ABSTRACT
ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α-Aminoadipic semialdehyde (α-AASA) and Δ1-piperideine-6-carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6-oxo-pipecolic acid (6-oxo-PIP) also accumulates in the urine, CSF and plasma of ALDH7A1-deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6-oxo-PIP in urine from a cohort of 30 patients where α-AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6-oxo-PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α-AASA levels. Longitudinal analysis of urine samples from ALDH7A1-deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6-oxo-PIP remained elevated whilst α-AASA decreased. Similar to α-AASA, we found that elevated urinary excretion of 6-oxo-PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6-oxo-PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long-term side effects.
ABSTRACT
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a neurometabolic disorder in the lysine metabolism pathway. In 2014 and 2021, the International PDE consortium published consensus guidelines about diagnosis and management. In this follow-on, a literature review was performed and nutrition management was evaluated through an international dietary questionnaire with 40 respondents. This manuscript discusses consensus dietary statements and the practical provision of lysine reduction therapies. Results from the questionnaire, statements from the PDE consensus guidelines, new data from the literature, as well as clinical practice experience of the metabolic dietitian group form the basis of these updated practical diet recommendations. These dietary management recommendations can support dietitians, nutritionists, and physicians in initiation and monitoring of lysine reduction therapies for PDE-ALDH7A1 patients and families.
ABSTRACT
The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendation (CADRe) framework proposes that key components of informed consent for genetic testing can be covered with a targeted discussion for many conditions rather than a time-intensive traditional genetic counseling approach. We surveyed US genetics professionals (medical geneticists and genetic counselors) on their response to scenarios that proposed core informed consent concepts for clinical genetic testing developed in a prior expert consensus process. The anonymous online survey included responses to 3 (of 6 possible) different clinical scenarios that summarized the application of the core concepts. There was a binary (yes/no) question asking respondents whether they agreed the scenarios included the minimum necessary and critical educational concepts to allow an informed decision. Respondents then provided open-ended feedback on what concepts were missing or could be removed. At least one scenario was completed by 238 respondents. For all but one scenario, over 65% of respondents agreed that the identified concepts portrayed were sufficient for an informed decision; the exome scenario had the lowest agreement (58%). Qualitative analysis of the open-ended comments showed no consistently mentioned concepts to add or remove. The level of agreement with the example scenarios suggests that the minimum critical educational components for pre-test informed consent proposed in our prior work is a reasonable starting place for targeted pre-test discussions. This may be helpful in providing consistency to the clinical practice of both genetics and non-genetics providers, meeting patients' informational needs, tailoring consent for psychosocial support, and in future guideline development.
Subject(s)
Counselors , Humans , Informed Consent/psychology , Disclosure , Genetic Testing , Educational Status , Genetic Counseling/psychologyABSTRACT
BACKGROUND AND OBJECTIVES: Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is a developmental epileptic encephalopathy characterized by seizure improvement after pyridoxine supplementation. Adjunct lysine reduction therapies reduce the accumulation of putative neurotoxic metabolites with the goal to improve developmental outcomes. Our objective was to examine the association between treatment with lysine reduction therapies and cognitive outcomes. METHODS: Participants were recruited from within the International Registry for Patients with Pyridoxine-Dependent Epilepsy from August 2014 through March 2021. The primary outcome was standardized developmental test scores associated with overall cognitive ability. The relationship between test scores and treatment was analyzed with multivariable linear regression using a mixed-effects model. A priori, we hypothesized that treatment in early infancy with pyridoxine and lysine reduction therapies would result in a normal developmental outcome. A sub-analysis was performed to evaluate the association between cognitive outcome and lysine reduction therapies initiated in the first six months of life. RESULTS: A total of 112 test scores from 60 participants were available. On average, treatment with pyridoxine and lysine reduction therapies was associated with a non-significant increase of 6.9 points (95% CI -2.7 to 16.5) on developmental testing compared to treatment with pyridoxine alone. For the sub-analysis, a total of 14 developmental testing scores were available from 8 participants. On average, treatment with pyridoxine and lysine reduction therapies in the first six months of life was associated with a significant increase of 21.9 points (95% CI 1.7 to 42.0) on developmental testing. DISCUSSION: Pyridoxine and lysine reduction therapies at any age was associated with mild improvement in developmental testing and treatment in early infancy was associated with a clinically significant increase in developmental test scores. These results provide insight into the mechanism of intellectual and developmental disability in PDE-ALDH7A1 and emphasize the importance of treatment in early infancy with both pyridoxine and lysine reduction therapies. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in PDE-ALDH7A1, pyridoxine plus lysine reduction therapies compared to pyridoxine alone is not significantly associated with overall higher developmental testing scores, but treatment in the first six months of life is associated with significantly higher developmental testing scores.
