NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Zellweger Spectrum Disorder

Synonym: ZSD

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

Author Information

Initial Posting: ; Last Update: October 29, 2020.

Estimated reading time: 28 minutes

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 defect in one of the ZSD-PEX genes 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 the long bones), and liver disease that 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 by identification of biallelic pathogenic variants in one of the 13 known ZSD-PEX genes. One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background.

Management.

Treatment of manifestations: The focus is on symptomatic therapy and may include gastrostomy to provide adequate calories, hearing aids, cataract removal, glasses to correct refractive errors, supplementation of fat-soluble vitamins, and cholic acid supplementation; varices can be treated with sclerosing therapies; antiepileptic drugs, early intervention services for developmental delay and intellectual disability; adrenal replacement therapy; vitamin D supplementation and consideration of bisphosphonates for osteopenia; treatment as per dentist for ameliogenesis imperfecta. Supportive treatment for renal oxalate stones has included hydration, lithotripsy, and surgical intervention. Annual influenza and respiratory syncytial virus vaccines should be provided.

Surveillance: Growth and nutrition should be assessed at each visit. Annual audiology and ophthalmologic evaluations; annual monitoring of liver function and coagulation factors, and ultrasound and/or fibroscan to evaluate liver architecture; monitor for changes in seizure activity; head MRI to evaluate for white matter changes that may explain changes in cognitive and/or motor ability; monitor developmental progress and educational needs; ACTH and cortisol levels by age one year and annually thereafter. Dental examinations every six months. Annual urine oxalate-to-creatinine ratio with consideration of renal imaging when performing liver imaging. Assessment of family needs at each visit.

Genetic counseling.

ZSD is typically inherited in an autosomal recessive manner (one PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state). At conception, each sib of an individual with biallelic ZSD-causing pathogenic variants 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 is possible if the pathogenic variants have been identified in an affected family member. Prenatal testing for a pregnancy at increased risk is possible by DNA testing if both ZSD-related pathogenic variants have been identified in an affected family member, or by biochemical testing if the biochemical defects have been confirmed in cultured fibroblasts from an affected family member.

GeneReview Scope

Zellweger Spectrum Disorder (ZSD): Included Phenotypes
  • Severe ZSD (previously called Zellweger syndrome)
  • Intermediate/milder ZSD (previously called neonatal adrenoleukodystrophy, infantile Refsum disease, or Heimler syndrome)

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

In newborns:

  • 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

In older infants and children:

  • 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 Zellweger Spectrum Disorder

CompoundTestExpected FindingsLimitations of Test
C26:0 LPC 1Dried blood spot concentrations↑ C26:0-LPC concentrationsPersons w/mild ZSD may not be detected.
VLCFAPlasma concentration↑ plasma concentrations of C26:0 & C26:1; ↑ ratios of C24/C22 & C26/C22 2Non-fasting samples, hemolyzed samples, or a person on a ketogenic diet can cause false positive results.
Phytanic acid & pristanic acid 3Plasma concentration↑ concentrations of phytanic acid &/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 concentrations↓ amounts of C16 & C18 plasmalogensPersons w/moderate-to-mild ZSD may have marginally↓-to-normal plasmalogen levels.
Pipecolic acidPlasma/urine concentration↑ concentration of pipecolic acid in both plasma & urineUrinary excretion of pipecolic acid is high in neonatal period but diminishes w/age. 4 Thus, urine should be tested in a neonate & plasma in an older child or adult.
Bile acidsPlasma/urine concentration↑ concentrations of C27 bile acid intermediates THCA & DHCAIn most cases plasma testing is more sensitive than urine analysis.

DHCA = dihydroxycholestanoic acid; LPC = lysophosphatidylcholine; THCA = trihydroxycholestanoic acid; VLCFA = very-long-chain fatty acids

1.

C26:0-LPC is measured in dried blood spots (DBS) in newborn screening programs for X-linked adrenoleukodystrophy (X-ALD) in many states in the USA [Vogel et al 2015, Moser et al 2016]. Elevated C26:0-LPC concentrations are also detected in individuals with ZSD. Clinical evaluation, molecular testing, and additional biochemical testing of newborns with elevated C26:0-LPC on DBS can help to distinguish those with peroxisomal disorders other than X-ALD.

2.

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. Persons 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.

3.

This analysis is usually included in VLCFA measurement.

4.

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 described in Suggestive Findings by identification of biallelic pathogenic variants in one of the 13 PEX genes listed in Table 2.

Note: One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background (see Molecular Genetics).

Note: Identification of biallelic variants of uncertain significance (or identification of one known pathogenic variant and one variant of uncertain significance) in one of the 13 PEX genes listed in Table 2 does not establish or rule out the diagnosis of this disorder.

