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Zellweger syndrome

December 20, 2023

Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual.[1] It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophies. Zellweger syndrome is named after Hans Zellweger (1909–1990), a Swiss-American pediatrician, a professor of pediatrics and genetics at the University of Iowa who researched this disorder.[2][3]

Zellweger syndrome
Other namesCerebrohepatorenal syndrome
Infant with Zellweger syndrome
SpecialtyMedical genetics 
Complicationspneumonia and respiratory distress.

Signs and symptoms edit

Zellweger syndrome is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD).[4] The other two disorders are neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD).[5][6] Although all have a similar molecular basis for disease, Zellweger syndrome is the most severe of these three disorders.[7]

Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and brain development.[4] In addition, individuals with Zellweger syndrome can show a reduction in central nervous system (CNS) myelin (particularly cerebral), which is referred to as hypomyelination. Myelin is critical for normal CNS functions, and in this regard, serves to insulate nerve fibers in the brain. Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision.[4]

Zellweger syndrome can also affect the function of many other organ systems. Patients can show craniofacial abnormalities (such as a high forehead, hypoplastic supraorbital ridges, epicanthal folds, midface hypoplasia, and a large fontanel), hepatomegaly (enlarged liver), chondrodysplasia punctata (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and renal cysts.[4] Newborns may present with profound hypotonia (low muscle tone), seizures, apnea, and an inability to eat.[4][7]

Cause edit

 
Autosomal recessive inheritance

Zellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins, proteins required for the normal assembly of peroxisomes. Most commonly, patients have mutations in the PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, or PEX26 genes.[8] In almost all cases, patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes.[citation needed]As a result of impaired peroxisome function, an individual's tissues and cells can accumulate very long chain fatty acids (VLCFA) and branched chain fatty acids (BCFA) that are normally degraded in peroxisomes. The accumulation of these lipids can impair the normal function of multiple organ systems, as discussed above. In addition, these individuals can show deficient levels of plasmalogens, ether-phospholipids that are especially important for brain and lung function.[citation needed]

Diagnosis edit

In addition to genetic tests involving the sequencing of PEX genes,[9][10] biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders. Typically, Zellweger syndrome patients show elevated very long chain fatty acids in their blood plasma. Cultured primary skin fibroblasts obtained from patients show elevated very long chain fatty acids, impaired very long chain fatty acid beta-oxidation, phytanic acid alpha-oxidation, pristanic acid alpha-oxidation, and plasmalogen biosynthesis.[4]

Treatment edit

The nutrient malabsorption resulting from a lack of bile acids has resulted in elemental formula being suggested for feeding. They are low in fat, with less than 3 per cent of calories being derived from long-chain triglycerides (LCT). However, reducing dietary very long chain fatty acids (VLCFA) has not been shown to reduce blood VLCFA levels,[11][12] likely because humans can endogenously produce most VLCFA. Plasma VLCFA levels are decreased when dietary VLCFA is reduced in conjunction with supplementation of Lorenzo's oil (a 4:1 mixture of glyceryl trioleate and glyceryl trierucate) in X-ALD patients.[13] Since docosahexaenoic acid (DHA) synthesis is impaired [14] [59], DHA supplementation was recommended, but a placebo-controlled study has since shown no clinical efficacy.[15] Due to defective bile acid synthesis, fat-soluble supplements of vitamins A, D, E, and K are recommended.[citation needed]

Prognosis edit

Currently, no cure for Zellweger syndrome is known, nor is there a standard course of treatment. Infections should be guarded against to prevent such complications as pneumonia and respiratory distress. Other treatment is symptomatic and supportive. Patients usually do not survive beyond one year of age.[4]

