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Zellweger Spectrum Disorder

Synonym: ZSD

, PhD, , MD, , MS, MD, and , BA.

Author Information

Initial Posting: ; Last Revision: December 21, 2017.

Summary

Clinical characteristics.

Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term ZSD is now used to refer to all individuals with a PEX gene defect regardless of phenotype.

Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and other long bones), and liver disease which can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress.

Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss); neurologic involvement (ataxia, polyneuropathy, and leukodystrophy); liver dysfunction; adrenal insufficiency; and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.

Diagnosis/testing.

The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above and identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes.

Management.

Treatment of manifestations: The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal in infancy, glasses, vitamin supplementation, primary bile acid therapy, adrenal replacement, antiepileptic drugs, and possibly monitoring for hyperoxaluria.

Surveillance: Annual hearing and ophthalmologic evaluations, monitoring of liver function and coagulation factors, ACTH/cortisol. A baseline brain MRI is recommended; a loss of motor and cognitive milestones could indicate a leukodystrophy.

Genetic counseling.

ZSD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if both ZSD-related pathogenic variants have been identified in an affected family member. Prenatal diagnosis by biochemical testing is also possible; however, the biochemical defects in cultured fibroblasts from an affected family member must be confirmed first, since the biochemical defects present in body fluids or liver may not be detectable in cultured cells (a phenomenon called "peroxisomal mosaicism").

GeneReview Scope

Zellweger Spectrum Disorder: Included Phenotypes
  • Zellweger syndrome
  • Neonatal adrenoleukodystrophy
  • Infantile Refsum disease

For synonyms and outdated names see Nomenclature.

Diagnosis

Suggestive Findings

Zellweger spectrum disorder (ZSD) should be suspected in children with the following clinical and laboratory findings.

Clinical findings. Newborns with:

  • Hypotonia
  • Poor feeding
  • Distinctive facies
  • Brain malformations
  • Seizures
  • Renal cysts
  • Hepatomegaly, cholestasis, and hepatic dysfunction
  • Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones

Older infants and children with:

  • Developmental delays with or without hypotonia (Note: Intellect can be normal.)
  • Failure to thrive
  • Hearing loss
  • Vision impairment
  • Liver dysfunction
  • Adrenal dysfunction
  • Leukodystrophy
  • Peripheral neuropathy and ataxia

Laboratory findings. The screening assays for ZSD are summarized in Table 1. Note that because some individuals with ZSD do not have abnormalities of these screening assays in body fluids or cultured cells, molecular genetic testing is necessary to establish the diagnosis (see Establishing the Diagnosis). Functional testing in fibroblasts remains an ancillary tool to confirm equivocal molecular and/or biochemical results.

Table 1.

Screening Assays for ZSD

CompoundTestExpected FindingsLimitations of Test
Very-long-chain fatty acids (VLCFA)Plasma concentrationElevated plasma concentrations of C26:0 & C26:1; elevated ratios of C24/C22 & C26/C22 1Non-fasting samples, hemolyzed samples, or an individual on a ketogenic diet can cause false positive results. Normal in RCDP.
Phytanic acid & pristanic acid 2Plasma concentrationIncreased concentrations of phytanic acid and/or pristanic acidBranched-chain fatty acid accumulation depends on dietary intake of phytanic acid, which is minimal in formula- & breast-fed infants. Thus, phytanic & pristanic acid levels are normal in a neonate w/ZSD.
PlasmalogensErythrocyte membrane concentrationsReduced amounts of C16 & C18 plasmalogensIndividuals w/mild ZSD may have marginally reduced to normal plasmalogen levels.
Pipecolic acidPlasma/urine concentrationIncreased concentration of pipecolic acid in both plasma & urineUrinary excretion of pipecolic acid is high in neonatal period, but diminishes w/age 3. Thus, urine should be tested in a neonate & plasma in an older child.
Bile acidsPlasma/urine concentrationIncreased concentrations of C27 bile acid intermediates THCA & DHCAIn most cases plasma testing is more sensitive than urine analysis.

DHCA = dihydroxycholestanoic acid

THCA = trihydroxycholestanoic acid

1.

Low plasma concentration of LDL and HDL can cause false negative results. In a person with low plasma concentrations of LDL and HDL without a defect in peroxisomal fatty acid metabolism, the plasma concentration of specific fatty acids (e.g., C22:0, C24:0, C26:0) are significantly lower than normal control levels. Individuals with defects in peroxisomal fatty acid metabolism and very low LDL and HDL concentrations do not have significant elevations in C26:0 and C26:1, but do have modest elevations in the ratios of C24/C22 and C26/C22.

2.

This analysis is usually included in VLCFA measurement.

3.

Pipecolic acid measurement is an adjunct to more definitive biomarkers such as plasma VLCFA and erythrocyte plasmalogen levels. Elevations in pipecolic acid can also occur in pyridoxine-dependent seizures [Plecko et al 2000].

Establishing the Diagnosis

The diagnosis of ZSD is established in a proband with the suggestive clinical and biochemical findings above and identification of biallelic pathogenic variants in one of the 13 PEX genes listed in Table 2.

