Zellweger syndrome

Zellweger syndrome
Classification and external resources
Specialty medical genetics
ICD-10 Q87.8
ICD-9-CM 277.86, 759.8
OMIM 214100
DiseasesDB 14248
MeSH D015211
Orphanet 912

Zellweger syndrome, also called cerebrohepatorenal 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 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]

Signs and symptoms

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

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.

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.

Diagnosis

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 primarily 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]

Prognosis

Currently, no cure for Zellweger syndrome is known, nor is a course of treatment made standard. 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]

Additional resources for patients and families

References

  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 442615Freely accessible. PMID 2454948.
  2. ↑ synd/1670 at Who Named It?
  3. ↑ Wiedemann, H. R. (1991). "Hans-Ulrich Zellweger (1909-1990)". European journal of pediatrics. 150 (7): 451–451. doi:10.1007/BF01958418. PMID 1915492.
  4. 1 2 3 4 5 6 7 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 inPEX2,PEX6,PEX10,PEX12, andPEX13in Zellweger spectrum patients". Human Mutation. 27 (11): 1157. doi:10.1002/humu.9462. PMID 17041890.
  7. 1 2 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 2649967Freely accessible. PMID 19105186.
  11. ↑ "La collecte Delipapier pour ELA se poursuit - Association ELA". www.ela-asso.com. Retrieved 2016-02-29.
  12. ↑ "Home - March of Dimes - A Fighting Chance For Every Baby". www.marchofdimes.org. Retrieved 2016-02-29.
  13. ↑ "The Global Foundation for Peroxisomal Disorders". Retrieved 2016-02-29.
  14. ↑ "United Leukodystrophy Foundation". www.ulf.org. Retrieved 2016-02-29.
  15. ↑ "Zellweger's Support Network (requires login)". Facebook. Retrieved 2016-02-29.
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