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Peroxisome biogenesis disorder(PBD, ZSS)

MedGen UID:
330407
Concept ID:
C1832200
Disease or Syndrome
Synonyms: ADRENOLEUKODYSTROPHY, AUTOSOMAL NEONATAL; ALD: Adrenoleukodystrophy, X-Linked; INFANTILE PHYTANIC ACID STORAGE DISEASE; PBD, ZSS; PEROXISOME BIOGENESIS DISORDER (NALD/IRD); PEROXISOME BIOGENESIS DISORDER (NEONATAL ADRENOLEUKODYSTROPHY/INFANTILE REFSUM DISEASE); Peroxisome biogenesis disorders, Zellweger syndrome spectrum
SNOMED CT: Peroxisome biogenesis disorder spectrum (742876007); Peroxisome biogenesis disorder (742876007); PBD-ZSS - Peroxisome biogenesis disorder Zellweger syndrome spectrum (742876007)
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).
 
Genes (locations): PEX12 (17q12); PEX16 (11p11.2); PEX6 (6p21.1)
 
Monarch Initiative: MONDO:0019234
OMIM® Phenotypic series: PS214100
Orphanet: ORPHA79189

Disease characteristics

Excerpted from the GeneReview: Zellweger Spectrum Disorder
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. [from GeneReviews]
Authors:
Steven J Steinberg  |  Gerald V Raymond  |  Nancy E Braverman, et. al.   view full author information

Additional description

From MedlinePlus Genetics
The severe, intermediate, and mild forms of Zellweger spectrum disorder were once thought to be distinct disorders. The severe form was known as Zellweger syndrome, the intermediate form was neonatal adrenoleukodystrophy (NALD), and the mild form was infantile Refsum disease. These conditions were renamed as a single condition when they were found to be part of the same condition spectrum. 

People with intermediate or mild Zellweger spectrum disorder have more variable features that progress more slowly than those with the severe form. Affected children usually do not develop signs and symptoms of the disease until late infancy or early childhood. Children with these intermediate and mild forms often have hypotonia, vision problems, hearing loss, liver dysfunction, developmental delay, and some degree of intellectual disability. Most people with the intermediate form survive into childhood, and those with the mild form may reach adulthood. In rare cases, individuals at the mildest end of the condition spectrum have developmental delay in childhood and hearing loss or vision problems beginning in adulthood and do not develop the other features of this disorder.

Children with severe Zellweger spectrum disorder also develop life-threatening problems in other organs and tissues, such as the liver, heart, and kidneys, and their liver or spleen may be enlarged. They may have skeletal abnormalities, including a large space between the bones of the skull (fontanelles) and characteristic bone spots known as chondrodysplasia punctata that can be seen on x-ray. Affected individuals can have eye abnormalities, including clouding of the lenses of the eyes (cataracts) or involuntary, side-to-side movements of the eyes (nystagmus). Severe Zellweger spectrum disorder involves distinctive facial features, including a flattened face, broad nasal bridge, high forehead, and widely spaced eyes (hypertelorism). Children with severe Zellweger spectrum disorder typically do not survive beyond the first year of life.

Individuals with severe Zellweger spectrum disorder usually have signs and symptoms at birth, which worsen over time. These infants experience weak muscle tone (hypotonia), feeding problems, hearing and vision loss, and seizures. These problems are caused by reduced myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. The part of the brain and spinal cord that contains myelin is called white matter. Reduced myelin (demyelination) leads to loss of white matter (leukodystrophy). 

Zellweger spectrum disorder is a condition that affects many parts of the body. Cases of Zellweger spectrum disorder are often categorizes as severe, intermediate, or mild.  https://medlineplus.gov/genetics/condition/zellweger-spectrum-disorder

Professional guidelines

PubMed

Muto Y, Suzuki M, Takei H, Saito N, Mori J, Sugimoto S, Imagawa K, Nambu R, Oguri S, Itonaga T, Ihara K, Hayashi H, Murayama K, Kakiyama G, Nittono H, Shimizu T
Mol Genet Metab 2023 Sep-Oct;140(1-2):107703. Epub 2023 Sep 28 doi: 10.1016/j.ymgme.2023.107703. PMID: 37802748
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
Lee S, Clinard K, Young SP, Rehder CW, Fan Z, Calikoglu AS, Bali DS, Bailey DB Jr, Gehtland LM, Millington DS, Patel HS, Beckloff SE, Zimmerman SJ, Powell CM, Taylor JL
JAMA Netw Open 2020 Jan 3;3(1):e1920356. doi: 10.1001/jamanetworkopen.2019.20356. PMID: 32003821Free PMC Article

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

Cheillan D
Adv Exp Med Biol 2020;1299:71-80. doi: 10.1007/978-3-030-60204-8_6. PMID: 33417208
Wangler MF, Hubert L, Donti TR, Ventura MJ, Miller MJ, Braverman N, Gawron K, Bose M, Moser AB, Jones RO, Rizzo WB, Sutton VR, Sun Q, Kennedy AD, Elsea SH
Genet Med 2018 Oct;20(10):1274-1283. Epub 2018 Feb 8 doi: 10.1038/gim.2017.262. PMID: 29419819Free 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
Nazarko TY
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Genomics 1995 Nov 20;30(2):366-8. doi: 10.1006/geno.1995.0032. PMID: 8586442

