PEX6 gene

• Overview
• Congenital cataract
• LCA/EOSRD
• Retinitis pigmentosa
• Additional information
• References

Overview

Gene (OMIM No.)	PEX6 (#601498)
Function of gene/protein	Protein: peroxisome biogenesis factor 6 Part of the PEX1-PEX6 AAA-ATPase family anchored by PEX26 Involved in peroxisome assembly and peroxisome matrix protein import via interaction with PEX5 Required for stability of the peroxisomal targeting signal 1 (PTS1) receptor 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 4A (PBD4A; Zellweger syndrome) (#614862) Peroxisome biogenesis disorder 4B (PBD4B; Neonatal adrenoleukodystrophy [NALD] and Infantile Refsum disease [IRD]) (#614863) Heimler syndrome 2 (#616617) PBD4A and PBD4B form a spectrum of peroxisome biogenesis disorders (Zellwenger syndrome spectrum [ZSS]) caused by pathogenic mutations in PEX6 with a continuum of severity
Inheritance	Autosomal recessive Autosomal dominant inheritance reported in individuals with the heterozygous p.Arg860Trp variant due to allelic expression imbalance
Ocular features	Congenital cataract Retinal dystrophy (LCA/EOSRD or retinitis pigmentosa) Cystoid macular oedema (CMO) Optic atrophy Short axial length and hypermetropia reported in Heimler syndrome
Systemic features	PBD4A/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 PBD4B/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 2 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: 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 diagnosis	Next generation sequencing Targeted gene panels (cataract) Whole exome sequencing Whole genome sequencing
Management	Ocular Management of congenital cataract Management of LCA/EOSRD Management of RP Systemic Multidisciplinary approach
Therapies under research	Drug screening and testing using cultured skin fibroblasts, induced pluripotent stem cells (iPSCs) and animal models Hydroxychloroquine Administration for Reduction of Pexophagy (HARP) study (NCT 03856866; phase 2) Arginine is a small molecule compound that has the potential to improve peroxisomal assembly in patients with mild PEX6 missense mutations Gene therapy for vision loss in milder ZSS phenotypes (animal models)
Further information	Medline Plus

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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 have two distinct clinical spectra, Zellwenger syndrome spectrum (ZSS) and rhizomelic chondrodysplasia punctata type 1 (due to mutations in PEX7).^[2]

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 PEX6 is the second most common cause of ZSS (after PEX1) and accounts for approximately 16% of all cases.^[3] It gives rise to PBD4A (Zellwenger syndrome), PBD4B (NALD and IRD) and Heimler syndrome 2. 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]

PBD4A (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.^[4] 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

PBD4B (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.^[4] 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 retinal dystrophy
• 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 milder or absent in NALD and IRD patients.^[4]

Heimler syndrome 2

Heimler syndrome is a relatively mild PBD phenotype caused by mutations in PEX1, PEX6 and PEX26.^[8,9] 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/Beau’s lines, 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.^[8,9] Variants in the AAA-ATPase region of PEX1 and PEX6 seem to be associated with the development of retinal dystrophy.^[9]

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References

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