Hetanshi Naik is an Associate Professor in the Department of Genetics and the Research Director of the MS Program in Human Genetics and Genetic Counseling. She is a board certified genetic counselor and clinical researcher with clinical expertise in the inborn errors of heme biosynthesis, the Porphyrias, lysosomal storage disorders (LSDs), and pharmacogenomics, and research expertise in clinical trials, patient reported outcomes (PROs), qualitative methods, and study design.
Her research interests include developing and evaluating PROs for genetic disorders and genomics, in particular assessing PROs as outcomes for clinical trials, pharmacogenomics implementation, and genetic counseling education and processes, as well as utilizing digital health technologies to improve clinical care, genetic counseling, patient reporting, trial efficacy, and outcomes.
Associate Professor (Teaching), Genetics
Research Director, MS Program in Human Genetics and Genetic Counseling, Stanford University School of Medicine (2022 - Present)
Boards, Advisory Committees, Professional Organizations
Research Faculty Working Group, Association of Genetic Counseling Program Directors (2022 - Present)
Board of Directors, United Porphyrias Association (2021 - Present)
Diversity Committee, Rare Diseases Clinical Research Network (2021 - Present)
Member, Rare Disease Diversity Coalition (2021 - Present)
Data Standards Committee, Rare Diseases Clinical Research Network (2020 - Present)
Founding Member, American Porphyrias Expert Collaborative (APEX) (2020 - Present)
PhD, Icahn School of Medicine at Mount Sinai, Clinical Research (2018)
MS, Mount Sinai School of Medicine, Genetic Counseling (2010)
BSc, McMaster University, Biology major, Genetics specialization (2008)
- Genetic Counseling Research Seminar
GENE 282A (Win)
- Genetic Counseling Research Seminar
GENE 282B (Spr)
- Independent Studies (2)
Prior Year Courses
- Genetic Counseling Research Seminar
GENE 282A (Win)
- Genetic Counseling Research Seminar
- Evidence based consensus guidelines for diagnosis and management of Protoporphyria-Related liver dysfunction in erythropoietic protoporphyria and X-Linked protoporphyria. Hepatology (Baltimore, Md.) 2023
Patient and Provider Experiences and Views on the Use of Telehealth in Genetics Clinics in Response to the COVID-19 Pandemic.
Telemedicine journal and e-health : the official journal of the American Telemedicine Association
Introduction: The 2019 Coronavirus Disease (COVID-19) pandemic necessitated a mass transition in genetics clinics nationwide from in-person care to virtual care through telehealth. Before the COVID-19 pandemic, there was limited research on the use of telehealth in genetics specialties. Therefore, the COVID-19 pandemic presented a unique opportunity to study this emerging mode of care delivery in the setting of genetics clinics. This study described the scope of telehealth use in genetics clinics nationally and determined how COVID-19 influenced patients' decisions regarding their genetic care. Methods: Two anonymous surveys for patients and providers were developed. The patient survey was offered online to all genetics patients seen through telehealth at a Manhattan-based practice between March and December 2020. The provider survey was distributed through several listservs to genetics providers nationwide. Results: Patients (n=242) and providers (n=150) responded. Telehealth was used in all specialty genetics clinics for both initial and follow-up visits. Telehealth was both effective and satisfactory to patients for both visit types and across specialties; however, Asian and Hispanic/Latino patients had significantly lower mean satisfaction scores compared with White patients (p=0.03 and 0.04, respectively). Patients appreciated telehealth for its convenience and to avoid COVID-19 exposure. Providers across specialties and provider types preferred telehealth for follow-up rather than initial visits. Several clinic initiatives related to telehealth were identified. Discussion: Telehealth was generally well received by both patients and providers, and is expected to become permanent option in genetics clinics. Further studies are needed to identify barriers to accessing telehealth.
View details for DOI 10.1089/tmj.2023.0021
View details for PubMedID 37294555
Ledipasvir/Sofosbuvir Is Effective as Sole Treatment of Porphyria Cutanea Tarda with Chronic Hepatitis C.
Digestive diseases and sciences
2023; 68 (6): 2738-2746
Chronic hepatitis C [CHC] is a risk factor for porphyria cutanea tarda [PCT]. To assess whether ledipasvir/sofosbuvir is effective for treating both PCT and CHC, we treated patients with CHC + PCT solely with ledipasvir/sofosbuvir and followed them for at least 1 year to assess cure of CHC and remission of PCT.Between September 2017 and May 2020, 15 of 23 screened PCT + CHC patients were eligible and enrolled. All were treated with ledipasvir/sofosbuvir at recommended doses and durations, according to their stage of liver disease. We measured plasma and urinary porphyrins at baseline and monthly for the first 12 months and at 16, 20, and 24 mos. We measured serum HCV RNA at baseline, 8-12, and 20-24 mos. Cure of HCV was defined as no detectable serum HCV RNA ≥ 12 weeks after the end of treatment (EOT). Remission of PCT was defined clinically as no new blisters or bullae and biochemically as urinary uro- plus hepta-carboxyl porphyrins ≤ 100 mcg/g creatinine.All 15 patients, 13 of whom were men, were infected with HCV genotype 1. 2/15 withdrew or were lost to follow-up. Of the remaining 13, 12 achieved cure of CHC; 1 had complete virological response, followed by relapse of HCV after ledipasvir/sofosbuvir but was subsequently cured by treatment with sofosbuvir/velpatasvir. Of the 12 cured of CHC, all achieved sustained clinical remission of PCT.Ledipasvir/sofosbuvir [and likely other direct-acting antivirals] is an effective treatment for HCV in the presence of PCT and leads to clinical remission of PCT without additional phlebotomy or low-dose hydroxychloroquine treatment.ClinicalTrials.gov NCT03118674.
View details for DOI 10.1007/s10620-023-07859-8
View details for PubMedID 36811718
View details for PubMedCentralID PMC9945827
Elective genetic testing: Genetics professionals' perspectives and practices.
