Acute Nutritional Ketosis in VLCAD Deficiency: testing the metabolic basis for therapeutic use

Very Long-Chain Acyl-CoA Dehydrogenase deficiency (VLCADD) is an inborn error
of fatty acid metabolism with a broad clinical presentation ranging from infant
fatality to exercise intolerance and elevated risk of exertional rhabdomyolysis
in symptomatic adult patients. We recently obtained evidence that these
symptoms are in part due to a lower energetic efficiency of upper leg muscle
fibers that aggravates reliance on carbohydrate stores in this disease,
rendering the organ vulnerable to an exertional energy crisis. While no
effective treatment has been available for VLCADD, it has long been proposed
that nutritional ketosis (NK) could be highly beneficial to patients. Amongst
others, ketone bodies could take on the role of primary energy source in
exercising muscle. The problem has been that, until now, no vehicle for
establishing NK in humans without undesired side effects has been available. A
breakthrough has finally been achieved by collaborator Kieran Clarke in Oxford
whose team has recently produced an edible ketone ester that can achieve acute
NK in human subjects via oral ingestion without any undesired side-effects. It
was found that the ketone ester produced significant physical performance
enhancement in rodents and human athletes. The effect has been attributed to
enhanced muscle mitochondrial function in addition to glycogen sparing. Here,
we will investigate if acute NK in adult symptomatic VLCAD deficient patients
can boost muscle mitochondrial function in vivo. If so, a rational basis will
have been established for therapeutic use in this metabolic myopathy. As such,
this study constitutes a vital first step towards possible validation of an
effective treatment for patients with VLCADD that may improve the quality of
life including an active lifestyle with overall health benefits.

To test if acute NK boosts muscle mitochondrial function in vivo in patients
with VLCADD in order to establish a rational basis for therapeutic use in this
disorder.
A secondary objective is to gather data to test the working hypothesis that the
positive effect of acute NK on muscle mitochondrial function results from
enhanced substrate supply to the tricyclic acid (TCA) cycle.

A randomised, blinded, placebo controlled, 2-way cross over trial.

The burden of collecting tissue samples from the quadriceps muscle by
microbiopsy is rated as moderate. As such, this intervention will only be
performed on a voluntary basis. The burden of microbiopsy is considered
justifiable.

In the short, maximum exercise test in session 1 anaerobic derived energy will
be used. As patients with VLCADD do not have a problem in glycolysis, the
burden for this test will be nihil.
The endurance test at submaximal level (session 2 and 3) might induce muscle
pain temporarily. The burden for patients is classified as minimal and patients
will be monitored accordingly during the study period.

Blood will be drawn intravenously from patients; this implies a minimal burden.

The safety of the nutritional drinks that will be administered and the expected
acute, transient mild ketosis has been thoroughly tested and documented in
healthy subjects. The drink has been designated as Generally Recognized as Safe
by the Federal Drug Administration of the United States allowing it to be used
as a foodstuff in the USA. No particular risk for VLCADD patients is expected
with respect to oral ingestion of the ketone ester since its metabolites are
natural, organic compounds.

Concerning the MRI-scanner, participants will be exposed to a field strength of
3 Tesla and scanner noise. Thus far, there is no evidence to suggest that
exposing humans to a magnetic field of this strenght has a negative influence
on health. With regard to the noise earplugs and headphones will be provided.