Diagnosis

Schilff M, Sargsyan Y, Hofhuis J, Thoms S
Biomolecules 2021 Jul 9;11(7) doi: 10.3390/biom11071006. PMID: 34356630Free PMC Article
Cheillan D
Adv Exp Med Biol 2020;1299:71-80. doi: 10.1007/978-3-030-60204-8_6. PMID: 33417208
Wangler MF, Hubert L, Donti TR, Ventura MJ, Miller MJ, Braverman N, Gawron K, Bose M, Moser AB, Jones RO, Rizzo WB, Sutton VR, Sun Q, Kennedy AD, Elsea SH
Genet Med 2018 Oct;20(10):1274-1283. Epub 2018 Feb 8 doi: 10.1038/gim.2017.262. PMID: 29419819Free 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
Levesque S, Morin C, Guay SP, Villeneuve J, Marquis P, Yik WY, Jiralerspong S, Bouchard L, Steinberg S, Hacia JG, Dewar K, Braverman NE
BMC Med Genet 2012 Aug 15;13:72. doi: 10.1186/1471-2350-13-72. PMID: 22894767Free PMC Article

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
Enns GM, Ammous Z, Himes RW, Nogueira J, Palle S, Sullivan M, Ramirez C
Mol Genet Metab 2021 Nov;134(3):217-222. Epub 2021 Sep 27 doi: 10.1016/j.ymgme.2021.09.007. PMID: 34625341
MacLean GE, Argyriou C, Di Pietro E, Sun X, Birjandian S, Saberian P, Hacia JG, Braverman NE
J Cell Biochem 2019 Mar;120(3):3243-3258. Epub 2018 Oct 26 doi: 10.1002/jcb.27591. PMID: 30362618
Sorlin A, Briand G, Cheillan D, Wiedemann A, Montaut-Verient B, Schmitt E, Feillet F
Neuropediatrics 2016 Jun;47(3):179-81. Epub 2016 Mar 4 doi: 10.1055/s-0036-1578798. PMID: 26947510
Gootjes J, Skovby F, Christensen E, Wanders RJ, Ferdinandusse S
Neurology 2004 Jun 8;62(11):2077-81. doi: 10.1212/01.wnl.0000127576.26352.d1. PMID: 15184617

Prognosis

Bose M, Yergeau C, D'Souza Y, Cuthbertson DD, Lopez MJ, Smolen AK, Braverman NE
Cells 2022 Jun 10;11(12) doi: 10.3390/cells11121891. PMID: 35741019Free PMC Article
Zaabi NA, Kendi A, Al-Jasmi F, Takashima S, Shimozawa N, Al-Dirbashi OY
Brain Dev 2019 Jan;41(1):57-65. Epub 2018 Aug 2 doi: 10.1016/j.braindev.2018.07.015. PMID: 30078639
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
Levesque S, Morin C, Guay SP, Villeneuve J, Marquis P, Yik WY, Jiralerspong S, Bouchard L, Steinberg S, Hacia JG, Dewar K, Braverman NE
BMC Med Genet 2012 Aug 15;13:72. doi: 10.1186/1471-2350-13-72. PMID: 22894767Free PMC Article
Ünay B, Kendirli T, Atac K, Gül D, Akın R, Gökc Ay E
Clin Dysmorphol 2005 Jul;14(3):165-167. PMID: 15930911

Clinical prediction guides

Khoddam S, Kamal N, Shiri A, Jafari Khamirani H, Manoochehri J, Dianatpour M, Tabei SMB, Dastgheib SA
Eur J Med Genet 2024 Apr;68:104928. Epub 2024 Feb 28 doi: 10.1016/j.ejmg.2024.104928. PMID: 38423277
Bose M, Yergeau C, D'Souza Y, Cuthbertson DD, Lopez MJ, Smolen AK, Braverman NE
Cells 2022 Jun 10;11(12) doi: 10.3390/cells11121891. PMID: 35741019Free PMC Article
Wangler MF, Hubert L, Donti TR, Ventura MJ, Miller MJ, Braverman N, Gawron K, Bose M, Moser AB, Jones RO, Rizzo WB, Sutton VR, Sun Q, Kennedy AD, Elsea SH
Genet Med 2018 Oct;20(10):1274-1283. Epub 2018 Feb 8 doi: 10.1038/gim.2017.262. PMID: 29419819Free 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
Levesque S, Morin C, Guay SP, Villeneuve J, Marquis P, Yik WY, Jiralerspong S, Bouchard L, Steinberg S, Hacia JG, Dewar K, Braverman NE
BMC Med Genet 2012 Aug 15;13:72. doi: 10.1186/1471-2350-13-72. PMID: 22894767Free PMC Article

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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