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Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum

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

Author Information
, PhD
The Peroxisomal Diseases Laboratory
Kennedy Krieger Institute
Neurology, Johns Hopkins University School of Medicine
Baltimore, Maryland
, MD
Neurogenetics
Kennedy Krieger Institute
Neurology, Johns Hopkins University School of Medicine
Baltimore, Maryland
, MS, MD
Departments of Human Genetics McGill University - Montreal Children's Hospital Research Institute
Montreal, Quebec, Canada
, BA
The Peroxisomal Diseases Laboratory
Kennedy Krieger Institute
Neurology, Johns Hopkins University School of Medicine
Baltimore, Maryland

Initial Posting: ; Last Revision: May 10, 2012.

Summary

Disease characteristics. Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS) is a continuum of three phenotypes — Zellweger syndrome (ZS), the most severe; neonatal adrenoleukodystrophy (NALD); and infantile Refsum disease (IRD), the least severe — that were originally described before the biochemical and molecular bases of these disorders had been fully determined. Individuals with PBD, ZSS usually come to clinical attention in the newborn period or later in childhood. In the newborn period, affected children are hypotonic, feed poorly, and have distinctive facies, seizures, and liver cysts with hepatic dysfunction. Bony stippling (chondrodysplasia punctata) of the patella(e) and other long bones may occur. Infants with ZS are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Older children have retinal dystrophy, sensorineural hearing loss, developmental delay with hypotonia, and liver dysfunction. The clinical courses of NALD and IRD are variable and may include developmental delays, hearing loss, vision impairment, liver dysfunction, episodes of hemorrhage, and intracranial bleeding. While some children can be very hypotonic, others learn to walk and talk. The condition is often slowly progressive.

Diagnosis/testing. The diagnosis of PBD, ZSS can be definitively determined by biochemical assays. Biochemical abnormalities detected in blood and/or urine should be confirmed in cultured fibroblasts. Measurement of plasma very-long-chain fatty acid (VLCFA) levels is the most commonly used and most informative initial screen. Elevation of C26:0 and C26:1 and the ratios C24/C22 and C26/C22 is consistent with a defect in peroxisomal fatty acid metabolism. Mutations in twelve different PEX genes (PEX1, PXMP3 [PEX2], PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26) — those that encode peroxins, the proteins required for normal peroxisome assembly — have been identified in PBD, ZSS. Mutations in PEX1, the most common cause of PBD, ZSS, are observed in about 68% of affected individuals. .

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, antiepileptic drugs, and possibly monitoring for hyperoxaluria.

Surveillance: Annual hearing and ophthalmologic evaluations, monitoring of coagulation factors, and tests of liver function.

Agents/circumstances to avoid: Cow's milk products to reduce exposure to phytanic acid.

Genetic counseling. The Zellweger syndrome spectrum of the peroxisome biogenesis disorders 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 disease-causing alleles of an affected family member have been identified. 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

Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum: Included Disorders
  • Zellweger syndrome
  • Neonatal adrenoleukodystrophy
  • Infantile Refsum disease

For synonyms and outdated names see Nomenclature.

Diagnosis

Testing

Biochemical testing. Biochemical assays can determine definitively whether an individual has a peroxisomal biogenesis disorder, Zellweger syndrome spectrum (PBD, ZSS).

The battery of biochemical analyses used to diagnose PBD is summarized in Table 1.

The measurement of plasma very-long-chain fatty acid (VLCFA) concentrations is the most commonly used and most informative initial screen. Elevation of the plasma concentrations of C26:0 and C26:1 and the ratios of C24/C22 and C26/C22 is consistent with a defect in peroxisomal fatty acid metabolism. The degree of VLCFA plasma concentration elevation may vary, with a small percentage of individuals demonstrating only modest elevations.

An elevation of only one or two of these parameters warrants further evaluation and may require repeat analysis of a fasting specimen or measurement of other analytes listed in Table 1.

Table 1. Specialized Biochemical Testing in PBD, ZSS

CompoundTest Expected FindingsLimitations of Test
Very-long-chain fatty acids (VLCFA)Plasma concentrationElevated plasma concentrations of C26:0 and C26:1; elevated ratios of C24/C22 and C26/C22 1 Non-fasting samples, hemolyzed samples, or an individual on a ketogenic diet can cause false-positive results. Normal in RCDP.
Phytanic acid and pristanic acid 2 Plasma concentrationIncreased concentrations of phytanic acid and/or pristanic acid Branched-chain fatty acid accumulation occurs only through dietary intake of phytanic acid. Thus, phytanic and pristanic acid levels are normal in a neonate with a PBD.
PlasmalogensErythrocyte membrane concentrationsProfoundly diminished concentration of C16 and C18 plasmalogens (possible)Concentration of erythrocyte plasmalogens may improve with age. Not all newborns with PBD have reduced levels.
Pipecolic acidPlasma/urine concentrationIncreased concentration of pipecolic acid in both plasma and urineUrinary excretion of pipecolic acid is high in the neonatal period and diminishes with age. 3
Bile acidsPlasma/urine concentrationAccumulation of intermediates THCA and DHCASome defects may be subtle.