Molecular genetic testing approaches can include gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing), depending on the phenotype.

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 that includes the 13 genes listed in Table 2 and other genes of interest (see Differential Diagnosis) 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.. 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. (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 clinical and laboratory findings in an affected individual do not lead to consideration of ZSD, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) can be the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

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 Gene 3Proportion of Pathogenic Variants 4 Detectable by 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 9
PEX264.2%17/17 9
PEX103.4%17/18 9
PEX23.1%19/22 9
PEX52.0%13/13 9
PEX131.5%7/7 9
PEX161.1%8/8 9
PEX30.7%3/3 9
PEX190.6%3/3 9
PEX140.5%1/2 9
PEX11B0.1%1/1 12
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 individuals 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 variants detected in these genes.

5.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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 used may 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]. 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, 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.

PEX11B: single case report [Ebberink et al 2012]. Taylor et al [2017] reported five additional individuals from three families. All had congenital cataracts and other clinical features, but normal or equivocal peroxisomal biomarkers in limited testing.

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 fontanelle, and widely split sutures. In severely affected children, bony stippling (chondrodysplasia punctata) at the patella(e) and the 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 are rarely 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

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

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], PEX11B-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, screening assays of individuals described as having these milder phenotypes do not show 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, frameshift variants) are most severe. In contrast, missense variants that retain some residual function have a less severe 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. While 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 has also formerly been referred to 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 or Heimler syndrome. The current preferred terminology is ZSD of severe, intermediate, or milder phenotype 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.

Prevalence

ZSD occurs worldwide with varying prevalence. In the past the incidence of ZSD had been estimated at 1:50,000 [Gould et al 2001]. More recent data from the New York state newborn screening laboratory confirmed 11 individuals with ZSD in more than 1.4 million screened for X-ALD using a biochemical assay (C26:0-LPC) that also detects ZSD (see Table 1) [Hubbard et al 2006, Hubbard et al 2009]. Thus, the confirmed incidence of ZSD in this population is 1:133,000 births [JJ Orsini, M Caggana, NY State Newborn Screening Laboratory Staff, personal communication, 2020]. Any estimate relying on a biochemical assay will be an underestimate because such assays fail to detect mild ZSD not associated with a definitive biochemical phenotype.

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, and the disorders summarized in Table 3.

Table 3.

Differential Diagnosis of ZSD in a Newborn with Profound Hypotonia

Gene(s) / Genetic MechanismDisorderMOI
DMPKCongenital myotonic dystrophy type 1AD
MTM1XL myotubular myopathyXL
PWCR / imprinting defectPrader-Willi syndromeSee footnote 1.
RYR1
SELENON
Multiminicore disease (OMIM 255320, 602771)AR
SMN1Spinal muscular atrophyAR
1.

The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.

Approximately 15% of individuals with a ZSD-like clinical phenotype and 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. Therefore, in children with elevated plasma VLCFA but no additional biochemical evidence of ZSD, a broader peroxisomal multigene panel that includes at least ACOX1 and HSD17B4 in addition to the 13 PEX genes is recommended.

Other differential diagnoses of peroxisomal and non-peroxisomal disorders that do not necessarily present as profound neonatal hypotonia are summarized in Tables 4a and 4b, respectively.

Table 4a.

Differential Diagnosis of ZSD – Other Peroxisomal Disorders

GeneDisorderMOIClinical FindingsBiochemical Findings
ABCD1XL adrenoleukodystrophy 1XLAffected males are almost always developmentally normal before initial presentation.↑ plasma VLCFA concentration in males; absence of other abnormalities of peroxisomes
ACBD5Retinal dystrophy w/leukodystrophy (OMIM 6188632ARZSD-like clinical phenotype↑ plasma VLCFA concentration, mild ↓ in plasmalogens
ACOX1Acyl-CoA oxidase deficiency (OMIM 2644703ARIntermediate ZSD-like clinical phenotype↑ plasma VLCFA concentration 3
DNM1LLethal encephalopathy due to defective mitochondrial peroxisomal fission 1 4 (OMIM 614388)AD
AR
Mildly dysmorphic facial features, truncal hypotonia, absent tendon reflexes, microcephaly, optic atrophy, failure to thrive, & severe DDMildly ↑ plasma VLCFA & persistent lactic acidemia
HSD17B4D-bifunctional enzyme deficiency (OMIM 2615152ARSpectrum of severity: from severe ZSD-like clinical phenotype (often presents w/severe seizures) to milder presentations w/normal biochemistry 5↑ plasma VLCFA concentration, branched chain fatty acids (pristanic & phytanic acids) & ↑ bile acid intermediates (THCA/DHCA)
SCP2Leukoencephalopathy w/dystonia & motor neuropathy (OMIM 6137242ARZSD-like clinical phenotype↑ plasma VLCFA concentration

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DHCA = dihydroxycholestanoic acid; Mat = maternal; MOI = mode of inheritance; SNHL = sensorineural hearing loss; THCA = trihydroxycholestanoic acid; VLCFA = very-long-chain fatty acid; XL = X-linked; ZSD = Zellweger spectrum disorder

1.

