title: A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents.
abstract: Sensorineural deafness and retinitis pigmentosa (RP) are the hallmarks of Usher syndrome (USH) but are also prominent features in peroxisomal biogenesis defects (PBDs); both are autosomal recessively inherited. The firstborn son of unrelated parents, who both had sensorineural deafness and RP diagnosed as USH, presented with sensorineural deafness, RP, dysmorphism, developmental delay, hepatomegaly, and hypsarrhythmia and died at age 17 mo. The infant was shown to have a PBD, on the basis of elevated plasma levels of very-long- and branched-chain fatty acids (VLCFAs and BCFAs), deficiency of multiple peroxisomal functions in fibroblasts, and complete absence of peroxisomes in fibroblasts and liver. Surprisingly, both parents had elevated plasma levels of VLCFAs and BCFAs. Fibroblast studies confirmed that both parents had a PBD. The parents' milder phenotypes correlated with relatively mild peroxisomal biochemical dysfunction and with catalase immunofluorescence microscopy demonstrating mosaicism and temperature sensitivity in fibroblasts. The infant and both of his parents belonged to complementation group C. PEX6 gene sequencing revealed mutations on both alleles, in the infant and in his parents. This unique family is the first report of a PBD with which the parents are themselves affected individuals rather than asymptomatic carriers. Because of considerable overlap between USH and milder PBD phenotypes, individuals suspected to have USH should be screened for peroxisomal dysfunction.
authors.affiliation: Department of Human Genetics, Hadassah University Hospital, Jerusalem 91120, Israel.
authors.forename: Annick
authors.initials: A
authors.lastname: Raas-Rothschild
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Petra A W
authors.initials: PA
authors.lastname: Mooijer
authors.forename: Jeannette
authors.initials: J
authors.lastname: Gootjes
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Alisa
authors.initials: A
authors.lastname: Gutman
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimozawa
authors.forename: Naomi
authors.initials: N
authors.lastname: Kondo
authors.forename: Gideon
authors.initials: G
authors.lastname: Eshel
authors.forename: Marc
authors.initials: M
authors.lastname: Espeel
authors.forename: Frank
authors.initials: F
authors.lastname: Roels
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Korman
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics*; D000328:Adult; D002478:Cells, Cultured; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D005260:Female; D005347:Fibroblasts; D005816:Genetic Complementation Test; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D009030:Mosaicism; D018901:Peroxisomal Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000503:physiopathology*; D013577:Syndrome; D013696:Temperature
chemical_list: D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C490759:PEX6 protein, human; C096998:Pex6 protein, rat