ABSTRACT
We describe a neonate and a 14-month-old child presenting with seizures that were not (completely) controlled with antiepileptic medications. There were no signs of infection, and electrolytes and neuroimaging were normal. In the neonate, pyridoxine was administered followed by cessation of seizures, and a diagnosis of pyridoxine-dependent epilepsy (PDE-ALDH7A1, a neurometabolic disorder of lysine metabolism) was genetically confirmed. The 14-month-old child received a genetic diagnosis of PDE-ALDH7A1 after abnormalities in the metabolic investigations. Both children were treated with pyridoxine and adjunct lysine reduction therapy (LRT). Seizures were controlled completely, but both children are developmentally delayed. During her second pregnancy, the mother of the neonate was started on pyridoxine treatment because of the risk of PDE-ALDH7A1. After delivery, pyridoxine treatment was continued in the neonate, who did not show any clinical symptoms. Molecular analysis identified the familial variants consistent with the diagnosis of PDE-ALDH7A1. Adjunct LRT was initiated. This child has never experienced seizures, and development has been completely normal thus far (age 2.9 years), despite the shared genotype with their sibling with developmental delays (DDs). In conclusion, in neonates, infants, and children presenting with seizures of unknown origin with partial or no response to common antiepileptic medications, the diagnosis of PDE-ALDH7A1 or other pyridoxine-responsive genetic epilepsies should be considered, prompting a trial of pyridoxine as "diagnostic therapeuticum." The digital application Treatable-ID (treatable-id.org) can support clinicians in the early diagnosis of treatable conditions in patients presenting with DD/intellectual disability of unknown cause.
Subject(s)
Anticonvulsants/therapeutic use , Clinical Reasoning , Pyridoxine/therapeutic use , Seizures/diagnosis , Vitamin B Complex/therapeutic use , Aldehyde Dehydrogenase/genetics , Aldehyde Dehydrogenase/therapeutic use , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Lysine/administration & dosage , Seizures/drug therapy , Seizures/etiology , Seizures/geneticsABSTRACT
BACKGROUND: Seventy-five percent of patients with pyridoxine-dependent epilepsy due to α-aminoadipic semialdehyde dehydrogenase deficiency (PDE-ALDH7A1) suffer intellectual developmental disability despite pyridoxine treatment. Adjunct lysine reduction therapies (LRT), aimed at lowering putative neurotoxic metabolites, are associated with improved cognitive outcomes. However, possibly due to timing of treatment, not all patients have normal intellectual function. METHODS: This retrospective, multi-center cohort study evaluated the effect of timing of pyridoxine monotherapy and pyridoxine with adjunct LRT on neurodevelopmental outcome. Patients with confirmed PDE-ALDH7A1 with at least one sibling with PDE-ALDH7A1 and a difference in age at treatment initiation were eligible and identified via the international PDE registry, resulting in thirty-seven patients of 18 families. Treatment regimen was pyridoxine monotherapy in ten families and pyridoxine with adjunct LRT in the other eight. Primary endpoints were standardized and clinically assessed neurodevelopmental outcomes. Clinical neurodevelopmental status was subjectively assessed over seven domains: overall neurodevelopment, speech/language, cognition, fine and gross motor skills, activities of daily living and behavioral/psychiatric abnormalities. RESULTS: The majority of early treated siblings on pyridoxine monotherapy performed better than their late treated siblings on the clinically assessed domain of fine motor skills. For siblings on pyridoxine and adjunct LRT, the majority of early treated siblings performed better on clinically assessed overall neurodevelopment, cognition, and behavior/psychiatry. Fourteen percent of the total cohort was assessed as normal on all domains. CONCLUSION: Early treatment with pyridoxine and adjunct LRT may be beneficial for neurodevelopmental outcome. When evaluating a more extensive neurodevelopmental assessment, the actual impairment rate may be higher than the 75% reported in literature. TAKE- HOME MESSAGE: Early initiation of lysine reduction therapies adjunct to pyridoxine treatment in patients with PDE-ALDH7A1 may result in an improved neurodevelopmental outcome.
