Sustained engraftment and tissue enzyme activity after liver cell transplantation for argininosuccinate lyase deficiency.
OBJECTIVE
Donor cell engraftment with expression of enzyme activity is the goal of liver cell transplantation for inborn errors of liver metabolism with a view to achieving sustained metabolic control.


METHODS
Sequential hepatic cell transplantations using male and female cells were performed in a 3.5-year-old girl with argininosuccinate lyase deficiency over a period of 5 months. Beside clinical, psychomotor, and metabolic follow-up, engraftment was analyzed in repeated liver biopsies (2.5, 5, 8, and 12 months after first infusion) by fluorescence in situ hybridization for the Y-chromosome and by measurement of tissue enzyme activity.


RESULTS
Metabolic control was achieved together with psychomotor catch-up, changing the clinical phenotype from a severe neonatal one to a moderate late-onset type. The child was no longer hospitalized and was able to attend normal school. Sustained engraftment of male donor liver cells was shown in repeated biopsies, reaching 19% at 8 months and 12.5% at the 12-month follow-up. XXYY tetraploid donor cells were mainly detected during the infusion period (2.5- and 5-month biopsies), whereas in the follow-up 8-month and 1-year biopsies, diploid donor cell subpopulations had become dominant. Moreover, argininosuccinate lyase activity, originally absent, became measurable in 2 different biopsy samples at 8 months, reaching 3% of control activity, indicating in situ metabolic effect and supporting the clinical evolution to a moderate form of the disease.


CONCLUSIONS
Liver cell transplantation can achieve donor cell engraftment in humans in a significant proportion, leading to sustained metabolic and clinical control with psychomotor catch-up.
Stéphenne
Xavier
X
Laboratoire d'hépatologie Pédiatrique et Transplantation Cellulaire, Département GYPE, Service de Pédiatrie, Université Catholique de Louvain & Cliniques St Luc, Brussels, Belgium.
Najimi
Mustapha
M
Sibille
Catherine
C
Nassogne
Marie-Cécile
MC
Smets
Françoise
F
Sokal
Etienne M
EM
D000641:Ammonia / Q000097:blood; D001123:Argininosuccinate Lyase / Q000378:metabolism; D001125:Argininosuccinic Acid / Q000097:blood / Q000652:urine; D056807:Argininosuccinic Aciduria; D002657:Child Development; D002675:Child, Preschool; D005260:Female; D006085:Graft Survival; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008099:Liver / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D008661:Metabolism, Inborn Errors / Q000503:physiopathology / Q000523:psychology / Q000601:surgery*; D011597:Psychomotor Performance; D013997:Time Factors; D018183:Transplantation Chimera; D000509:alpha-Fetoproteins / Q000378:metabolism
D000509:alpha-Fetoproteins; D001125:Argininosuccinic Acid; D000641:Ammonia; D001123:Argininosuccinate Lyase