Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups☆,☆☆,★,★★
Section snippets
Patients
All patients included in this study had the phenotypes associated with disorders of peroxisome assembly13 (Table II), or had biochemical abnormalities characteristic of these disorders.13 More than 600 patients in these categories have been identified in our laboratory through a diagnostic program in which we perform biochemical assays on samples of plasma, erythrocytes, or cultured skin fibroblasts from patients in whom the referring physician has suspected a peroxisomal disorder. We selected
Number, characteristics, and relative frequencies of complementation groups
By use of the criteria described in the Methods section, above, the 173 cell lines examined in this study were subdivided into 16 complementation groups (Table III). In groups 1 to 10 the clinical phenotype most commonly conformed to the ZS-NALD-IRD category. Table II lists the major clinical features associated with these three phenotypes, which are now thought to represent a continuum, with ZS the most severe, IRD the least severe, and NALD with intermediate severity. The 61-member group 1
DISCUSSION
The underlying principle of complementation analysis is that cell lines that complement each other represent distinct genotypes. The existence of 10 complementation groups among patients with impaired peroxisome assembly and the ZS-NALD-IRD phenotype thus indicates that the phenotype can be associated with at least 10 separate genetic defects. The molecular defects have been defined for two of these groups. Members of group 10 (referred to as group F in Japan) have a mutation in peroxisome
Acknowledgements
We thank the patients and their families for their cooperation and the numerous referring physicians for providing clinical and biochemical data. We thank Drs. R. Wanders and N. Shimozawa for permitting us to study fibroblast cell lines of their patients.
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Cochlear implantation and audiological findings in a child with Zellweger spectrum disorder
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2019, Pediatric NeurologyCitation Excerpt :The milder neonatal forms of adrenoleukodystrophy and infantile Refsum disease are characterized by a prominent leukodystrophy, and symptoms may not develop until late infancy. Rhizomelic CDP has a distinct phenotype characterized by rhizomelia, seizures, recurrent respiratory tract infections, and congenital cataracts.4,5 CDP can also be seen in babies born to mothers with autoimmune disease and in warfarin embryotoxicity.1
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2018, MacSween's Pathology of the LiverAllelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder
2017, American Journal of Human GeneticsCitation Excerpt :The seven unrelated individuals (Figure 1B) were diagnosed with a ZSD on the basis of their clinical symptoms (Table 1), aberrant peroxisomal metabolite levels in blood and fibroblasts (Tables 2 and S2), and an import defect of peroxisomal matrix proteins in fibroblasts (Figures 1C and S1). By means of functional genetic complementation of cultured primary skin fibroblasts3 (of individuals P1, P3, and P4) or fused cell complementation19 (of individual P6), we identified a defective PEX6 gene as the cause of the ZSD in four affected individuals. When we subsequently Sanger sequenced PEX6 (GenBank: NM_000287.3) to identify the disease-causing mutations, we detected only the heterozygous variant c.2578C>T (p.Arg860Trp) (rs61753230) in all four individuals, but no second potentially pathogenic variant (Table 3).
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From the Kennedy Krieger Institute and the Departments of Neurology and Pediatrics, Johns Hopkins University, Baltimore, Maryland; the Berg Gaard Centralinstitutt for habilitering and Rikshospitalet, Oslo, Norway; the Neuroscience Laboratory and the Department of Neurology, University of Michigan, Ann Arbor; the Massachusetts Eye and Ear Infirmary, Boston; Pediatric Neurology Services, Helena, Montana; the Department of Medical Genetics, Jefferson Medical College, Philadelphia, Pennsylvania; the Division of Clinical Genetics, New England Medical Center, Boston, Massachusetts; and the Department of Pediatrics, Rikshospitalet, University of Oslo, Norway
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Supported in part by March of Dimes grant No. 6FY92-769 and by National Institutes of Health grants RR00052, RR00722, HD 10981, and HD 24061. Dr. Rasmussen received support from the American Women's club of Oslo and the Berg Gaard Central Institute for Habilitering in Oslo.
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Reprint requests: Hugo W. Moser, MD, Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205.
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