Subject(s)
Lysine , Pyridoxine , Activities of Daily Living , Cohort Studies , Epilepsy , Humans , Pyridoxine/therapeutic use , Retrospective StudiesABSTRACT
Pyridoxine-dependent epilepsy due to mutations in ALDH7A1 (PDH-ALDH7A1) is a highly treatable developmental and epileptic encephalopathy. Pharmacologic doses of pyridoxine are associated with dramatic clinical seizure improvement, and most patients achieve adequate seizure control with pyridoxine alone. Unfortunately, some patients with PDE-ALDH7A1 have died prior to when the diagnosis was made and subsequent treatment with pyridoxine could be implemented, highlighting the importance of a timely diagnosis. Although critical for seizure control, pyridoxine treatment alone is not sufficient for normal outcomes as most patients suffer intellectual and developmental delay. Adjunct lysine reduction therapies are associated with significant developmental improvements, although these treatments have limited efficacy if delayed after the first few months of life. Recently two biomarkers were identified that overcome previous technical hurdles for newborn screening. Herein we provide commentary that PDE-ALDH7A1 meets both current and historic criteria for newborn screening, and that a neonatal diagnosis and treatment can both reduce mortality from uncontrolled seizures and significantly improve the cognitive delay that is pervasive in this treatable disorder.
Subject(s)
Neonatal Screening , Pyridoxine , Aldehyde Dehydrogenase/genetics , Epilepsy , Humans , Infant, Newborn , Pyridoxine/therapeutic use , Seizures/diagnosis , Seizures/geneticsABSTRACT
PURPOSE: Informed consent for genetic testing has historically been acquired during pretest genetic counseling, without specific guidance defining which core concepts are required. METHODS: The Clinical Genome Resource (ClinGen) Consent and Disclosure Recommendations Workgroup (CADRe) used an expert consensus process to identify the core concepts essential to consent for clinical genetic testing. A literature review identified 77 concepts that are included in informed consent for genetic tests. Twenty-five experts (9 medical geneticists, 8 genetic counselors, and 9 bioethicists) completed two rounds of surveys ranking concepts' importance to informed consent. RESULTS: The most highly ranked concepts included: (1) genetic testing is voluntary; (2) why is the test recommended and what does it test for?; (3) what results will be returned and to whom?; (4) are there other types of potential results, and what choices exist?; (5) how will the prognosis and management be impacted by results?; (6) what is the potential family impact?; (7) what are the test limitations and next steps?; and (8) potential risk of genetic discrimination and legal protections. CONCLUSION: Defining the core concepts necessary for informed consent for genetic testing provides a foundation for quality patient care across a variety of healthcare providers and clinical indications.
ABSTRACT
One of the most vital elements of management for patients with inborn errors of intermediary metabolism is the promotion of anabolism, the state in which the body builds new components, and avoidance of catabolism, the state in which the body breaks down its own stores for energy. Anabolism is maintained through the provision of a sufficient supply of substrates for energy, as well as critical building blocks of essential amino acids, essential fatty acids, and vitamins for synthetic function and growth. Patients with metabolic diseases are at risk for decompensation during prolonged fasting, which often occurs during illnesses in which enteral intake is compromised. During these times, intravenous nutrition must be supplied to fully meet the specific nutritional needs of the patient. We detail our approach to intravenous management for metabolic patients and its underlying rationale. This generally entails a combination of intravenous glucose and lipid as well as early introduction of protein and essential vitamins. We exemplify the utility of our approach in case studies, as well as scenarios and specific disorders which require a more careful administration of nutritional substrates or a modification of macronutrient ratios.
