Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS) is a group of autosomal recessive disorders affecting the formation of functional peroxisomes, characterized by sensorineural hearing loss, pigmentary retinal degeneration, multiple organ dysfunction, and psychomotor impairment, and it comprises the phenotypic variants Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease.
Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD-ZSS) occur worldwide, although variation is observed among different populations. The estimated incidence of PBD/ZSS is 1 in 50,000 in USA and Europe 1 and 1 in 500,000 in Japan 2.
Peroxisome biogenesis disorders, Zellweger syndrome spectrum includes the following phenotypes 3:
- Zellweger syndrome
- Neonatal adrenoleukodystrophy
- Infantile Refsum disease
Zellweger syndrome is characterized by presentation in the neonatal period with profound hypotonia, characteristic facies, seizures, inability to feed, liver cysts with hepatic dysfunction, and chondrodysplasia punctata 1, 3. Infants with this condition are significantly impaired and usually die during their first year of life, usually having made no developmental progress. Death is usually secondary to progressive apnea or respiratory compromise from infection.
Children with neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease have many of the same features seen in Zellweger syndrome but with slower progression 3. NALD and infantile Refsum disease commonly present in the newborn period, but generally come to attention in infancy because of developmental delays, hearing loss, or visual impairment. Affected children also show episodes of hemorrhage, including intracranial bleeding. The condition is often slowly progressive, with hearing and vision worsening with time. Some individuals may develop progressive degeneration of the myelin, which may lead to loss of previously acquired skills and ultimately to death. Children affected with the non-progressive disease course have a 77% probability of reaching school age 6.
Refsum disease is characterized by anosmia and early-onset retinitis pigmentosa, which are both universal findings with variable combinations of neuropathy, deafness, ataxia, and ichthyosis 1, 3. Onset of symptoms is variable, ranging from seven months to older than 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems which develop later in life.
Peroxisome biogenesis disorders (PBD) are autosomal recessive disorders characterized by defective peroxisome biosynthesis, assembly, and biochemical functions 3. PBDs are primarily caused by mutations in one of the “PEX genes”. Mutations in the genes listed in the table are known to cause PBD/ZSS in humans. These genes encode proteins required for peroxisome biogenesis 3. Peroxisomes are membrane-bound organelles found in almost all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, and polyamines, reduction of reactive oxygen species, and biosynthesis of phospholipids critical for the normal function of mammalian brains and lungs.
PEX1 is the most affected gene among patients with a PBD-ZSS disorder and mutations in PEX1 account for ~68% of all affected individuals 3, 4. The most common mutation in PEX1 is a missense mutation in the second ATP-binding domain (c.2528G>A) leading to p.G843D 3. This mutation reduces the binding between PEX1 and PEX6 and is known for its temperature sensitivity. The second most common mutation in PEX1 is c.2079_2098insT, which results in a frame shift predicted to cause a truncated PEX1 protein 3. The c.2926delA mutation is the third most common mutation in PEX1; this mutation leads to a frame shift.
Mutations in PEX6, PEX10, PEX12, and PEX26 account for another 26% of all individuals with PBD, ZSS. In conjunction with PEX1 defects, more than 90% of all affected individuals have a defect in one of these five PEX genes 3. Also, mutations in PEX2, PEX3, PEX5, PEX13, PEX14, PEX16, and PEX19 account for about 6% of all individuals with PBD-ZSS 3.
An additional genetic study revealed that sequence analysis of PEX1 exons 13, 15, 18, and 19; PEX2 exon 4; PEX6 exon 1; PEX10 exons 4 and 5; PEX12 exons 2 and 3; and PEX26 exons 2 and 3 detects about 79% of PBD, ZSS-causing alleles 9. Furthermore, the detection frequency for at least one pathogenic variant of sequence analysis of PEX1 exons 13 and 15, PEX2 exon 4, PEX10 exons 4 and 5, PEX12 exons 2 and 3, and PEX26 exons 2 and 3 is approximately 72% 3, 9.
Genotype-phenotype correlations in disorders of peroxisome biogenesis could be illustrated with the following findings 7:
- Frameshift mutations in the PEX genes are associated with more severe defects in peroxisome assembly and, consequently, with more severe clinical phenotypes
- Homozygosity for the PEX1 p.Ile700TyrfsTer42 common allele is associated with a more severe phenotype
- Compound heterozygosity for PEX1 alleles p.Ile700TyrfsTer42 and p.Gly973AlafsTer16 also appears on the more severe end of the clinical spectrum. Cells in such individuals also have more severe defects in the import of peroxisomal matrix proteins
- In contrast, the PEX1 p.Gly843Asp allele has been associated with the less severe end of the phenotypic clinical continuum and peroxisomal matrix protein import is nearer to normal
- Homozygosity for PEX1 p.Gly843Asp has thus far been associated with a milder phenotype
- Homozygosity for PEX12 p.Ser320Phe is associated with type 1 mosaicism and the milder end of the clinical spectrum 8.