See Tran et al [2014] for an example of a PEX6 defect mistaken for X-linked adrenoleukodystrophy.

2.
3.

See Watkins et al [1995] for a comparison of acyl-CoA oxidase deficiency and ZSD.

4.
5.

Contiguous ABCD1/DXS1375E deletion syndrome (CADDS). An increase in plasma VLCFA concentration consistent with a defect in peroxisomal fatty acid metabolism can also be observed in CADDS, a contiguous deletion syndrome with a critical region spanning ABCD1 and BCAP31 [Corzo et al 2002].

Table 4b.

Differential Diagnosis of ZSD – Non-Peroxisomal Disorders

Gene(s)Disorder / PhenotypeMOIClinical Findings
>100 genes 1Hereditary hearing loss & deafnessAD
AR
XL
Mat
SNHL
>24 genes 2Leber congenital amaurosis / early-onset severe retinal dystrophyAR
(AD)
Progressive visual loss
~350 genes 3Mitochondrial diseaseAR
AD
Mat
May only affect a single organ or may involve multiple organ systems; often presents w/prominent neurologic & myopathic features
>80 genes 4Retinitis pigmentosaAD
AR
XL
(Digenic)
Progressive visual loss
ADGRV1
CDH23
CIB2
MYO7A
PCDH15
USH1C
USH1G
USH1H
USH2A
WHRN
Usher syndrome type I & type IIAR
  • Type 1: Congenital, bilateral, profound SNHL, vestibular areflexia, & RP
  • Type 2: Congenital, bilateral SNHL & RP
>100 genesHereditary leukodystrophies 5AD
AR
XL
Mat
Progressive spasticity w/loss of previous skills

AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss; XL = X-linked

1.
2.
3.
4.
5.

See Parikh et al [2015], Table 2: Major neurologic signs and symptoms in the leukodystrophies.

Management

Klouwer et al [2015] (full text) and Braverman et al [2016] (full text) have published management and treatment guidelines for Zellweger spectrum disorder (ZSD).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ZSD, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Zellweger Spectrum Disorder

System/ConcernEvaluationComment
Gastrointestinal/
Feeding
Feeding & nutrition assessment
  • To incl eval of aspiration risk & nutritional status
  • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk.
HearingAudiologic evalAssess for hearing loss.
EyesComprehensive ophthalmologic assessmentOCT exam in compliant patients has shown cystoid macular edema [Ventura et al 2016].
Hepatic
  • Liver function testing (AST, ALT, total & direct bilirubin, PT, PTT, INR)
  • C27 bile acid intermediates (DHCA & THCA)
  • Ultrasound eval &/or liver fibroscan
Liver fibrosis can occur insidiously over time; portal hypertension & esophageal varices can occur; rare adults have developed hepatocellular carcinoma in the setting of fibrosis [Berendse et al 2019, Heubi & Bishop 2018].
NeurologicNeurologic eval
  • To incl brain MRI
  • Consider EEG if seizures are a concern.
DevelopmentDevelopmental assessment
  • To incl motor, adaptive, cognitive, & speech/language eval
  • Eval for early intervention / special education
Endocrine
  • Eval of adrenal function (ACTH & cortisol)
  • Consideration of ACTH stimulation test as appropriate
Adrenal insufficiency may occur during periods of stress.
  • Eval of bone density by DEXA
  • Consider serum vitamin D level.
Pathologic fractures have occurred in persons at all ages; evaluate as clinically indicated [Rush et al 2016].
RenalUrine oxalate /creatinine ratio, serial renal ultrasound (can be done w/liver ultrasounds)Some patients develop urolithiasis & nephrocalcinosis assoc w/urinary oxalate load [van Woerden et al 2006].
DentalDental evalAmeliogenesis imperfects, typically of secondary teeth, requires extensive dental interventions.
Genetic counselingBy genetics professionals 1To inform patients & families re nature, MOI, & implications of ZSD in order to facilitate medical & personal decision making
Family support/
resources
Assess:

DEXA = dual-energy x-ray absorptiometry; DHCA = dihydroxycholestanoic acid; MOI= mode of inheritance; OCT = optical coherence tomography; THCA = trihydroxycholestanoic acid

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Treatment focuses on symptomatic therapy.