Subject(s)
Metabolism, Inborn Errors/complications , Metabolism, Inborn Errors/therapy , Metabolism , Administration, Intravenous , Child , Diet, Ketogenic , Glucose/administration & dosage , Humans , Lipids/administration & dosage , Nutritional Status , Vitamins/administration & dosageABSTRACT
BACKGROUND: Genetic information is increasingly relevant across healthcare. Traditional genetic counseling (GC) may limit access to genetic information and may be more information and support than some individuals need. We report on the application and clinical implications of a framework to consistently integrate genetics expertise where it is most useful to patients. METHODS: The Clinical Genome Resource's (ClinGen) Consent and Disclosure Recommendations (CADRe) workgroup designed rubrics to guide pre- and post-genetic test communication. Using a standard set of testing indications, pre- and post-test rubrics were applied to 40 genetic conditions or testing modalities with diverse features, including variability in levels of penetrance, clinical actionability, and evidence supporting a gene-disease relationship. Final communication recommendations were reached by group consensus. RESULTS: Communication recommendations were determined for 478 unique condition-indication or testing-indication pairs. For half of the conditions and indications (238/478), targeted discussions (moderate communication depth) were the recommended starting communication level for pre- and post-test conversations. Traditional GC was recommended pre-test for adult-onset neurodegenerative conditions for individuals with no personal history and post-test for most conditions when genetic testing revealed a molecular diagnosis as these situations are likely higher in complexity and uncertainty. A brief communication approach was recommended for more straightforward conditions and indications (e.g., familial hypercholesterolemia; familial variant testing). CONCLUSIONS: The CADRe recommendations provide guidance for clinicians in determining the depth of pre- and post-test communication, strategically aligning the anticipated needs of patients with the starting communication approach. Shorter targeted discussions or brief communications are suggested for many tests and indications. Longer traditional GC consultations would be reserved for patients with more complex and uncertain situations where detailed information, education, and psychological support can be most beneficial. Future studies of the CADRe communication framework will be essential for determining if CADRe-informed care supports quality patient experience while improving access to genetic information across healthcare.
Subject(s)
Communication , Genetic Testing , Disclosure , Humans , Informed ConsentABSTRACT
Segmental duplications (SDs) are a class of long, repetitive DNA elements whose paralogs share a high level of sequence similarity with each other. SDs mediate chromosomal rearrangements that lead to structural variation in the general population as well as genomic disorders associated with multiple congenital anomalies, including the 7q11.23 (Williams-Beuren Syndrome, WBS), 15q13.3, and 16p12.2 microdeletion syndromes. Population-level characterization of SDs has generally been lacking because most techniques used for analyzing these complex regions are both labor and cost intensive. In this study, we have used a high-throughput technique to genotype complex structural variation with a single molecule, long-range optical mapping approach. We characterized SDs and identified novel structural variants (SVs) at 7q11.23, 15q13.3, and 16p12.2 using optical mapping data from 154 phenotypically normal individuals from 26 populations comprising five super-populations. We detected several novel SVs for each locus, some of which had significantly different prevalence between populations. Additionally, we localized the microdeletion breakpoints to specific paralogous duplicons located within complex SDs in two patients with WBS, one patient with 15q13.3, and one patient with 16p12.2 microdeletion syndromes. The population-level data presented here highlights the extreme diversity of large and complex SVs within SD-containing regions. The approach we outline will greatly facilitate the investigation of the role of inter-SD structural variation as a driver of chromosomal rearrangements and genomic disorders.