Journal of genetic counseling
2023; 32 (3): 607-617
Elective genetic testing (EGT) to identify disease risk in individuals who may or may not meet clinical criteria for testing is increasingly being offered in clinical practice. However, little is known about how EGT is currently implemented and how genetics professionals perceive this type of testing. We conducted a mixed-methods survey study to evaluate genetics professionals' perspectives and attitudes about EGT and describe the current landscape of EGT practices in the United States (U.S.) and Canada. Six clinical geneticists and 131 genetic counselors responded to the online survey, among whom 44% reported offering EGT in their practice. Over 84% of survey respondents agreed that EGT may improve health outcomes and understanding of genotype-phenotype correlations, and 85% agreed that potential risks include result misinterpretation and contribution to economic health disparities. Though most respondents felt comfortable providing pretest (77%) and post-test (86%) counseling for EGT, lack of provider resources (such as time and personnel) and prioritization of diagnostic testing were cited most frequently in free-text responses as reasons for not offering EGT. Of those offering EGT, 88% reported positive overall experiences. Qualitative analysis of open-ended questions identified benefits of EGT as expanding access to genetic testing, providing potential health benefits, and providing psychological benefits for patients. Disadvantages included prohibitive costs, limited clinical utility, and strain on resources. Overall, we found that genetics providers perceive both potential benefits and harms of EGT and that those offering this testing had generally positive experiences, although ethical reservations and practical limitations exist.
View details for DOI 10.1002/jgc4.1666
View details for PubMedID 36575824
Frequency of Epistaxis and Telangiectasia in patients with Hereditary Hemorrhagic Telangiectasia (HHT) in comparison with the General Population: Curaçao Diagnostic Criteria Revisited.
Genetics in medicine : official journal of the American College of Medical Genetics
The Curaçao criteria are well-established diagnostic criteria for HHT but lack details regarding a predictive presentation of epistaxis and telangiectasias. This study collects and compares data in HHT and population cohorts to inform the application of these criteria.In-person interviews regarding epistaxis and targeted examination for telangiectases in a general population cohort (n=204) and an HHT cohort (n=432).Frequency of epistaxis, rather than intensity or duration, was the best discriminator of HHT. A cut-off of 4 or more nosebleeds per year, alone, yielded a diagnostic sensitivity of 97%, and specificity of 84%. The mean number of telangiectases at the sites investigated was 0.4 in the general population cohort and 26.5 in the HHT cohort. The most distinctive sites for telangiectases in HHT were lips and palmar fingers; whereas telangiectases of the face and dorsum of the hand were comparable in both cohorts.We propose that the Curaçao criteria be modified to include the following cutoffs: 1) epistaxis frequency of 4 or more nosebleeds per year, 2) telangiectasia count of at least 2 in characteristic locations (palmar aspect of fingers, lips and oral cavity); and that cutaneous telangiectases at other sites not be considered relevant for diagnostic purposes.
View details for DOI 10.1016/j.gim.2023.100865
View details for PubMedID 37125633
Key terms and definitions in acute porphyrias: Results of an international Delphi consensus led by the European porphyria network.
Journal of inherited metabolic disease
Acute porphyrias are a group of rare inherited disorders causing acute neurovisceral attacks. Many terms used frequently in the literature and clinical practice are ambiguous, which can lead to confusion in the way patients are managed, studied, and reported in clinical studies. Agreed definitions are a necessary first step in developing management guidelines and will facilitate communication of results of future clinical research. The Delphi method was used to generate consensus on key terms and definitions in acute porphyria. The process started with a brainstorming phase offered to all members of the European Porphyria Network followed by two Delphi rounds among international experts in the field of porphyria (the Acute Porphyria Expert Panel). A consensus of 75% or more was defined as the agreement threshold. A total of 63 respondents from 26 countries participated in the brainstorming phase, leading to the choice of nine terms and definitions. A total of 34 experts were invited to take part in the Delphi rounds. Seven of the initial nine terms and definitions which entered the first Delphi round achieved the threshold for agreement. Following a second Delphi round, all nine definitions achieved agreement. Agreement on the definitions for nine important terms describing acute porphyrias represents a significant step forward for the porphyria community. It will facilitate more accurate comparison of outcomes among porphyria centres and in clinical trials and provide a strong framework for developing evidence-based clinical guidelines.
View details for DOI 10.1002/jimd.12612
View details for PubMedID 37067064
A pilot study of oral iron therapy in erythropoietic protoporphyria and X-linked protoporphyria.
Molecular genetics and metabolism reports
2022; 33: 100939
The use of iron supplementation for anemia in erythropoietic protoporphyria (EPP) is controversial with both benefit and deterioration reported in single case reports. There is no systematic study to evaluate the benefits or risks of iron supplementation in these patients. We assessed the potential efficacy of oral iron therapy in decreasing erythrocyte protoporphyrin (ePPIX) levels in patients with EPP or X-linked protoporphyria (XLP) and low ferritin in an open-label, single-arm, interventional study. Sixteen patients (≥18 years) with EPP or XLP confirmed by biochemical and/or genetic testing, and serum ferritin ≤30 ng/mL were enrolled. Baseline testing included iron studies, normal hepatic function, and elevated plasma porphyrins and ePPIX levels. Oral ferrous sulfate 325 mg twice daily was administered for 12 months. The primary efficacy outcome was the relative difference in total ePPIX level between baseline and 12 months after starting treatment with iron. Secondary measures included improvement in serum ferritin, plasma porphyrins, and clinical symptoms. Thirteen patients had EPP (8 females, 5 males) and 3 had XLP (all females) and the mean age of participants was 38.8 years (SD 14.5). Ten patients completed all study visits limiting interpretation of results. In EPP patients, a transient increase in ePPIX levels was observed at 3 months in 9 of 12 (75%) patients. Iron was discontinued in 2 of these patients after meeting the protocol stopping rule of a 35% increase in ePPIX. Seven patients withdrew before study end. Ferritin levels increased on iron replacement indicating an improvement in iron status. A decrease in ePPIX was seen in both XLP patients who completed the study (relative difference of 0.67 and 0.5 respectively). No substantial changes in ePPIX were seen in EPP patients at the end of the study (n = 8; median relative difference: -0.21 (IQR: -0.44, 0.05). The most common side effects of iron treatment were gastrointestinal symptoms. Hepatic function remained normal throughout the study. Our study showed that oral iron therapy repletes iron stores and transiently increases ePPIX in some EPP patients, perhaps due to a transient increase in erythropoiesis, and may decrease ePPIX in XLP patients. Further studies are needed to better define the role of iron repletion in EPP. Trial registration: NCT02979249.
