FINAL DIAGNOSIS: PEROXISOME BIOGENESIS DISORDER, CLINICALLY CONSISTENT WITH ZELLWEGER SYNDROME.
Introduction: Peroxisome biogenesis disorders, Zellweger syndrome spectrum is a continuum of three phenotypes - Zellweger syndrome, the most severe; neonatal adrenoleukodystrophy; and infantile Refsum disease, the least severe - that were originally described before the biochemical and molecular bases of these disorders had been fully determined. 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.
Pathogenesis: Peroxisomes are cytoplasmic organelles found in animal cells, especially liver, kidney and brain cells. They are the site of a variety of anabolic and catabolic pathways; -oxidation and plasmalogen synthesis are two fundamental pathways localized there. The peroxisomal -oxidation enzymes are distinct from the mitochondrial system. Straight-chain very-long-chain fatty acid (VLCFA) -oxidation requires the enzymes very-long-chain acyl CoA synthetase, acyl CoA oxidase, D-bifunctional protein (enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase), and peroxisomal -ketothiolase. The defect in peroxisomal fatty acid -oxidation accounts for the increase in VLCFA straight- and branched-chain fatty acids. At least 29 special proteins (peroxins) encoded by PEX genes are required for peroxisome membrane biogenesis, fission, and protein import to form competent organelles. The biogenesis of membranes is not well understood, but mutations in three human PEX genes (PEX3, 16, and 19) are associated with an absence of any peroxisome membrane structures. The remaining proteins encoded by known PEX genes (PEX1, 6, 26, 10, 12, 2, 5, 13 and 14) most probably contribute to the machinery required for matrix protein import. In addition to these genes, which map to various chromosomes including 1, 7q21, 8q, 6q, 12, and 6p, a Zellweger syndrome locus on 7q11 is suspected on the basis of reported chromosomal aberrations.
Clinical: The clinical course is variable and may include developmental delays, vision impairment, hearing loss, liver dysfunction, episodes of hemorrhage, and intracranial bleeding. Because of the breadth of phenotypic variation, individuals with peroxisome biogenesis disorders, Zellweger syndrome spectrum can come to clinical attention in the newborn period or later in childhood and occasionally in adulthood. The condition is often slowly progressive. In the newborn period, affected children are hypotonic with resultant poor feeding. Neonatal seizures are frequent. Liver dysfunction may be evident as neonatal jaundice and elevation in liver function tests. Distinctive craniofacial features include flattened facies, large anterior fontanelle, widely split sutures, and broad nasal bridge. In severely affected children, bony stippling (chondrodysplasia punctata) at the patella and other long bones may be noted. Older children manifest retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. Children may first come to attention because of a failed hearing screen. Onset and severity of the hearing and visual problems are variable, but a peroxisome biogenesis disorder should be considered in any individual who manifests both conditions. Liver dysfunction may be first identified in children with severe bleeding episodes caused by a vitamin K-responsive coagulopathy. Older children may develop adrenal insufficiency. The overall prognosis for infants with Zellweger syndrome is poor. Most patients do not survive past the first 6 months, and usually succumb to respiratory distress, gastrointestinal bleeding, or liver failure.
Diagnosis/testing: The diagnosis of peroxisome biogenesis disorders, Zellweger syndrome can be made by biochemical assays. 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. 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.
Genetic counseling and prenatal diagnosis: Peroxisome biogenesis disorders, Zellweger syndrome spectrum are inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele. The risk for subsequent pregnancies is 25%.
Management: Primarily symptomatic - gastrostomy to provide adequate calories, hearing aids, early cataract removal, glasses, vitamin supplementation, primary bile acid therapy, anti-epileptic drugs, and possibly monitoring for hyperoxaluria. Surveillance includes annual hearing and ophthalmologic evaluations, monitoring of coagulation factors, and tests of liver function. Avoidance of cow's milk products is recommended to reduce exposure to phytanic acid.
CONCLUSIONS: Positive screen for Very Long Chain Fatty Acids levels together with the clinical findings and presentation of the twins point to severe entities of the peroxisome biogenesis disorder spectrum (such as Zellweger syndrome) with a very poor prognosis. Confirmatory studies on cultured fibroblasts are pending. Molecular genetic studies of the twins will follow and have also been offered to the parents for potential future pregnancies.
ACKNOWLEDGEMENTS: The authors would like to thank Mrs. Lorna Cropcho and Mrs. Darla Lower for consistent help and support.
Contributed by Marie Dvorakova, MD and K. Michael Gibson, PhD, FACMG