Subject(s)
Chromosome Disorders/genetics , Craniofacial Abnormalities/genetics , Genomic Structural Variation , Heart Defects, Congenital/genetics , Intellectual Disability/genetics , Segmental Duplications, Genomic , Seizures/genetics , Williams Syndrome/genetics , Chromosome Breakpoints , Chromosome Deletion , Chromosomes, Human, Pair 15/genetics , Chromosomes, Human, Pair 16/genetics , Developmental Disabilities/genetics , Humans , Mental Disorders/geneticsABSTRACT
BACKGROUND: As severe obesity continues to rise among youth, metabolic and bariatric surgery (MBS) will increasingly be used as a treatment of choice for durable weight loss and improvement of obesity-related complications. MBS for youth with intellectual and developmental disabilities (IDD) and for preadolescents has raised ethical questions. OBJECTIVES: The purpose of this article is to present the creation and application of an ethical framework that supports why MBS should be considered in pediatrics based on the principle of justice without automatic exclusions. This framework also provides a guide for how to conduct a robust, ethically grounded evaluation of pediatric patients presenting for MBS in general, and among subpopulations including youth with IDD and preadolescents. SETTING: Academic medical center, United States. METHODS: An ethical framework was developed and applied through a collaboration between an MBS center at a children's hospital and the institution's ethics consult service. RESULTS: Application of the ethical framework to address 4 core ethical questions is illustrated using 2 hypothetical cases: 1 that highlights an adolescent with IDD and 1 that highlights a preadolescent. CONCLUSIONS: We have demonstrated the application of a novel, overarching framework to conduct the ethical evaluation of youth presenting for MBS. This framework resulted from a collaboration between MBS and ethics consult teams and has the potential to be used as a prototype for other youth-focused MBS programs. Next steps include prospective data collection to test the framework and determine its validity in the target population.
Subject(s)
Bariatric Surgery , Obesity, Morbid , Pediatrics , Adolescent , Child , Humans , Obesity, Morbid/surgery , Prospective Studies , United States , Weight LossABSTRACT
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive condition due to a deficiency of α-aminoadipic semialdehyde dehydrogenase, which is a key enzyme in lysine oxidation. PDE-ALDH7A1 is a developmental and epileptic encephalopathy that was historically and empirically treated with pharmacologic doses of pyridoxine. Despite adequate seizure control, most patients with PDE-ALDH7A1 were reported to have developmental delay and intellectual disability. To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy. These lysine-reduction therapies have resulted in improved biochemical parameters and cognitive development in many but not all patients. The goal of these consensus guidelines is to re-evaluate and update the two previously published recommendations for diagnosis, treatment, and follow-up of patients with PDE-ALDH7A1. Members of the International PDE Consortium initiated evidence and consensus-based process to review previous recommendations, new research findings, and relevant clinical aspects of PDE-ALDH7A1. The guideline development group included pediatric neurologists, biochemical geneticists, clinical geneticists, laboratory scientists, and metabolic dieticians representing 29 institutions from 16 countries. Consensus guidelines for the diagnosis and management of patients with PDE-ALDH7A1 are provided.
Subject(s)
Arginine/administration & dosage , Dietary Supplements , Epilepsy/diet therapy , Epilepsy/diagnosis , Aldehyde Dehydrogenase/deficiency , Consensus , Epilepsy/drug therapy , Humans , International Cooperation , Lysine/deficiency , Pyridoxine/therapeutic useABSTRACT
Glutaric aciduria type 1 (GA-1) is a cerebral organic aciduria characterized by striatal injury and progressive movement disorder. Nutrition management shifted from a general restriction of intact protein to targeted restriction of lysine and tryptophan. Recent guidelines advocate for a low-lysine diet using lysine-free, tryptophan-reduced medical foods. GA-1 guideline recommendations for dietary management of patients over the age of six are unclear, ranging from avoiding excessive intake of intact protein to counting milligrams of lysine intake. A 22-question survey on the nutrition management of GA-1 was developed with the goal of understanding approaches to diet management for patients identified by newborn screening under age six years compared to management after diet liberalization, as well as to gain insight into how clinicians define diet liberalization. Seventy-six responses (25% of possible responses) to the survey were received. Nutrition management with GA-1 is divergent among surveyed clinicians. There was congruency among survey responses to the guidelines, but there is still uncertainty about how to counsel patients on diet optimization and when diet liberalization should occur. Ongoing clinical research and better understanding of the natural history of this disease will help establish stronger recommendations from which clinicians can best counsel families.