Molecular genetic testing approaches can include gene-targeted testing (multigene panel) or more comprehensive genomic testing (exome sequencing or genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the suggestive clinical and biochemical findings of ZSD described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a nondistinct phenotype that does not suggest a specific diagnosis are more likely to be diagnosed using genomic testing (see Option 2). Note: Single-gene testing (i.e., sequence analysis of one of the PEX genes, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. A multigene panel and/or exome sequencing are typically used in lieu of single-gene testing.

Option 1

A multigene panel for peroxisome biogenesis disorders should include the 13 genes listed in Table 1 as well as some of the disorders with similar clinical or laboratory findings that are the differential diagnosis of ZSD. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the patient’s findings do not lead to consideration of ZSD, comprehensive genomic testing (when clinically available) is likely to be the diagnostic modality selected. Comprehensive genomic testing includes exome sequencing and genome sequencing. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 2.

Molecular Genetic Testing Used in Zellweger Spectrum Disorder (ZSD)

Gene 1, 2% of ZSD Attributed to Pathogenic Variants in This Gene 3Proportion of Pathogenic Variants 4 Detectable by This Test Method
Sequence analysis 5, 6Gene-targeted deletion/duplication analysis 7
PEX160.5%~98% 8~2% 8
PEX614.5%77/77 9, 10Unknown 11
PEX127.6%43/43 9Unknown 11
PEX264.2%17/17 9Unknown 11
PEX103.4%17/18 9Unknown 11
PEX23.1%19/22 9Unknown 11
PEX52.0%13/13 9Unknown 11
PEX131.5%7/7 9Unknown 11
PEX161.1%8/8 9Unknown 11
PEX30.7%3/3 9Unknown 11
PEX190.6%3/3 9Unknown 11
PEX140.5%1/2 9Unknown 11
PEX11β0.1%1/1 12Unknown 11
1.

Genes are listed from most frequent to least frequent genetic cause of ZSD.

2.
3.

Based on complementation studies using somatic cell hybridization and/or cDNA complementation analysis in 810 patients with biochemical confirmation of ZSD (197 at Kennedy Krieger Institute [unpublished] and 613 reported by Ebberink et al [2011]).

4.

See Molecular Genetics for information on pathogenic allelic variants detected.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

6.

An estimate, based on the assumption that large deletions or promoter and deep intronic pathogenic variants would be missed; however, these types of variants do not appear to be common in ZSD.

7.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

8.

This estimate is based on the number of individuals identified with a PEX1 defect, defined by having two pathogenic PEX1 variants, one of which was a deletion detected by MLPA [Molly Sheridan, PhD; Johns Hopkins DNA Diagnostic Laboratory].

9.

Based on Ebberink et al [2011], Table 1. The numerator is the number of individuals belonging to this complementation group who had two pathogenic variants identified and the denominator is the total number of individuals belonging to this complementation group who underwent sequencing of that gene.

10.

One PEX6 variant, c.2578C>T (p.Arg860Trp), has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background [Falkenberg et al [2017]; see Molecular Genetics).

11.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

12.

PEX11β: Ebberink et al [2012], single case report

Clinical Characteristics

Clinical Description

Zellweger spectrum disorder (ZSD) is defined by a continuum of three phenotypes described before the biochemical and molecular bases of these disorders had been fully determined: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD) [Braverman et al 2016].

The ZSD phenotypic spectrum is broad; some affected individuals have mild manifestations, mainly sensory deficits and/or mild developmental delay. Recently, individuals with normal intellect have been identified [Ratbi et al 2015, Ratbi et al 2016, Smith et al 2016] by genomic testing methods. Nonetheless, all of the peroxisome assembly disorders cause significant morbidity, frequently resulting in death in childhood.

Although the phenotypic designations listed above may be useful when evaluating undiagnosed individuals and counseling their families, one should not place too much emphasis on assigning a phenotypic label to an affected individual given that these phenotypes lie on a continuum. Thus, the terms severe, intermediate, and milder ZSD are now preferred. Because of the breadth of the phenotypic spectrum, individuals with ZSD mainly come to clinical attention in the newborn period or later in childhood. Occasionally, the subtlety of symptoms delays diagnosis until adulthood.

Newborns are hypotonic with resultant poor feeding. Neonatal seizures are frequent and caused by underlying neuronal migration defects. Liver dysfunction may be evident as neonatal jaundice and elevation in liver function tests. Distinctive craniofacial features include flat face, broad nasal bridge, large anterior fontanel, and widely split sutures. In severely affected children, bony stippling (chondrodysplasia punctata) at the patella(e) and other long bones may be noted, as well as renal cysts.

Older children manifest retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. Children may first come to attention because of a failed hearing screen. Onset and severity of the hearing and visual problems vary. A few children with a clinical diagnosis of neonatal adrenoleukodystrophy had transient leopard spot pigmentary retinopathy [Lyons et al 2004]. Liver dysfunction may be first identified in children with severe bleeding episodes caused by a vitamin K-responsive coagulopathy. Older children may develop adrenal insufficiency [Berendse et al 2014] and osteopenia [Rush et al 2016].

Adults rarely are diagnosed with ZSD, but exceptions have been reported. Usually these are individuals with predominantly sensory deficits but normal neurologic development [Moser et al 1995, Raas-Rothschild et al 2002, Majewski et al 2011, Ratbi et al 2015, Ratbi et al 2016, Smith et al 2016].