Table 6.

Treatment of Manifestations in Individuals with Zellweger Spectrum Disorder

Manifestation/
Concern
TreatmentConsiderations/Other
Feeding &
nutrition
  • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues.
  • No specific metabolic diet recommended 1
W/many children having some degree of malabsorption, elemental formulas may be better tolerated.
HearingHearing aids in children found to have hearing impairmentSee also Hereditary Hearing Loss and Deafness Overview for discussion of management issues.
Vision
impairment
  • Cataract removal to preserve vision
  • Glasses to correct refractive errors
Liver
dysfunction
  • Supplementation of vitamin K & other fat-soluble vitamins
  • CholbamTM (cholic acid) supplementation 2
  • Varices can be treated w/sclerosing therapies.
Cholic acid supplementation can worsen liver disease in individuals with preexisting fibrosis & advanced liver disease [Berendse et al 2016].
SeizuresStandard treatment w/AEDs by experienced neurologistNo type of AED is contraindicated. Seizures may be difficult to control despite use of appropriate medication.
DD/IDProvide early-intervention services.
Adrenal
insufficiency
Adrenal replacement therapy
Osteopenia
  • Vitamin D supplementation
  • Consider bisphosphonate.
Benefits of bisphosphonate treatment noted in 1 case report [Rush et al 2016]
Ameliogenesis
imperfecta
Treatment per dentistTran et al [2011], Acharya et al [2012]
Renal oxalate
stones
Supportive treatment has included hydration, lithotripsy, surgical intervention.Pyridoxine treatment did not ↓ oxalate excretion in 1 study [van Woerden et al 2006].
VaccinationAnnual influenza & respiratory syncytial virus vaccines as well as usual vaccination schedule

AED = antiepileptic drug; DD = developmental delay; ID = intellectual disability

1.

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.

2.

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.

Surveillance

Table 7.

Recommended Surveillance for Individuals with Zellweger Spectrum Disorder

System/ConcernEvaluationFrequency
Feeding
  • Measurement of growth parameters
  • Eval of nutritional status & safety of oral intake
At each visit
HearingAudiology evalAnnually
Eyes
  • Ophthalmologic eval
  • Visual field testing
Hepatic
  • Coagulation factors & other synthetic liver functions (PT, PTT, AST, ALT, total & direct bilirubin)
  • Ultrasound &/or fibroscan to evaluate liver architecture
Annually; persons w/overt hepatic dysfunction require more frequent monitoring.
NeurologicMonitor those w/seizures as clinically indicated.At each visit
Head MRI to evaluate for white matter changes that may explain changes in cognitive &/or motor abilityAs needed
DevelopmentMonitor developmental progress & educational needs.At each visit
EndocrineAssess adrenal function (ACTH & cortisol).By age 1 yr; annually thereafter
DentalDental examEvery 6 mos after dental eruption
Renal stones
  • Urine oxalate-to-creatinine ratio
  • Consider renal imaging when performing liver imaging.
Annually
Miscellaneous/
Other
Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources) & care coordination.At each visit

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 in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

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

Note: One PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state due to allelic expression imbalance dependent on allelic background (see Table 9).

Risk to Family Members – Autosomal Recessive Inheritance

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for a ZSD-causing pathogenic variant, each sib of an affected individual has at conception 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.
  • In general, greater clinical variation is observed in families in which affected sibs are on the milder end of ZSD.
  • 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 ZSD-causing pathogenic variant).

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

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk relatives requires prior identification of the ZSD-causing pathogenic variants in the family.

Note: 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/preimplantation genetic 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 Testing

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

Biochemical testing. Biochemical testing using CVS or amniocytes may be used for prenatal diagnosis after confirming the biochemical defects in cultured fibroblasts from an affected family member. This approach may be helpful if DNA testing in the proband yields equivocal results or if DNA testing in the proband is not possible. (Note: Only a few specialized laboratories offer biochemical prenatal testing for ZSD.)

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

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 Pathogenesis

Biallelic pathogenic variants in any one of the 13 PEX genes listed in Table 2 are known to cause Zellweger spectrum disorder (ZSD) in humans. These PEX genes encode proteins required for peroxisome biogenesis called "peroxins." Several peroxins are necessary for membrane biogenesis (PEX3, PEX16, and PEX19) and division (PEX11b), while the remaining genes associated with ZSD encode proteins comprising the peroxisomal matrix import machinery [Waterham & Ebberink 2012, Fujiki 2016].

Mechanism of disease causation. PEX gene defects associated with ZSD reported to date are predicted to be loss-of-function variants.