RCDP = rhizomelic chondrodysplasia punctata

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 (C22:0, C24:0, C26:0, etc) 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 occur in pyridoxine-dependent seizures [Plecko et al 2000] and in individuals with psychomotor retardation who have normal levels of other peroxisomal metabolites [Baas et al 2002]. Thus, isolated elevation of plasma concentration of pipecolic acid is not necessarily indicative of a primary defect in peroxisomal metabolism.

Peroxisomal mosaicism. An issue in interpreting biochemical test results is peroxisomal mosaicism. Nomenclature for describing peroxisomal mosaicism has not been established, but data support the presence of two main subtypes (type 1 and type 2) of peroxisomal mosaicism. Type 1 and type 2 peroxisomal mosaicism may be observed in the same individual.

  • Type 1. A disparity is found between biochemical or cellular results obtained in blood, cultured fibroblasts, or liver (or other tissue) from the same individual. Thus, plasma VLCFA concentration may be increased while fibroblast VLCFA content is normal. Type 1 peroxisomal mosaicism has been reported in an individual with PEX6 deficiency [Pineda et al 1999, Depreter et al 2003]. More recently, it has been shown that individuals with PEX12 deficiency and p.Ser320Phe homozygosity have type 1 mosaicism when fibroblasts are cultured at 37° C, but when challenged at 40°C, defects in peroxisome assembly can be detected by immunocytochemistry [Gootjes et al 2004].
  • Type 2. A disparity is found in the matrix protein import in peroxisomes in adjacent cells from the same tissue specimen or culture from the same individual. Specifically, some fibroblasts may import catalase or other PTS1 and PTS2 proteins while other fibroblasts do not. One to ten percent of hepatocytes may have peroxisomal structures not observed in the majority of hepatocytes. Type 2 peroxisomal mosaicism has been reported in individuals with a milder phenotype and PEX1, PXMP3 (PEX2), and PEX6 mutations [Pineda et al 1999, Shimozawa et al 2000, Weller et al 2000].

Complementation analysis. Complementation analyses allow one to infer which gene is defective. Classic complementation analysis relies on somatic cell hybridization and biochemical assay [Moser et al 1995] or cDNA complementation analysis followed by immunocytochemical analysis.

Molecular Genetic Testing

Genes. Mutations in twelve different PEX genes — those that encode peroxins, the proteins required for normal peroxisome assembly — have been identified in PBD, ZSS (Table 2) [Gould et al 2001, Matsumoto et al 2003, Shimozawa et al 2004].

Other loci. As of now there is no evidence that mutation of any other PEX genes is associated with ZSS disorders. Although Ebberink et al [2011] reported that 100% of fibroblast cell lines from 613 affected individuals had an identifiable mutation involving PEX1, 2, 3, 5, 6, 10, 12, 13, 14, 16, 19, or 26, it is nonetheless possible that mutations of other genes not detected using currently available methods cause milder or different biochemical and clinical phenotypes.

Clinical testing

PEX1 mutation is the most common cause of PBD, ZSS, associated with about 68% of all affected individuals. Two common PEX1 mutations have been identified: p.Ile700TyrfsTer42 (in exon 13) and p.Gly843Asp (in exon 15). About 80% of individuals with a PEX1 defect have at least one of these two common alleles [Collins & Gould 1999, Walter et al 2001, Maxwell et al 2002].

  • Sequence analysis of the coding region and associated splice sites of PEX1 detects these common mutations and virtually all other pathologic allelic variants.
  • Sequence analysis of PEX1 exons 13 and 15, where the common pathologic variants p.Ile700TyrfsTer42 and p.Gly843Asp are located, respectively, identifies at least one of these common mutations or a previously unknown mutation in slightly more than 50% of individuals with PBD, ZSS [Gould et al 2001, Steinberg et al 2004].

PEX6, PEX26, PEX10, PEX12

  • Sequence analysis or sequence analysis of select exons. Mutations in PEX6, PEX10, PEX12, and PEX26 account for another 26% of all individuals with PBD, ZSS (Table 2).

    In conjunction with PEX1 defects, more than 90% of all affected individuals have a defect in one of these five PEX genes.

    Sequence analysis of PEX1 exons 13 and 15, PXMP3 (PEX2) exon 4, PEX10 exons 4 and 5, PEX12 exons 2 and 3, and PEX26 exons 2 and 3 detects about 72% of pathologic alleles of PBD, ZSS [Steinberg et al 2004].

