Fanconi anemia (FA) is a rare inherited syndrome characterized not only by a high incidence of bone marrow failure, but also a high risk of hematopoietic and epithelial malignancies in children, adolescents, and young adults. Many individuals with FA present with congenital malformations. Minor anomalies can also be present suc h as low height and weight, microcephaly and/or microphthalmia. Emotionally speaking, individuals with FA are at risk for rejection by their peers and the general population due to these physical differences. Previous studies have found that 22-38% of persons with FA are underweight, suggestive of increased risk of developing malnutrition. Many persons with FA experience gastrointestinal problems, such as nausea, diarrhea and/or constipation, early satiety, poor appetite and poor weight gain. It is likely that persons with FA are more prone to being malnourished because of the metabolic burden related to their disease and studies have also found that more than 50% have depleted muscle mass. Malnutrition and sarcopenia in an immunocompromised population can contribute to increased morbidity and mortality. Morbidity includes increased post-operative complications, prolonged hospitalizations that often times result from greater exposure to infectious agents and a lessened response to t reatment, as well as an overall poorer quality of life. As both standards of care and accurate nutritional/body compositionn assessments have evolved and improved, more studies are needed to address the association between sarcopenia, malnutrition and the mortality/morbidity of persons with FA.
To address the relationships between metabolic dysfunction and adverse outcomes, we first used steady-state NMR-based metabolomics to identify metabolic abnormalities relating to FA. We noted a number of metabolic abnormalities based on both urine and plasma profiles of persons with FA compared to non-FA matched controls, including accumulation of ketone bodies in the urine, dysregulation of compounds relating to thyroid hormone synthesis and acetaldehyde metabolism, and increased presence of free amino acids suggesting an increased push towards protein degradation in this population. We employed NMR-based SIRM techniques using orally administered uniformly 13C-labeled glucose for both pe rsons with FA and healthy non-FA matched controls under fasted conditions to determine impairments in glucose uptake and processing. We paired this approach with bionutritional assessments, indirect calorimetry for quantitative basal metabolic rate measurements and screening assays to assess hormone production and secretion to obtain a more robust picture of the overall impact of metabolic dysfunction in the FA population. With the goal to improve the clinical care affecting the growth and nutritional status in the FA community, our work aims are focused to develop treatment targets and nutritional supplement protocols that will improve the overall physical and emotional health and body image of persons with FA.