Table 8.

Zellweger Spectrum Disorder: Gene-Specific Laboratory Considerations

Gene 1Special Consideration
PEX5Alternative splicing of the PEX5 mRNA produces 2 functional protein variants. The longer variant, PEX5L, contains an additional 37 amino acids compared to the shorter PEX5S [Ebberink et al 2009 and references therein]. The reference sequence for PEX5L (X84899 or NM_001131025​.12 should be used for sequence analysis.
PEX6Common variant in the 3-UTR (c.*442_445delTAAA3
1.

Genes from Table 1 in alphabetic order

2.

Sequences of coding region are identical.

3.

See Table 9.

Table 9.

Zellweger Spectrum Disorder: Notable Pathogenic Variants by Gene

Gene 1Reference SequencesDNA Nucleotide
Change (Alias 2)
Predicted
Protein Change
Comment [Reference]
PEX1NM_000466​.2
NP_000457​.1
c.2097dupTp.Ile700TyrfsTer42Most common PEX1 variants; ~80% of persons w/a PEX1 pathogenic variant have at least 1 of these common alleles. (See Prevalence & Genotype-Phenotype Correlations.) 3
c.2528G>Ap.Gly843Asp
PEX6NM_000287​.3
NP_000278​.3
c.2578C>Tp.Arg860TrpAssoc w/ZSD in the heterozygous state, acting in an apparent dominant fashion due to allelic expression imbalance assoc w/common variant NM_000287​.3:c.*442_445delTAAA in the 3' UTR that disrupts 1 of 2 polyadenylation sites. Persons who have c.*442_445delTAAA on both chromosomes are unaffected; but those who have c.2578C>T (p.Arg860Trp) on the c.*442_445delTAAA background but lack c.*442_445delTAAA on the opposite chromosome have a 2- to 3-fold ↑ in abnormal PEX6 (compared to controls) & biochemical & clinical features consistent w/ZSD [Falkenberg et al 2017].
PEX10NM_002617​.3
NP_002608​.1
c.814_815delCT
(PEX10Δ814/815)
p.Leu272ValfsTer66Common allele in the Japanese population, where it appears to have arisen once on an ancestral haplotype [Shimozawa et al 2003]

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

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

1.

Genes from Table 1 in alphabetic order

2.

Variant designation that does not conform to current naming conventions

3.

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.

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 is greatly missed by his family, friends, colleagues, and patients.

Revision History

  • 29 October 2020 (sw) Comprehensive update posted live
  • 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

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 10-26-20. [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 10-26-20.