    Recurrent mutations have been described, including the PEX10 mutation c.814_815delCT in the Japanese population.

PXMP3 (PEX2), PEX3, PEX5, PEX13, PEX14, PEX16, PEX19

  • Sequence analysis. Mutations in PXMP3 (PEX2), PEX3, PEX5, PEX13, PEX14, PEX16, and PEX19 account for only about 6% of all individuals with PBD, ZSS.

Table 2. Summary of Molecular Genetic Testing Used in Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum

Gene 1% of PBD, ZSS Attributed to Mutations in This Gene Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
PEX168% 4; 58% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
Sequence analysis 4 of exons 13,15,18 & 19 8, 9Sequence variants100% for known variants in select exons
PEX610.7% 4; 16% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
Sequence analysis 6 of exon8, 9Sequence variants in select exons100% for known variants in select exons
PEX266.6% 4; 3% 5Sequence analysis 6 of all coding exons Sequence variants~95% 7
Sequence analysis 6 of exons 2 and 3 8, 9Sequence variants in select exons100% for known variants in select exons
PEX10 4.6% 4; 3% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
Sequence analysis 6 of exons 4 and 5 8, 9Sequence variants in select exons100% for known variants in select exons
PEX124.1% 4; 9% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
Sequence analysis 6 of exons 2 and 3 8, 9Sequence variants in select exons100% for variants in select exons 7
PXMP3 (PEX2)1% 4; 4% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
Sequence analysis 6 of the one coding exon 10Sequence variants in select exons100% for variants in select exons 7
PEX31.5% 4; <1% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
PEX51.5% 4; 2% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
PEX13 1% 4; 1% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
PEX140.5% 4, 11; <1% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
PEX16 0.5% 4; 1% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7
PEX190.5% 4; <1% 5Sequence analysis 6 of all coding exonsSequence variants~95% 7

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Based on the experience at the Kennedy Krieger Institute using complementation analysis on a total of 197 individuals with biochemically demonstrated PBD, ZSS, except PEX14 (see footnote 11)

5. Ebberink et al [2011] (613 patient fibroblast cell lines studied)

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

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

8. Exons sequenced and detection rates may vary by laboratory.

9. Sequence analysis of PEX1 exons 13, 15, 18, and 19; PXMP3 (PEX2) exon 4; PEX6 exon 1; PEX10 exons 4 and 5; PEX12 exons 2 and 3; and PEX26 exons 2 and 3 detects about 79% of pathologic alleles of PBD, ZSS [Steinberg et al 2004].

10. PXMP3 has only one coding exon.

11. Mutation in PEX14 was identified in one individual with PBD, ZSS by Shimozawa et al [2004]; thus, PEX14 was not a recognized complementation group when studies were performed at Kennedy Krieger Institute.

Testing Strategy

To confirm/establish the diagnosis in a proband. Biochemical abnormalities detected in blood and/or urine should be confirmed in cultured fibroblasts.

In some individuals, liver biopsy may be necessary.

PEX molecular genetic testing algorithm. To circumvent the need for complementation studies, which require cultured fibroblasts, two slightly different algorithms for analysis of a subset of PEX exons have been developed:

  • The mutation detection frequency of sequence analysis of PEX1 exons 13, 15, and 18, PEX2 exon 4, PEX6 exon 1, PEX10 exons 3-5, PEX12 exons 2 and 3, and PEX26 exons 2 and 3 is 79% [Steinberg et al 2004].
  • The detection frequency for at least one mutation of sequence analysis of PEX1 exons 13 and 15, PEX2 exon 4, PEX10 exons 4 and 5, PEX12 exons 2 and 3, and PEX26 exons 2 and 3 is approximately 72%.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family. Prenatal diagnosis by biochemical testing is also possible; ideally, the biochemical defects in cultured fibroblasts from an affected family member should be confirmed first.

Clinical Description

Natural History

Peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS) are 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) [Gould et al 2001].

All of the peroxisome assembly disorders are serious disorders, frequently resulting in death in childhood. ZS is the most severe and IRD the least severe of these phenotypes. The generalizations that these labels represent are still useful when facing undiagnosed individuals and counseling their families, but one should not place too much emphasis on assigning an affected individual to one of these categories. Because of the breadth of phenotypic variation, individuals with PBD, ZSS mainly come to clinical attention in the newborn period or later in childhood. Occasionally, the subtlety of symptoms delays diagnosis until adulthood.

In the newborn period, affected children are hypotonic with resultant poor feeding. Neonatal seizures are frequent. Liver dysfunction may be evident as neonatal jaundice and elevation in liver function tests. Distinctive craniofacial features include flattened facies, large anterior fontanelle, widely split sutures, and broad nasal bridge. In severely affected children, bony stippling (chondrodysplasia punctata) at the patella(e) and other long bones may be noted.

