Genotype and protein expression after bone marrow transplantation for adrenoleukodystrophy.
BACKGROUND
X-linked adrenoleukodystrophy (X-ALD) is the most common inherited peroxisomal disorder. It is caused by impaired function of ALD protein that results in accumulation of very long-chain fatty acids in tissues and body fluids. So far, hematopoietic stem cell transplantation (HSCT) constitutes the only curative approach able to prevent the progression of cerebral X-ALD. However, biological mechanisms of this beneficial approach are still unknown.


OBJECTIVE
To describe the effect of HSCT in a family with various X-ALD disease forms by ALD mutation and protein expression analysis.


METHODS
In a family with various X-ALD forms, an ALD mutation screening was performed. Two boys had cerebral X-ALD and underwent HSCT. One of them is alive and well without any further neurological deterioration, whereas his cousin died of transplantation-related complications at day 76. The postmortem specimens were analyzed by genotyping and immunohistochemical assays.


RESULTS
All of the affected family members carry an as-yet-undescribed large ALD gene deletion (NC_000023:g.152512130-152520645del) resulting in a complete lack of ALD protein expression on immunofluorescence analysis. After engraftment, both patients who underwent HSCT showed complete chimerism in blood. Postmortem studies in 1 patient revealed both mutant and wild-type ALD sequences in each of 23 analyzed tissues, indicating mixed chimerism. Furthermore, immunohistochemical staining for ALD protein revealed no differences between patient and control tissues including blood cells, bone marrow, and glial cells as well as neurons.


CONCLUSIONS
To our knowledge, our analysis provides the first evidence for the stable development of a wild-type X-ALD genotype and peroxisomal ALD protein expression in a great variety of human tissues following HSCT.
Schönberger
Stefan
S
Clinic for Pediatric Oncology, Hematology, and Immunology, University Children's Hospital, Heinrich-Heine-University, Düsseldorf, Germany. schoenberger@med.uni-duesseldorf.de
Roerig
Peter
P
Schneider
Dominik T
DT
Reifenberger
Guido
G
Göbel
Ulrich
U
Gärtner
Jutta
J
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000293:Adolescent; D000326:Adrenoleukodystrophy / Q000235:genetics / Q000378:metabolism / Q000601:surgery; D000328:Adult; D016026:Bone Marrow Transplantation / Q000379:methods*; D002648:Child; D046528:Chimerism; D005192:Family Health; D005260:Female; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation
C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters