Nutritional interventions in primary mitochondrial disorders: Developing an evidence base.

In December 2014, a workshop entitled "Nutritional Interventions in Primary Mitochondrial Disorders: Developing an Evidence Base" was convened at the NIH with the goals of exploring the use of nutritional interventions in primary mitochondrial disorders (PMD) and identifying knowledge gaps regarding their safety and efficacy; identifying research opportunities; and forging collaborations among researchers, clinicians, patient advocacy groups, and federal partners. Sponsors included the NIH, the Wellcome Trust, and the United Mitochondrial Diseases Foundation. Dietary supplements have historically been used in the management of PMD due to their potential benefits and perceived low risk, even though little evidence exists regarding their effectiveness. PMD are rare and clinically, phenotypically, and genetically heterogeneous. Thus patient recruitment for randomized controlled trials (RCTs) has proven to be challenging. Only a few RCTs examining dietary supplements, singly or in combination with other vitamins and cofactors, are reported in the literature. Regulatory issues pertaining to the use of dietary supplements as treatment modalities further complicate the research and patient access landscape. As a preface to exploring a research agenda, the workshop included presentations and discussions on what PMD are; how nutritional interventions are used in PMD; challenges and barriers to their use; new technologies and approaches to diagnosis and treatment; research opportunities and resources; and perspectives from patient advocacy, industry, and professional organizations. Seven key areas were identified during the workshop. These areas were: 1) defining the disease, 2) clinical trial design, 3) biomarker selection, 4) mechanistic approaches, 5) challenges in using dietary supplements, 6) standards of clinical care, and 7) collaboration issues. Short- and long-term goals within each of these areas were identified. An example of an overarching goal is the enrollment of all individuals with PMD in a natural history study and a patient registry to enhance research capability. The workshop demonstrates an effective model for fostering and enhancing collaborations among NIH and basic research, clinical, patient, pharmaceutical industry, and regulatory stakeholders in the mitochondrial disease community to address research challenges on the use of dietary supplements in PMD.

Expanding research to provide an evidence base for nutritional interventions for the management of inborn errors of metabolism.

A trans-National Institutes of Health initiative, Nutrition and Dietary Supplement Interventions for Inborn Errors of Metabolism (NDSI-IEM), was launched in 2010 to identify gaps in knowledge regarding the safety and utility of nutritional interventions for the management of inborn errors of metabolism (IEM) that need to be filled with evidence-based research. IEM include inherited biochemical disorders in which specific enzyme defects interfere with the normal metabolism of exogenous (dietary) or endogenous protein, carbohydrate, or fat. For some of these IEM, effective management depends primarily on nutritional interventions. Further research is needed to demonstrate the impact of nutritional interventions on individual health outcomes and on the psychosocial issues identified by patients and their families. A series of meetings and discussions were convened to explore the current United States' funding and regulatory infrastructure and the challenges to the conduct of research for nutritional interventions for the management of IEM. Although the research and regulatory infrastructure are well-established, a collaborative pathway that includes the professional and advocacy rare disease community and federal regulatory and research agencies will be needed to overcome current barriers.

Reduced expression of the cystic fibrosis transmembrane conductance regulator gene in the hypothalamus of patients with Alzheimer's disease.

BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an approximately 150-165 kD glycoprotein that is mutated in individuals with cystic fibrosis. Previous studies demonstrated expression of the CFTR gene in the hypothalamus, suggesting a potential role for this molecule in the regulation of systemic metabolic functions. Individuals with cystic fibrosis often exhibit wasting and marked reductions in body fat content. Since the hypothalamus is a late target of neurodegeneration in Alzheimer's disease (AD), we postulated that patients with end-stage AD and bodily wasting would have reduced levels of CFTR expression in the hypothalamus. METHODS: CFTR mRNA and protein were examined in postmortem hypothalamic tissue from 11 AD and 7 aged controls using in situ hybridization and immunohistochemical staining. Standardized sections that included the supra-optic, paraventricular, anterior, and ventromedial nuclei, and the lateral hypothalamus were studied. RESULTS: The density of CFTR+ neurons and the intensity of the CFTR hybridization signals were strikingly reduced in AD. Immunohistochemical staining studies demonstrated CFTR immunoreactivity most prominently distributed in small clusters of neurites (5 to 20 in number). Digital image quantification showed that the density of CFTR+ neurites was significantly reduced in AD relative to aged control samples (P=0.001). However, there was no evidence for selective involvement of particular hypothalamic nuclei. CONCLUSIONS: CFTR gene expression is down-regulated and its corresponding immunoreactivity reduced in AD relative to control hypothalamic tissue. Reduced CFTR expression in the hypothalamus may represent an important mechanism by which AD neurodegeneration contributes to body wasting in the late stages of disease.