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 are variable, but a peroxisome biogenesis disorder should be considered in any individual who manifests both conditions. 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.

It is rare for an individual with PBD, ZSS to present as an adult, but instances of individuals presenting initially with predominantly sensory deficits have been reported [Moser et al 1995]. See the example of PEX6 deficiency (Genetically Related Disorders).

Zellweger syndrome is characterized by presentation in the neonatal period with profound hypotonia, characteristic facies, seizures, inability to feed, liver cysts with hepatic dysfunction, and chondrodysplasia punctata. Infants with this condition 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.

Neonatal adrenoleukodystrophy and infantile Refsum disease may present in the newborn period, but generally come to attention later because of developmental delays, hearing loss, or visual impairment. Liver dysfunction may lead to a vitamin K-responsive coagulopathy. Children have also come to attention with episodes of hemorrhage, and 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. The condition is often slowly progressive with hearing and vision worsening with time. Some individuals may develop progressive degeneration of the 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].

Neuroimaging. Magnetic resonance imaging studies may identify hypomyelination, cortical gyral abnormalities, and germinolytic cysts that are highly suggestive of Zellweger syndrome [Barkovich & Peck 1997].

More recent studies in a small number of individuals with PBD, ZSS have shown that diffusion-weighted imaging and diffusion tensor imaging can be used to discern white matter damage not detected by standard imaging [ter Rahe et al 2004].

Genotype-Phenotype Correlations

Mutations 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 mutations in PEX10, PEX12, and PEX26.

PEX3, PEX16, and PEX19 mutations, described in only one or two individuals, are associated exclusively with the most severe phenotype (ZS). Mutations in these three genes cause a cellular phenotype detected by immunocytochemical analysis. Peroxisomal membrane formation is completely absent in cell lines from these individuals.

No direct association exists between the biochemical phenotype and mutation in PEX. Thus, it is not possible to identify the candidate gene based solely on the biochemical phenotype. However, a report suggests that two biochemical findings (DHAP-AT and C26:0 β-oxidation activity) are predictors of survival in individuals with PBD, ZSS [Gootjes et al 2002].

A general relationship appears to exist among the genotype, cellular phenotype (i.e., import of peroxisomal matrix proteins), and clinical phenotype [Moser 1999]:

  • Frameshift mutations are associated with more severe defects in peroxisome assembly and, consequently with more severe clinical phenotypes.
  • Homozygosity for the PEX1 p.Ile700TyrfsTer42 common allele is associated with a more severe phenotype.
  • Compound heterozygosity for PEX1 alleles p.Ile700TyrfsTer42 and p.Gly973AlafsTer16 also appears on the more severe end of the clinical spectrum. Cells from such individuals also have more severe defects in the import of peroxisomal matrix proteins.
  • In contrast, the PEX1 p.Gly843Asp allele has been associated with the less severe end of the phenotypic clinical continuum and peroxisomal matrix protein import is nearer to normal.
  • Homozygosity for PEX1 p.Gly843Asp has thus far been associated with a milder phenotype, usually IRD but sometimes NALD. Differences in the clinical picture within the same family are reported in compound heterozygotes for PEX1 p.[Gly843Asp]+ [Ile700TyrfsTer42]. Thus, other factors must contribute to developmental outcome and survival [Poll-The et al 2004].
  • Homozygosity for PEX12 p.Ser320Phe is associated with type 1 mosaicism and the milder end of the clinical spectrum [Gootjes et al 2004].

Nomenclature

Peroxisome biogenesis disorders (PBD) can be divided into two subtypes: the Zellweger syndrome spectrum and the rhizomelic chondrodysplasia punctata spectrum, of which RCDP1 is one subtype.

Individuals with RCDP1 have mutations in PEX7, a receptor that recognizes peroxisomal 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 PBD, Zellweger syndrome spectrum. (See Rhizomelic Chondrodysplasia Punctata Type 1 for an in-depth description.)

PBD, ZSS may also be 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 PBD, ZSS were initially described as having hyperpipcolatemia.

Note: Infantile Refsum disease and Refsum disease are distinct clinical entities with different molecular basis (see Differential Diagnosis).

Prevalence

The prevalence of PBD, ZSS is estimated at 1:50,000 [Gould et al 2001].

These disorders occur worldwide, although variation is observed among populations. The main diagnostic center for peroxisomal diseases in Japan reported only 31 Japanese individuals over a 20-year period, with an estimated birth prevalence of only 1:500,000 [Shimozawa et al 2003].

Differential Diagnosis

Differential diagnoses vary with the age of presentation and most prominent feature of presentation.

