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Zellweger spectrum disorders(ZS)

MedGen UID:
21958
Concept ID:
C0043459
Disease or Syndrome
Synonyms: Zellweger Spectrum; Zellweger Spectrum Disorder; Zellweger syndrome; ZS
SNOMED CT: Zellweger's syndrome (88469006); Zellweger syndrome (88469006); Cerebrohepatorenal syndrome (88469006)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Monarch Initiative: MONDO:0019609
OMIM®: 214100
Orphanet: ORPHA912

Definition

Zellweger syndrome is an autosomal recessive systemic disorder characterized clinically by severe neurologic dysfunction, craniofacial abnormalities, and liver dysfunction, and biochemically by the absence of peroxisomes. Most severely affected individuals with classic Zellweger syndrome phenotype die within the first year of life (summary by Wanders, 2004). 'Zellweger syndrome' is the prototype of a large group of peroxisomal disorders, which can be classified into 2 main groups: (1) disorders of peroxisome biogenesis and (2) single peroxisomal enzyme deficiencies (see 264470). The peroxisome biogenesis disorders (PBDs) fall into 4 main phenotypic classes. Three of them, Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD), have multiple complementation groups and form a spectrum of overlapping features, with the most severe being the Zellweger syndrome and the least severe infantile Refsum disease. The fourth group, rhizomelic chondrodysplasia punctata (RCDP1; 215100), is a distinct PBD phenotype (summary by Moser et al., 1995, Wanders, 2004). Heimler syndrome, a rare autosomal recessive disorder encompassing sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities, represents a discrete phenotypic entity at the mildest end of the PBD spectrum (Ratbi et al., 2015). Genetic Heterogeneity of Zellweger Syndrome Zellweger syndrome (denoted by the suffix 'A' in the symbol) is a genetically heterogeneous disorder and can be caused by mutation in any one of several genes, known as pexins, involved in peroxisome biogenesis. The pexin (PEX) genes encode proteins essential for the assembly of functional peroxisomes (summary by Distel et al., 1996). Forms of Zellweger syndrome include PBD1A, caused by mutation in the PEX1 gene on chromosome 7q21; PBD2A (214110), caused by mutation in the PEX5 (600414) gene on chromosome 12p13; PBD3A (614859), caused by mutation in the PEX12 (601758) gene on chromosome 17; PBD4A (614862), caused by mutation in the PEX6 (601498) gene on chromosome 6p21; PBD5A (614866), caused by mutation in the PEX2 (170993) gene on chromosome 8q21; PBD6A (614870), caused by mutation in the PEX10 (602859) gene on chromosome 1p36; PBD7A (614872), caused by mutation in the PEX26 (608666) gene on chromosome 22q11; PBD8A (614876), caused by mutation in the PEX16 (603360) gene on chromosome 11p12; PBD10A (614882), caused by mutation in the PEX3 (603164) gene on chromosome 6q23-q24; PBD11A (614883), caused by mutation in the PEX13 (601789) gene on chromosome 2p15; PBD12A (614886), caused by mutation in the PEX19 (600279) gene on chromosome 1q22; and PBD13A (614887), caused by mutation in the PEX14 gene (601791) on chromosome 1p36.2. Mutation in the pexin genes also causes the less severe phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD); see PBD1B (601539) for a phenotypic description and discussion of genetic heterogeneity of these PBDs. Heimler syndrome-1 (HMLR1; 234580) and -2 (HMLR2; 616617) are caused by mutation in the PEX1 and PEX6 genes, respectively. The rhizomelic chondrodysplasia subtype of PBD (RCDP1, PBD9; 215100), and a PBD without rhizomelia (PBD9B; 614879), are caused by mutation in the PEX7 gene (601757) on chromosome 6q22-q24. In addition to the defects in peroxisome assembly, Distel et al. (1996) noted that peroxisomal disorders include a number of single peroxisomal enzyme deficiencies: X-linked adrenoleukodystrophy (ALD; 300100), acyl-coenzyme A oxidase deficiency (264470), DHAPAT deficiency (222765), alkyl-DHAP synthase deficiency (600121), glutaric aciduria type III (231690), classic Refsum disease (266500), hyperoxaluria type I (259900), and acatalasia (115500). A peroxisomal and mitochondrial fission defect results in a lethal encephalopathy (EMPF; 614388). [from OMIM]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVZellweger spectrum disorders
Follow this link to review classifications for Zellweger spectrum disorders in Orphanet.

