National Organization For Rare Disorders Research Articles

Rare diseases with temporomandibular joint manifestations: a systematic review

Background: Rare diseases (RDs) are serious often chronic progressive diseases that affect a smaller number of individuals. RDs can manifest in any region of the body and have systemic effects that are detrimental to individual health. Although RDs are individually rare, there are various debilitating disorders arising from RDs. One of the disorders that have been shown to have a negative impact on the health of RD patients is temporomandibular disorders (TMD). There is a dearth of data on the rare diseases and potential manifestations of TMD. The objective of this systematic review is to provide an overview of rare diseases and temporomandibular joint (TMJ) manifestations. Method: The criterion for analysis of a rare disease and temporomandibular manifestations was inclusion in the Orphanet Classification of Rare Diseases and/or the National Organization for Rare Disorders (NORD)/The Genetic and Rare Diseases (GARD) databases. Only rare diseases with TMJ manifestations were recorded. Results: A total of 54 RDs with TMJ manifestations and different TMD diagnoses were recorded. There were thirty-five studies derived from the Pubmed search, and the Orphanet input had 19 results. Overall, 13 different types of TMJ manifestations and TMD diagnoses were recorded in rare diseases. Conclusion: TMJ manifestations associated with rare diseases are not uncommon. Healthcare professionals can play an important role in diagnosing and managing the complexity of RDs with TMJ manifestations. A multidisciplinary approach to TMD patients with rare diseases is advisable.

A Case Report on Ichthyosis Vulgaris; Ayurvedic View and Management

Ichthyosis are a heterogeneous group of Hereditary and acquired disorders of keratinization characterized by the presence of visible scales on skin surface. The word is derived from Greek root for fish – icthys. There are two major types of ichthyosis that is Congenital and Acquired. Ichthyosis vulgaris one among congenital ichthyosis is the most common with an estimated incidence rate of 1 in 250 births, with an onset in early childhood characterized by fine, whitish scales which often sheds off. The severity of symptoms can vary enormously from mildest, most common types such as Ichthyosis vulgaris, up to life threatening condition such as Harlequin Ichthyosis. In general all types of Ichthyosis has been identified as rare disease by National Organization for Rare Disorders (NORD). There is currently no cure for ichthyosis only symptomatic management is done. Topical application is the major treatment according to modern medicine, which should be used daily In Ayurveda skin diseases have been described under the heading Kushta; which is again classified into Mahakushta and Kshudrakushta. Ekakushta, one among Kshudrakushta having Dosa predominance of Vata Kapha shares features more or less similar to ichthyosis vulgaris. Ayurvedic management aims at clearing the Srotas and providing internal and external Snehana has produced a markable change in a case of congenital ichthyosis.

The potential role of vitamin E in patients with glucose-6-phosphate dehydrogenase deficiency: A systematic review and meta-analysis.

As an antioxidant, vitamin E (VitE) may benefit the erythrocytes by protecting glutathione from oxidation by free radicals and peroxide-generating processes. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines when reporting this systematic review. We searched 6 electronic databases (PubMed, Scopus, Web of Science, and Cochrane Library) until May 8, 2022. We included all relevant studies. According to the study design, the Cochrane assessment tool (Risk of Bias 2), Risk Of Bias In Non-randomized Studies - of Interventions checklists, and National Institutes of Health tools were used to assess the risk of bias.Continuous data were pooled as a mean difference (MD) with a relative 95% confidence interval. The protocol was registered on PROSPERO (CRD42022333848). Six studies were included in the meta-analysis with a total of 181 patients. Compared with the control group, VitE significantly improved the hemoglobin level for chronic hemolysis (MD = 2.72 g/dL, P < .0001) and for acute hemolysis (MD = 1.18 g/dL, P < .0001). It also decreased the reticulocyte level for chronic hemolysis (MD = -1.39 P < .0001) and for acute hemolysis (MD = -1.42%, P < .0001). For before and after studies, the use of VitE significantly improved the level of packed cell volume (MD = 0.56%, P < .00001), red blood cell half-life (MD = 2.19 days, P < .0001), and decreased the reticulocytes level (MD = -1.41%, P < .00001). Among patients with glucose-6-phosphate dehydrogenase deficiency, VitE might provide benefits such as increasing the hemoglobin, packed cell volume levels, red blood cell half-life, and decreasing the reticulocyte level, so reducing hemolysis. Further high-quality, well-designed randomized controlled trials are recommended.

