limb oedema with gradual progression. We present a 16-year-old woman who presented with a history of swelling of the left lower limb for 6 years. There was the presence of isolated left lower limb oedema, which was a non-pitting type. The patient underwent imaging studies and was diagnosed to have primary lymphoedema. The patient was managed conservatively as the patient did not have any other problems other than the left lower limb oedema.

PMID:34535495 | DOI:10.1136/bcr-2021-245353

Eur J Case Rep Intern Med. 2021 Aug 5;8(8):002740. doi: 10.12890/2021_002740. eCollection 2021.

ABSTRACT

Gorham-Stout disease (GSD) is a rare clinical entity of unknown aetiology, with osseous resorption, vascular structure proliferation and inflammation of adjacent soft tissues. The clinical spectrum varies from asymptomatic patients to patients with pain, functional limitation or deformity. GSD may affect 1 or multiple bones in any location; however, predilection for the maxillofacial area and upper limbs has been described. We present the case report of a 33-year-old male patient with facial pain and loss of dental pieces; imaging showed extensive lytic involvement of the mandible and cranial bones. After exclusion of malignant, metabolic, infectious, or autoimmune disease, a diagnosis of GSD was made. Treatment with sirolimus was prescribed, achieving a symptomatic improvement and stability of imaging findings. The importance of the knowledge of this orphan disease is highlighted, to achieve a prompt diagnosis and medical treatment.

LEARNING POINTS: Gorham-Stout syndrome constitutes an orphan disease with an unknown aetiology, it must be considered in young patients with osteolysis of unknown cause.The diagnosis of Gorham-Stout syndrome is an exclusion one.Drugs with antiproliferative and antiangiogenic activity such as mTOR inhibitors are an attractive option for the management of this disease.

PMID:34527618 | PMC:PMC8436849 | DOI:10.12890/2021_002740

Mol Genet Genomic Med. 2021 Sep 14:e1809. doi: 10.1002/mgg3.1809. Online ahead of print.

ABSTRACT

The phenotypic variability associated with pathogenic variants in Lysine Acetyltransferase 6B (KAT6B, a.k.a. MORF, MYST4) results in several interrelated syndromes including Say-Barber-Biesecker-Young-Simpson Syndrome and Genitopatellar Syndrome. Here we present 20 new cases representing 10 novel KAT6B variants. These patients exhibit a range of clinical phenotypes including intellectual disability, mobility and language difficulties, craniofacial dysmorphology, and skeletal anomalies. Given the range of features previously described for KAT6B-related syndromes, we have identified additional phenotypes including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported. We surveyed clinicians to qualitatively assess the ways families engage with genetic counselors upon diagnosis. We found that 56% (10/18) of individuals receive diagnoses before the age of 2 years (median age = 1.96 years), making it challenging to address future complications with limited accessible information and vast phenotypic severity. We used CRISPR to introduce truncating variants into the KAT6B gene in model cell lines and performed chromatin accessibility and transcriptome sequencing to identify key dysregulated pathways. This study expands the clinical spectrum and addresses the challenges to management and genetic counseling for patients with KAT6B-related disorders.

PMID:34519438 | DOI:10.1002/mgg3.1809

HGG Adv. 2021 Jul;2(3):100035. doi: 10.1016/j.xhgg.2021.100035. Epub 2021 May 11.

ABSTRACT

Effective genetic diagnosis requires the correlation of genetic variant data with detailed phenotypic information. However, manual encoding of clinical data into machine-readable forms is laborious and subject to observer bias. Natural language processing (NLP) of electronic health records has great potential to enhance reproducibility at scale but suffers from idiosyncrasies in physician notes and other medical records. We developed methods to optimize NLP outputs for automated diagnosis. We filtered NLP-extracted Human Phenotype Ontology (HPO) terms to more closely resemble manually extracted terms and identified filter parameters across a three-dimensional space for optimal gene prioritization. We then developed a tiered pipeline that reduces manual effort by prioritizing smaller subsets of genes to consider for genetic diagnosis. Our filtering pipeline enabled NLP-based extraction of HPO terms to serve as a sufficient replacement for manual extraction in 92% of prospectively evaluated cases. In 75% of cases, the correct causal gene was ranked higher with our applied filters than without any filters. We describe a framework that can maximize the utility of NLP-based phenotype extraction for gene prioritization and diagnosis. The framework is implemented within a cloud-based modular architecture that can be deployed across health and research institutions.

PMID:34514437 | PMC:PMC8432593 | DOI:10.1016/j.xhgg.2021.100035

Cell. 2021 Sep 4:S0092-8674(21)01002-3. doi: 10.1016/j.cell.2021.08.028. Online ahead of print.