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

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 and Retinitis Pigmentosa Overview), Cockayne syndrome, or congenital infections. Leukodystrophies may result from lysosomal storage diseases including Krabbe disease and metachromatic leukodystrophy (see Arylsulfatase A Deficiency) or mitochondrial disease (see Mitochondrial Diseases Overview) and often are the first consideration.

At least 15% of individuals presenting with a clinical phenotype in the Zellweger syndrome spectrum 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 mutation in a PEX gene. Diagnosis of these disorders is possible by biochemical testing (Table 3).

  • D-bifunctional enzyme deficiency is more common and in general more severe, often presenting with severe seizures within the first days of life; thus, it more closely resembles ZS.
  • Acyl-CoA oxidase deficiency has a less pronounced biochemical and clinical phenotype and in general follows a disease course more similar to NALD (see Watkins et al [1995] for comparison of the two).

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 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 mutations in PHYH, the gene that encodes phytanoyl-CoA hydroxylase, in more than 90% of affected individuals, and mutations in PEX7, the gene that encodes the PTS2 receptor, in fewer than 10% of affected individuals. Individuals with adult Refsum disease have a biochemical profile distinct from PBD, ZSS 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 could be associated with four main disease types: (1) PBD, ZSS; (2) a single-enzyme deficiency (SED) of the peroxisomal β-oxidation enzymes D-bifunctional protein (D-BP) or acyl-CoA oxidase (AOx) [Watkins et al 1995]; (3) X-linked adrenoleukodystrophy (X-ALD) or adrenomyeloneuropathy (AMN), caused by mutations in ABCD1; and (4) CADDS, a contiguous deletion syndrome with a critical region spanning ABCD1 and BAP31 [Corzo et al 2002].

  • An increase in plasma concentration of C26:1 is not observed in X-ALD; however, individuals with CADDS have a VLCFA profile very similar to that seen in individuals with PBD.
  • X-ALD and AMN are clinically distinct (see X-ALD) from these other disorders, and the biochemical findings should not cause any diagnostic quandaries. In contrast, the clinical phenotypes for PBD, SED, and CADDS overlap and can only be distinguished by further testing of blood and cultured fibroblasts (Table 3). In an individual with increased plasma VLCFA concentration and a phenotype consistent with a PBD, a fibroblast cell line established from a skin biopsy can be helpful in completing the diagnostic evaluation. Individuals with a PBD do not necessarily have a classic biochemical phenotype. Thus, the full array of studies listed in Table 3 may be required to determine whether an individual has a PBD or SED. In some individuals, complementation studies and/or molecular analysis may be required to establish that an atypical biochemical phenotype is consistent with the diagnosis of PBD, ZSS. Occasionally, when the enzymatic defects that should correspond to the abnormalities observed in blood and urine are not detected in cultured fibroblasts, analysis of skin biopsies from other sites or a liver biopsy may help detect peroxisomal mosaicism.

Table 3. Testing to Distinguish PBD, ZSS from a Single-Enzyme Deficiency or CADDS

PBD, ZSSSingle-Enzyme DeficiencyCADDS
D-Bifunctional Protein DeficiencyAcyl-CoA Oxidase Deficiency
Plasma ConcentrationsVLCFAIncreasedIncreasedIncreasedIncreased
Phytanic acidNormal to increasedNormal to increasedNormalNormal
Bile acidsTHCA/DHCA presentTHCA/DHCA presentNormalIncreased amount
Urine ConcentrationsPipecolic acidNormal to increasedNormalNormalNormal
Epoxydicarboxylic acidsPresent to absentPresent to absentPresent to absentAbsent
Bile acidsTHCA/DHCA presentTHCA/DHCA presentNormalIncreased amount
Erythrocyte MembranesPlasmalogensDeficient to normalNormalNormalNormal
Fibroblasts, CulturedVLCFA concentrationsIncreasedIncreasedIncreasedIncreased
VLCFA -oxidationDeficientDeficientDeficientDeficient
Plasmalogen synthesisDeficient to normalNormalNormalNormal
DHAP-AT activityDeficient to normalNormalNormalNormal
ADHAP-S activityDeficient to normalNormalNormalNormal
Phytanic acid oxidationDeficientDeficientNormalNormal
Pristanic acid oxidationDeficientDeficientNormalNormal
Catalase solubilityIncreasedNormalNormalNormal
Immunohisto-
chemistry
Peroxisome structureAbsent to enlarged & reduced in numberEnlarged & reduced in numberEnlarged & reduced in numberNormal
Catalase importAbsent to partialNormalNormalNormal