Emerging roles and opportunities for rare disease patient advocacy groups.

Patient advocacy groups (PAGs) serve a vital role for rare disease patients and families by providing educational resources, support, and a sense of community. Motivated by patient need, PAGs are increasingly at the forefront of policy, research, and drug development for their disease of interest. The study explored the current landscape of PAGs in order to guide new and existing PAGs on available resources and challenges to research engagement. We aim to inform industry, advocates, and healthcare personnel about PAG achievements and ways they are increasingly involved in research. We chose PAGs from the Rare Diseases Clinical Research Network (RDCRN) Coalition for Patient Advocacy Groups (CPAG) listserv and the National Organization for Rare Disorders (NORD) 'Find a patient organization'. We surveyed eligible PAG leaders about the demographics, goals, and research activities of their organization. For analysis, PAGs were bucketed by size, age, prevalence of disease, and budget. Data were de-identified for cross-tabulation and multinomial logistic regression analysis with R. Research engagement was an extremely important goal for most PAGs (81%), though ultra-rare disease and high-budget PAGs were most likely to cite it as the top priority. In total, 79% reported research engagement in some capacity, including registries, translational research, and clinical trials. 'Ultra-rare' PAGs were less likely than 'rare' PAGs to have an ongoing clinical trial. While PAGs of varying sizes, budgets, and maturity levels reported an interest in research, limited funding and lack of disease awareness continue to create barriers to achieving their goals. While support tools exist to make research more accessible, often their utility depends on the funding, sustainability, maturity of the PAG itself, and the level of investment of collaborators. Despite the availability of current support systems, there are challenges related to both the start-up and sustainability of patient-centric research efforts.

Addressing Clinical Management Challenges in the Treatment of Rare, Non-Malignant Hematologic Disorders through Educational Interventions

BACKGROUND: Despite continuous progress, the management of rare, non-malignant hematologic disorders is still fraught with challenges, including delays in diagnosis, a paucity of targeted therapies and treatment guidelines, suboptimal clinical outcomes, limited clinical trials, and access to information and support. To improve competence in navigating some of these challenges and incorporate patient perspectives in treatment selection, educational initiatives focusing on three rare hematologic disorders were designed in collaboration with the National Organization for Rare Disorders (NORD). METHODS: As part of the Second Annual Rare Cancers and Blood Disorders series, three CME activities on AL amyloidosis (60 minutes), paroxysmal nocturnal hemoglobinuria (PNH) (30 minutes), and cold agglutinin disease (CAD) (30 minutes) were broadcast on OMedLive in April 2022 and remain on-demand through April 2023. A 90-minute complementary PNH program was broadcast live-online on OMedLive in May 2022 and remains on-demand through May 2023. All programs were led by expert hematologists in each subject area. Live programs featured an interactive panel of physicians and live Q&A. Additionally, the 90-minute PNH program featured patient vignettes to elevate clinicians' awareness of patient experiences. For each program, knowledge and competence questions were administered pre-, immediate post-, and 2 months post-activity. Provider-reported barriers and challenges managing patients with rare blood disorders, and intent to modify treatment plans post-program were also assessed. RESULTS: As of July 13th, 2022, 297 clinicians have participated in these activities, 92% of whom are physicians, advanced practitioners (NP/PA), and nurses. Sixty percent of clinicians see between 1 and 10 patients each week with any of these rare disorders (AL, CAD, or PNH). CME questions administered across all programs revealed low baseline knowledge and competence as shown in Table 1. Following the educational activities, improvements ranging from 19% to 59% were seen for pre/post paired responses across all CME questions. Limited knowledge about clinical presentation and differential diagnoses were noted as the top barriers to diagnosis of all three disorders. The greatest challenges in managing patients were identified as "time to diagnosis" for AL amyloidosis and PNH and "lack of novel therapies" for CAD; and most clinicians (41%) perceived "adhering to treatment schedules" as the greatest treatment-related challenge faced by patients. Ninety-four percent of clinicians were motivated to modify treatment plans according to their patients' treatment response. Qualitative and 2-month follow-up data on clinical practice change and impact on patient outcomes will be shared. CONCLUSIONS: Online education on rare, non-malignant hematologic disorders improves clinician knowledge of evidence-based management strategies, uncovers persistent gaps in barriers to care, and stimulates clinical practice change that incorporates patient perspectives, leading to better patient outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Alone We Are Rare, Together We Are Strong: A Review of the National Organization for Rare Disorders (NORD®)