View details for DOI 10.1016/j.ymgmr.2022.100939
View details for PubMedID 36406817
View details for PubMedCentralID PMC9672425
- Prospective observational pilot study of quantitative light dosimetry in erythropoietic protoporphyria. Journal of the American Academy of Dermatology 2022
Evidence-based consensus guidelines for the diagnosis and management of erythropoietic protoporphyria and X-linked protoporphyria.
Journal of the American Academy of Dermatology
Erythropoietic protoporphyria and X-linked protoporphyria are rare genetic photodermatoses. Limited expertise with these disorders among physicians leads to diagnostic delays. Here, we present evidence-based consensus guidelines for the diagnosis, monitoring, and management of erythropoietic protoporphyria and X-linked protoporphyria. A systematic literature review was conducted, and reviewed among subcommittees of experts, divided by topic. Consensus on guidelines was reached within each subcommittee and then among all members of the committee. The appropriate biochemical and genetic testing to establish the diagnosis is reviewed in addition to the interpretation of results. Prevention of symptoms, management of acute phototoxicity, and pharmacologic and nonpharmacologic treatment options are discussed. The importance of ongoing monitoring for liver disease, iron deficiency, and vitamin D deficiency is discussed with management guidance. Finally, management of pregnancy and surgery and the safety of other therapies are summarized. We emphasize that these are multisystemic disorders that require longitudinal monitoring. These guidelines provide a structure for evidence-based diagnosis and management for practicing physicians. Early diagnosis and management of these disorders are essential, particularly given the availability of new and emerging therapies.
View details for DOI 10.1016/j.jaad.2022.08.036
View details for PubMedID 36041558
Attitudes on pharmacogenomic results as secondary findings among medical geneticists.
Pharmacogenetics and genomics
OBJECTIVES: As evidence mounts supporting the utility of pharmacogenomic-guided medication management, incorporating pharmacogenomic genes into secondary finding results from sequencing panels is increasingly under consideration. We studied medical geneticists' attitudes on receiving pharmacogenomic results as secondary finding.METHODS: Four focus groups with 16 medical geneticists total were conducted followed by thematic analysis.RESULTS: All participants ordered genetic sequencing tests; however, the majority had rarely or never ordered pharmacogenomic tests (10/16) or prescribed medications with established response variability (11/16). In total 81.3% expressed low comfort interpreting pharmacogenomic results without appropriate clinical resources (13/16). The positives of receiving pharmacogenomic results as secondary finding included prevention of adverse drug reactions in adults, grateful information-seeking patients, the ability to rapidly prescribe more effective treatments and appreciation of the recent advances in both pharmacogenomic knowledge and available guidelines. Negatives included laboratory reporting issues, exclusivity of pharmacogenomic results to certain populations, lengthy reports concealing pharmacogenomic results in patient charts and laboratories marketing to individuals without prior pharmacogenomic knowledge or targeting inappropriate populations. The most desirable pharmacogenomic resources included a universal electronic health record clinical decision support tool to assist identifying and implementing pharmacogenomic results, a specialized pharmacist as part of the care team, additional pharmacogenomic training during medical/graduate school, and a succinct interpretation of pharmacogenomic results included on laboratory reports.CONCLUSIONS: The majority of participants agreed that adding certain actionable pharmacogenomic genes to the American College of Medical Genetics and Genomics SF list is reasonable; however, this was qualified with a need for additional resources to support implementation.
View details for DOI 10.1097/FPC.0000000000000479
View details for PubMedID 35916546
Hepatocellular Carcinoma in Acute Hepatic Porphyrias: Results from the Longitudinal Study of the U.S. Porphyrias Consortium.
Hepatology (Baltimore, Md.)
2021; 73 (5): 1736-1746
The risk for hepatocellular carcinoma (HCC) is increased in acute hepatic porphyrias (AHP). The aim of this study was to explore the clinicopathologic characteristics, outcomes, and frequency of HCC in patients with AHP in the United States.This cross-sectional analysis evaluated patients with HCC in a multicenter, longitudinal study of AHP. Among 327 patients with AHP, 5 (1.5%) were diagnosed with HCC. Of the 5 HCC cases, 4 had acute intermittent porphyria and 1 had variegate porphyria, confirmed by biochemical and/or genetic testing. All patients were white females, with a median age of 27 years (range 21-75) at diagnosis. The median age at HCC diagnosis was 69 years (range 61-74). AHP was asymptomatic in 2 patients; 2 reported sporadic attacks; and 1 reported recurrent attacks (>4 attacks/year). All patients had a single HCC lesion on liver imaging that was 1.8-6.5 centimeters in diameter. Serum alpha fetoprotein levels were below 10 ng/mL in all 4 patients with available results. Four patients underwent liver resection, and 1 was treated with radioembolization. No significant inflammation or fibrosis was found in adjacent liver tissues of 3 patients who underwent liver resection. Two patients developed recurrence of HCC at 22 and 26 months following liver resection. All patients are alive with survival times from HCC diagnosis ranging from 26-153 months.In this U.S. study, 1.5% of patients with AHP had HCC. HCC in AHP occurred in the absence of cirrhosis, which contrasts with other chronic liver diseases. Patients with AHP, regardless of clinical attacks, should be screened for HCC, beginning at age 50. The pathogenesis of hepatocarcinogenesis in AHP is unknown and needs further investigation.
View details for DOI 10.1002/hep.31460
View details for PubMedID 32681675
Pharmacogenomic education among genetic counseling training programs in North America.