Subject(s)
Amino Acid Metabolism, Inborn Errors/diet therapy , Brain Diseases, Metabolic/diet therapy , Child Nutritional Physiological Phenomena/physiology , Diet Therapy/methods , Dietary Proteins/administration & dosage , Glutaryl-CoA Dehydrogenase/deficiency , Infant Nutritional Physiological Phenomena/physiology , Lysine/adverse effects , Tryptophan/adverse effects , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Practice Guidelines as Topic , Recommended Dietary Allowances , Surveys and QuestionnairesABSTRACT
We used whole-exome sequencing (WES) to determine the genetic etiology of a patient with a multi-system disorder characterized by a seizure phenotype. WES identified a heterozygous de novo missense mutation in the GABRA1 gene (c.875C>T). GABRA1 encodes the alpha subunit of the gamma-aminobutyric acid receptor A (GABAAR). The GABAAR is a ligand gated ion channel that mediates the fast inhibitory signals of the nervous system, and mutations in the subunits that compose the GABAAR have been previously associated with human disease. To understand the mechanisms by which GABRA1 regulates brain development, we developed a zebrafish model of gabra1 deficiency. gabra1 expression is restricted to the nervous system and behavioral analysis of morpholino injected larvae suggests that the knockdown of gabra1 results in hypoactivity and defects in the expression of other subunits of the GABAAR. Expression of the human GABRA1 protein in morphants partially restored the hypomotility phenotype. In contrast, the expression of the c.875C>T variant did not restore these behavioral deficits. Collectively, these results represent a functional approach to understand the mechanisms by which loss-of-function alleles cause disease.
Subject(s)
Gene Expression , Motor Activity/genetics , Protein Subunits/genetics , Receptors, GABA-A/genetics , Zebrafish , Alleles , Amino Acid Sequence , Animals , Gene Knockdown Techniques , Genetic Association Studies , Heterozygote , Humans , Larva , Locomotion/genetics , Mutation , Phenotype , Protein Subunits/chemistry , Receptors, GABA-A/chemistry , Receptors, GABA-A/metabolismABSTRACT
Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.
Subject(s)
Hydrogen Sulfide/metabolism , Leigh Disease/enzymology , Mitochondria/metabolism , Oxidoreductases Acting on Sulfur Group Donors/genetics , Quinone Reductases/physiology , Acidosis, Lactic/pathology , Brain Diseases/pathology , Child, Preschool , Electron Transport Complex IV/metabolism , Family , Female , Homozygote , Humans , Hydrogen Sulfide/chemistry , Kinetics , Leigh Disease/metabolism , Magnetic Resonance Imaging , Male , Oxidation-Reduction , Quinone Reductases/chemistryABSTRACT
The National Institutes of Health (NIH) established the Rare Diseases Clinical Research Network to address the unique challenges of performing research on rare diseases. The Urea Cycle Disorders Consortium (UCDC) was one of the original ten consortia established. The UCDC represents a unique partnership among clinicians, patients, and the NIH with a primary goal of increasing the development of therapeutics that improve patient outcomes for persons affected with a UCD. Based in part on financial incentives associated with the Orphan Drug Act biopharmaceutical and investment entities have an intense interest in engaging with research consortia like the UCDC, which have compiled potentially valuable longitudinal data characterizing outcomes in a relatively large number of affected individuals. We describe the UCDC experience and the bases for evaluating partnerships with such private entities. We review early industry interactions, the development of policies and procedures, and describe the establishment of an Industry Relations Committee, including guiding principles. Challenges encountered, particularly in the transition when products are approved, and potential solutions are discussed. By building a framework for industry partnerships that guides us in resolving inevitable challenges, we can enthusiastically pursue novel and promising collaborations that can lead to breakthroughs in therapeutic interventions for patients.
Subject(s)
Orphan Drug Production/legislation & jurisprudence , Rare Diseases/drug therapy , Urea Cycle Disorders, Inborn/drug therapy , Drug Industry , Humans , National Institutes of Health (U.S.) , Public-Private Sector Partnerships , United StatesABSTRACT
Historically, both pretest and posttest genetic counseling has been standard of care for genetic testing. This model should be adapted for primary care providers (PCPs) willing to learn critical information about the test and key concepts that patients need to make an informed testing decision. It is helpful for PCPs to discuss a few initial patients with a genetic counselor to prepare for the key concepts of pretest and posttest counseling. This article provides guidance about the recommended level of involvement of PCPs based on the test indication, test complexity, disorder management, and the potential for psychosocial sequela.