The National Organization for Rare Disorders, or NORD®, is a robust resource suitable for patients, families, clinicians, researchers, and advocates of those living with or impacted by rare diseases. Given that rare diseases affect around 30 million people in the United States, half of which are estimated to be children, it is vital to have access to credible and accessible information. An added bonus of NORD is their staunch advocacy platform, which brings to light other consumer health information which may otherwise be hard to find. This consumer health resource review covers the consumer-focused aspects of NORD.

MDS-516 A Rare Case of X-Linked Recessive Sideroblastic Anemia (XLSA) Masquerading as Myelodysplastic Syndrome-Refractory Anemia With Ringed Sideroblasts (MDS - RARS)

XLSA may be confused clinically with MDS-RARS, which can have patient management implications. Sideroblastic anemia is categorized as a rare type of anemia by National Organization for Rare Disorders. Fewer than 200 cases with less than 100 unrelated probands have been described for X-linked recessive sideroblastic anemia (XLSA). XLSA is the most common type of non-syndromic congenital sideroblastic anemias (CSA), with almost 40% of all CSA cases involving mutations in the ALAS2 (δ- aminolaevulinic acid synthase) gene. Male patients (two-thirds of known cases) usually present in childhood or adolescence with symptoms of anemia, while female patients present in middle age. We present a case of XLSA in a male patient with symptom-onset in middle age. He initially presented with symptoms of anemia and received multiple blood transfusions over a period of 10 years. Subsequent bone marrow biopsy showed a hypercellular bone marrow with erythroid hyperplasia, increased iron and ringed sideroblasts consistent with refractory anemia with ringed sideroblasts, no abnormal karyotype in cytogenetics, and normal flow cytometry results. A liver biopsy showed hemosiderotic changes, and he was initially considered to have myelodysplastic syndrome-refractory anemia with ringed sideroblasts (MDS-RARS). Genetic testing, including SF3B1 gene mutation, revealed no findings suggestive of MDS. The patient was then started on iron chelating agents and pyridoxine with improvement in anemia and did not require any further transfusions with significant improvement in his symptoms. A hereditary anemia NGS gene sequencing and deletion/duplication panel was then done which showed pathogenic X-linked recessive hemizygous mutation involving ALAS2 gene-OMIM 301300. Response to the pyridoxine treatment, absence of SF3B1 gene mutation, and presence of ALAS2 gene mutation helped confirm the diagnosis of XLSA in our patient. This case report highlights the necessity for extensive workup in patients with sideroblastic anemia, given the rarity of XLSA and similarity in its clinical symptoms to MDS-RARS, and the need for its early diagnosis. In our patient, iron overload and subsequent liver cirrhosis developed due to multiple transfusions for refractory sideroblastic anemia which was treated as MDS-RARS and could have been avoided if XLSA had been suspected earlier in the course of the disease.

Cytochrome C Oxidase Deficiency Detection Using SECM in Living Cells

Cytochrome c Oxidase Deficiency (COXD) is an inherited disorder characterized by the absence, abnormality, or mutation in the genes encoding for the Cytochrome c Oxidase protein (COX)1. COXD results in severe muscle weakness, heart, liver and kidney problems and brain damage in infants, leading to death at birth or shortly thereafter2. With no cure for this disorder, finding an efficient, inexpensive, and early way of diagnosis is essential, as muscle biopsy, the current method of detection, is expensive, invasive, and time-consuming. Using electrochemistry, Cytochrome c Oxidase activity has successfully been quantified in bacteria, specifically in Bacillus subtilis and Escherichia coli by employing the redox mediator N, N, N’,N’-tetramethyl-para-phenylene-diamine (TMPD)3. This presentation demonstrates that by means of Scanning Electrochemical Microscopy (SECM), Cytochrome c Oxidase activity can also be quantified in living human epithelial and cancer cells. Thereby, COX oxidizes TMPD to TMPD+•, which is reduced at a microelectrode, regenerating TMPD. The resulting change in electrochemical current enables the quantification of COX activity. The presented research will form the basis for an analytical assay for the detection of COXD in infants, allowing for early intervention and saving lives of children. References 1,2 NORD. (n.d.). Cytochrome c Oxidase Deficiency. National Organization for Rare Disorders (NORD). https://rarediseases.org/rare-diseases/cytochrome-c-oxidase-deficiency/ 3 Kuss, S. et al. (2017). Electrochemical recognition and quantification of cytochrome c expression in Bacillus subtilis and aerobe/anaerobe Escherichia coli using N,N,N′,N′-tetramethyl-para-phenylene-diamine (TMPD). Chemical Science, (11). https://doi.org/10.1039/c7sc03498a