Severe ZSD (previously called Zellweger syndrome [ZS]) typically presents in the neonatal period with profound hypotonia, characteristic facies, gyral malformations, seizures, inability to feed, renal cysts, hepatic dysfunction, and chondrodysplasia punctata. Infants with severe ZSD are significantly impaired and usually die during the first year of life, usually having made no developmental progress. Death is usually secondary to progressive apnea or respiratory compromise from infection.

Intermediate/milder ZSD (previously called neonatal adrenoleukodystrophy [NALD] and infantile Refsum disease [IRD]) may present in the newborn period, but generally comes to attention later because of developmental delays, hearing loss, and/or visual impairment. Liver dysfunction may lead to a vitamin K-responsive coagulopathy. Children have also come to attention with episodes of hemorrhage; several children have presented in the first year of life with intracranial bleeding.

The clinical course is variable: while many children are very hypotonic, many learn to walk and talk.

Intermediate/milder ZSD is a progressive disorder with hearing and vision worsening with time. Some individuals may develop progressive degeneration of CNS myelin, a leukodystrophy, which may lead to loss of previously acquired skills and ultimately death.

Children who survive the first year and who have a non-progressive course have a 77% probability of reaching school age [Poll-The et al 2004]. Some have normal intellect. They are at risk for adrenal insufficiency over time. Typically, they also have ameliogenesis imperfecta of the secondary teeth.

Other. Individuals with atypical ZSD do not show sensory losses but have ataxia and peripheral neuropathy, and may have congenital cataracts (e.g., those with PEX2-ZSD [Sevin et al 2011], PEX11β-ZSD [Ebberink et al 2012], PEX10-ZSD [Steinberg et al 2009], PEX12-ZSD [Gootjes et al 2004], and PEX16-ZSD [Ebberink et al 2010]).

Note that although Heimler syndrome [Ratbi et al 2015, Ratbi et al 2016, Smith et al 2016] and ataxia (see Régal et al [2010], Renaud et al [2016]) have been reported as unique phenotypes associated with PEX gene defects, the authors consider them part of the ZSD continuum. In general, individuals described as having these milder phenotypes do not have – on screening assays – the biochemical profile typical of ZSD (Table 1).

Neuroimaging. MRI may identify cortical gyral abnormalities and germinolytic cysts that are highly suggestive of severe ZSD. Other brain MRI findings have been identified over time in individuals with milder ZSD.

In a small number of individuals with ZSD diffusion-weighted imaging and diffusion tensor imaging can be used to discern white matter damage not detected by standard imaging [Patay 2005]. A demyelinating leukodystrophy can occur, but it is not clear which affected individuals are at increased risk for this development, or how it progresses in the individual.

Phenotype Correlations by Gene

Biallelic pathogenic variants in the two most commonly involved genes, PEX1 and PEX6, are associated with the full continuum of clinical phenotypes. This clinical variability, in general, is also found in individuals with biallelic pathogenic variants in PEX10, PEX12, and PEX26. Although in the past, defects in some of the less common PEX genes appeared to be associated with severe clinical phenotypes, more recently the phenotypic spectrum of defects in all PEX genes has been found to include both severely and mildly affected individuals. Overall clinical and biochemical severity appears to be most related to the genotype and not a particular PEX gene.

Genotype-Phenotype Correlations

A general relationship appears to exist among the genotype, cellular phenotype (i.e., import of peroxisomal matrix proteins), and clinical phenotype [Moser 1999]. PEX gene defects are associated with loss-of-function variants; hence, variants that abolish activity (e.g., large deletions, nonsense and frameshift variants) are most severe. In contrast, missense variants that retain some residual function are less severe regarding the effect on peroxisome assembly; however, it should be noted that not all missense variants have residual activity.

Due to the overall rarity of ZSD the opportunities to rigorously assess genotype and phenotype are limited. The PEX1 variants p.Ile700TyrfsTer42 and p.Gly843Asp are exceptions, as hundreds of individuals homozygous or compound heterozygous for these variants have been identified (mostly in molecular research studies or clinical laboratories and not as part of a thorough natural history assessment).

Nomenclature

Peroxisome biogenesis disorders (PBD) can be divided into two subtypes: the Zellweger spectrum disorder (ZSD) and the rhizomelic chondrodysplasia punctata spectrum, of which rhizomelic chondrodysplasia punctata type 1 (RCDP1) is one subtype. RCDP1 is caused by biallelic pathogenic variants in PEX7, the receptor that recognizes peroxisome enzymes containing peroxisomal targeting signal 2. Although individuals with RCDP1 have a perturbation in matrix protein import consistent with a peroxisomal assembly defect, they have a biochemical, cellular, and clinical phenotype distinct from ZSD. (See Rhizomelic Chondrodysplasia Punctata Type 1 for an in-depth description.)

ZSD may also have been referred to in the past as cerebrohepatorenal syndrome, generalized peroxisomal disorders, Zellweger syndrome, neonatal adrenoleukodystrophy, or infantile Refsum disease (also known as infantile phytanic acid oxidase deficiency). Some individuals later shown to have ZSD were initially described as having hyperpipecolatemia. The current preferred terminology is ZSD – of severe, intermediate, or milder phenotypes – in order to recognize the common etiology, variations, and atypical presentations now being documented in individuals with biallelic pathogenic variants in any one of the 13 ZSD-PEX genes.