Literature Cited

  • Abu-Safieh L, Alrashed M, Anazi S, Alkuraya H, Khan AO, Al-Owain M, Al-Zahrani J, Al-Abdi L, Hashem M, Al-Tarimi S, Sebai MA, Shamia A, Ray-Zack MD, Nassan M, Al-Hassnan ZN, Rahbeeni Z, Waheeb S, Alkharashi A, Abboud E, Al-Hazzaa SA, Alkuraya FS. Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes. Genome Res. 2013;23:236–47. [PMC free article: PMC3561865] [PubMed: 23105016]
  • Acharya BS, Ritwik P, Velasquez GM, Fenton SJ. Medical-dental findings and management of a child with infantile Refsum disease: a case report. Spec Care Dentist. 2012;32:112–7. [PubMed: 22591434]
  • Berendse K, Engelen M, Linthorst GE, van Trotsenburg AS, Poll-The BT. High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders. Orphanet J Rare Dis. 2014;9:133. [PMC free article: PMC4164755] [PubMed: 25179809]
  • Berendse K, Klouwer FC, Koot BG, Kemper EM, Ferdinandusse S, Koelfat KV, Lenicek M, Schaap FG, Waterham HR, Vaz FM, Engelen M, Jansen PL, Wanders RJ, Poll-The BT. Cholic acid therapy in Zellweger spectrum disorders. J Inherit Metab Dis. 2016;39:859–68. [PMC free article: PMC5065608] [PubMed: 27469511]
  • Berendse K, Koot BGP, Klouwer FCC, Engelen M, Roels F, Lacle MM, Nikkels PGJ, Verheij J, Poll-The BT. Hepatic symptoms and histology in 13 patients with a Zellweger spectrum disorder. J Inherit Metab Dis. 2019;42:955–65. [PubMed: 31150129]
  • 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. Mol Genet Metab. 2016;117:313–21. [PMC free article: PMC5214431] [PubMed: 26750748]
  • Collins CS, Gould SJ. Identification of a common PEX1 mutation in Zellweger syndrome. Hum Mutat. 1999;14:45–53. [PubMed: 10447258]
  • Corzo D, Gibson W, Johnson K, Mitchell G, LePage G, Cox GF, Casey R, Zeiss C, Tyson H, Cutting GR, Raymond GV, Smith KD, Watkins PA, Moser AB, Moser HW, Steinberg SJ. Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: a novel neonatal phenotype similar to peroxisomal biogenesis disorders. Am J Hum Genet. 2002;70:1520–31. [PMC free article: PMC419992] [PubMed: 11992258]
  • Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PA, Dekker CJ, Spooner C, Ngu LH, De Sousa C, Wanders RJ, Fietz MJ, Clayton PT, Waterham HR, Ferdinandusse S. Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. J Med Genet. 2010;47:608–15. [PubMed: 20647552]
  • Ebberink MS, Koster J, Visser G, Spronsen F, Stolte-Dijkstra I, Smit GP, Fock JM, Kemp S, Wanders RJ, Waterham HR. A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene. J Med Genet. 2012;49:307–13. [PubMed: 22581968]
  • 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. Hum Mutat. 2011;32:59–69. [PubMed: 21031596]
  • Ebberink MS, Mooyer PA, Koster J, Dekker CJ, Eyskens FJ, Dionisi-Vici C, Clayton PT, Barth PG, Wanders RJ, Waterham HR. Genotype-phenotype correlation in PEX5-deficient peroxisome biogenesis defective cell lines. Hum Mutat. 2009;30:93–8. [PubMed: 18712838]
  • Falkenberg KD, Braverman NE, Moser AB, Steinberg SJ, Klouwer FCC, Schlüter A, Ruiz M, Pujol A, Engvall M, Naess K, van Spronsen F, Körver-Keularts I, Rubio-Gozalbo ME, Ferdinandusse S, Wanders RJA, Waterham HR. Allelic expression imbalance promoting a mutant PEX6 allele causes Zellweger spectrum disorder. Am J Hum Genet. 2017;101:965–76. [PMC free article: PMC5812895] [PubMed: 29220678]
  • Ferdinandusse S, Falkenberg KD, Koster J, Mooyer PA, Jones R, van Roermund CWT, Pizzino A, Schrader M, Wanders RJA, Vanderver A, Waterham HR. ACBD5 deficiency causes a defect in peroxisomal very long-chain fatty acid metabolism. J Med Genet. 2017;54:330–7. [PubMed: 27799409]
  • Fujiki Y. Peroxisome biogenesis and human peroxisome-deficiency disorders. Proc Jpn Acad Ser B Phys Biol Sci. 2016;92:463–77. [PMC free article: PMC5328784] [PubMed: 27941306]
  • Gootjes J, Skovby F, Christensen E, Wanders RJ, Ferdinandusse S. Reinvestigation of trihydroxycholestanoic acidemia reveals a peroxisome biogenesis disorder. Neurology. 2004;62:2077–81. [PubMed: 15184617]
  • Gould SJ, Raymond GV, Valle D. The peroxisome biogenesis disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:3181-218.
  • Heubi JE, Bishop WP. Long-Term Cholic Acid Treatment in a Patient with Zellweger Spectrum Disorder. Case Rep Gastroenterol. 2018;12:661–70. [PMC free article: PMC6276768] [PubMed: 30519152]