What Rare Disease Patient Advocacy Groups Are Doing to Mitigate the Effects of Disparities

Compared with chronic diseases affecting larger populations, rare disease (RD) patients experience great inequities in diagnosis, care, and research. Within RDs, health disparities compound these inequities, as marginalized communities experience additional barriers in accessing clinical care and are often underrepresented from participation in research and clinical trials. For almost 40 years, the National Organization for Rare Disorders (NORD), a RD umbrella organization with over 300 nonprofit organizational members, has led efforts to understand and address inequities for the RD community through innovative research, programming, and collaboration with patients, caregivers, practitioners, and external stakeholders. The beginning of the COVID-19 pandemic in 2020 brought to light longstanding disparities and discrimination for marginalized communities as well as pivotal racial justice movements. These events spurred many RD nonprofit organizations’ interest in increasing outreach and engagement with minoritized communities within RDs and diversifying their organization internally. Building on the increased interest in diversity, equity, and inclusion (DEI), NORD has focused on collecting case studies from within NORD and its member organizations to capture current efforts to improve DEI within the RD ecosystem. One way clinicians can work to mitigate the effects of disparities is to collaborate with RD patient organizations; this article provides a means by which clinicians and researchers can understand some of the challenges RD nonprofit organizations face in bridging disparities and learn about solutions to supporting marginalized patients within their communities. Clinicians are encouraged to join NORD in our policy efforts advocating to ensure patient access to health care providers practicing in a different state vis-à-vis telehealth.

Guest Editors' Memo: Disparities in Pulmonary Arterial Hypertension Care: Challenges and Solutions

Health disparities have a detrimental effect on the clinical outcomes and quality of care received by minorities in the United States. Compared with the rest of the population, minorities with pulmonary hypertension (PH) are at risk for worse outcomes due to difficulty accessing healthcare, lack of or limited insurance, poor socioeconomic status, and distrust of the healthcare system, among other factors. By disproportionately impacting vulnerable patients, the delay to diagnosis and the barriers to introducing therapies has the potential to worsen health disparities in PH, especially when compounded by the challenges facing patients and families during the COVID-19 pandemic. At present, there is a major unmet need for health policy initiatives to protect minorities, likely due to the lack of studies demonstrating the extent of health disparities. This issue of Advances in Pulmonary Hypertension is part of an ongoing effort by the Pulmonary Hypertension Association (PHA) to advocate research avenues and changes in health policy in favor of minorities that could have a profound and lasting impact on improving the quality of healthcare experienced by minority populations afflicted with PH.In “The Impact of Socioeconomic, Racial, and Ethnic Disparities on Pulmonary Hypertension Diagnosis and Treatment”, Talwar and colleagues provide a comprehensive review of available evidence that points at how genetics, sex, age, race and socioeconomic status influence the quality and outcomes directly associated with health care delivery. Most importantly, the authors advocate for the prioritization of research efforts seeking to understand the individual contribution of these factors and the potential long-term benefit for improving clinical outcomes in vulnerable populations of PH patients across the United States.In the article “What Rare Disease Patient Advocacy Groups Are Doing to Mitigate the Effects of Disparities”, Drell and her colleagues from National Organization for Rare Disorders (NORD) share case studies that exemplify the current social and health care challenges faced by patients suffering from rare diseases who belong to minority groups. The important role that non-profit advocacy organizations play in helping patients face discrimination and health care inequalities is discussed and recommendations are made to guide clinicians, health care practitioners and caregivers on how to support those patients who are most vulnerable to experience health inequity due to limited resources and access to medical care.In the article “Hispanic Ethnicity and Social Determinants of health: Harnessing Data from The Pulmonary Hypertension Association registry” Bernardo and Colleagues discuss the interplay between biologic, socioeconomic and racial factors in PAH with special emphasis on the Hispanic population. The authors also point towards the noticeable underrepresentation of minorities such as Hispanics in most PAH registries and even in randomized clinical trials. The implications of underrepresentation in research are far reaching and may further contribute to disparate care of the minority patients.Finally, in the round table discussion, Dr. Talwar moderates a lively discussion with healthcare providers and members of the PHA centered around their own experiences managing patients at risk for health disparities, their efforts to advocate for wider PH medication access, and their vision for what changes must be implemented in our health care system to avoid placing PH patients at a disadvantage as a result of socioeconomic status, race/ethnicity and other risk factors associates with disparities. Solutions to address and ultimately eradicate disparities will need to eliminate healthcare bias, increase patient access, and increase diversity and inclusion in healthcare providers.Addressing health disparities is a challenge that requires the pooling of federal, community, and professional resources to facilitate the development of research projects, interventions, educational materials, and health policy designed to change clinical outcome among vulnerable minority groups. We thank all the authors who provide their time and effort to help prepare this issue of Advances and hope that the information herein will serve to spark initiatives to address health inequities and improve health care access for all our PH patients.

