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PEX2 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: peroxisome biogenesis factor 2
  • Involved in peroxisome matrix protein import through the recycling of PEX5 proteins via mono-ubiquitination
  • Peroxisomes are cellular structures involved in breaking down fatty acids, uric acids and reactive oxygen species
  • Also involved in biosynthesis of plasmalogens (a type of phospholipid crucial to normal functioning of the brain and lungs)
Clinical phenotype
(OMIM phenotype no.)
  • Peroxisome biogenesis disorder 5A (PBD5A; Zellweger syndrome) (#614866)
  • Peroxisome biogenesis disorder 5B (PBD5B; Neonatal adrenoleukodystrophy [NALD] and Infantile Refsum disease [IRD]) (#614867)
  • PBD5A and PBD5B form a spectrum of peroxisome biogenesis disorders (Zellwenger syndrome spectrum [ZSS]) caused by pathogenic mutations in PEX2 with a continuum of severity
Inheritance
  • Autosomal recessive
Ocular features
Systemic featuresPBD5A/Zellwenger syndrome (ZS)
  • Most severe phenotype due to severely reduced/absent PEX2 function
  • Earliest onset and usually result in death within the 1st year of life
  • Neuronal migration defects causing structural abnormalities in the brain (microgyria, pachygyria and heterotopia) resulting in seizures and hypotonia
  • Characteristic craniofacial dysmorphism (large anterior frontanelle, prominent and high forehead, hypertelorism, epicanthic folds, high arched palate, micrognathia)
  • Liver dysfunction
  • Other features in Additional information
PBD5B/NALD and IRD
  • Milder manifestations of ZSS (NALD—intermediate severity; IRD—mild severity)
  • Usually later onset compared to ZS (after newborn period) with variable symptomology
  • Progressive peroxisome dysfunction instead of congenital malformations seen in ZS
  • Most do not survive past late childhood with NALD
  • Neurologic abnormalities (hypotonia, visual loss, sensorineural hearing loss, seizures, cerebellar ataxia, peripheral neuropathy, leukodystrophy)
  • Amelogenesis imperfecta
  • Failure to thrive, psychomotor delay
  • Live dysfunction
  • Adrenal insufficiency
  • Renal stones
  • Osteopaenia resulting in pathological fractures
Key investigations
  • B-scan USS to measure axial length to document microphthalmia and detect any posterior abnormalities
  • Electrophysiology: absent rod and cone responses/rod-cone dystrophy in full field ERG
  • FAF and OCT: Progressive outer retinal disruption and thinning +/- CMO
  • Systemic assessment with a pediatrician and other relevant specialists
  • MRI brain
  • Biochemical investigations to assess the various peroxisomal pathways (blood, urine and cultured skin fibroblasts)
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (cataract)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcularSystemic
  • Multidisciplinary approach
Therapies under research
Further information

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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]

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References

  1.  Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17(3):187-196
  2.  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
  3.  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
  4.  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
  5.  Argyriou C, D’Agostino MD, Braverman N. Peroxisome biogenesis disorders. Transl Sci Rare Dis. 2016;1(2):111-144

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Updated on November 30, 2020
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