Living‐donor liver transplantation for mild Zellweger spectrum disorder: Up to 17 years follow‐up

Abstract

Mild Zellweger spectrum disorder, also described as Infantile Refsum disease, is attributable to mutations in PEX genes. Its clinical course is characterized by progressive hearing and vision loss, and neurodevelopmental regression. Supportive management is currently considered the standard of care, as no treatment has shown clinical benefits. LT was shown to correct levels of circulating toxic metabolites, partly responsible for chronic neurological impairment. Of three patients having undergone LT for mild ZSD, one died after LT, while the other two displayed significant neurodevelopmental improvement on both the long-term (17 years post-LT) and short-term (9 months post-LT) follow-up. We documented a sustained improvement of biochemical functions, with a complete normalization of plasma phytanic, pristanic, and pipecolic acid levels. This was associated with stabilization of hearing and visual functions, and improved neurodevelopmental status, which has enabled the older patient to lead a relatively autonomous lifestyle on the long term. The psychomotor acquisitions have been markedly improved as compared to their affected siblings, who did not undergo LT and exhibited a poor neurological outcome with severe disabilities. We speculate that LT performed before the onset of severe sensorineural defects in mild ZSD enables partial metabolic remission and improved long-term clinical outcomes.

High Dose Versus Low Dose Syngeneic Hepatocyte Transplantation in Pex1-G844D NMRI Mouse Model is Safe but Does Not Achieve Long Term Engraftment

“…Yet, after short term effect resulting probably from circulating cells (up to day 5) spontaneous trend to biochemical normalization cannot be excluded as it has been reported in some mild ZSD patients [40]. Compared to LT, HT biochemical impact is reduced in ZSD patients [7].…”

“…Based on our experience of dramatic plasma pipecolic acid levels decrease shortly after LT and HT in ZSD patients [7,8], we chose to focus on this biochemical marker for the high dose HT protocol. As previously reported in our ZSD mouse model [18], plasma pipecolic acid levels were increased in ZSD mice.…”

“…Most mild ZSD patients survive into childhood, however no validated treatment is able to impact their progressive hepatic dysfunction and developmental delay [4]. In this context, we and others have obtained proof-of principle that liver-targeted therapies such as living donor liver transplantation (LT) and hepatocyte transplantation (HT) can modify disease progression in mild ZSD patients [5][6][7][8].…”

Hepatic symptoms and histology in 13 patients with a Zellweger spectrum disorder

“…Unfortunately, detailed data of C 27 -bile acid intermediates are missing. 32,33 A possible cause of the liver abnormalities are the C 27bile acid intermediates (ie, DHCA and THCA), which were increased in all patients (in groups 1 and 2). Due to impaired bile acid synthesis, these intermediates accumulate in plasma and organs of ZSD patients.…”

“…These studies showed normalization of phytanic acid, pristanic acid, and pipecolic acid in plasma after liver transplantation. Unfortunately, detailed data of C 27 ‐bile acid intermediates are missing …”