The economics of moonshots: Value in rare disease drug development.

The economics of moonshots: Value in rare disease drug development.

Rarely mentioned: how we arrived at the quantitative definition of a rare disease

Patients’ difficulty obtaining medications for rare diseases and the advocacy of mothers led to a compelling and convoluted story of the development of the Orphan Drug Act (ODA) of 1983. While valid criticisms of the ODA remain, articles continue to be published on its ongoing beneficent influence. As hoped, ODA tax incentives stimulated research to develop pharmaceutical interventions for rare diseases. The initial ODA defined rare diseases qualitatively, but the 1984 Amendments established that <200,000 American citizens afflicted with a specific disease would be the numerical starting point. Considerable sleuthing was required to determine not only the source of this iconic number, but the reason this number was proposed. A coalition of Food and Drug Administration representatives, pharmaceutical executives, academic researchers, and members of rare disease advocacy organizations met in Washington, DC, and helped formulate the nuts and bolts of the ODA. As it turns out, two women at the conference brokered a deal in the restroom during a break and finalized this number. Paradoxically, rare diseases are not rare. Collectively, about 5000 to 7000 rare diseases are recognized and affect over 300,000 million people worldwide. Physicians should recognize that the collaboration of patient advocacy groups is an increasingly socially and politically effective force, bringing cohesion and recognition to associations such as the National Organization for Rare Disorders.

Bullous Pemphigoid: Readability, Quality, and Treatments of Online Health Resources

Bullous Pemphigoid: Readability, Quality, and Treatments of Online Health Resources

Rare Diseases - Orphan Drugs

Rare diseases (RDs) are a class of diseases that do not affect most of the population. Apart from the common diseases that affect most people, some severely rare diseases often pose unique challenges to society and the healthcare systems in India. According to the National Institute of Health (NIH), the F.D.A., and the National Organization for Rare Disorders (NORD), a rare disease is any disease, disorder, illness or condition affecting fewer than 200,000 people in the United States as defined by the Orphan Drug Designation Program. However, 95% of rare diseases currently have no treatment available. Healthcare Experts estimate that around 7000 rare diseases have been identified globally, out of which 450 have been reported in India, like hemophilia, thalas-semia, sickle cell anemia, and Pompe’s disease. Rare diseases come in many forms, including cancers and auto-immune diseases. Drugs for rare diseases are among the highest-priced medications on the market than other common drugs. A medical advisory board of nationally recognized and specialized physicians can help build in-depth case management tools and clinical decision support systems to develop and advance novel therapies. Recognition of carriers harbouring clinically pathogenic genetic vari-ations is essential to provide proper genetic counselling to the patient and management. The precise delineation of distinct RDs is possible through a meticulous clinical evaluation of the patients and their genetic screening. The Electronic Health Record (E.H.R.) helps foster collaboration and better outcomes. A holistic approach should be integrated across health care providers, both at the pharmacy and medical level, that helps improve patient experience and outcomes and reduce costs. Strong health poli-cies and initiatives are required both from private and government institutions for orphan drug development. A separate course on Clinical Genetics must be included in the academic curriculum of medical students in order to provide them knowledge on the basic concepts of genetics and its applications in human health.