References edit

  1. ^ Brul, S.; Westerveld, A.; Strijland, A.; Wanders, R.; Schram, A.; Heymans, H.; Schutgens, R.; Van Den Bosch, H.; Tager, J. (June 1988). "Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions. A study using complementation analysis". Journal of Clinical Investigation (Free full text). 81 (6): 1710–1715. doi:10.1172/JCI113510. PMC 442615. PMID 2454948.
  2. ^ Zellweger's syndrome at Who Named It?
  3. ^ Wiedemann, H. R. (1991). "Hans-Ulrich Zellweger (1909-1990)". European Journal of Pediatrics. 150 (7): 451. doi:10.1007/BF01958418. PMID 1915492. S2CID 34905299.
  4. ^ a b c d e f g Steinberg, S.; Dodt, G.; Raymond, G.; Braverman, N.; Moser, A.; Moser, H. (2006). "Peroxisome biogenesis disorders". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1763 (12): 1733–48. doi:10.1016/j.bbamcr.2006.09.010. PMID 17055079.
  5. ^ GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum
  6. ^ Krause, C.; Rosewich, H.; Thanos, M.; Gärtner, J. (2006). "Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients". Human Mutation. 27 (11): 1157. doi:10.1002/humu.9462. PMID 17041890. S2CID 9905589.
  7. ^ a b Raymond, G. V.; Watkins, P.; Steinberg, S.; Powers, J. (2009). "Peroxisomal Disorders". Handbook of Neurochemistry and Molecular Neurobiology. pp. 631–670. doi:10.1007/978-0-387-30378-9_26. ISBN 978-0-387-30345-1.
  8. ^ Online Mendelian Inheritance in Man (OMIM): Zellweger syndrome; ZS - 214100
  9. ^ Steinberg, S.; Chen, L.; Wei, L.; Moser, A.; Moser, H.; Cutting, G.; Braverman, N. (2004). "The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum". Molecular Genetics and Metabolism. 83 (3): 252–263. doi:10.1016/j.ymgme.2004.08.008. PMID 15542397.
  10. ^ Yik, W. Y.; Steinberg, S. J.; Moser, A. B.; Moser, H. W.; Hacia, J. G. (2009). "Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders". Human Mutation. 30 (3): E467–E480. doi:10.1002/humu.20932. PMC 2649967. PMID 19105186.
  11. ^ Van Duyn, MA; Moser, AE; Brown FR, 3rd; et al. (August 1984). "The design of a diet restricted in saturated very long-chain fatty acids: therapeutic application in adrenoleukodystrophy". The American Journal of Clinical Nutrition. 40 (2): 277–84. doi:10.1093/ajcn/40.2.277. PMID 6465061.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  12. ^ Brown FR, 3rd; Van Duyn, MA; Moser, AB; et al. (October 1982). "Adrenoleukodystrophy: effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids". The Johns Hopkins Medical Journal. 151 (4): 164–72. PMID 7120720.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  13. ^ Moser, AB; Borel, J; Odone, A; et al. (March 1987). "A new dietary therapy for adrenoleukodystrophy: biochemical and preliminary clinical results in 36 patients". Annals of Neurology. 21 (3): 240–9. doi:10.1002/ana.410210305. PMID 2440378. S2CID 29043456.
  14. ^ Martinez, M (26 June 1992). "Abnormal profiles of polyunsaturated fatty acids in the brain, liver, kidney and retina of patients with peroxisomal disorders". Brain Research. 583 (1–2): 171–82. doi:10.1016/s0006-8993(10)80021-6. PMID 1504825. S2CID 20508763.
  15. ^ Paker, AM; Sunness, JS; Brereton, NH; et al. (31 August 2010). "Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial". Neurology. 75 (9): 826–30. doi:10.1212/WNL.0b013e3181f07061. PMC 3013498. PMID 20805528.

External links edit

  • Steinberg SJ, Raymond GV, Braverman NE, et al. (2020). Adam MP, Ardinger HH, Pagon RA, et al. (eds.). "Zellweger Spectrum Disorder". GeneReviews® [Internet]. University of Washington. PMID 20301621. NBK1448.