ABSTRACT

Replacing or editing disease-causing mutations holds great promise for treating many human diseases. Yet, delivering therapeutic genetic modifiers to specific cells in vivo has been challenging, particularly in large, anatomically distributed tissues such as skeletal muscle. Here, we establish an in vivo strategy to evolve and stringently select capsid variants of adeno-associated viruses (AAVs) that enable potent delivery to desired tissues. Using this method, we identify a class of RGD motif-containing capsids that transduces muscle with superior efficiency and selectivity after intravenous injection in mice and non-human primates. We demonstrate substantially enhanced potency and therapeutic efficacy of these engineered vectors compared to naturally occurring AAV capsids in two mouse models of genetic muscle disease. The top capsid variants from our selection approach show conserved potency for delivery across a variety of inbred mouse strains, and in cynomolgus macaques and human primary myotubes, with transduction dependent on target cell expressed integrin heterodimers.

PMID:34506722 | DOI:10.1016/j.cell.2021.08.028

Calcif Tissue Int. 2021 Sep 8. doi: 10.1007/s00223-021-00908-2. Online ahead of print.

ABSTRACT

Hypoparathyroidism is an orphan disease with ill-defined epidemiology that is subject to geographic variability. We conducted this study to assess the demographics, etiologic distribution, treatment patterns and complication frequency of patients with chronic hypoparathyroidism in Turkey. This is a retrospective, cross-sectional database study, with collaboration of 30 endocrinology centers located in 20 cities across seven geographical regions of Turkey. A total of 830 adults (mean age 49.6 ± 13.5 years; female 81.2%) with hypoparathyroidism (mean duration 9.7 ± 9.0 years) were included in the final analysis. Hypoparathyroidism was predominantly surgery-induced (n = 686, 82.6%). The insulting surgeries was carried out mostly due to benign causes in postsurgical group (SG) (n = 504, 73.5%) while patients in nonsurgical group (NSG) was most frequently classified as idiopathic (n = 103, 71.5%). The treatment was highly dependent on calcium salts (n = 771, 92.9%), calcitriol (n = 786, 94.7%) and to a lower extent cholecalciferol use (n = 635, 76.5%) while the rate of parathyroid hormone (n = 2, 0.2%) use was low. Serum calcium levels were most frequently kept in the normal range (sCa 8.5-10.5 mg/dL, n = 383, 46.1%) which might be higher than desired for this patient group. NSG had a lower mean plasma PTH concentration (6.42 ± 5.53 vs. 9.09 ± 7.08 ng/l, p < 0.0001), higher daily intake of elementary calcium (2038 ± 1214 vs. 1846 ± 1355 mg/day, p = 0.0193) and calcitriol (0.78 ± 0.39 vs. 0.69 ± 0.38 mcg/day, p = 0.0057), a higher rate of chronic renal disease (9.7% vs. 3.6%, p = 0.0017), epilepsy (6.3% vs. 1.6%, p = 0.0009), intracranial calcifications (11.8% vs. 7.3%, p < 0.0001) and cataracts (22.2% vs. 13.7%, p = 0.0096) compared to SG. In conclusion, postsurgical hypoparathyroidism is the dominant etiology of hypoparathyroidism in Turkey while the nonsurgical patients have a higher disease burden with greater need for medications and increased risk of complications than the postsurgical patients.

PMID:34495356 | DOI:10.1007/s00223-021-00908-2

Z Evid Fortbild Qual Gesundhwes. 2021 Oct;165:68-76. doi: 10.1016/j.zefq.2021.06.004. Epub 2021 Sep 3.

ABSTRACT

INTRODUCTION: Due to the high variability and, at the same time, rare occurrence of rare diseases, the diagnosis of these patients (approx. 4 million people in Germany) can turn into an odyssey. The large time interval between the appearance of symptoms and the final diagnosis of the rare disease leads to a delay in the appropriate treatment. The often long period of uncertainty about the cause of symptoms as well as non-specific or even wrong therapies can have negative effects on both the course of disease and the patients' quality of life. For a better understanding of the current care situation and IT landscape, the interdisciplinary care pathway for people with rare diseases will be modelled and the possible uses of IT applications identified that have the potential to improve diagnosis, treatment and therapy of rare diseases.

METHODS: In order to achieve these goals, an initial care pathway was modelled on the basis of process descriptions which are commonly used in the literature, discussed in detail, and agreed upon in a first workshop with six experts from outpatient and inpatient care as well as employees of Centers for Rare Diseases. In a second workshop, ten experts analyzed the resulting care pathway with regard to the possible use of IT applications, and the identification was agreed upon. The experts included those involved in the process, in particular physicians, patients / patient representatives, health care researchers, and experts in hospital IT, IT security, and data protection.