Building a Bridge for Batten Disease

Background. Neuronal Ceroid Lipofuscinosis, or Batten disease, is a neurodegenerative disorder that results in seizures, vision loss, vegetative state, and premature death. This project aims to understand the value of disease organizations in the management of Batten disease progression.&#x0D; Methods. Seven semi-structured interviews with caregivers of children with Batten disease were conducted at a national family conference. Also, five semi-structured telephone interviews with disease organizations were conducted, two of which were Batten disease specific.&#x0D; Results. Most caregiver participants reported difficulties in getting a diagnosis. All participants reported significant benefit from involvement in the Batten Disease Support and Research Association (BDSRA) and associated family conference. Some of the most challenging aspects of care centered around a lack of in-home aid, medical equipment, and the education system. The disease advocacy organizations included Rare KC, the National Organization for Rare Disorders (NORD), Global Genes, Noah’s Hope, and Taylor’s Tale. Disease organizations encourage rare disease families to thrive by providing the bridge that connects patients, physicians, and researchers. A central organization implements an avenue for individuals to share information and meet people in the rare disease community.&#x0D; Conclusions. The participants provided clear examples of the benefits families received from being involved in a rare disease organization.

A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

A Single-Arm, Open-Label, Long-Term Efficacy and Safety Study of Subcutaneous (SC) Romiplostim in Children with Immune Thrombocytopenia (ITP)

Addressing gaps in care for patients with rare cancers and blood disorders: The impact of a collaborative digital education initiative.

e23005 Background: Clinicians are uniquely challenged to manage patients with rare cancers and blood disorders due to a lack of knowledge of diagnosis and management guidelines for these conditions. These conditions comprise a larger proportion of diagnosed cancers in minority populations, among whom a worse 5-year survival is realized in adults versus adolescents and children. Patients often experience delayed diagnoses, have limited treatment options, access to specialists, and limited clinical trials. Education surrounding rare cancers and blood disorders, diagnostic criteria, approved agents, and emerging novel agents is essential to improve treatment outcomes for patients with these rare malignancies. Methods: A 2-part CE and American Board of Internal Medicine (ABIM) Maintenance of Certification activity was launched live-online in October and November, 2020, and remains on-demand through November, 2021 at OMedLive.com, comprising 9 hours of virtual education. This first annual activity was launched in partnership with National Organization for Rare Disorders (NORD), and featured key opinion leaders with extensive expertise in rare cancers and blood disorders. Session components included case presentations, downloadable resources, live polling, and audience real-time Q&amp;A. Knowledge and competence questions were administered pre- and immediate post-activity. Patient and clinical practice impact questions were also asked at 2-month follow-up. Data from these questions were analyzed to determine engagement, remaining gaps, and the unique challenges of managing rare cancers and blood disorders. Results: 996 clinicians have participated in the activity to date. All 28 CE test questions reflected improvements in knowledge and competence regarding symptom recognition, diagnosis, clinical trial data, guidelines, treatment options, and adverse event management. At 2-mos. follow up, 71% reported improvements in clinical practice and 67% reported improvements in patient impact (n = 66). Almost half (48%) indicated diagnosis as their most significant challenge, with other noted barriers including: limited access to molecular testing (29%) and limited knowledge of tests to order (17%). The top 3 reported treatment challenges were: a lack of clinical evidence (24%), limited treatment options (22%), and high treatment cost (16%). Updated and expanded data will be shared. Conclusions: Following the targeted collaborative educational initiative, clinicians demonstrated clear knowledge and competency improvements in critical areas such as recognition, diagnosis, and management, and reported significant improvements in patient outcomes and clinical practice. The results of the two-month impact survey demonstrated a need for further tailored education on diagnostic testing and clinical evidence on treatment options for rare malignancies.

Targeted Therapeutic Approach in Patients With Familial Partial Lipodystrophy Type 3

