Living-Donor Liver Transplantation From a Heterozygous Parent for Infantile Refsum Disease

Abstract

Infantile Refsum disease (IRD) is a rare autosomal recessive disorder of peroxisome biogenesis characterized by generalized peroxisomal metabolic dysfunction, including accumulation of very long-chain fatty acids (VLCFAs) and phytanic acid (PA), as well as decreased plasmalogen contents (PL). An effective therapy for this intractable disease has not been established, and only supportive management with docosahexaenoic acid supplementation and low PA diet has been reported so far. A boy of 3 years and 8 months presented with facial dysmorphism, transaminitis, and psychomotor retardation. Biochemical analysis showed elevated PA and VLCFAs, with reduced PL in the serum. Immunofluorescence study of fibroblasts from the patient indicated a mosaic pattern of catalase-positive and -negative particles, and molecular analysis revealed compound heterozygous mutations of PEX6. The failure of medical management to prevent the progression of clinical symptoms and abnormal biochemistry prompted us to consider liver transplantation (LT). With the chances of receiving a deceased donor liver being poor, we performed a living-donor LT from the patient’s heterozygous mother. At 6-month follow-up, the patient’s serum PA levels had normalized. VLCFAs and PL levels had declined and increased, respectively. To the best of our knowledge, this is the second reported case in which IRD was treated by living-donor LT by using a heterozygous donor. Only long-term follow-up will reveal if there is any clinical improvement in the present case. With the liver being a major site for peroxisomal pathways, its replacement by LT may work as a form of partial enzyme therapy for patients with IRD.

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

“…Following LT, the phytanic acid levels normalized in all patients as the new allografted liver cleared the toxic metabolite (Figure , Table ). Similar observation was made by the Japanese team that has also recently performed LT for mild ZSD . In the long term, P #1's low‐phytanic acid diet became more liberal (ie, she now eats green vegetables, fish, and red meat).…”

“…Moreover, ZSD diagnosis before neurological deficit appears is rendered possible as C26:0‐lysophosphatidylcholine level assessment has recently been added to the newborn screening in the United States for the early detection of X‐linked adrenoleukodystrophy, a related peroxisomal disorder . Although we and others have achieved significant improvements in this disease usually associated with dismal outcomes, further evaluation is required to strengthen the place of LT as a therapy to modify the natural history of ZSD and to identify children who would most likely benefit from this approach. Among the promising future therapies, adult‐derived liver stem/progenitor cells hold significant promise as demonstrated by initial in vitro data…”

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 …”

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

“…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].…”