Of note, although Heimler syndrome [Ratbi et al 2015, Ratbi et al 2016, Smith et al 2016] and ataxia (see Régal et al [2010], Renaud et al [2016]) have been reported as unique phenotypes associated with PEX gene defects, the authors consider them part of the ZSD continuum.

Note: Refsum disease is clinically and molecularly distinct from infantile Refsum disease (see Differential Diagnosis).

Prevalence

In the past the incidence of ZSD had been estimated at about 1:50,000 [Gould et al 2001]. However, recent data from the first two years eight months of New York state newborn screening for X-linked adrenoleukodystrophy (X-ALD) link (using biochemical testing that also detects ZSD) identified ZSD in eight of 630,000 newborns (incidence of 1 in 78,750) [Moser et al 2016].

Since newborn screening for X-ALD has been added to the recommended uniform screening panel (RUSP) [Kemper et al 2017], it is expected that as more states add X-ALD to their newborn screening panels data on the incidence of ZSD in the United States will be further refined. Nonetheless, any estimate relying on a biochemical assay will be an underestimate because such assays will fail to detect very mild ZSD not associated with a definitive biochemical phenotype.

ZSD occurs worldwide; variation is observed among populations. The main diagnostic center for peroxisomal diseases in Japan reported only 31 affected individuals over a 20-year period, with an estimated birth prevalence of 1:500,000 [Shimozawa et al 2003]. This lower incidence in Japan is mainly due to the absence of the common European PEX1 variants p.Ile700TyrfsTer42 and p.Gly843Asp.

Differential Diagnosis

The differential diagnosis of Zellweger spectrum disorder (ZSD) varies with age at presentation and most prominent feature of the presentation.

ZSD in newborns is most often confused with other conditions that result in profound hypotonia including Down syndrome, other chromosome abnormalities, Prader-Willi syndrome, spinal muscular atrophy, congenital myotonic dystrophy type 1, and congenital myopathies such as X-linked myotubular myopathy and multiminicore disease.

Older children have been initially presumed to have Usher syndrome type I or Usher syndrome type II and other disorders of sensorineural hearing loss and retinitis pigmentosa, Leber congenital amaurosis [Lambert et al 1989, Michelakakis et al 2004] (see also Hereditary Hearing Loss and Deafness Overview, Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy Overview, and Retinitis Pigmentosa Overview), Cockayne syndrome, or congenital infections.

Leukodystrophies may result from lysosomal storage diseases including Krabbe disease and metachromatic leukodystrophy, from mitochondrial disease, or from X-linked adrenoleukodystrophy (see Tran et al [2014] for an example of a PEX6 defect mistaken for X-ALD), and often are the first consideration (see also Leukodystrophy Overview).

At least 15% of individuals with a ZSD clinical phenotype and demonstrating increased plasma VLCFA concentration actually have a single-enzyme deficiency of peroxisomal β-oxidation (i.e., D-bifunctional enzyme deficiency or acyl-CoA oxidase deficiency) and do not have a pathogenic variant in a PEX gene.

  • D-bifunctional enzyme deficiency (OMIM 261515) is more common and in general more severe, often presenting with severe seizures within the first days of life; thus, it more closely resembles severe ZSD. The milder forms are at risk of developing a leukodystrophy.
  • Acyl-CoA oxidase deficiency (OMIM 264470) has a less pronounced biochemical and clinical phenotype and in general follows a disease course more similar to intermediate ZSD (see Watkins et al [1995] for comparison of the disorders).
  • Other rarer single-enzyme defects affecting β-oxidation include SCP2 and ACDB5 [Abu-Safieh et al 2013, Ferdinandusse et al 2017].

It is important to differentiate peroxisome assembly defects from other single-enzyme defects of peroxisomal metabolism. Children may be erroneously diagnosed as having a variant of X-linked adrenoleukodystrophy [Tran et al 2014] or adult Refsum disease. This most often occurs secondary to lack of familiarity with the underlying defect and the unfortunate redundancy of eponyms.

  • X-linked adrenoleukodystrophy is characterized by an elevation of plasma concentrations of VLCFAs without other abnormalities of peroxisomes. Males with this condition are almost always developmentally normal before their initial presentation.
  • Adult Refsum disease is caused by pathogenic variants in PHYH (encoding phytanoyl-CoA hydroxylase) in more than 90% of affected individuals and pathogenic variants in PEX7 (encoding the PTS2 receptor) in fewer than 10% of affected individuals. Individuals with adult Refsum disease have a biochemical profile distinct from ZSD and are developmentally normal before presenting in their late teens or twenties.

An increase in plasma VLCFA concentration consistent with a defect in peroxisomal fatty acid metabolism can also be observed in CADDS (OMIM 300475), a contiguous deletion syndrome with a critical region spanning ABCD1 and BAP31 [Corzo et al 2002].