December 20, 2023
zellweger, syndrome, rare, congenital, disorder, characterized, reduction, absence, functional, peroxisomes, cells, individual, family, disorders, called, zellweger, spectrum, disorders, which, leukodystrophies, named, after, hans, zellweger, 1909, 1990, swiss. Zellweger syndrome is a rare congenital disorder characterized by the reduction or absence of functional peroxisomes in the cells of an individual 1 It is one of a family of disorders called Zellweger spectrum disorders which are leukodystrophies Zellweger syndrome is named after Hans Zellweger 1909 1990 a Swiss American pediatrician a professor of pediatrics and genetics at the University of Iowa who researched this disorder 2 3 Zellweger syndromeOther namesCerebrohepatorenal syndromeInfant with Zellweger syndromeSpecialtyMedical genetics Complicationspneumonia and respiratory distress Contents 1 Signs and symptoms 2 Cause 3 Diagnosis 4 Treatment 5 Prognosis 6 References 7 External linksSigns and symptoms editZellweger syndrome is one of three peroxisome biogenesis disorders which belong to the Zellweger spectrum of peroxisome biogenesis disorders PBD ZSD 4 The other two disorders are neonatal adrenoleukodystrophy NALD and infantile Refsum disease IRD 5 6 Although all have a similar molecular basis for disease Zellweger syndrome is the most severe of these three disorders 7 Zellweger syndrome is associated with impaired neuronal migration neuronal positioning and brain development 4 In addition individuals with Zellweger syndrome can show a reduction in central nervous system CNS myelin particularly cerebral which is referred to as hypomyelination Myelin is critical for normal CNS functions and in this regard serves to insulate nerve fibers in the brain Patients can also show postdevelopmental sensorineuronal degeneration that leads to a progressive loss of hearing and vision 4 Zellweger syndrome can also affect the function of many other organ systems Patients can show craniofacial abnormalities such as a high forehead hypoplastic supraorbital ridges epicanthal folds midface hypoplasia and a large fontanel hepatomegaly enlarged liver chondrodysplasia punctata punctate calcification of the cartilage in specific regions of the body eye abnormalities and renal cysts 4 Newborns may present with profound hypotonia low muscle tone seizures apnea and an inability to eat 4 7 Cause edit nbsp Autosomal recessive inheritanceZellweger syndrome is an autosomal recessive disorder caused by mutations in genes that encode peroxins proteins required for the normal assembly of peroxisomes Most commonly patients have mutations in the PEX1 PEX2 PEX3 PEX5 PEX6 PEX10 PEX12 PEX13 PEX14 PEX16 PEX19 or PEX26 genes 8 In almost all cases patients have mutations that inactivate or greatly reduce the activity of both the maternal and paternal copies of one these aforementioned PEX genes citation needed As a result of impaired peroxisome function an individual s tissues and cells can accumulate very long chain fatty acids VLCFA and branched chain fatty acids BCFA that are normally degraded in peroxisomes The accumulation of these lipids can impair the normal function of multiple organ systems as discussed above In addition these individuals can show deficient levels of plasmalogens ether phospholipids that are especially important for brain and lung function citation needed Diagnosis editIn addition to genetic tests involving the sequencing of PEX genes 9 10 biochemical tests have proven highly effective for the diagnosis of Zellweger syndrome and other peroxisomal disorders Typically Zellweger syndrome patients show elevated very long chain fatty acids in their blood plasma Cultured primary skin fibroblasts obtained from patients show elevated very long chain fatty acids impaired very long chain fatty acid beta oxidation phytanic acid alpha oxidation pristanic acid alpha oxidation and plasmalogen biosynthesis 4 Treatment editThe nutrient malabsorption resulting from a lack of bile acids has resulted in elemental formula being suggested for feeding They are low in fat with less than 3 per cent of calories being derived from long chain triglycerides LCT However reducing dietary very long chain fatty acids VLCFA has not been shown to reduce blood VLCFA levels 11 12 likely because humans can endogenously produce most VLCFA Plasma VLCFA levels are decreased when dietary VLCFA is reduced in conjunction with