RESULTS: The two workshops resulted in process models including the specification of possible uses for IT applications. The most important steps in the care pathway for people with rare diseases in Germany include: neonatal screening, seeking medical advice, outpatient care by general practitioners, outpatient care by specialists, care by specialist outpatient clinic, care by clinic, care by a Center for Rare Diseases: case review and case conference and treatment and therapy. The discussion of the possible uses of IT applications resulted in a focus on registers (e. g. with regard to experts, treatment and therapy options) as well as on digital tools, such as "digital findings and findings platform" and "digital referral with referral tracking".

DISCUSSION: Our results show that the care pathway is very heterogeneous and complex. Thus, the sub-processes show different variants with many branches and repetitions. They also illustrate that the care for people with rare diseases requires a high level of interdisciplinary collaboration; diagnosis as well as treatment and therapy often take place across sectors and in cooperation between different medical health care institutions and professions. When analyzing the current IT landscape, it becomes clear that IT applications can be used at many process steps in the care for people with rare diseases and have a high potential. Therefore, they must be used to inform decisions about the adequate diagnosis and treatment as well as communication about the clinical pictures and the patient's case between practitioners and medical care sectors.

CONCLUSION: The interdisciplinary collaboration highlights the need for cooperation between the various parties involved in the process, which requires the identification and implementation of interfaces between the stakeholders and their systems. However, it is not enough to include the view of the processes; the data perspective is also required. Creating interoperability also enables the use of IT applications. The basis for this is the results obtained.

PMID:34483074 | DOI:10.1016/j.zefq.2021.06.004

EMBO Mol Med. 2021 Sep 6:e14554. doi: 10.15252/emmm.202114554. Online ahead of print.

ABSTRACT

This work employs adult polyglucosan body disease (APBD) models to explore the efficacy and mechanism of action of the polyglucosan-reducing compound 144DG11. APBD is a glycogen storage disorder (GSD) caused by glycogen branching enzyme (GBE) deficiency causing accumulation of poorly branched glycogen inclusions called polyglucosans. 144DG11 improved survival and motor parameters in a GBE knockin (Gbeys/ys ) APBD mouse model. 144DG11 reduced polyglucosan and glycogen in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic polyglucosan. At the cellular level, 144DG11 increased glycolytic, mitochondrial, and total ATP production. The molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. 144DG11 also enhanced mitochondrial activity and modulated lysosomal features as revealed by bioenergetic, image-based phenotyping and proteomics analyses. As an effective lysosomal targeting therapy in a GSD model, 144DG11 could be developed into a safe and efficacious glycogen and lysosomal storage disease therapy.

PMID:34486811 | DOI:10.15252/emmm.202114554

Orphanet J Rare Dis. 2021 Sep 4;16(1):376. doi: 10.1186/s13023-021-02004-y.

ABSTRACT

BACKGROUND: Patient data registries that are FAIR-Findable, Accessible, Interoperable, and Reusable for humans and computers-facilitate research across multiple resources. This is particularly relevant to rare diseases, where data often are scarce and scattered. Specific research questions can be asked across FAIR rare disease registries and other FAIR resources without physically combining the data. Further, FAIR implies well-defined, transparent access conditions, which supports making sensitive data as open as possible and as closed as necessary.

RESULTS: We successfully developed and implemented a process of making a rare disease registry for vascular anomalies FAIR from its conception-de novo. Here, we describe the five phases of this process in detail: (i) pre-FAIRification, (ii) facilitating FAIRification, (iii) data collection, (iv) generating FAIR data in real-time, and (v) using FAIR data. This includes the creation of an electronic case report form and a semantic data model of the elements to be collected (in this case: the "Set of Common Data Elements for Rare Disease Registration" released by the European Commission), and the technical implementation of automatic, real-time data FAIRification in an Electronic Data Capture system. Further, we describe how we contribute to the four facets of FAIR, and how our FAIRification process can be reused by other registries.

CONCLUSIONS: In conclusion, a detailed de novo FAIRification process of a registry for vascular anomalies is described. To a large extent, the process may be reused by other rare disease registries, and we envision this work to be a substantial contribution to an ecosystem of FAIR rare disease resources.

PMID:34481493 | PMC:PMC8418729 | DOI:10.1186/s13023-021-02004-y

Mayo Clin Proc. 2021 Sep;96(9):2305-2308. doi: 10.1016/j.mayocp.2020.12.041.

NO ABSTRACT

PMID:34481596 | DOI:10.1016/j.mayocp.2020.12.041