DNM1L (dynamin 1-like) (OMIM 614388) is characterized by encephalopathy due to defective mitochondrial and peroxisomal fission 1. In the initial report a dominant-negative de novo heterozygous DNM1L pathogenic variant was detected in an infant [Waterham et al 2007]. Clinical findings were mild dysmorphic facial features, truncal hypotonia, absent tendon reflexes, microcephaly, optic atrophy, failure to thrive, and severe developmental delay. Biochemical findings included mildly elevated plasma VLCFA and persistent lactic acidemia. Immunocytochemical studies in cultured fibroblasts suggested a defect in mitochondrial and peroxisomal fission. Several other individuals with a de novo DNM1L missense variant have been reported [Sheffer et al 2016, Vanstone et al 2016], as well as two individuals with autosomal recessive DNM1L loss-of-function pathogenic variants [Yoon et al 2016].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Zellweger spectrum disorder (ZSD) the following are recommended if they have not already been completed:

  • Feeding and nutrition assessment
  • Hearing assessment
  • Comprehensive ophthalmologic assessment
    Note: Electroretinogram (ERG) and visual field testing are useful in the diagnosis of retinal dystrophy. OCT examinations in compliant patients have shown cystoid macular edema [Ventura et al 2016].
  • Liver function testing
  • Neurologic examination as well as possible brain MRI and EEG if findings warrant
  • Developmental assessment
  • Evaluation of adrenal function given that adrenal insufficiency may occur during periods of stress
  • Dental evaluation
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Klouwer et al [2015] (full text) and Braverman et al [2016] (full text) have published management and treatment guidelines for ZSD. Treatment focuses on symptomatic therapy.

Feeding and nutrition. Supplying adequate calorie intake for affected children often entails the placement of a gastrostomy tube to allow simpler home management. No specific metabolic diet is recommended. With many children having some degree of malabsorption, elemental formulas may be better tolerated.

Note: A diet low in phytanic acid has been proposed, based mainly on the weak analogy with adult Refsum disease, in which accumulation of phytanic acid is pathogenic and treatment involves restricted dietary intake of phytanic acid (including avoidance of full fat cow's milk products and high fat meat products from ruminants). Its effectiveness in ZSD has never been proven. All standard infant formulas are already low in phytanic acid.

Hearing. Hearing aids should be used in children found to have hearing impairment. (See also Hereditary Hearing Loss and Deafness Overview for discussion of management issues.)

Vision. Cataract removal in early infancy to preserve vision is appropriate. Glasses should be used as needed to correct refractive errors.

Liver. Supplementation of vitamin K and other fat-soluble vitamins is recommended.

Liver dysfunction may lead to varices that respond to sclerosing therapies.

CholbamTM (cholic acid) supplementation to treat the liver disease in patients with ZSD has been recently approved. By providing the final C24 bile acid product, the bile acid pathway undergoes feedback inhibition, thus reducing the levels of elevated C27 bile acid intermediates that are thought to be toxic to the liver. Cholic acid therapy does in fact decrease C27 bile acid intermediates (which should be measured), but its clinical effect in ZSD is not yet known. Furthermore, cholic acid supplementation can worsen liver disease in patients with evidence of preexisting fibrosis and advanced liver disease [Berendse et al 2016].

Neurologic. Early-intervention services should be provided for those with developmental delays.

Standard antiepileptic drugs (AEDs) may be used to treat seizures. No type of AED is contraindicated. Seizures may be difficult to control despite use of appropriate medication.

Bone. Evaluation of (1) bone density by dual-energy x-ray absorptiometry (DXA) and (2) vitamin D levels should be considered. The benefits of bisphosphonate treatment have been reported in a case report [Rush et al 2016].

Teeth. Semiannual dental visits are recommended.

Vaccination. In addition to the usual vaccination schedule for children, patients with ZSD should receive annual influenza and respiratory syncytial virus vaccines.

Surveillance

Hearing should be evaluated annually.

Annual ophthalmologic evaluation is indicated. (Although electroretinogram is useful in the diagnosis of a retinal dystrophy, it is not useful in follow up; visual field testing is much more helpful.)

Coagulation factors and other synthetic liver functions should be monitored. Persons with overt hepatic dysfunction require more routine monitoring.

The use of routine neuroimaging is uncertain. Individuals with peroxisomal disorders may develop a progressive leukodystrophy. No effective therapy exists, but identification of white matter changes may explain changes in cognitive and/or motor ability.

Adrenal function should be assessed beginning at age one year and regularly thereafter.

Longer-surviving affected individuals should be monitored for hyperoxaluria, which can lead to stone formation and end-stage renal disease.

Evaluation of Relatives at Risk

When the proband is on the milder end of the ZSD spectrum, it is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs in order to identify as early as possible those who are affected and, thus, would benefit from annual hearing and ophthalmologic evaluation, and routine monitoring of coagulation factors, adrenal function, and liver function. Note that molecular genetic testing for the pathogenic variants identified in the family is warranted as the results of screening assays (Table 1) in persons at the mild end of the ZSD spectrum may be highly variable.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Zellweger spectrum disorder (ZSD) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one ZSD-PEX gene pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband

  • In general, affected individuals do not reproduce.
  • Some individuals with milder phenotypes may reproduce; the offspring of such individuals are obligate heterozygotes (carriers of a pathogenic variant in a ZSD-PEX gene).

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier of a ZSD-PEX gene pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the ZSD-PEX gene pathogenic variants in the family.

Biochemical testing is not accurate for carrier testing as the biochemical markers in carriers are normal.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Molecular genetic testing. Once the ZSD-PEX gene pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for ZSD are possible.