DHCA = dihydroxycholestanoic acid

THCA = trihydroxycholestanoic acid

DHAP-AT = dihydroxyacetone phosphate-acyl transferase

ADHAP-S = alkyl-dihydroxyacetone phosphate synthase

DLP1 (dynamin-like protein 1 gene). In one report a dominant-negative heterozygous mutation (p.Ala395Asp) was detected in an infant girl, but not in either parent [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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with peroxisome biogenesis disorders, Zellweger syndrome spectrum (PBD, ZSS), evaluations of the following are recommended:

  • Feeding
  • Hearing
  • Vision (comprehensive ophthalmologic assessment)
    Note: Electroretinogram (ERG) and visual field testing are useful in the diagnosis of retinal dystrophy.
  • Liver function
  • Neurologic function (possible MRI of the brain and EEG)
  • Development
  • Possible endocrine evaluation of adrenal function as adrenal insufficiency may occur during periods of stress

Treatment of Manifestations

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.

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.

Primary bile acid therapy may improve liver function by reducing the accumulation of cholestanoic acids [Setchell et al 1992].

Neurologic function. Early intervention services should be provided.

Seizures are present in approximately one third of affected individuals. Standard antiepileptic drugs (AEDs) may be used. No type of AED is contraindicated. Seizures may be difficult to control despite use of appropriate medication.

Prevention of Primary Manifestations

No curative therapy is presently available for PBD, ZSS.

Prevention of Secondary Complications

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

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.

Agents/Circumstances to Avoid

Avoidance of cow's milk and related products reduces exposure to phytanic acid.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

The use of docosahexaenoic acid (DHA) has been suggested as a treatment for PBD, ZSS. This compound, which is important in brain and retinal function, is low in PBD, ZSS.

  • Martinez [2001] and Noguer & Martinez [2010] have reported that DHA ethyl ester supplements restore DHA levels and improve liver function and visual function in some study participants, especially in those treated in the first six months of life.
  • Paker et al [2010] performed a double-blind placebo-controlled trial in 48 children with PBD, ZSS who were supplemented daily with 100 mg/kg of DHA. Over a one-year period this study found no benefit from DHA supplementation in the two outcome measures used: growth and visual function.

Although no clinical trial has been performed, anecdotal evidence suggests that all patients with PBD, ZSS who are treated with DHA benefit from primary bile acid supplementation [Setchell et al 1992].

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

Other

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. Its effectiveness in PBD, ZSS has never been proven. All standard infant formulas are already low in phytanic acid.

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

PBD, ZSS is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

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.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

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).

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

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

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

Related Genetic Counseling Issues

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

Biochemical testing

  • It is important to confirm the biochemical defects in cultured fibroblasts from the proband, as the biochemical defects detected in body fluids or liver are not always apparent in cultured cells (i.e., type 1 peroxisomal mosaicism is present). Biochemical test sensitivity is slightly reduced in cases that have not been confirmed in fibroblasts from an index case because the biochemical phenotype is non-penetrant in cultured cells of a small number (<5%) of individuals with Zellweger spectrum disorder.
  • Prenatal diagnosis may be more challenging technically when the biochemical diagnosis of PBD, ZSS in the index case was made using blood, but cultured skin fibroblasts did not demonstrate all of the corresponding defects (i.e., type 1 peroxisomal mosaicism was present). It is possible that the cultured cells derived from chorionic villi or amniocytes in a fetus with PBD, ZSS and type 1 peroxisomal mosaicism would not express the defect. Thus, biochemical and immunocytochemical methods not routinely used by a laboratory may be required to offer accurate prenatal diagnosis. For this reason, it is best to document deficiencies in the cultured fibroblasts from the index case before offering prenatal diagnosis using a given assay.
  • Some individuals with PBD, ZSS have elevated VLCFA in cultured cells, but normal plasmalogen synthesis. Both VLCFA content and plasmalogen synthesis can be measured in cultured CVS or amniocytes. The growth conditions are critical for measurement of VLCFA content and should only be performed in a center that has examined numerous specimens. Reports of false negative results have been described in the literature [Carey et al 1994, Gray et al 1995].
  • Bile acid metabolites can be quantitated in the amniotic fluid [Stellaard et al 1991].
  • Immunocytochemical analysis of chorionic villus sampling (CVS) can be used as an adjunct to confirm that all cells have normal peroxisome morphology and import peroxisomal matrix proteins.
  • Direct CVS can be assayed for DHAP-AT, one of the deficient enzymes required for plasmalogen synthesis [Steinberg et al 1999], and immunoblot analysis for β-oxidation enzymes [Wanders et al 1995].
  • It is important to perform studies to rule out maternal cell contamination (MCC) in cultured CVS [Steinberg et al 2005]. Because individuals heterozygous for PEX gene mutations do not have any biochemical phenotype, MCC could cause a false negative result in an affected fetus, but not a false positive result in a normal fetus. Based on cell mixing experiments, the authors estimate that MCC would probably need to be greater than 30% for VLCFA or plasmalogen synthesis results to be completely normalized, although the extent of the deficiency in the proband would need to be considered.