supplementation of Lorenzo s oil a 4 1 mixture of glyceryl trioleate and glyceryl trierucate in X ALD patients 13 Since docosahexaenoic acid DHA synthesis is impaired 14 59 DHA supplementation was recommended but a placebo controlled study has since shown no clinical efficacy 15 Due to defective bile acid synthesis fat soluble supplements of vitamins A D E and K are recommended citation needed Prognosis editCurrently no cure for Zellweger syndrome is known nor is there a standard course of treatment Infections should be guarded against to prevent such complications as pneumonia and respiratory distress Other treatment is symptomatic and supportive Patients usually do not survive beyond one year of age 4 References edit Brul S Westerveld A Strijland A Wanders R Schram A Heymans H Schutgens R Van Den Bosch H Tager J June 1988 Genetic heterogeneity in the cerebrohepatorenal Zellweger syndrome and other inherited disorders with a generalized impairment of peroxisomal functions A study using complementation analysis Journal of Clinical Investigation Free full text 81 6 1710 1715 doi 10 1172 JCI113510 PMC 442615 PMID 2454948 Zellweger s syndrome at Who Named It Wiedemann H R 1991 Hans Ulrich Zellweger 1909 1990 European Journal of Pediatrics 150 7 451 doi 10 1007 BF01958418 PMID 1915492 S2CID 34905299 a b c d e f g Steinberg S Dodt G Raymond G Braverman N Moser A Moser H 2006 Peroxisome biogenesis disorders Biochimica et Biophysica Acta BBA Molecular Cell Research 1763 12 1733 48 doi 10 1016 j bbamcr 2006 09 010 PMID 17055079 GeneReviews Peroxisome Biogenesis Disorders Zellweger Syndrome Spectrum Krause C Rosewich H Thanos M Gartner J 2006 Identification of novel mutations in PEX2 PEX6 PEX10 PEX12 and PEX13 in Zellweger spectrum patients Human Mutation 27 11 1157 doi 10 1002 humu 9462 PMID 17041890 S2CID 9905589 a b Raymond G V Watkins P Steinberg S Powers J 2009 Peroxisomal Disorders Handbook of Neurochemistry and Molecular Neurobiology pp 631 670 doi 10 1007 978 0 387 30378 9 26 ISBN 978 0 387 30345 1 Online Mendelian Inheritance in Man OMIM Zellweger syndrome ZS 214100 Steinberg S Chen L Wei L Moser A Moser H Cutting G Braverman N 2004 The PEX Gene Screen molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum Molecular Genetics and Metabolism 83 3 252 263 doi 10 1016 j ymgme 2004 08 008 PMID 15542397 Yik W Y Steinberg S J Moser A B Moser H W Hacia J G 2009 Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders Human Mutation 30 3 E467 E480 doi 10 1002 humu 20932 PMC 2649967 PMID 19105186 Van Duyn MA Moser AE Brown FR 3rd et al August 1984 The design of a diet restricted in saturated very long chain fatty acids therapeutic application in adrenoleukodystrophy The American Journal of Clinical Nutrition 40 2 277 84 doi 10 1093 ajcn 40 2 277 PMID 6465061 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint numeric names authors list link Brown FR 3rd Van Duyn MA Moser AB et al October 1982 Adrenoleukodystrophy effects of dietary restriction of very long chain fatty acids and of administration of carnitine and clofibrate on clinical status and plasma fatty acids The Johns Hopkins Medical Journal 151 4 164 72 PMID 7120720 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint numeric names authors list link Moser AB Borel J Odone A et al March 1987 A new dietary therapy for adrenoleukodystrophy biochemical and preliminary clinical results in 36 patients Annals of Neurology 21 3 240 9 doi 10 1002 ana 410210305 PMID 2440378 S2CID 29043456 Martinez M 26 June 1992 Abnormal profiles of polyunsaturated fatty acids in the brain liver kidney and retina of patients with peroxisomal disorders Brain Research 583 1 2 171 82 doi 10 1016 s0006 8993 10 80021 6 PMID 1504825 S2CID 20508763 Paker AM Sunness JS Brereton NH et al 31 August 2010 Docosahexaenoic acid therapy in peroxisomal diseases results of a double blind randomized trial Neurology 75 9 826 30 doi 10 1212 WNL 0b013e3181f07061 PMC 3013498 PMID 20805528 External links editZellweger Syndrome at NINDS Zellweger syndrome at NIH s Office of Rare DiseasesSteinberg SJ Raymond GV Braverman NE et al 2020 Adam MP Ardinger HH Pagon RA et al eds Zellweger Spectrum Disorder GeneReviews Internet University of Washington PMID 20301621 NBK1448 Retrieved from https en wikipedia org w index php title Zellweger syndrome amp oldid 1170974596, wikipedia, wiki, book, books, library,

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