Cholic acid treatment in Peroxisomal Biogenesis Disorders (Zellweger spectrum): biochemical and clinical effects.

Zellweger spectrum disorder is a severe disabling disorder with a short life
expectancy. At least some of the clinical abnormalities including severe liver
dysfunction, growth retardation and neurological abnormalities in this disorder
are caused by the accumulation of bile acid intermediates. Bile acid
supplementation by cholic acid has been shown to decrease endogenous bile acid
production, stimulate bile secretion and to improve bile flow and micellar
solubilization. We hypothesize that cholic acid supplementation improves liver
function and alleviates neurological symptoms by suppressing the endogenous
bile acid synthesis and stimulating bile flow, thus decreasing the accumulation
of toxic and cholestatic bile acid intermediates. In addition, we hypothesize
that cholic acid suppletion in mild Zellweger spectrum patients improves
intestinal fat absorption and growth by increasing the amount of intraluminal
bile acids, thus promoting micellar solubilization.

To investigate the effect of cholic acid supplementation on the clinical and
biochemical parameters of Zellweger spectrum disorder

The original study was an open label pilot study with a 9-month run in period
and a 9 months treatment period. We will extend the treatment phase with one
additional year.
Cholic acid will be supplemented at a regular dose

cholic acid supplementation during 1 year and 9 months

Zellweger spectrum disorder is a unique congenital disease and progressive
damage starts in utero and continues from birth onwards. Therapeutic treatment
from young age is therefore most relevant. This therapeutic study studies
clinical outcomes of cholic acid supplementation which are relevant for the
participating subjects.
The burden to the subjects is limited as most investigations are performed
during 2 standard clinical visits and blood sampling is part of standard care
during these visits (650uL blood extra is sampled at each visit). During the
standard visits the extra interventions are urine collection using urine
collection bags, neurological mile stone determination, fibroscan measurements,
handing over the food diary and in those with epilepsy also a diary of
convulsions. The neurological evaluation an will be only be a minimal time
burden. Fibroscan maeasurement is a one minute, safe, non-invasive and painless
procedure. Diet evaluation using a diary and keeping a diary of convulsions is
a limited effort for patients or care-takers.
Only one extra visit to the hospital is required (week 26). Length and weight
are measured, extra blood sampling is performed (volume 550 uL) and urine is
collected using an urine collection bag(minimal volume 5 ml).
Cholic acid is an endogenous substance and excellent safety reports of long
term use have been published in one case of Zellweger spectrum and several
cases of other bile acid metabolism disorders.