Introduction: Familial partial lipodystrophy (FPLD) syndromes are genetic disorders characterized by selective lipoatrophy affecting the upper and lower extremities leading to severe insulin resistance and metabolic complications. We describe a patient diagnosed with a pathogenic variant in the peroxisome proliferator-activated receptor γ (PPARγ) gene that causes FPLD type 3 (FPLD3) subsequently treated with pioglitazone with excellent response. Clinical Case: A 52-year-old Hispanic woman with type 2 diabetes mellitus and hypertension presented with epigastric pain and vomiting. Workup revealed elevated lipase to 1889 U/L and triglycerides to 4117 mg/dL, consistent with hypertriglyceridemia-induced pancreatitis. CT abdomen showed acute pancreatitis with hepatic steatosis. Family history was significant for hypertension, diabetes, and hyperlipidemia in her father, mother, and five siblings. Examination revealed facial and truncal obesity, lipoatrophy of her limbs and buttocks, acanthosis nigricans, and hepatomegaly. The patient was treated with an insulin drip with decline in triglyceride levels (450 mg/dL) and discharged on atorvastatin, fenofibrate, metformin, and pioglitazone. Laboratory evaluation revealed an HbA1c of 9%, normal thyroid and liver function tests, and a serum leptin of 1.2 ng/ ml (N females: 4.7–23.7 ng/ml). Lipoprotein electrophoresis showed type 4 lipoproteinemia. A liver fibroscan showed hepatic steatosis with portal fibrosis. Genetic testing was notable for an autosomal dominant pathogenic heterozygous loss-of-function mutation in the ligand binding domain AF-2 region of PPARγ (c.452 A>G) confirming FPLD3. Pioglitazone was increased to 30mg/day with improvement in HbA1c to 8.3% and dyslipidemia at three-month follow up. Conclusion: FPLD3 is caused by loss-of-function mutations in PPARγ, a transcription factor involved in adipogenesis1. FPLD is estimated to affect 1 per 1 million, with FPLD3 reported in approximately 30 individuals worldwide per National Organization for Rare Disorders. Treatment is currently directed at reducing insulin resistance, dyslipidemia, and their sequelae of pancreatitis and cardiovascular disease. Thiazolidinediones (TZDs), PPARγ agonists targeting insulin sensitivity and adipocyte differentiation, have been used in FPLD with variable results. Different mutations in the ligand-binding domains of PPARγ may affect the binding capacity to synthetic agonists, affecting clinical response. Use of TZDs in individuals with PPARγ mutations (R308P, A261E) have been shown to improve hyperglycemia and dyslipidemia2. Our patient was treated with pioglitazone with excellent response to therapy in three months. TZDs may offer a targeted approach to treat FPLD3 based on PPARγ ligand-dependent responsiveness.

Improving the Diagnosis of Fibrodysplasia Ossificans Progressiva

Fibrodysplasia ossificans progressiva (FOP) is a distinctive but often-overlooked disorder, owing to its extreme rarity and insidious presentation. However, the signs of classic FOP are evident at birth, and the disease clinically manifests typically within the first decade of life. The characteristic and invariably early sign of FOP is congenital malformation of the great toes (Figure 1). 1 Pignolo R.J. Wang H. Kaplan F.S. Fibrodysplasia ossificans progressiva (FOP): a segmental progeroid syndrome. Front Endocrinol (Lausanne). 2020; 10: 908 Crossref PubMed Scopus (12) Google Scholar , 2 Pignolo R.J. Shore E.M. Kaplan F.S. Fibrodysplasia ossificans progressiva: clinical and genetic aspects. Orphanet J Rare Dis. 2011; 6: 80 Crossref PubMed Scopus (159) Google Scholar , 3 National Organization for Rare Disorders [homepage on the Internet]. 2020https://rarediseases.org/rare-diseases/fibrodysplasia-ossificans-progressiva/ Google Scholar In 50% of cases, the thumbs are similarly affected. Other findings at birth may include a broad femoral neck and bony malformation of the cervical spine. 4 Meyers C. Lisiecki J. Miller S. Levin A. Fayad L. Ding C. et al. Heterotopic ossification: a comprehensive review. JBMR Plus. 2019; 3: e10172 Crossref PubMed Scopus (95) Google Scholar , 5 The International Clinical Council on FOP (ICC) and Consultants [homepage on the Internet]. 2019https://d3n8a8pro7vhmx.cloudfront.net/ifopa/pages/212/attachments/original/1559059247/FOP_TREATMENT_GUIDELINES_June_2019.pdf Google Scholar , 6 International Fibrodysplasia Ossificans Progressiva Association (IFOPA) [homepage on the Internet]. 2020www.ifopa.org/what_is_fop Google Scholar Heterotopic ossification, the abnormal growth of bone in extraskeletal tissues, typically is not present at birth, although areas of soft-tissue swelling may be evident in neonates. Infants and children with FOP may present to pediatric orthopedic surgeons with progressive “bunions” or malformed great toes. However, it is rare that the disease is recognized at this stage. In most cases, unfortunately, the diagnosis of FOP is not made until affected persons have consulted several physicians and the associated deformity and disability are undeniable. 7 Kapan F. Xu M. Glaser D.L. Collins F. Connor M. Kitterman J. et al. Early diagnosis of fibrodysplasia ossificans progressiva. Pediatrics. 2008; 121: e1295-e1300 Crossref PubMed Scopus (113) Google Scholar It is estimated that 3500-4000 people worldwide have FOP, although the disorder has been diagnosed in only about 900 people. 3 National Organization for Rare Disorders [homepage on the Internet]. 2020https://rarediseases.org/rare-diseases/fibrodysplasia-ossificans-progressiva/ Google Scholar Although there are currently no approved treatments for FOP, early recognition and diagnosis is important to prevent unnecessary trauma, such as intramuscular vaccination or surgery, that may induce disease flares.