Journal of genetic counseling
The increasing number of genetic counselors participating directly in clinical pharmacogenomic post-test counseling prompted our evaluation of pharmacogenomic education across genetic counseling training programs in North America. Thirty-one program leadership participants from both the United States (U.S.) and Canada responded to a survey assessing pharmacogenomics education and the role of genetic counselors. Eighty-five percent of respondents agreed pharmacogenomics is currently within the scope of genetic counseling practice, and 96.3% indicated their training programs currently provide education on pharmacogenomics, with the majority reporting<7hr of education. Lectures on pharmacogenomics were the most common method for didactics; however, some programs also included practical modalities (e.g., case studies, clinical rotations) and online resources. Barriers to expanding pharmacogenomic education included the constrained timeline of training, and lack of resources and local expertise. Moreover, participants suggested that genetic counselors ideally should be able to order pharmacogenomic tests and counsel patients on pharmacogenomics, including result interpretation, as they believe pharmacogenomics does fall within the scope of practice of genetic counseling. Our novel results also confirm that training program leadership support a pharmacogenomic service delivery model that includes a combined effort between genetic counselors and pharmacists to utilize their synergistic expertise. However, this model likely still necessitates expanding pharmacogenomic didactics in genetic counseling training programs through more practical training and/or by leveraging online pharmacogenomic courses dedicated to supporting clinical implementation.
View details for DOI 10.1002/jgc4.1417
View details for PubMedID 33882174
Experiences from the epicenter: Professional impact of the COVID-19 pandemic on genetic counselors in New York.
American journal of medical genetics. Part C, Seminars in medical genetics
2021; 187 (1): 28-36
The COVID-19 pandemic disrupted the delivery of healthcare services, including genetic counseling. This study assessed the professional impact of the pandemic on genetic counselors (GCs) and evaluated how genetics service delivery models changed in New York State (NYS). One hundred sixty-five NYS GCs participated in an anonymous survey. Clinic structure, telegenetics (video and/or telephone consultations) use and acceptability, and professional practices before and during the pandemic were compared. The most frequently reported consultation type shifted from in-person only (49%) before the pandemic to telegenetics only (39%) during. Most were satisfied with video (93.1%) and telephone (81.4%) telegenetics. Additionally, 93.5% of participants expressed a desire to continue using telegenetics after the pandemic resolves. Common obstacles included difficulties coordinating sample collection (60.2%) and obtaining written consent for testing (57.6%). Billing methods for consultations during the pandemic did not change significantly. Participants were asked about NYS's lack of licensure, which restricts billing options. Most felt that genetic counseling licensure would benefit the profession (92.6%), the public (88.5%), and their institution/company (74.5%). This study provides insight into the effects of the rapid adoption of telegenetics and can guide future discussions about best practices for its use even after the health crisis resolves.
View details for DOI 10.1002/ajmg.c.31855
View details for PubMedID 33225573
View details for PubMedCentralID PMC7753596
Evidence in the UK Biobank for the underdiagnosis of erythropoietic protoporphyria.
Genetics in medicine : official journal of the American College of Medical Genetics
2021; 23 (1): 140-148
Erythropoietic protoporphyria (EPP), characterized by painful cutaneous photosensitivity, results from pathogenic variants in ferrochelatase (FECH). For 96% of patients, EPP results from coinheriting a rare pathogenic variant in trans of a common hypomorphic variant c.315-48T>C (minor allele frequency 0.05). The estimated prevalence of EPP derived from the number of diagnosed individuals in Europe is 0.00092%, but this may be conservative due to underdiagnosis. No study has estimated EPP prevalence using large genetic data sets.Disease-associated FECH variants were identified in the UK Biobank, a data set of 500,953 individuals including 49,960 exome sequences. EPP prevalence was then estimated. The association of FECH variants with EPP-related traits was assessed.Analysis of pathogenic FECH variants in the UK Biobank provides evidence that EPP prevalence is 0.0059% (95% confidence interval [CI]: 0.0042-0.0076%), 1.7-3.0 times more common than previously thought in the UK. In homozygotes for the common c.315-48T>C FECH variant, there was a novel decrement in both erythrocyte mean corpuscular volume (MCV) and hemoglobin.The prevalence of EPP has been underestimated secondary to underdiagnosis. The common c.315-48T>C allele is associated with both MCV and hemoglobin, an association that could be important both for those with and without EPP.
View details for DOI 10.1038/s41436-020-00951-8
View details for PubMedID 32873934
View details for PubMedCentralID PMC7796935
Gaucher disease and SARS-CoV-2 infection: Experience from 181 patients in New York.
Molecular genetics and metabolism
2021; 132 (1): 44-48
SARS-CoV-2 infection carries high morbidity and mortality in individuals with chronic disorders. Its impact in rare disease populations such as Gaucher disease (GD) is unknown. In GD, decreased acid β-glucosidase activity leads to the accumulation of inflammatory glycosphingolipids and chronic myeloid cell immune activation which a priori could predispose to the most severe effects of SARS-CoV-2. To evaluate the determinants of SARS-CoV-2 infection in GD, we conducted a cross-sectional study in a large cohort. 181 patients were enrolled, including 150 adults and 31 children, with a majority of patients on treatment (78%). Information on COVID-19 exposure, symptoms, and SARS-CoV-2 nucleic acid and/or antibody testing was obtained during the peak of the pandemic in the New York City metropolitan area. Forty-five adults reported a primary exposure to someone with COVID-19 and 17 (38%) of these patients reported at least one COVID-19 symptom. A subset of adults was tested (n = 88) and in this group 18% (16/88) were positive. Patients testing positive for SARS-CoV-2 had significantly more symptoms (4.4 vs 0.3, p < 0.001) than patients testing negative. Among patients who were antibody-positive, quantitative titers indicated moderate to high antibody response. In GD adults, male gender, older age, increased BMI, comorbidities, GBA genotype, prior splenectomy and treatment status were not associated with the probability of reporting symptoms or testing positive. No patient required COVID-19-specific treatments and there were no deaths. Our data suggests that GD does not confer a heightened risk for severe effects of SARS-CoV-2 infection feared based on the known chronic inflammatory state in these patients.
View details for DOI 10.1016/j.ymgme.2020.12.288
View details for PubMedID 33353808
View details for PubMedCentralID PMC7834197
Digital Health Applications for Pharmacogenetic Clinical Trials.