Biochemical testing. Biochemical testing in cultured fibroblasts is still valuable when molecular testing has not identified biallelic pathogenic variants in a ZSD-PEX gene. In these cases, a definitive abnormality confirmed in cultured fibroblasts could then be used for prenatal testing in cultured CVS samples or amniocytes. Note that it is important to perform studies to rule out maternal cell contamination in cultured CVS samples [Steinberg et al 2005].

Biochemical testing of cultured amniocytes may also be useful when abnormalities suggestive of ZSD are detected on prenatal ultrasound examination.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Global Foundation for Peroxisomal Disorders
    5147 South Harvard Avenue
    Suite 181
    Tulsa OK
    Fax: 918-516-0227
    Email: contactus@thegfpd.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • NCBI Genes and Disease
  • United Leukodystrophy Foundation (ULF)
    224 North Second Street
    Suite 2
    DeKalb IL 60115
    Phone: 800-728-5483 (toll-free); 815-748-3211
    Fax: 815-748-0844
    Email: office@ulf.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Zellweger Spectrum Disorder: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Zellweger Spectrum Disorder (View All in OMIM)

170993PEROXISOME BIOGENESIS FACTOR 2; PEX2
202370PEROXISOME BIOGENESIS DISORDER 2B; PBD2B
214100PEROXISOME BIOGENESIS DISORDER 1A (ZELLWEGER); PBD1A
266510PEROXISOME BIOGENESIS DISORDER 3B; PBD3B
600279PEROXISOME BIOGENESIS FACTOR 19; PEX19
600414PEROXISOME BIOGENESIS FACTOR 5; PEX5
601498PEROXISOME BIOGENESIS FACTOR 6; PEX6
601758PEROXISOME BIOGENESIS FACTOR 12; PEX12
601789PEROXISOME BIOGENESIS FACTOR 13; PEX13
601791PEROXISOME BIOGENESIS FACTOR 14; PEX14
602136PEROXISOME BIOGENESIS FACTOR 1; PEX1
602859PEROXISOME BIOGENESIS FACTOR 10; PEX10
603164PEROXISOME BIOGENESIS FACTOR 3; PEX3
603360PEROXISOME BIOGENESIS FACTOR 16; PEX16
603867PEROXISOME BIOGENESIS FACTOR 11B; PEX11B
608666PEROXISOME BIOGENESIS FACTOR 26; PEX26

Molecular Genetic Pathogenesis

Pathogenic variants in the 13 PEX genes listed in Tables 2 and 3 are known to cause Zellweger spectrum disorder (ZSD) in humans. These PEX genes encode proteins required for peroxisome biogenesis called "peroxins"; the nomenclature for naming the genes is "PEX" followed by a number. A few of the peroxins appear to be essential for peroxisome membrane formation. However, the majority of known affected individuals have pathogenic variants in PEX genes encoding proteins essential for the import of peroxisomal matrix proteins.

Peroxisomes: biogenesis and assembly. At least 29 peroxins are required for peroxisome membrane biogenesis, fission, and protein import to form competent organelles. Much of our understanding of the function of these peroxins stems from work performed in a variety of yeast strains. The biogenesis of membranes is not well understood, but pathogenic null variants in three human PEX genes (PEX3, PEX16, and PEX19) are associated with an absence of any peroxisome membrane structures [Ghaedi et al 2000].

The remaining proteins encoded by the known PEX genes contribute to the machinery required for matrix protein import, a complex process currently under active study. In general, peroxisomal matrix proteins are encoded by nuclear genes that are translated on free polyribosomes.

PEX5 (also known as PXR1) encodes a receptor that recognizes proteins containing peroxisomal targeting sequence 1 (PTS1), defined by the carboxy terminal consensus sequence serine-lysine-leucine (SKL).

PEX7 encodes the PTS2 receptor and recognizes proteins with an N-terminal motif present in fewer matrix proteins. Pathogenic variants in PEX7 are associated with the clinically distinct disorder rhizomelic chondrodysplasia punctata.

Two subcomplexes within peroxisome membranes are essential for the transfer of peroxisomal enzymes from the cytosol to the peroxisome matrix. The first complex (comprising PEX13 and PEX14) plays a role in the docking of the PTS1 and PTS2 receptors and their associated proteins; the second complex (comprising PEX2, PEX10, and PEX12) appears to be part of the translocation apparatus for matrix proteins. In contrast, PEX1 and PEX6 form a complex that may play a role in the recycling of the receptors encoded by PEX5 and PEX7. Epistasis studies in yeast indicate that PEX1 and PEX6 act late in the import pathway, perhaps after the translocation process [Collins et al 2000]. However, the identification of PEX26 has shown that the encoded protein directly interacts with PEX1-PEX6 complexes. Thus, all three proteins may play a critical role in the presentation of PTS1 and PTS2 proteins to the peroxisomal membrane.

