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PEX1 gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: peroxisome biogenesis factor 1
  • Part of the PEX1-PEX6 AAA-ATPase family anchored by PEX26
  • Involved in peroxisome assembly and peroxisome matrix protein import via interaction with PEX5
  • 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)
  • Dysfunction of the AAA-ATPase complex leads to an upregulation of peroxisome degradation by macroautophagy (pexophagy)
Clinical phenotype
(OMIM phenotype no.)
  • Peroxisome biogenesis disorder 1A (PBD1A; Zellweger syndrome) (#214100)
  • Peroxisome biogenesis disorder 1B (PBD1B; Neonatal adrenoleukodystrophy [NALD] and Infantile Refsum disease [IRD]) (#601539)
  • Heimler syndrome 1 (#234580)
  • PBD1A and PBD1B form a spectrum of peroxisome biogenesis disorders (Zellwenger syndrome spectrum [ZSS]) caused by pathogenic mutations in PEX1 with a continuum of severity
Inheritance
  • Autosomal recessive
Ocular features
Systemic featuresPBD1A/Zellwenger syndrome (ZS)
  • Most severe phenotype due to severely reduced/absent PEX1 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
PBD1B/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
Heimler syndrome
  • Mildest phenotype
  • Sensorineural hearing loss
  • Enamel hypoplasia of secondary dentition
  • Nail abnormalities (Beau’s lines, leukonychia)
  • Learning difficulties in some cases
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: Outer retinal and RPE disruption/loss and CMO in patients with Heimler syndrome
  • 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 PEX1 is the most common cause of ZSS and account for 70% of all cases.[3,4] It gives rise to PBD1A (Zellwenger syndrome), PBD1B (NALD and IRD) and Heimler syndrome. 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.[2,5,6]

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, the most common being the p.Ile700Tyrfs42* variant which results in a truncated and dysfunctional PEX1 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

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.[6] Presence of the common p.Gly843Asp missense mutation (compound heterozygous/homozygous) is associated with milder ZSS phenotypes (NALD/IRD) due to residual PEX1 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.[6]

Heimler syndrome

Heimler syndrome is a relatively mild PBD phenotype caused by mutations in PEX1, PEX6 and PEX26.[7,8] It is characterized by[7-9]:

  • Amelogenesis imperfecta resulting in enamel hypoplasia of the secondary dentition (constant feature)
  • Sensorineural hearing loss (constant feature)
  • Nail abnormalities (transverse ridges of the toenails, leukonychia)
  • Progressive retinal dystrophy (rod-cone phenotype with CMO)
  • Learning difficulties

It is hypothesised that Heimler syndrome is a result of hypomorphic mutations in the associated PEX genes.[7,8] Variants in the AAA-ATPase region of PEX1 and PEX6 are associated with the development of retinal dystrophy.[7]

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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.  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
  4.  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
  5.  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
  6.  Preuss N, Brosius U, Biermanns M, Muntau AC, Conzelmann E, Gartner J. PEX1 mutations in complementation group 1 of Zellweger spectrum patients correlate with severity of disease. Pediatr Res. 2002;51(6):706-714
  7.  Argyriou C, D’Agostino MD, Braverman N. Peroxisome biogenesis disorders. Transl Sci Rare Dis. 2016;1(2):111-144
  8.  Gao FJ, Hu FY, Xu P, et al. Expanding the clinical and genetic spectrum of Heimler syndrome. Orphanet J Rare Dis. 2019;14(1):290
  9.  Ratbi I, Falkenberg KD, Sommen M, et al. Heimler Syndrome Is Caused by Hypomorphic Mutations in the Peroxisome-Biogenesis Genes PEX1 and PEX6. Am J Hum Genet. 2015;97(4):535-545
  10.  Heimler A, Fox JE, Hershey JE, Crespi P. Sensorineural hearing loss, enamel hypoplasia, and nail abnormalities in sibs. Am J Med Genet. 1991;39(2):192-195
  11.  Law KB, Bronte-Tinkew D, Di Pietro E, et al. The peroxisomal AAA ATPase complex prevents pexophagy and development of peroxisome biogenesis disorders. Autophagy. 2017;13(5):868-884

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Updated on November 30, 2020
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