Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

Clinical trial: Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome

Summary: Background:
  Nicotinamide riboside (NR) is a vitamin B3 dietary supplement. It may help improve muscle function, that may in turn may improve a person s exercise capacity. Researchers want to study how skeletal muscle responds to NR in an individual who has Li-Fraumeni Syndrome and slow muscle energy recovery after exercise.
  Objective:
  To study how nicotinamide riboside affects skeletal muscle after exercise.
  Eligibility:
  One person at least 18 years old with Li-Fraumeni syndrome and a certain gene mutation
  Design:
  The participant will be screened with a medical history, physical exam, and blood and urine tests.
  The participant may also have a heart test.
  The participant will maintain their regular diet and supplements during the study.
  The participant will take the study drug as 1-4 tablets twice a day for 12 weeks. The participant may be contacted with reminders and questions about side effects.
  The participant will have 4-5 visits over 18-30 weeks. At visits, the participant will repeat screening tests. At some visits they will also have:
  -  Ultrasound of the heart with a wand placed on the chest.
  -  Test of oxygen used at rest and exercise, while wearing a face mask.
  -  Exercise test on a treadmill or bicycle with electrodes on the skin.
  -  Magnetic resonance spectroscopy. The participant will have no caffeine for 12 hours. Then they will lie in a machine for about 2 hours. Sometimes they will lie still. Sometimes they will be asked to move.
  Health questionnaire
  The participant may have a skin sample taken by needle.
  The participant will be withdrawn from the study if they become pregnant.

Detailed description: We have previously reported that inherited mutations of TP53, which causes the premature cancer disorder Li-Fraumeni syndrome (LFS), can promote mitochondrial function both in patients and mouse models. In the course of our follow up studies, we encountered a LFS patient with a long-standing history of fatigue and muscle weakness of unclear etiology. Notably, we observed in vivo evidence of markedly decreased mitochondrial function in her leg skeletal muscle during exercise using noninvasive phosphorus-31 magnetic resonance spectroscopy (31P-MRS), a technique that has previously been used to study patients with primary mitochondrial disorders. The decrease in mitochondrial function was also confirmed by the patient s skin fibroblasts in vitro using standard biochemical measurements.
  There is growing evidence that nicotinamide adenine dinucleotide (NAD+) homeostasis plays a significant role in maintaining the mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. Remarkably, we observed that culturing the LFS patient s fibroblasts in medium containing NR rescued the severe deficit in mitochondrial respiration. While continuing our investigations into the molecular mechanism(s) underlying the mitochondrial dysfunction observed in this patient, the in vitro rescue of the respiratory deficiency by NR presents a unique opportunity to investigate whether it can also be observed in vivo using skeletal muscle 31P-MRS. We propose to explore the effect of NR, currently available as a dietary supplement, on in vivo mitochondrial function in this LFS patient.

Eligibility: -  INCLUSION CRITERIA:
  -  At least 18-years of age and able to give informed consent
  -  Have delayed PCr recovery time constant >45 sec by 31P-MRS testing and a history of fatigue symptoms
  -  Ability to undergo study procedures, including scheduled visits, blood draws and skeletal muscle exercise NMR spectroscopy
  -  Have Li-Fraumeni syndrome and confirmed TP53 mutation by genetic testing
  -  Committed to using reliable contraception which may include abstinence during study participation
  -  Female participants of child-bearing ability and potential willing to commit to reliable contraception while participating in the study
  EXCLUSION CRITERIA:
  -  Current systemic treatment for cancer
  -  Unable to perform required study visits or procedures
  -  MRI incompatible hardware
  -  Pregnant or breastfeeding women
  -  History of intolerance to NR precursor compounds, including niacin or nicotinamide

Relevance to patient case: not relevant