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; anti-seizure medication, 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.

Suggestive Findings

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

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 (or likely pathogenic) variants in one of the 13 PEX genes listed in Table 2.

1.

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). (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (3) Identification of biallelic variants of uncertain significance (or 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.

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.

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].

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).

• Homozygosity for PEX1 p.Ile700TyrfsTer42 is associated with a more severe phenotype.
• Homozygosity for PEX1 p.Gly843Asp has to date been associated with a milder ZSD phenotype and sometimes with an intermediate phenotype [Poll-The et al 2004]. In addition, an adult with a normal neurologic examination and an ocular phenotype was reported [Majewski et al 2011].

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.

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.

Treatment of Manifestations

Treatment focuses on symptomatic therapy.

Surveillance

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.

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

• The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one ZSD-causing pathogenic variant based on family history).
• Once the causative pathogenic variants have been identified in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a ZSD-causing pathogenic variant and to allow reliable recurrence risk assessment. (De novo variants are known to occur at a low but appreciable rate in autosomal recessive disorders [Jónsson et al 2017].)
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

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 carrier testing for at-risk relatives requires prior identification of the ZSD-causing 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/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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

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.

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.

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

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 11-1-22.
• 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 11-1-22.

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