Peroxisome biogenesis disorders (or Zellweger syndrome spectrum) is a continuum of three main phenotypes:
Zellweger syndrome, the most severe;
neonatal adrenoleukodystrophy;
infantile Refsum disease, the least severe.
Based on case reports of the new, unusual malformation syndrome from the early 1960s, the patients had severe, generalized hypotonia and absent Moro response, characteristic craniofacial abnormalities, cortical renal cysts and hepatomegaly.
The postmortem histological examination of the brains showed sudanophilic leukodystrophy.
Combination of these characteristic findings resulted in the designation "cerebrohepatorenal syndrome" that was later changed to Zellweger syndrome after one of the first scientists who described the entity.
Classification
The human disorders of peroxisome biogenesis (PBDs) are subdivided into 12 complementation groups (CGs).
Zellweger disease
neonatal adrenoleukodystrophy
Refsum disease
rhizomelic chondrodysplasia punctata type 1
CG8 is one of the more common of these and is associated with varying phenotypes, ranging from the most severe, Zellweger syndrome (ZS), to the milder neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD).
Synopsis
developmental delays
vision impairment
hearing loss
liver dysfunction
hemorrhages
intracranial bleeding.
hypotonia
poor feeding
neonatal seizures
neonatal jaundice
elevation in liver function tests.
distinctive craniofacial features
- flattened facies
- large anterior fontanelle
- widely split sutures
- broad nasal bridge
bony stippling (chondrodysplasia punctata) at the patella and other long bones
retinal dystrophy
sensorineural hearing loss
developmental delay
failed hearing screen
vitamin K-responsive coagulopathy
adrenal insufficiency
respiratory distress
gastrointestinal bleeding
liver failure
Laboratory
Biochemical abnormalities detected in blood and/or urine should be confirmed in cultured fibroblasts.
Measurement of plasma VLCFA levels is the most commonly used and most informative initial screen. Elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22 are consistent with a defect in peroxisomal fatty acid metabolism.
Molecular biology
Mutations in twelve different PEX genes - those that encode peroxins, the proteins required for normal peroxisome assembly - have been identified.
Mutations in PEX1, the most common cause of peroxisome biogenesis disorders, Zellweger syndrome spectrum, are observed in about 68% of affected individuals.
See also
Reverences
Wanders RJ, Waterham HR. Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders. Clin Genet. 2005 Feb;67(2):107-33. PMID: 15679822
Wanders RJ. Metabolic and molecular basis of peroxisomal disorders: a review. Am J Med Genet. 2004 May 1;126A(4):355-75. PMID: 15098234
Gould SJ, Valle D. Peroxisome biogenesis disorders: genetics and cell biology. Trends Genet. 2000 Aug;16(8):340-5. PMID: 10904262
Braverman N, Dodt G, Gould SJ, Valle D. Disorders of peroxisome biogenesis. Hum Mol Genet. 1995;4 Spec No:1791-8. Review. PMID: 8541879