Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders.
X-linked adrenoleukodystrophy (X-ALD) results from mutations in ABCD1. ABCD1 resides on Xq28 and encodes an integral peroxisomal membrane protein (ALD protein [ALDP]) that is of unknown function and that belongs to the ATP-binding cassette-transporter superfamily. Individuals with ABCD1 mutations accumulate very-long-chain fatty acids (VLCFA) (carbon length >22). Childhood cerebral X-ALD is the most devastating form of the disease. These children have the earliest onset (age 7.2 +/- 1.7 years) among the clinical phenotypes for ABCD1 mutations, but onset does not occur at <3 years of age. Individuals with either peroxisomal biogenesis disorders (PBD) or single-enzyme deficiencies (SED) in the peroxisomal beta-oxidation pathway--disorders such as acyl CoA oxidase deficiency and bifunctional protein deficiency--also accumulate VLCFA, but they present during the neonatal period. Until now, it has been possible to distinguish unequivocally between individuals with these autosomal recessively inherited syndromes and individuals with ABCD1 mutations, on the basis of the clinical presentation and measurement of other biochemical markers. We have identified three newborn boys who had clinical symptoms and initial biochemical results consistent with PBD or SED. In further study, however, we showed that they lacked ALDP, and we identified deletions that extended into the promoter region of ABCD1 and the neighboring gene, DXS1357E. Mutations in DXS1357E and the ABCD1 promoter region have not been described previously. We propose that the term "contiguous ABCD1 DXS1357E deletion syndrome" (CADDS) be used to identify this new contiguous-gene syndrome. The three patients with CADDS who are described here have important implications for genetic counseling, because individuals with CADDS may previously have been misdiagnosed as having an autosomal recessive PBD or SED
Corzo
Deyanira
D
Division of Genetics, The Children's Hospital, Boston, Massachusetts, USA.
Gibson
William
W
Johnson
Kisha
K
Mitchell
Grant
G
LePage
Guy
G
Cox
Gerald F
GF
Casey
Robin
R
Zeiss
Carolyn
C
Tyson
Heidi
H
Cutting
Garry R
GR
Raymond
Gerald V
GV
Smith
Kirby D
KD
Watkins
Paul A
PA
Moser
Ann B
AB
Moser
Hugo W
HW
Steinberg
Steven J
SJ
D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000326:Adrenoleukodystrophy / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017668:Age of Onset; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics; D005260:Female; D005347:Fibroblasts; D005816:Genetic Complementation Test; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D018901:Peroxisomal Disorders / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D020675:Peroxisomes / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011296:Prenatal Diagnosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D013577:Syndrome; D014960:X Chromosome / Q000235:genetics*
C115572:ABCD1 protein, human; D000074063:ATP Binding Cassette Transporter, Subfamily D, Member 1; D018528:ATP-Binding Cassette Transporters; C091247:BCAP31 protein, human; C515482:CCL22 protein, human; D054422:Chemokine CCL22; D019742:Chemokines, CC; D008565:Membrane Proteins; D011506:Proteins