2020; 11 (11)
Digital health (DH) is the use of digital technologies and data analytics to understand health-related behaviors and enhance personalized clinical care. DH is increasingly being used in clinical trials, and an important field that could potentially benefit from incorporating DH into trial design is pharmacogenetics. Prospective pharmacogenetic trials typically compare a standard care arm to a pharmacogenetic-guided therapeutic arm. These trials often require large sample sizes, are challenging to recruit into, lack patient diversity, and can have complicated workflows to deliver therapeutic interventions to both investigators and patients. Importantly, the use of DH technologies could mitigate these challenges and improve pharmacogenetic trial design and operation. Some DH use cases include (1) automatic electronic health record-based patient screening and recruitment; (2) interactive websites for participant engagement; (3) home- and tele-health visits for patient convenience (e.g., samples for lab tests, physical exams, medication administration); (4) healthcare apps to collect patient-reported outcomes, adverse events and concomitant medications, and to deliver therapeutic information to patients; and (5) wearable devices to collect vital signs, electrocardiograms, sleep quality, and other discrete clinical variables. Given that pharmacogenetic trials are inherently challenging to conduct, future pharmacogenetic utility studies should consider implementing DH technologies and trial methodologies into their design and operation.
View details for DOI 10.3390/genes11111261
View details for PubMedID 33114567
EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks.
Hepatology (Baltimore, Md.)
2020; 71 (5): 1546-1558
Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients.EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization.Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies.
View details for DOI 10.1002/hep.30936
View details for PubMedID 31512765
View details for PubMedCentralID PMC7255459
Evaluating the Patient-Reported Outcomes Measurement Information System scales in acute intermittent porphyria.
Genetics in medicine : official journal of the American College of Medical Genetics
2020; 22 (3): 590-597
Acute intermittent porphyria (AIP) is a rare inborn error of heme biosynthesis characterized by life-threatening acute attacks. Few studies have assessed quality of life (QoL) in AIP and those that have had small sample sizes and used tools that may not have captured important domains.Baseline data from the Porphyrias Consortium's Longitudinal Study were obtained for 259 patients, including detailed disease and medical history data, and the following Patient-Reported Outcomes Measurement Information System (PROMIS) scales: anxiety, depression, pain interference, fatigue, sleep disturbance, physical function, and satisfaction with social roles. Relationships between PROMIS scores and clinical and biochemical AIP features were explored.PROMIS scores were significantly worse than the general population across all domains, except depression. Each domain discriminated well between asymptomatic and symptomatic patients with symptomatic patients having worse scores. Many important clinical variables like symptom frequency were significantly associated with domain scores in univariate analyses, showing responsiveness of the scales, specifically pain interference and fatigue. However, most regression models only explained ~20% of the variability observed in domain scores.Pain interference and fatigue were the most responsive scales in measuring QoL in this AIP cohort. Future studies should assess whether these scales capture longitudinal disease progression and treatment response.
View details for DOI 10.1038/s41436-019-0683-y
View details for PubMedID 31690837
View details for PubMedCentralID PMC7060090
The N370S/R496H genotype in type 1 Gaucher disease - Natural history and implications for pre symptomatic diagnosis and counseling.
Molecular genetics and metabolism reports
2020; 22: 100567
Type 1 Gaucher disease (GD1) patients with the N370S/R496H (N409S/R535H) genotype are increasingly identified through carrier and newborn screening panels. However, limited information is available on the phenotype associated with this genotype. Here, we report our experience with 14 patients with this genotype. Our data suggests that most patients with N370S/R496H present with mild manifestations and often do not require treatment. This information is important for counseling newly diagnosed patients and GD1 carrier couples.
View details for DOI 10.1016/j.ymgmr.2020.100567
View details for PubMedID 32042592
View details for PubMedCentralID PMC7000790
Knowledge and attitudes of Parkinson's disease risk in the Gaucher population.
Journal of genetic counseling
2020; 29 (1): 105-111
Individuals with Gaucher disease have an increased risk of developing Parkinson's disease as compared to the general population. Though the association is well-known in the scientific community, it is unclear if individuals with Gaucher disease are being counseled on the increased risk. To date, no studies have been performed assessing whether Gaucher disease patients are aware of the increased risk of developing Parkinson's disease. Furthermore, it is unknown how and when individuals with Gaucher disease wish to learn of the increased risk. To assess this, an online survey was administered to Gaucher disease patients. We hypothesized that most individuals with Gaucher disease have been informed of the risk, and that they wish to be told of the risk by their health care provider at the time of diagnosis. Study results revealed that of 125 individuals with Gaucher disease, 80% previously knew about the association with Parkinson's disease, 83.7% preferred to find out about the increased risk from a health care provider, and 71.0% wanted to find out at the time of Gaucher disease diagnosis. These results suggest that health care providers should counsel Gaucher disease patients about the increased Parkinson's disease risk, and they should do so at the time of diagnosis.
View details for DOI 10.1002/jgc4.1185
View details for PubMedID 31663662
Knowledge and attitudes on pharmacogenetics among pediatricians.
Journal of human genetics
2020; 65 (5): 437–44
Increasing enthusiasm for clinical pharmacogenetic testing and the availability of pharmacogenetic-based guidelines indicate that pediatricians will increasingly be expected to interpret and apply pharmacogenetic test results into medical care. Previous studies have identified a lack of knowledge on pharmacogenetics across many physician specialties; however, this has not been systematically assessed among pediatricians. To evaluate pediatrician knowledge, attitude, and educational interest in pharmacogenetics, we surveyed physician cohorts from both the United States (U.S.) and Japan. A total of 282 pediatricians (210 from the U.S. and 72 from Japan) participated in an anonymous survey (online or hardcopy) on pharmacogenetics knowledge, perception, and education. Over 50% of all respondents had >10 years of clinical experience and >75% had some prior education in genetics. However, <10% felt they were familiar with pharmacogenetics, which was very consistent with <20% of the U.S. pediatricians correctly responding to a codeine/CYP2D6 pharmacogenetics knowledge question and <10% of U.S. pediatricians being aware of the Clinical Pharmacogenetics Implementation Consortium (CPIC). Despite being generally unfamiliar with pharmacogenetics, >80% of all respondents indicated that implementation of clinical pharmacogenetic testing will improve efficacy and safety, and that pediatricians should be capable of applying this testing to their practice. Moreover, the majority (83.1%) were interested in educational opportunities on pharmacogenetics, particularly on result interpretation and therapeutic recommendations. Taken together, these data indicate that although practical knowledge of pharmacogenetics among pediatricians in the U.S. and Japan is currently very low, their interest in clinical pharmacogenetics and related education is high, which will likely facilitate future implementation.
View details for DOI 10.1038/s10038-020-0723-0
View details for PubMedID 31983733
View details for PubMedCentralID PMC7109006
Implementing a pharmacogenetic-driven algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics: protocol for a non-randomised clinical trial.
2020; 10 (8): e038936
Minority populations in the USA are disproportionately affected by cardiovascular conditions. Reduced responsiveness to clopidogrel among carriers of CYP2C19 variants has been reported in patients with either coronary artery disease (CAD) or acute coronary syndrome (ACS) after the percutaneous coronary intervention (PCI). Previous studies have evaluated CYP2C19 genotyping-guided antiplatelet therapy in selected populations; however, this has yet to be tested among Hispanics. Given the paucity of clinical research on CYP2C19 and antiplatelet clinical outcomes in Hispanics, our study will test the safety and efficacy of a genetic-driven treatment algorithm to guide dual antiplatelet therapy (DAPT) in Caribbean Hispanics.This is a multicentre, prospective, non-randomised clinical trial that proposes an assessment of pharmacogenomic-guided DAPT in post-PCI Caribbean Hispanic patients with ACS or CAD. We will recruit 250 patients to be compared with a matched non-concurrent cohort of 250 clopidogrel-treated patients (standard-of-care). Major adverse cardiovascular events (MACEs) such as all-cause death, myocardial infarction (MI), stroke, coronary revascularisation, stent thrombosis and bleedings over 6 months will be the study endpoints. Among the recruited, high-risk patients will be escalated to ticagrelor and low-risk patients will remain on clopidogrel. The primary objective is to determine whether genetic-guided therapy is superior to standard of care. The secondary objective will determine if clopidogrel treatment in low-risk patients is not associated with a higher rate of MACEs compared with escalated antiplatelet therapy in high-risk patients. Patients will be enrolled up to the group's completion.Approval was obtained from the Institutional Review Board of the University of Puerto Rico Medical Sciences Campus (protocol # A4070417). The study will be carried out in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice Guidelines. Findings will be published in a peer-reviewed journal and controlled access to experimental data will be available.NCT03419325; Pre-results.
View details for DOI 10.1136/bmjopen-2020-038936
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- Clinical Pharmacogenetic Testing and the Posttest Counseling Conundrum. Clinical pharmacology and therapeutics 2020; 108 (5): 924–28
Evaluating quality of life tools in North American patients with erythropoietic protoporphyria and X-linked protoporphyria.
2019; 50 (1): 9-19
Erythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare photodermatoses presenting with severe phototoxicity. Although anecdotally, providers who treat EPP patients acknowledge their life-altering effects, tools that fully capture their impact on quality of life (QoL) are lacking.Adult patients with EPP/XLP were given four validated QoL tools: the Patient Reported Outcomes Measurement Information System 57 (PROMIS-57), the Hospital Anxiety and Depression Scale (HADS), the Illness Perception Questionnaire Revised (IPQR), and an EPP-Specific tool. All patients received the PROMIS-57 while the HADS, IPQR, and EPP-Specific tools were introduced at a later date. Associations between responses and clinical phenotypes were explored.Two hundred and two patients were included; 193 completed PROMIS-57, 104 completed IPQR, 103 completed HADS, and 107 completed the EPP-Specific tool. The IPQR showed that patients strongly believed EPP/XLP had a negative impact on their lives. Mean scores in anxiety and depression domains of both HADS and PROMIS-57 were normal; however, anxiety scores from HADS were borderline/abnormal in 20% of patients. The EPP-Specific tool revealed a decreased QoL in most patients. The PROMIS-57 showed that 21.8% of patients have clinically significant pain interference. Several tool domains correlated with measures of disease severity, most being from the PROMIS-57.Impaired QoL is an important consequence of EPP/XLP. PROMIS-57 was most sensitive in evaluating impaired QoL in EPP/XLP. Further research is needed to compare the effectiveness of it for assessing response to treatment.
View details for DOI 10.1002/jmd2.12052
View details for PubMedID 31741822
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Psychosocial issues in erythropoietic protoporphyria - the perspective of parents, children, and young adults: A qualitative study.
Molecular genetics and metabolism
2019; 128 (3): 314-319
Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses, generally presenting in childhood with severe and painful phototoxicity. EPP has been reported to negatively affect quality of life (QoL), but there is limited information on the psychosocial issues faced by patients and families. To address this, an online focus group study was conducted to explore the perspective of parents of children with EPP, and young adults and children with EPP. Five focus groups were conducted in a semi-structured format, with moderator-led discussions exploring the impact on QoL. Three focus groups included parents of children with EPP, one with children aged 10-11 years, and another with young adults aged 24-25 years, for a total of 24 participants. Thematic data analysis showed that parents experience guilt for being unable to protect their children and frustration with the current state of knowledge of EPP. Parents also admitted that the disease can lead to stress within family members which is difficult to manage. Young adults expressed embarrassment over having to explain the disease to others. They reported that the teenage years were the most difficult to navigate; however, they learned to adapt to their disease as they grew older. Children expressed that they had limited understanding of their disease and wished they were told what symptoms to expect by physicians earlier in life. Our findings emphasize the significant impact on QoL for these families and a lack of age appropriate information for children with EPP. These findings can help improve counseling and support resources for patients and caregivers.
View details for DOI 10.1016/j.ymgme.2019.01.023
View details for PubMedID 30711301
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Diagnostic Delay in Erythropoietic Protoporphyria.