Assessing Patient and Provider Perspectives, Clinical Practice, Behaviors, and Knowledge on Hemophilia A Care

BACKGROUND: The management of severe hemophilia A with and without inhibitors is evolving rapidly. Clinicians who manage patients with hemophilia A may lack confidence in how to optimally utilize extended half-life factor replacement agents as well as non-factor replacement agents for prophylaxis, and in managing complications such as inhibitor development in those with severe hemophilia. Patients with hemophilia and their families are burdened by the complexity of managing their care and would benefit from improved understanding of the disease state, treatment options, how to decrease bleeding episodes, and optimize their quality of life. For these reasons, a web-based joint educational initiative for patients/caregivers and HCPs was created. METHODS: In collaboration with Hemophilia Federation of America, National Hemophilia Foundation, and National Organization for Rare Disorders, a 1-hour online video-based CME activity for HCPs and 1-hour healthcare education activity for patients were created in June, 2020 to address identified practice and knowledge needs among HCPs, and knowledge, communication and self-efficacy behaviors among patients. Each activity consisted of slides, polling and live questions, and remains on-demand for 12 months at www.OMedLive.com and RareDiseaseLive.com, and on Facebook video for patients and caregivers. Test questions were administered at 3 time points (pre-, immediate post-, and 2 mos. post-activity). Data from these test questions, responses to live polling questions, and learner-submitted questions during live Q&amp;A were analyzed to determine engagement, lessons learned and continuing education gaps. RESULTS: As of August 2020, 235 HCPs and 2,384 patients took part in the ongoing activities. Post education, HCP learners (n=79) anticipated the education would positively impact patient clinical outcomes (84%) and their practice behavior (80%). Improvements in pre/post knowledge and case-based competence questions were realized in all 4 administered HCP pre/post questions. For patients and caregivers, knowledge improvements were observed in 3 out of 4 pre/post questions, and a shift was also observed towards preference for more shared models of decision making, and towards increased confidence with HCP communication and managing their own care/the care of the person for whom they care. Differences were observed in patient versus provider perceptions of hemophilia-related challenges. Behavioral changes indicated by patients and providers following the educational activities will be reported and grouped by theme. Two-month follow up post-tests will be administered to HCPs and patient-caregivers who took part in the educational programs, and statistical significance of change and effect size for all repeated test questions will be reported. CONCLUSIONS: Joint CME and patient education can yield insights into clinical practice behaviors; patient healthcare communication, preferences, and confidence; and treatment knowledge of Hemophilia A. Together, aligned education directed to HCPs and patients can improve the ability to provide evidence-based treatment for patients. Disclosures Croteau: Bayer: Consultancy; Genentech: Consultancy; Pfizer: Consultancy; Novo Nordisk: Research Funding; CSL-Behring: Consultancy; Spark Therapeutics: Research Funding; ATHN: Research Funding; Sigilon Therapeutics: Consultancy; National Hemophilia Foundation: Honoraria; Hemophilia Federation of America: Honoraria. Pipe:Apcintex, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, F. Hoffmann-La Roche Ltd/Genentech, Inc., Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, uniQure: Consultancy; Siemens: Research Funding; Medical and Scientific Advisory Council to the National Hemophilia Foundation; Medical Advisory Board to World Federation of Hemophilia: Membership on an entity's Board of Directors or advisory committees. Tickle:National Hemophilia Foundation: Other, Research Funding; Platform Q Health: Honoraria.