Molecular genetic testing. If the disease-causing mutations have been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

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)
    2304 Highland Drive
    Sycamore IL 60178
    Phone: 800-728-5483 (toll-free)
    Fax: 815-895-2432
    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. Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum (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
608666PEROXISOME BIOGENESIS FACTOR 26; PEX26

Molecular Genetic Pathogenesis

Mutations in the twelve genes listed in Table 4 are known to cause PBD, ZSS in humans. These 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 mutations 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. Thus far, mutations in 13 genes that encode peroxins are associated with human disease. The biogenesis of membranes is not well understood, but mutations 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 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. PXR1 (PEX5) 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. Mutations in PEX7 are associated with the clinically distinct disorder RCDP. Two sub-complexes have been proposed to be anchored by Pex8p, which is associated with the more lumenal aspect of the peroxisomal membrane [Agne et al 2003]. The two sub-complexes comprise the proteins (1) PEX14, PEX17, and PEX13, and (2) PEX10, PEX12, and PEX2. The first sub-complex plays a role in the docking of the PTS1 and PTS2 receptors and their associated proteins and the second sub-complex 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, PEX6, PEX4 and PEX22 act late in the import pathway, perhaps after the translocation process [Collins et al 2000]. However, the recent 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 such as 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 mutation, the impact on peroxisome assembly, and the clinical severity.

The online database www.dbpex.org/home.php chronicles mutations identified in the 13 PEX genes associated with human disease. Mutations are those reported in peer-reviewed manuscripts and those submitted by clinical laboratories.

The impact of any PEX mutation can be assessed by evaluating 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 defects 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 mutation(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 ZS and only minimally impaired in an individual on the milder end of the clinical spectrum [Shimozawa et al 1999a].

Careful immunocytochemical analysis in fibroblasts that are deficient in a variety of PEX genes (PEX6, PEX5, PEX26, PEX1, PXMP3 [PEX2], 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 missense mutations, it has been hypothesized that culturing the cells at a lower temperature allows the mutant 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 4. Structure of the 12 PEX Genes Associated with PBD, ZSS

GeneExonsGenomic DNA (kb)cDNA (kb)Protein
(# amino acids)
PEX1 2441.53.91283
PXMP3 (PEX2) 47.41.5626
PEX3 12391.1373
PEX5 1518.91.8602 & 639
PEX6 1715.12.4980
PEX10 67.81326 & 345 1
PEX12 33.81.1359
PEX13 431.21.2403
PEX14 9135.51.1377
PEX16 118.41346
PEX19 85.70.9299
PEX26 510.70.9305

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 allelic variants. Table 5 through Table 9 summarize the common mutations (accounting for >90% of affected individuals) in the five PEX genes most often associated with PBD, ZSS.

PEX1

Twenty-five allelic variants have been described [Collins & Gould 1999, Walter et al 2001, Maxwell et al 2002, Steinberg et al 2004]. The variants p.Gly843Asp and p.Ile700TryfsTer42 represented about 63% of all alleles in 94 individuals with PBD. It has been proposed that the PEX1 p.Ile700TryfsTer42 and p.Gly843Asp alleles reside on specific haplotypes and arose as founder mutations [Collins & Gould 1999], thus suggesting that these sites are not hot spots for recurrent mutations. Approximately 80% of individuals with a PEX1 mutation have at least one of these common alleles.

Maxwell et al [2002] reported an exon 18 frameshift mutation (p.Gly973fs) that approached an allele frequency of 10% in their cohort of affected individuals. It is only 3.7% of the total alleles reported by the three main groups, but 21% of alleles were unidentified, so this mutation may have been missed by other groups if some affected individuals were only screened for the p.Gly843Asp and p.Ile700TryfsTer42 alleles. Otherwise, no other common PEX1 mutations have been described.

Recently, two sequence variants in the PEX1 promoter region have been identified (c.-137T>C and c.-53C>G) and in vitro reporter assays showed that one increased PEX1 expression, one reduced PEX1 expression, and when present in tandem they cancelled each other out. The authors postulated that these promoter variants could modulate the severity of pathogenic PEX1 alleles [Maxwell et al 2005].

Table 5. Selected PEX1 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid Change
(Alias 1)
Reference Sequences
c.-137T>C 2--NM_000466​.2
NP_000457​.1
c.-53C>G 2--
c.2097_2098insTp.Ile700TyrfsTer42 3
(p.Ile700fs)
c.2528G>Ap.Gly843Asp 3
c.2916delAp.Gly973AlafsTer16
(p.Gly973fs)

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Associated with altered gene expression [Maxwell et al 2005]

3. About 80% of individuals with a PEX1 mutation have at least one of these two common alleles [Collins & Gould 1999, Walter et al 2001, Maxwell et al 2002].