The Journal of pediatrics
2018; 202: 320-323.e2
Erythropoietic protoporphyria is a photodermatosis presenting in childhood with severe pain on sun exposure. The diagnosis is often delayed because of the lack of awareness among pediatricians. We describe the diagnostic odyssey of 2 children presenting with symptoms of erythropoietic protoporphyria and report results of a survey of 129 affected individuals.
View details for DOI 10.1016/j.jpeds.2018.06.001
View details for PubMedID 30041937
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Parkinson's disease prevalence in Fabry disease: A survey study.
Molecular genetics and metabolism reports
2018; 14: 27-30
Recent research has suggested a possible link between Parkinson's disease (PD) and Fabry disease. To test this relationship, we administered a self-report and family history questionnaire to determine the prevalence of PD in Fabry disease patients and family members with likely pathogenic alpha-galactosidase A (GLA) mutations. A total of 90 Fabry patients (77 from the online survey and 13 from the Icahn School of Medicine at Mount Sinai (ISMMS)) were included in the analysis. Two of the Fabry disease patients who completed the online survey were diagnosed with PD (2/90, 2.2%). Among probands older than 60, 8.3% (2/24) were diagnosed with PD. Using Kaplan Meier survival analysis, the age-specific risk of PD by age 70 was 11.1%. Family history was available on 72 Fabry families from the online study and 9 Fabry families from ISMMS. Among these 81 families, 6 (7.4%) had one first degree relative who fit the criteria for a conservative diagnosis of PD. The results of this study suggest that there may be an increased risk of developing PD in individuals with GLA mutations, but these findings should be interpreted with caution given the limitations of the study design.
View details for DOI 10.1016/j.ymgmr.2017.10.013
View details for PubMedID 29159076
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Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria.
2017; 153 (8): 789-796
Autosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.To describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP.A prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database.Results of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP.Of the 226 patients in the study (113 female and 113 male patients; mean [SD] age, 36.7 [17.0] years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3-48T>C, and only 1 patient had 2 FECH mutations. Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients' mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 µg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 µg/dL; P ≤ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 µg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 µg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 µg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.These data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a framework for clinical monitoring and management of these disorders.
View details for DOI 10.1001/jamadermatol.2017.1557
View details for PubMedID 28614581
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Institutional profile: translational pharmacogenomics at the Icahn School of Medicine at Mount Sinai.
2017; 18 (15): 1381–86
For almost 50 years, the Icahn School of Medicine at Mount Sinai has continually invested in genetics and genomics, facilitating a healthy ecosystem that provides widespread support for the ongoing programs in translational pharmacogenomics. These programs can be broadly cataloged into discovery, education, clinical implementation and testing, which are collaboratively accomplished by multiple departments, institutes, laboratories, companies and colleagues. Focus areas have included drug response association studies and allele discovery, multiethnic pharmacogenomics, personalized genotyping and survey-based education programs, pre-emptive clinical testing implementation and novel assay development. This overview summarizes the current state of translational pharmacogenomics at Mount Sinai, including a future outlook on the forthcoming expansions in overall support, research and clinical programs, genomic technology infrastructure and the participating faculty.
View details for DOI 10.2217/pgs-2017-0137
View details for PubMedID 28982267
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Acute Intermittent Porphyria in children: A case report and review of the literature.
Molecular genetics and metabolism
2016; 119 (4): 295-299
Acute Intermittent Porphyria (AIP), an autosomal dominant inborn error of heme metabolism, typically presents in adulthood, most often in women in the reproductive age group. There are limited reports on the clinical presentation in children, and in contrast to the adults, most of the reported pediatric cases are male. While acute abdominal pain is the most common presenting symptom in children, seizures are commonly seen and may precede the diagnosis of AIP. As an example, we report a 9year old developmentally normal pre-pubertal boy who presented with acute abdominal pain, vomiting and constipation followed by hyponatremia, seizures, weakness and neuropathy. After a diagnostic odyssey, his urine porphobilinogen was found to be significantly elevated and genetic testing showed a previously unreported consensus splice-site mutation IVS4-1G>A in the HMBS gene confirming the diagnosis of AIP. Here, we discuss the clinical presentation in this case, and 15 reported pediatric cases since the last review 30years ago and discuss the differential diagnosis and challenges in making the diagnosis in children. We review the childhood-onset cases reported in the Longitudinal Study of the Porphyrias Consortium. Of these, genetically and biochemically confirmed patients, 11 of 204 (5%) reported onset of attacks in childhood. Most of these patients (91%) reported recurrent attacks following the initial presentation. Thus, AIP should be considered in the differential diagnosis of children presenting with unexplained abdominal pain, seizures, weakness and neuropathy.
View details for DOI 10.1016/j.ymgme.2016.10.005
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Experiences and concerns of patients with recurrent attacks of acute hepatic porphyria: A qualitative study.
Molecular genetics and metabolism
2016; 119 (3): 278-283
The acute hepatic porphyrias (AHPs) are rare inborn errors of heme biosynthesis, characterized clinically by life-threatening acute neurovisceral attacks. Patients with recurrent attacks have a decreased quality of life (QoL); however, no interactive assessment of these patients' views has been reported. We conducted guided discussions regarding specific topics, to explore patients' disease experience and its impact on their lives.Sixteen AHP patients experiencing acute attacks were recruited to moderator-led online focus groups. Five groups (3-4 patients each) were conducted and thematic analyses to identify, examine, and categorize patterns in the data was performed.All patients identified prodromal symptoms that began days prior to acute severe pain; the most common included confusion ("brain fog"), irritability, and fatigue. Patients avoided hospitalization due to prior poor experiences with physician knowledge of AHPs or their treatment. All patients used complementary and alternative medicine treatments to avoid hospitalization or manage chronic pain and 81% reported varying degrees of effectiveness. All patients indicated their disease impacted personal relationships due to feelings of isolation and difficulty adjusting to the disease's limitations.Patients with recurrent attacks recognize prodromal warning symptoms, attempt to avoid hospitalization, turn to alternative treatments, and have markedly impaired QoL. Counseling and individualized support is crucial for AHP patients with recurrent attacks.
View details for DOI 10.1016/j.ymgme.2016.08.006
View details for PubMedID 27595545
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The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda.