Professional guidelines

PubMed

Albersen M, van der Beek SL, Dijkstra IME, Alders M, Barendsen RW, Bliek J, Boelen A, Ebberink MS, Ferdinandusse S, Goorden SMI, Heijboer AC, Jansen M, Jaspers YRJ, Metgod I, Salomons GS, Vaz FM, Verschoof-Puite RK, Visser WF, Dekkers E, Engelen M, Kemp S
J Inherit Metab Dis 2023 Jan;46(1):116-128. Epub 2022 Oct 26 doi: 10.1002/jimd.12571. PMID: 36256460Free PMC Article
Anderson JN, Ammous Z, Eroglu Y, Hernandez E, Heubi J, Himes R, Palle S
Orphanet J Rare Dis 2021 Sep 14;16(1):388. doi: 10.1186/s13023-021-01940-z. PMID: 34521419Free PMC Article
Raina R, Chakraborty R, Sethi SK, Kumar D, Gibson K, Bergmann C
Am J Kidney Dis 2021 Jul;78(1):125-141. Epub 2021 Jan 6 doi: 10.1053/j.ajkd.2020.10.021. PMID: 33418012

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated lysophosphatidylcholines, X-Linked Adrenoleukodystrophy (X-ALD), 2023

ACMG Algorithm, X-ALD: Elevated lysophosphatidylcholines C24:0, C26:0, 2023

Recent clinical studies

Etiology

Albersen M, van der Beek SL, Dijkstra IME, Alders M, Barendsen RW, Bliek J, Boelen A, Ebberink MS, Ferdinandusse S, Goorden SMI, Heijboer AC, Jansen M, Jaspers YRJ, Metgod I, Salomons GS, Vaz FM, Verschoof-Puite RK, Visser WF, Dekkers E, Engelen M, Kemp S
J Inherit Metab Dis 2023 Jan;46(1):116-128. Epub 2022 Oct 26 doi: 10.1002/jimd.12571. PMID: 36256460Free PMC Article
Wanders RJA, Baes M, Ribeiro D, Ferdinandusse S, Waterham HR
Physiol Rev 2023 Jan 1;103(1):957-1024. Epub 2022 Aug 11 doi: 10.1152/physrev.00051.2021. PMID: 35951481
Anderson JN, Ammous Z, Eroglu Y, Hernandez E, Heubi J, Himes R, Palle S
Orphanet J Rare Dis 2021 Sep 14;16(1):388. doi: 10.1186/s13023-021-01940-z. PMID: 34521419Free PMC Article
Honsho M, Okumoto K, Tamura S, Fujiki Y
Adv Exp Med Biol 2020;1299:45-54. doi: 10.1007/978-3-030-60204-8_4. PMID: 33417206
Klouwer FC, Huffnagel IC, Ferdinandusse S, Waterham HR, Wanders RJ, Engelen M, Poll-The BT
Neuropediatrics 2016 Aug;47(4):205-20. Epub 2016 Apr 18 doi: 10.1055/s-0036-1582140. PMID: 27089543

Diagnosis

Albersen M, van der Beek SL, Dijkstra IME, Alders M, Barendsen RW, Bliek J, Boelen A, Ebberink MS, Ferdinandusse S, Goorden SMI, Heijboer AC, Jansen M, Jaspers YRJ, Metgod I, Salomons GS, Vaz FM, Verschoof-Puite RK, Visser WF, Dekkers E, Engelen M, Kemp S
J Inherit Metab Dis 2023 Jan;46(1):116-128. Epub 2022 Oct 26 doi: 10.1002/jimd.12571. PMID: 36256460Free PMC Article
Raina R, Chakraborty R, Sethi SK, Kumar D, Gibson K, Bergmann C
Am J Kidney Dis 2021 Jul;78(1):125-141. Epub 2021 Jan 6 doi: 10.1053/j.ajkd.2020.10.021. PMID: 33418012
Klouwer FC, Huffnagel IC, Ferdinandusse S, Waterham HR, Wanders RJ, Engelen M, Poll-The BT
Neuropediatrics 2016 Aug;47(4):205-20. Epub 2016 Apr 18 doi: 10.1055/s-0036-1582140. PMID: 27089543
Klouwer FC, Berendse K, Ferdinandusse S, Wanders RJ, Engelen M, Poll-The BT
Orphanet J Rare Dis 2015 Dec 1;10:151. doi: 10.1186/s13023-015-0368-9. PMID: 26627182Free PMC Article
Poll-The BT, Gärtner J
Biochim Biophys Acta 2012 Sep;1822(9):1421-9. Epub 2012 Mar 28 doi: 10.1016/j.bbadis.2012.03.011. PMID: 22483868