  • Hubbard WC, Moser AB, Tortorelli S, Liu A, Jones D, Moser H. Combined liquid chromatography-tandem mass spectrometry as an analytical method for high throughput screening for X-linked adrenoleukodystrophy and other peroxisomal disorders: preliminary findings. Mol Genet Metab. 2006;89:185–7. [PubMed: 16828324]
  • Hubbard WC, Moser AB, Liu AC, Jones RO, Steinberg SJ, Lorey F, Panny SR, Vogt RF Jr, Macaya D, Turgeon CT, Tortorelli S, Raymond GV. Newborn screening for X-linked adrenoleukodystrophy (X-ALD): validation of a combined liquid chromatography-tandem mass spectrometric (LC-MS/MS) method. Mol Genet Metab. 2009;97:212–20. [PubMed: 19423374]
  • Jónsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E, Hardarson MT, Hjorleifsson KE, Eggertsson HP, Gudjonsson SA, Ward LD, Arnadottir GA, Helgason EA, Helgason H, Gylfason A, Jonasdottir A, Jonasdottir A, Rafnar T, Frigge M, Stacey SN, Th Magnusson O, Thorsteinsdottir U, Masson G, Kong A, Halldorsson BV, Helgason A, Gudbjartsson DF, Stefansson K. Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017;549:519–22. [PubMed: 28959963]
  • Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. [PMC free article: PMC4666198] [PubMed: 26627182]
  • Lines MA, Jobling R, Brady L, Marshall CR, Scherer SW, Rodriguez AR, Lee L, Lang AE, Mestre TA, Wanders RJ, Ferdinandusse S, Tarnopolsky MA, et al. Peroxisomal D-bifunctional protein deficiency: three adults diagnosed by whole-exome sequencing. Neurology. 2014;82:963–8. [PMC free article: PMC3963001] [PubMed: 24553428]
  • Lyons CJ, Castano G, McCormick AQ, Applegarth D. Leopard spot retinal pigmentation in infancy indicating a peroxisomal disorder. Br J Ophthalmol. 2004;88:191–2. [PMC free article: PMC1772012] [PubMed: 14736770]
  • Majewski J, Wang Z, Lopez I, Al Humaid S, Ren H, Racine J, Bazinet A, Mitchel G, Braverman N, Koenekoop RK. A new ocular phenotype associated with an unexpected but known systemic disorder and mutation: novel use of genomic diagnostics and exome sequencing. J Med Genet. 2011;2011;48:593–6. [PubMed: 21862673]
  • Moser AB, Jones RO, Hubbard WC, Tortorelli S, Orsini JJ, Caggana M, Vogel BH, Raymond GV. Newborn Screening for X-Linked Adrenoleukodystrophy. Int J Neonatal Screen. 2016;2:15. [PMC free article: PMC6715319] [PubMed: 31467997]
  • Moser AB, Rasmussen M, Naidu S, Watkins PA, McGuinness M, Hajra AK, Chen G, Raymond G, Liu A, Gordon D, et al. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr. 1995;127:13–22. [PubMed: 7541833]
  • Moser HW. Genotype-phenotype correlations in disorders of peroxisome biogenesis. Mol Genet Metab. 1999;68:316–27. [PubMed: 10527683]
  • Parikh S, Bernard G, Leventer RJ, van der Knaap MS, van Hove J, Pizzino A, McNeill NH, Helman G, Simons C, Schmidt JL, Rizzo WB, Patterson MC, Taft RJ, Vanderver A. GLIA Consortium. A clinical approach to the diagnosis of patients with leukodystrophies and genetic leukoencephelopathies. Mol Genet Metab. 2015;114:501–15. [PMC free article: PMC4390485] [PubMed: 25655951]
  • Patay Z. Diffusion-weighted MR imaging in leukodystrophies. Eur Radiol. 2005;15:2284–303. [PubMed: 16021451]
  • Pierce SB, Walsh T, Chisholm KM, et al. Mutations in the DBP-deficiency protein HSD17B4 cause ovarian dysgenesis, hearing loss, and ataxia of Perrault Syndrome. Am J Hum Genet. 2010;87:282–8. [PMC free article: PMC2917704] [PubMed: 20673864]
  • Plecko B, Stockler-Ipsiroglu S, Paschke E, Erwa W, Struys EA, Jakobs C. Pipecolic acid elevation in plasma and cerebrospinal fluid of two patients with pyridoxine-dependent epilepsy. Ann Neurol. 2000;48:121–5. [PubMed: 10894227]
  • Poll-The BT, Gootjes J, Duran M, De Klerk JB, Wenniger-Prick LJ, Admiraal RJ, Waterham HR, Wanders RJ, Barth PG. Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. Am J Med Genet A. 2004;126A:333–8. [PubMed: 15098231]
  • Raas-Rothschild A, Wanders RJ, Mooijer PA, Gootjes J, Waterham HR, Gutman A, Suzuki Y, Shimozawa N, Kondo N, Eshel G, Espeel M, Roels F, Korman SH. A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents. Am J Hum Genet. 2002;70:1062–8. [PMC free article: PMC379104] [PubMed: 11873320]