2016; 11 (9): e0163322
Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT. Recently, a polymorphic variant (D519G, c.1556A>G, rs11558492) of glyceronephosphate O-acyltransferase (GNPAT) was shown to be enriched in male patients with type I hereditary hemochromatosis (HFE C282Y homozygotes) who presented with a high iron phenotype, suggesting that GNPAT D519G, like HFE C282Y, is a modifier of iron homeostasis that favors iron absorption. To challenge this hypothesis, we investigated the frequency of GNPAT D519G in patients with both familial and sporadic PCT. Patients were screened for GNPAT D519G and allelic variants of HFE (both C282Y and H63D). Nucleotide sequencing of uroporphyrinogen decarboxylase (URO-D) identified mutant alleles. Patients with low erythrocyte URO-D activity or a damaging URO-D variant were classified as familial PCT (fPCT) and those with wild-type URO-D were classified as sporadic PCT (sPCT). GNPAT D519G was significantly enriched in the fPCT patient population (p = 0.0014) but not in the sPCT population (p = 0.4477). Both HFE C282Y and H63D (c.187C>G, rs1799945) were enriched in both PCT patient populations (p<0.0001) but showed no greater association with fPCT than with sPCT.GNPAT D519G is a risk factor for fPCT, but not for sPCT.
View details for DOI 10.1371/journal.pone.0163322
View details for PubMedID 27661980
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Pitfalls in Erythrocyte Protoporphyrin Measurement for Diagnosis and Monitoring of Protoporphyrias.
2015; 61 (12): 1453-6
Laboratory diagnosis of erythropoietic protoporphyria (EPP) requires a marked increase in total erythrocyte protoporphyrin (300-5000 μg/dL erythrocytes, reference interval <80 μg/dL) and a predominance (85%-100%) of metal-free protoporphyrin [normal, mostly zinc protoporphyrin (reference intervals for the zinc protoporphyrin proportion have not been established)]; plasma porphyrins are not always increased. X-linked protoporphyria (XLP) causes a similar increase in total erythrocyte protoporphyrin with a lower fraction of metal-free protoporphyrin (50%-85% of the total).In studying more than 180 patients with EPP and XLP, the Porphyrias Consortium found that erythrocyte protoporphyrin concentrations for some patients were much higher (4.3- to 46.7-fold) than indicated by previous reports provided by these patients. The discrepant earlier reports, which sometimes caused the diagnosis to be missed initially, were from laboratories that measure protoporphyrin only by hematofluorometry, which is intended primarily to screen for lead poisoning. However, the instrument can calculate results on the basis of assumed hematocrits and reports results as "free" and "zinc" protoporphyrin (with different reference intervals), implying separate measurements of metal-free and zinc protoporphyrin. Such misleading reports impair diagnosis and monitoring of patients with protoporphyria.We suggest that laboratories should prioritize testing for EPP and XLP, because accurate measurement of erythrocyte total and metal-free protoporphyrin is essential for diagnosis and monitoring of these conditions, but less important for other disorders. Terms and abbreviations used in reporting erythrocyte protoporphyrin results should be accurately defined.
View details for DOI 10.1373/clinchem.2015.245456
View details for PubMedID 26482161
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Afamelanotide for Erythropoietic Protoporphyria.
The New England journal of medicine
2015; 373 (1): 48-59
Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life.We conducted two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide. Patients in the European Union (74 patients) and the United States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of five implants in the European Union study and three in the U.S study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. Quality of life was assessed with the use of validated questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. The primary efficacy end point was the number of hours of direct exposure to sunlight without pain.In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04). In both trials, quality of life improved with afamelanotide therapy. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug.Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.).
View details for DOI 10.1056/NEJMoa1411481
View details for PubMedID 26132941
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Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver.
Molecular medicine (Cambridge, Mass.)
2015; 21: 487-95
Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic porphyrin precursors 5-aminolevulinic acid (ALA) and porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1 mRNA and activity were elevated approximately ~3- and 5-fold, and ALA and PBG concentrations were increased ~3- and 1,760-fold, respectively; (b) uroporphyrin III concentration was elevated; (c) microsomal heme content was sufficient, and representative cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e) iron concentration was slightly elevated; and (f) heme oxygenase I mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative hyperplasia, previously not reported in AIP livers, and minimal iron deposition, despite the large number of hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks.
View details for DOI 10.2119/molmed.2015.00099
View details for PubMedID 26062020
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Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium.
The American journal of medicine
2014; 127 (12): 1233-41
Recent descriptions of the clinical and laboratory features of subjects with acute porphyrias in the US are lacking. Our aim was to describe clinical, biochemical, and genetic features of 108 subjects.Between September 2010 and December 2012, 108 subjects with acute porphyrias (90 acute intermittent porphyrias, 9 hereditary coproporphyrias, 9 variegate porphyrias) were enrolled into an observational study. Genetic testing was performed at a central genetic testing laboratory and clinical information entered into a central database. Selected features were compared with data for adults in the US.Most subjects (88/108, 81%) were female, with self-reported onset of symptoms in the second through fourth decades of life. The most common symptom was abdominal pain. Appendectomies and cholecystectomies were common before a diagnosis of porphyria. The diagnosis was delayed by a mean of 15 years. Anxiety and depression were common, and 18% complained of chronic symptoms, especially neuropathic and other pains. The incidences of systemic arterial hypertension, chronic kidney disease, seizure disorders, and psychiatric conditions were markedly increased. Mutations of the known causative genes were found in 102/105 of those tested, with novel mutations being found in 37, including in 7/8 subjects with hereditary coproporphyria. Therapy with intravenous hematin was the most effective therapy both for treatment of acute attacks and for prevention of recurrent attacks.Acute porphyrias often remain undiagnosed for more than a decade after first symptoms develop. Intravenous hematin is the treatment of choice, both for treatment of acute attacks and for prevention of recurrent attacks.
View details for DOI 10.1016/j.amjmed.2014.06.036
View details for PubMedID 25016127
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- An uncommon 3.4-Mb interstitial deletion at 3q29. Clinical dysmorphology 2010; 19 (3): 133-136