Overview of single genes associated with Zellweger syndrome
|Gene||Locus||Associated syndromes||OMIM disease||Mutation frequency|
|7q21.1||Peroxisome biogenesis disorder 1A (Zellweger) |
Infantile Refsum disease
|8q21.13||Peroxisome biogenesis disorder 5A (Zellweger) |
Peroxisome biogenesis disorder 5B
|1%-5% 3, 4|
|6q24.2||Peroxisome biogenesis disorder 5A (Zellweger) |
Peroxisome biogenesis disorder 5B
|1%-1.5% 3, 4|
|12p13.31||Peroxisome biogenesis disorder 2A (Zellweger) |
Peroxisome biogenesis disorder 2B
Rhizomelic chondrodysplasia type 5
|1.5%-2% 3, 4|
|6p21.1||Peroxisome biogenesis disorder 4A (Zellweger) |
Peroxisome biogenesis disorder 4B
Heimler syndrome type 2
|10.7%-16% 3, 4|
|1p36.32||Peroxisome biogenesis disorder 6A (Zellweger) |
Peroxisome biogenesis disorder 6B
|3%-4.6% 3, 4|
|17q12||Peroxisome biogenesis disorder 3A (Zellweger) |
Peroxisome biogenesis disorder 3B
|4.1%-9% 3, 4|
|2p15||Peroxisome biogenesis disorder 11A (Zellweger) |
Peroxisome biogenesis disorder 11B
|1p36.22||Peroxisome biogenesis disorder 13A (Zellweger)||614887||0.5%3, 5|
|11p11.2||Peroxisome biogenesis disorder 8A (Zellweger) |
Peroxisome biogenesis disorder 8B
|1q23.2||Peroxisome biogenesis disorder 12A (Zellweger)||614886||0.5%-1% 3, 4|
|22q11.21||Peroxisome biogenesis disorder 7A (Zellweger) |
Peroxisome biogenesis disorder 7B
There is no cure for Zellweger syndrome, however, the focus is on symptomatic therapy, which may include: gastrostomy to provide adequate calories, hearing aids, cataract removal in infancy, glasses, vitamin supplementation, primary bile acid therapy, antiepileptic drugs, and possibly monitoring for hyperoxaluria.
CENTOGENE offers full gene sequencing and deletion/duplication analysis for the Zellweger syndrome panel (genes: PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, PEX26). We also offer single gene tests for each gene included in the panel.
The differential diagnosis of autosomal recessive forms of Zellweger syndrome related disorders – depending on the major symptoms in the initial case – includes the following diseases:
- Neonatally-presenting disorder characterized by profound hypotonia (Down syndrome, Prader-Willi syndrome, Spinal muscular atrophy, Congenital myotonic dystrophy, Congenital myopathies and others)
- Childhood presenting Usher syndrome type I, Usher syndrome type II, and other disorders of sensorineural hearing loss and retinitis pigmentosa
- D-bifunctional enzyme deficiency
- Acyl-CoA oxidase deficiency
- X-linked adrenoleukodystrophy
- Adult Refsum disease
- Rhizomelic Chondrodysplasia Punctata.
CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage.
To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Zellweger syndrome using NGS Panel Genomic targeted towards this specific phenotype:
Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Zellweger syndrome panel. Copy Number Variants analysis derived from NGS data is also included.
Step 2: If no mutation is identified after analysis of the Zellweger syndrome panel, we further recommend continuing the bioinformatics analysis of the data obtained using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.
The following individuals are candidates for this particular gene testing:
- Individuals with a family history of Zellweger syndrome and presentation of the most common symptoms
- Individuals without a positive family history, but with symptoms resembling Zellweger syndrome
- Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).
Sequencing, deletion/duplication of Zellweger syndrome related genes should be performed in all individuals suspected of having this particular phenotype. In parallel, other genes reported to be related with Zellweger syndrome should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.
Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of Zellweger syndrome, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.
More information on CENTOGENE´s Zellweger syndrome panel can be found in our genetic test catalogue.