Peroxisomes: metabolic pathways. A variety of anabolic and catabolic pathways occur in the peroxisome. β-oxidation and plasmalogen synthesis are two fundamental pathways localized there. The peroxisomal β-oxidation enzymes are distinct from the mitochondrial system. Straight-chain VLCFA β-oxidation requires the enzymes very-long-chain acyl-CoA synthetase, acyl-CoA oxidase, D-bifunctional protein (enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase), and peroxisomal β-ketothiolase. All of these proteins have PTS1 signals except for peroxisomal β-ketothiolase, which is imported in a proform via a PTS2 signal. These proteins also play an important role in the side-chain modification of C27 bile acids. Thus, the defect in peroxisomal fatty acid β-oxidation accounts for the increase in VLCFA branched-chain fatty acids (e.g., pristanic acid) and C27 bile acids. A unique branched-chain acyl-CoA oxidase is used for bile acids and pristanic acid, thus explaining why these metabolites are normal in acyl-CoA oxidase deficiency. The initial steps of plasmalogen synthesis occur in the peroxisome and the final stages of synthesis are completed in the endoplasmic reticulum. Dihydroxyacetone phosphate (DHAP)-acyl transferase and alkyl-DHAP-synthase are PTS1 and PTS2 proteins, respectively.

It is not possible to determine the defective PEX gene based solely on the clinical, biochemical, or cellular phenotype. However, a good correlation often exists between the defective PEX gene, the type of pathogenic variant, the impact on peroxisome assembly, and clinical severity.

Research-based testing can evaluate the effect of any PEX pathogenic variant by assessing the morphology of peroxisomes in cultured fibroblasts and their ability to import proteins with a PTS1 or PTS2 signal. Catalase is often used as a marker for PTS1 import, although an antibody to carboxy terminal -SKL is quite valuable for evaluating general PTS1 import. Antibodies to β-ketothiolase, phytanoyl CoA hydroxylase, or alkyl DHAP synthase can be used for evaluating PTS2 import. Individuals with PEX3, PEX16, or PEX19 null variants are likely to lack any peroxisomal membrane remnants, detected by immunostaining peroxisomal membrane proteins such as ALDP or PMP70. In contrast, individuals with other PEX gene defects are likely to have peroxisomes that can be visualized if a peroxisomal membrane protein antibody is used. However, these peroxisomal structures are likely to be enlarged in size and reduced in number. The type of pathogenic variant(s) in the particular PEX gene determines the impact on PTS1 and PTS2 import. A large number of cells need to be evaluated to assess the impact on import. PTS1 or PTS2 import may be completely absent in an individual with ZSD and only minimally impaired in an individual on the milder end of the clinical spectrum [Shimozawa et al 1999a].

Detailed immunocytochemical analysis in fibroblasts that are deficient in a variety of PEX genes (PEX6, PEX5, PEX26, PEX1, PEX2 [PXMP3], PEX13) has resulted in the identification of a phenomenon called "temperature sensitivity" [Imamura et al 1998, Shimozawa et al 1999b, Imamura et al 2000, Ito et al 2001, Akiyama et al 2002, Matsumoto et al 2003]. PEX-deficient fibroblasts incubated at 37°C may have a more severe cellular phenotype based on PTS1 and PTS2 import than cell lines cultured at 30°C. Since this phenomenon has been described in cell lines with pathogenic missense variants, it has been hypothesized that culturing the cells at a lower temperature allows the mutated protein to attain a more relaxed conformation that enhances function. The identification of small molecules in vivo that would mimic the effect of lowering incubation temperature may have therapeutic relevance. Similarly, culturing cells at 40°C can be used to exacerbate the defect in cells exhibiting a milder import phenotype. This may be particularly useful for cells exhibiting mosaicism [Gootjes et al 2003].

Table 3.

Molecular Structure of the 13 PEX Genes Associated with ZSD

GeneExonsGenomic DNA (kb)cDNA (kb)Protein
(# of amino acids)
PEX12441.53.91283
PEX2 (PXMP3)47.41.5626
PEX312391.1373
PEX51518.91.8602 & 639
PEX61715.12.4980
PEX1067.81326 & 345 1
PEX11b47.51.7259
PEX1233.81.1359
PEX13431.21.2403
PEX149135.51.1377
PEX16118.41346
PEX1985.70.9299
PEX26510.70.9305

1. According to in silico analysis, it may be up to 346 amino acids, depending on splicing of the alternate intron 3 acceptor site. It is unclear which is preferred in vivo.

Pathogenic variants. PEX gene defects associated with ZSD thus far reported are due to loss-of-function variants. These variants span the full gamut of DNA nucleotide substitutions and indel variation (small and large) associated with human disease. Ebberink et al [2011] provide the most comprehensive summary of PEX gene variants identified by them (in >600 patients) and by others as reported in the literature.

PEX1. The only common variants are found in PEX1 (p.Ile700TyrfsTer42 and p.Gly843Asp) and account for its disproportionate contribution to ZSD. The PEX1 variants represented about 63% of all alleles in 94 individuals with ZSD [Steinberg et al 2004]. It has been proposed that the two common alleles reside on specific haplotypes and arose as founder variants [Collins & Gould 1999], suggesting that these sites are not hot spots for recurrent pathogenic variants. Approximately 80% of individuals with a PEX1 pathogenic variant have at least one of these common alleles.

PEX6. There are no common PEX6 variants. However, recently the PEX6 variant c.2578C>T (p.Arg860Trp) was shown to be associated with ZSD in the heterozygous state, acting in an apparent dominant fashion, due to allelic expression imbalance associated with the common variant c.*442_445delTAAA in the 3’ UTR that disrupts one of two polyadenylation sites. Individuals who have c.*442_445delTAAA on both chromosomes are unaffected; but individuals who have c.2578C>T (p.Arg860Trp) on the c.*442_445delTAAA background but lack c.*442_445delTAAA on the opposite chromosome have a two- to threefold increase in abnormal PEX6 compared to controls, and have biochemical and clinical features consistent with ZSD [Falkenberg et al 2017].

