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 | PBD5A/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 PEX2 give rise to PBD5A (Zellwenger syndrome) and PBD5B (NALD and IRD).[3] Disease severity 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.[2,4]
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.[5] It is usually associated with biallelic null mutations and 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
PBD5B (NALD and IRD)
NALD and IRD have features that overlap with ZS but of milder severity. Symptoms usually present after the neonatal period, but disease onset and rate of progression are highly variable. Generally, NALD children tend to develop more complications at earlier times and most do not survive past late childhood; those with IRD are less severely affected with fewer symptoms and can survive through adulthood.[5] Presence of missense mutations (compound heterozygous/homozygous) is associated with milder ZSS phenotypes (NALD/IRD) due to residual PEX2 function.[2,5] Apart from the aforementioned features in ZS, other features that may be observed in NALD and IRD include:
- Leukodystrophy
- Peripheral neuropathy and cerebellar ataxia
- Progressive visual decline due to cataract and retinal degeneration
- Amelogeneis imperfecta
- Variable psychomotor delay and intellect (some with later onset disease have normal cognition)
- Renal stones
- Osteopaenia leading to pathological fractures
In contrast to ZS, neuronal migration defects and craniofacial dysmorphism are mild or absent in NALD and IRD patients.[5]
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
- 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
- Mignarri A, Vinciguerra C, Giorgio A, et al. Zellweger Spectrum Disorder with Mild Phenotype Caused by PEX2 Gene Mutations. JIMD Rep. 2012;6:43‐46
- Argyriou C, D’Agostino MD, Braverman N. Peroxisome biogenesis disorders. Transl Sci Rare Dis. 2016;1(2):111-144