PEX6

There are no common pathogenic allelic variants. The largest cohort of affected individuals (N=13) reported were clinically severely affected; 70% of the alleles were frameshift/nonsense and 10% were small in-frame deletions [Zhang et al 1999].

Table 6. Selected PEX6 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
c.1715C>Tp.Thr572IleNM_000287​.3
NP_000278​.3
c.2094+2T>C
(IVS10+2T>C)
--
c.2426C>Tp.Ala809Val
c.2534T>Cp.Ile845Thr

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

PEX26

Of the eight individuals studied originally, PEX26 mutations were reported for seven. All of the reported mutations occurred in exons 2 and 3 [Matsumoto et al 2003]. Two unrelated individuals with ZS were homozygous for p.Gly89Arg and two unrelated individuals with NALD were homozygous for p.Arg98Trp. Two individuals with IRD were compound heterozygotes for p.[Arg98Trp]+[Leu85fs] and p.[Met1Thr]+[Leu45Pro]. Another individual with ZS was homozygous for p.Leu12ProfsTer103. The fourth individual with ZS had no PEX26 RNA, but a genomic mutation was not reported. Recent studies identified mutations in five additional individuals, two of whom had one allele in regions beyond exons 2 and 3 [Steinberg et al 2004]. Weller et al [2005] reported PEX26 mutations in ten individuals comprising those originally identified by complementation studies at Kennedy Krieger Institute (Table 2).

Table 7. Selected PEX26 Pathogenic Allelic Variants

DNA Nucleotide Change
(Alias 1)
Protein Amino Acid Change
(Alias 1)
Reference Sequences
c.2T>Cp.Met1ThrNM_001127649​.1
NP_001121121​.1
c.34dupC
(Nt35insC)
p.Leu12ProfsTer103
c.134T>Cp.Leu45Pro
c.254dupTp.Cys86ValfsTer29
(Leu85fs)
c.265G>Ap.Gly89Arg
c.292C>Tp.Arg98Trp

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

PEX10

The majority of reported mutations have been in individuals with ZS, who have frameshift and nonsense mutations [Okumoto et al 1998a, Warren et al 1998, Warren et al 2000]. The mutation c.814_815delCT is a common allele, especially among the Japanese population, where it appears to have arisen once on an ancestral haplotype [Shimozawa et al 2003].

Table 8. Selected PEX10 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.814_815delCTp.Leu271ValfsTer66
(L271fs)
NM_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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

PEX12

Of ten individuals reported in the literature, only one had PEX12 missense mutations on both alleles [Chang et al 1997, Chang & Gould 1998, Okumoto et al 1998b]. The majority had nonsense/frameshift/aberrant splicing mutations and severe clinical phenotypes. One individual with an IRD phenotype had genomic mutations that would be predicted to be severe (frameshift and aberrant splicing), but translation initiation downstream to the initiator ATG yielded a partially functional protein that accounted for the milder IRD phenotype.

Table 9. Selected PEX12 Pathogenic Allelic Variants

DNA Nucleotide Change Protein Amino Acid ChangeReference Sequences
c.959C>Tp.Ser320PheNM_000286​.2
NP_000277​.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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

References

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Suggested Reading

  1. Mandel H, Korman SH. Phenotypic variability (heterogeneity) of peroxisomal disorders. Adv Exp Med Biol. 2003;544:9–30. [PubMed: 14713208]
  2. Oglesbee D. An overview of peroxisomal biogenesis disorders. Mol Genet Metab. 2005;84:299–301. [PubMed: 15875330]
  3. Shimozawa N, Nagase T, Takemoto Y, Funato M, Kondo N, Suzuki Y. Molecular and neurologic findings of peroxisome biogenesis disorders. J Child Neurol. 2005;20:326–9. [PubMed: 15921234]
  4. Wanders RJ. Metabolic and molecular basis of peroxisomal disorders: a review. Am J Med Genet A. 2004;126A:355–75. [PubMed: 15098234]
  5. Wanders RJ, Waterham HR. Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders. Clin Genet. 2005;67:107–33. [PubMed: 15679822]
  6. Weller S, Gould SJ, Valle D. Peroxisome biogenesis disorders. Annu Rev Genomics Hum Genet. 2003;4:165–211. [PubMed: 14527301]

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

  • 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 to live Web site
  • 1 October 2004 (sjs) Revision
  • 12 December 2003 (me) Review posted to live Web site
  • 1 August 2003 (sjs) Original submission
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