Therapy

Cheung A, Argyriou C, Yergeau C, D'Souza Y, Riou É, Lévesque S, Raymond G, Daba M, Rtskhiladze I, Tkemaladze T, Adang L, La Piana R, Bernard G, Braverman N
Neurogenetics 2022 Apr;23(2):115-127. Epub 2022 Feb 2 doi: 10.1007/s10048-022-00684-7. PMID: 35106698
Klouwer FCC, Koot BGP, Berendse K, Kemper EM, Ferdinandusse S, Koelfat KVK, Lenicek M, Vaz FM, Engelen M, Jansen PLM, Wanders RJA, Waterham HR, Schaap FG, Poll-The BT
J Inherit Metab Dis 2019 Mar;42(2):303-312. Epub 2019 Feb 21 doi: 10.1002/jimd.12042. PMID: 30793331
Zeynelabidin S, Klouwer FCC, Meijers JCM, Suijker MH, Engelen M, Poll-The BT, van Ommen CH
J Inherit Metab Dis 2018 Mar;41(2):249-255. Epub 2017 Nov 14 doi: 10.1007/s10545-017-0113-8. PMID: 29139025Free PMC Article
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
J Inherit Metab Dis 2016 Nov;39(6):859-868. Epub 2016 Jul 28 doi: 10.1007/s10545-016-9962-9. PMID: 27469511Free PMC Article
Rush ET, Goodwin JL, Braverman NE, Rizzo WB
Mol Genet Metab 2016 Jan;117(1):33-7. Epub 2015 Nov 24 doi: 10.1016/j.ymgme.2015.11.009. PMID: 26643206

Prognosis

Borgia P, Baldassari S, Pedemonte N, Alkhunaizi E, D'Onofrio G, Tortora D, Calì E, Scudieri P, Balagura G, Musante I, Diana MC, Pedemonte M, Vari MS, Iacomino M, Riva A, Chimenz R, Mangano GD, Mohammadi MH, Toosi MB, Ashrafzadeh F, Imannezhad S, Karimiani EG, Accogli A, Schiaffino MC, Maghnie M, Soler MA, Echiverri K, Abrams CK, Striano P, Fortuna S, Maroofian R, Houlden H, Zara F, Fiorillo C, Salpietro V
Orphanet J Rare Dis 2022 Jul 19;17(1):286. doi: 10.1186/s13023-022-02415-5. PMID: 35854306Free PMC Article
Horlenko O, Lenchenko A, Pushkarenko O, Kossey G, Tomey A
Georgian Med News 2021 Sep;(318):60-67. PMID: 34628380
Zeynelabidin S, Klouwer FCC, Meijers JCM, Suijker MH, Engelen M, Poll-The BT, van Ommen CH
J Inherit Metab Dis 2018 Mar;41(2):249-255. Epub 2017 Nov 14 doi: 10.1007/s10545-017-0113-8. PMID: 29139025Free PMC Article
Klouwer FCC, Meester-Delver A, Vaz FM, Waterham HR, Hennekam RCM, Poll-The BT
Clin Genet 2018 Mar;93(3):613-621. Epub 2017 Dec 1 doi: 10.1111/cge.13130. PMID: 28857144
Poll-The BT, Gärtner J
Biochim Biophys Acta 2012 Sep;1822(9):1421-9. Epub 2012 Mar 28 doi: 10.1016/j.bbadis.2012.03.011. PMID: 22483868

Clinical prediction guides

Bhandari S, Kim YI, Nam IK, Hong K, Jo Y, Yoo KW, Liao W, Lim JY, Kim SJ, Um JY, Kim PK, Lee HS, Ryu D, Kim SH, Kwak S, Park R, Choe SK
Cell Mol Life Sci 2023 Feb 23;80(3):69. doi: 10.1007/s00018-023-04700-3. PMID: 36821008Free PMC Article
Borgia P, Baldassari S, Pedemonte N, Alkhunaizi E, D'Onofrio G, Tortora D, Calì E, Scudieri P, Balagura G, Musante I, Diana MC, Pedemonte M, Vari MS, Iacomino M, Riva A, Chimenz R, Mangano GD, Mohammadi MH, Toosi MB, Ashrafzadeh F, Imannezhad S, Karimiani EG, Accogli A, Schiaffino MC, Maghnie M, Soler MA, Echiverri K, Abrams CK, Striano P, Fortuna S, Maroofian R, Houlden H, Zara F, Fiorillo C, Salpietro V
Orphanet J Rare Dis 2022 Jul 19;17(1):286. doi: 10.1186/s13023-022-02415-5. PMID: 35854306Free PMC Article
Thistlethwaite LR, Li X, Burrage LC, Riehle K, Hacia JG, Braverman N, Wangler MF, Miller MJ, Elsea SH, Milosavljevic A
Sci Rep 2022 Apr 21;12(1):6556. doi: 10.1038/s41598-022-10415-5. PMID: 35449147Free PMC Article
Honsho M, Okumoto K, Tamura S, Fujiki Y
Adv Exp Med Biol 2020;1299:45-54. doi: 10.1007/978-3-030-60204-8_4. PMID: 33417206
Klouwer FCC, Meester-Delver A, Vaz FM, Waterham HR, Hennekam RCM, Poll-The BT
Clin Genet 2018 Mar;93(3):613-621. Epub 2017 Dec 1 doi: 10.1111/cge.13130. PMID: 28857144

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
      See practice and clinical guidelines in PubMed. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2023
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Elevated lysophosphatidylcholines, X-Linked Adrenoleukodystrophy (X-ALD), 2023
    • ACMG Algorithm, 2023
      ACMG Algorithm, X-ALD: Elevated lysophosphatidylcholines C24:0, C26:0, 2023

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