PEX10. The pathogenic PEX10 variant c.814_815delCT is a common allele in the Japanese population, where it appears to have arisen once on an ancestral haplotype [Shimozawa et al 2003].

Table 4.

PEX Pathogenic Variants Discussed in This GeneReview

GeneDNA Nucleotide Change
(Alias 1)
Predicted Protein ChangeReference Sequences
PEX1c.2097dupTp.Ile700TyrfsTer42NM_000466​.2
NP_000457​.1
c.2528G>Ap.Gly843Asp
PEX6c.2578C>Tp.Arg860TrpNM_000287​.3
NP_000287​.3
PEX10c.814_815delCT
(PEX10Δ814/815)
p.Leu272ValfsTer66NM_002617​.3
NP_002608​.1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

References

Published Guidelines / Consensus Statements

  • Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia JG, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. Available online. 2016. Accessed 9-28-18. [PMC free article: PMC5214431] [PubMed: 26750748]
  • Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Available online. 2015. Accessed 9-28-18.

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  • Vanstone JR, Smith AM, McBride S, Naas T, Holcik M, Antoun G, Harper ME, Michaud J, Sell E, Chakraborty P, Tetreault M, Majewski J, Baird S, Boycott KM, Dyment DA, MacKenzie A, Lines MA, et al. DNM1L-related mitochondrial fission defect presenting as refractory epilepsy. Eur J Hum Genet. 2016;24:1084–8. [PMC free article: PMC5070894] [PubMed: 26604000]
  • Ventura MJ, Wheaton D, Xu M, Birch D, Bowne SJ, Sullivan LS, Daiger SP, Whitney AE, Jones RO, Moser AB, Chen R, Wangler MF. Diagnosis of a mild peroxisomal phenotype with next-generation sequencing. Mol Genet Metab Rep. 2016;9:75–78. [PMC free article: PMC5109284] [PubMed: 27872819]
  • Waterham HR, Koster J, van Roermund CWT, Mooyer PAW, Wanders RJA, Loenard JV. A lethal defect of mitochondrial and peroxisomal fission. N Engl J Med. 2007;356:1736–41. [PubMed: 17460227]
  • Watkins PA, McGuinness MC, Raymond GV, Hicks BA, Sisk JM, Moser AB, Moser HW. Distinction between peroxisomal bifunctional enzyme and acyl-CoA oxidase deficiencies. Ann Neurol. 1995;38:472–7. [PubMed: 7668838]
  • Yoon G, Malam Z, Paton T, Marshall CR, Hyatt E, Ivakine Z, Scherer SW, Lee KS, Hawkins C, Cohn RD., Finding of Rare Disease Genes (FORGE) in Canada Consortium Steering Committee. Lethal disorder of mitochondrial fission caused by mutations in DNM1L. J Pediatr. 2016;171:313–6.e1. [PubMed: 26825290]

Suggested Reading

  • Rosewich H, Dechent P, Krause C, Ohlenbusch A, Brockmann K, Gärtner J. Diagnostic and prognostic value of in vivo proton MR spectroscopy for Zellweger syndrome spectrum patients. J Inherit Metab Dis. 2016;39:869–876. [PubMed: 27488561]
  • van der Knaap MS, Wassmer E, Wolf NI, Ferreira P, Topçu M, Wanders RJ, Waterham HR, Ferdinandusse S. MRI as diagnostic tool in early-onset peroxisomal disorders. Neurology. 2012;78:1304–8. [PubMed: 22459681]
  • Waterham HR, Ferdinandusse S, Wanders RJ. Human disorders of peroxisome metabolism and biogenesis. Biochim Biophys Acta. 2016;1863:922–33. [PubMed: 26611709]

Chapter Notes

Author History

Nancy E Braverman, MS, MD (2003 – present)
Ann B Moser, BA (2003 – present)
Hugo W Moser, MD (2003 – 2007*)
Gerald V Raymond, MD (2003 – present)
Steven J Steinberg, PhD (2003 – present)

*Hugo W Moser, MD was Professor of Neurology and Pediatrics at Johns Hopkins University School of Medicine and former Director of the Kennedy Krieger Institute in Baltimore. He was a world-renowned expert in the field of neurogenetics. He was best known for his leadership role in understanding, diagnosing, and treating adrenoleukodystrophy (ALD). Dr Moser died of cancer on January 20, 2007 at age 82. He will be greatly missed by his family, friends, colleagues, and patients.

Revision History

  • 21 December 2017 (sjs) Revision: PEX6 pathogenic variant added
  • 16 November 2017 (bp) Comprehensive update posted live
  • 10 May 2012 (cd) Revision: to clarify that prenatal testing using biochemical methods is possible
  • 18 January 2011 (me) Comprehensive update posted live
  • 26 April 2006 (me) Comprehensive update posted live
  • 1 October 2004 (sjs) Revision
  • 12 December 2003 (me) Review posted live
  • 1 August 2003 (sjs) Original submission
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