peroxisomal diseases

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.

Disorders in peroxisomal biogenesis (absence or diminished numbers of peroxisomes) and specific enzymatic defects in peroxisome-based lipid oxidation include a group of diseases that present an important phenotypical overlap, with variability in the type of liver disease developed.

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.

Bile acid anomalies

The cerebro-hepato-renal syndrome of Zellweger is probably the condition in which hepatic function is most affected; atypical mono-, di- and tri- hydroxy C-27 bile acids with low amounts of primary bile acids are present in this disease.

Apart from AMACR, other peroxisomal enzymes involved in the beta-oxidation of the bile acid side-chain are branched-chain acyl-CoA oxidase, D-bifunctional protein and sterol carrier protein X (SCPx).

Deficiencies in these enzymes, associated with abnormalities in bile acid synthesis, have also been reported.

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

 peroxisomes

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