  • Ratbi I, Falkenberg KD, Sommen M, Al-Sheqaih N, Guaoua S, Vandeweyer G, Urquhart JE, Chandler KE, Williams SG, Roberts NA, El Alloussi M, Black GC, Ferdinandusse S, Ramdi H, Heimler A, Fryer A, Lynch SA, Cooper N, Ong KR, Smith CE, Inglehearn CF, Mighell AJ, Elcock C, Poulter JA, Tischkowitz M, Davies SJ, Sefiani A, Mironov AA, Newman WG, Waterham HR, Van Camp G. Heimler syndrome is caused by hypomorphic mutations in the peroxisome-biogenesis genes PEX1 and PEX6. Am J Hum Genet. 2015;97:535–45. [PMC free article: PMC4596894] [PubMed: 26387595]
  • Ratbi I, Jaouad IC, Elorch H, Al-Sheqaih N, Elalloussi M, Lyahyai J, Berraho A, Newman WG, Sefiani A. Severe early onset retinitis pigmentosa in a Moroccan patient with Heimler syndrome due to novel homozygous mutation of PEX1 gene. Eur J Med Genet. 2016;59:507–11. [PubMed: 27633571]
  • Régal L, Ebberink MS, Goemans N, Wanders RJ, De Meirleir L, Jaeken J, Schrooten M, Van Coster R, Waterham HR. Mutations in PEX10 are a cause of autosomal recessive ataxia. Ann Neurol. 2010;68:259–63. [PubMed: 20695019]
  • Renaud M, Guissart C, Mallaret M, Ferdinandusse S, Cheillan D, Drouot N, Muller J, Claustres M, Tranchant C, Anheim M, Koenig M. Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia. J Neurol. 2016;263:1552–8. [PubMed: 27230853]
  • Rush ET, Goodwin JL, Braverman NE, Rizzo WB. Low bone mineral density is a common feature of Zellweger spectrum disorders. Mol Genet Metab. 2016;117:33–7. [PubMed: 26643206]
  • Sevin C, Ferdinandusse S, Waterham HR, Wanders RJ, Aubourg P. Autosomal recessive cerebellar ataxia caused by mutations in the PEX2 gene. Orphanet J Rare Dis. 2011;6:8. [PMC free article: PMC3064617] [PubMed: 21392394]
  • Sheffer R, Douiev L, Edvardson S, Shaag A, Tamimi K, Soiferman D, Meiner V, Saada A. Postnatal microcephaly and pain insensitivity due to a de novo heterozygous DNM1L mutation causing impaired mitochondrial fission and function. Am J Med Genet A. 2016;170:1603–7. [PubMed: 26992161]
  • Shimozawa N, Nagase T, Takemoto Y, Ohura T, Suzuki Y, Kondo N. Genetic heterogeneity of peroxisome biogenesis disorders among Japanese patients: Evidence for a founder haplotype for the most common PEX10 gene mutation. Am J Med Genet. 2003;120A:40–3. [PubMed: 12794690]
  • Smith CE, Poulter JA, Levin AV, Capasso JE, Price S, Ben-Yosef T, Sharony R, Newman WG, Shore RC, Brookes SJ, Mighell AJ, Inglehearn CF. Spectrum of PEX1 and PEX6 variants in Heimler syndrome. Eur J Hum Genet. 2016;24:1565–71. [PMC free article: PMC5026821] [PubMed: 27302843]
  • Steinberg SJ, Snowden A, Braverman NE, Chen L, Watkins PA, Clayton PT, Setchell KD, Heubi JE, Raymond GV, Moser AB, Moser HW. A PEX10 defect in a patient with no detectable defect in peroxisome assembly or metabolism in cultured fibroblasts. J Inherit Metab Dis. 2009;32:109–19. [PubMed: 19127411]
  • Taylor RL, Handley MT, Waller S, et al. Novel PEX11B mutations extend the peroxisome biogenesis disorder 14B phenotypic spectrum and underscore congenital cataract as an early feature. Invest Ophthalmol Vis Sci. 2017;58:594–603. [PMC free article: PMC5841568] [PubMed: 28129423]
  • Tran D, Greenhill W, Wilson S. Infantile refsum disease with enamel defects: a case report. Pediatr Dent. 2011;33:266–70. [PubMed: 21703082]
  • Tran C, Hewson S, Steinberg SJ, Mercimek-Mahmutoglu S. Late-onset Zellweger spectrum disorder caused by PEX6 mutations mimicking X-linked adrenoleukodystrophy. Pediatr Neurol. 2014;51:262–5. [PubMed: 25079577]
  • van Woerden CS, Groothoff JW, Wijburg FA, Duran M, Wanders RJ, Barth PG, Poll-The BT. High incidence of hyperoxaluria in generalized peroxisomal disorders. Mol Genet Metab. 2006;88:346–50. [PubMed: 16621644]
  • 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]
  • Vogel BH, Bradley SE, Adams DJ, D'Aco K, Erbe RW, Fong C, Iglesias A, Kronn D, Levy P, Morrissey M, Orsini J, Parton P, Pellegrino J, Saavedra-Matiz CA, Shur N, Wasserstein M, Raymond GV, Caggana M. Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol Genet Metab. 2015;114:599–603. [PubMed: 25724074]
  • 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]
  • Waterham HR, Ebberink MS. Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim Biophys Acta. 2012;1822:1430–41. [PubMed: 22871920]
  • 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]
Copyright © 1993-2021, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2021 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1448PMID: 20301621

Views

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...