Overview
Gene (OMIM No.) |
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Function of gene/protein |
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Clinical phenotype (OMIM phenotype no.) |
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Inheritance |
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Ocular features |
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Systemic features | PBD12A/Zellwenger syndrome (ZS)
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Key investigations |
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Molecular diagnosis | Next generation sequencing
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Management | OcularSystemic
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Therapies under research |
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Further information |
Additional information
Peroxisome biogenesis disorders (PBDs) are disorders of peroxisome assembly and function due to mutations in any of the 14 peroxin encoding genes (PEX).[1] PBDs manifest as either Zellwenger syndrome spectrum (ZSS) or rhizomelic chondrodysplasia punctata type 1 (due to mutations in PEX7).[2]
The ZSS encompasses conditions of variable severity (related to age of onset) with overlapping features. Three distinct phenotypes have been described historically which are now classed under the ZSS umbrella. These conditions are:
- Zellwenger syndrome (ZS; most severe phenotype with the earliest onset)
- Neonatal adrenoleukodystrophy (NALD; intermediate phenotype)
- Infantile Refsum disease (IRD; mild phenotype)
Pathogenic mutations in PEX19 give rise to PBD12A (Zellwenger syndrome), a phenotype that lies on the severe end of the spectrum.[3] The disease severity of ZSS depends upon the type of mutation where missense variants tend to be associated with a milder form of disease, while null mutations result in more severe clinical phenotypes.[2,5]
Zellwenger syndrome
The most severe phenotype, Zellwenger syndrome is an early onset (neonatal period) and fatal disease, with death usually occurring within the first year of life.[6] It is usually associated with biallelic null mutations, which results in a truncated and dysfunctional PEX19 protein.[6] ZS is characterised by:
- Severe neurological dysfunction (neonatal seizures and hypotonia) due to neuronal migration defects
- Characteristic craniofacial dysmorphism– large anterior frontanelle, prominent and high forehead, hypertelorism, epicanthic folds, high arched palate, micrognathia
- Liver dysfunction and hepatomegaly
- Failure to thrive, poor feeding
- Psychomotor delay
- Congenital cataract
- Severe sensorineural hearing loss
- Chondrodysplasia punctata (especially in the knees and hips)
- Cardiovascular and respiratory anomalies
- Renal cysts
- Adrenal insufficiency
References
- Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17(3):187-196
- Braverman NE, Raymond GV, Rizzo WB, et al. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321
- Yik WY, Steinberg SJ, Moser AB, Moser HW, Hacia JG. Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. Hum Mutat. 2009;30(3):E467-E480
- Ebberink MS, Mooijer PA, Gootjes J, Koster J, Wanders RJ, Waterham HR. Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder
- Walter C, Gootjes J, Mooijer PA, et al. Disorders of peroxisome biogenesis due to mutations in PEX1: phenotypes and PEX1 protein levels. Am J Hum Genet. 2001;69(1):35-48
- Argyriou C, D’Agostino MD, Braverman N. Peroxisome biogenesis disorders. Transl Sci Rare Dis. 2016;1(2):111-144
- Mohamed S, El-Meleagy E, Nasr A, Ebberink MS, Wanders RJ, Waterham HR. A mutation in PEX19 causes a severe clinical phenotype in a patient with peroxisomal biogenesis disorder. Am J Med Genet A. 2010;152A(9):2318-2321
- Götte K, Girzalsky W, Linkert M, et al. Pex19p, a farnesylated protein essential for peroxisome biogenesis. Mol Cell Biol. 1998;18(1):616-628