Zellweger syndrome: Difference between revisions

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{{short description|Congenital disorder of nervous system}}

{{Infobox_Disease |

{{Infobox medical condition (new)

Name = {{PAGENAME}} |

| name Image = |Zellweger syndrome

| Captionsynonyms = |'''Cerebrohepatorenal syndrome'''

| image = Cerebro-Hepato-Renal Syndrome 2.jpg

DiseasesDB = 14248 |

| caption ICD10 = Infant =with {{ICD10|Q|87|8|q|80}}Zellweger |syndrome

| pronounce =

ICD9 = {{ICD9|277.86}}, {{ICD9|759.8}} |

| ICDOfield = |

|| OMIM symptoms = 214100 |

| complications = [[pneumonia]] and respiratory distress.

MedlinePlus = |

| onset =

eMedicineSubj = |

| duration =

eMedicineTopic = |

| types MeshID = D015211 |

| causes =

| risks =

| diagnosis =

| differential =

| prevention =

| treatment =

| medication =

| prognosis =

| frequency =

| deaths =

}}

''' Zellweger syndrome''' is a rare [[congenital disorder]] characterized by the reduction or absence of functional [[peroxisome]]s in the cells of an individual.<ref name="pmid2454948">{{Cite journal |last=Brul |first=S. |last2=Westerveld |first2=A. |last3=Strijland |first3=A. |last4=Wanders |first4=R. |last5=Schram |first5=A. |last6=Heymans |first6=H. |last7=Schutgens |first7=R. |last8=Van Den Bosch |first8=H. |last9=Tager |first9=J. |date=June 1988 |title=Genetic heterogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions. A study using complementation analysis |journal=Journal of Clinical Investigation |type=Free full text |volume=81 |issue=6 |pages=1710–1715 |doi=10.1172/JCI113510 |pmc=442615 |pmid=2454948}}</ref> It is one of a family of disorders called [[Zellweger spectrum disorders]] which are [[leukodystrophy|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 [[Disease|disorder]].<ref>{{WhoNamedIt|synd|1670|Zellweger's syndrome}}</ref><ref name="pmid1915492">{{Cite journal |last=Wiedemann |first=H. R. |year=1991 |title=Hans-Ulrich Zellweger (1909-1990) |journal=European Journal of Pediatrics |volume=150 |issue=7 |pages=451 |doi=10.1007/BF01958418 |pmid=1915492 |s2cid=34905299}}</ref>

'''Zellweger syndrome''' is a rare, [[congenital disorder]] (present at birth), characterized by the reduction or absence of [[peroxisome]]s (cell structures that rid the body of toxic substances) in the cells of the [[liver]], [[kidney]]s, and [[brain]]. It is characterized by an individual's inability to [[beta-oxidation|beta-oxidize]] very-long chain [[fatty acids]] in the [[peroxisome]]s of the cell, due to a [[genetic disorder]] in one of the several genes involved with [[peroxisome]] [[biogenesis]]. The disorder is one of three [[peroxisome biogenesis disorders]] which are also known as the Zellweger spectrum. The other two diseases are [[neonatal adrenoleukodystrophy]] (NALD), and [[infantile Refsum disease]] (IRD)<ref>http://www.genetests.org/query?dz=pbd</ref>

== Signs and symptoms ==

==Eponym==

Zellweger syndrome is one of three [[peroxisome biogenesis disorders]] that belong to the Zellweger spectrum of peroxisome biogenesis disorders (PBD-ZSD).<ref name="pmid17055079">{{Cite journal |last=Steinberg |first=S. |last2=Dodt |first2=G. |last3=Raymond |first3=G. |last4=Braverman |first4=N. |last5=Moser |first5=A. |last6=Moser |first6=H. |year=2006 |title=Peroxisome biogenesis disorders |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |volume=1763 |issue=12 |pages=1733–48 |doi=10.1016/j.bbamcr.2006.09.010 |pmid=17055079}}</ref> The other two disorders are [[neonatal adrenoleukodystrophy]] (NALD), and [[infantile Refsum disease]] (IRD).<ref>[http://www.genetests.org/query?dz=pbd GeneReviews: Peroxisome Biogenesis Disorders, Zellweger Syndrome Spectrum<!-- Bot generated title -->]</ref><ref name="pmid17041890">{{Cite journal |last=Krause |first=C. |last2=Rosewich |first2=H. |last3=Thanos |first3=M. |last4=Gärtner |first4=J. |year=2006 |title=Identification of novel mutations in PEX2, PEX6, PEX10, PEX12, and PEX13 in Zellweger spectrum patients |journal=Human Mutation |volume=27 |issue=11 |pages=1157 |doi=10.1002/humu.9462 |pmid=17041890 |s2cid=9905589}}</ref> Although all have a similar molecular basis for disease, Zellweger syndrome is the most severe of these three disorders.<ref name="doi10.1007/978-0-387-30378-9_26">{{Cite book |last=Raymond |first=G. V. |title=Handbook of Neurochemistry and Molecular Neurobiology |last2=Watkins |first2=P. |last3=Steinberg |first3=S. |last4=Powers |first4=J. |year=2009 |isbn=978-0-387-30345-1 |pages=631–670 |chapter=Peroxisomal Disorders |doi=10.1007/978-0-387-30378-9_26}}</ref>

Named after [[Hans Zellweger]], a former professor of [[Pediatrics]] and [[Genetics]] at the [[University of Iowa]] who did research into the [[disease]].<ref>{{WhoNamedIt|synd|1670}}</ref>

Zellweger syndrome is associated with impaired neuronal migration, neuronal positioning, and [[brain development]].<ref name="pmid17055079" /> In addition, individuals with Zellweger syndrome can show a reduction in [[central nervous system]] (CNS) [[myelin]] (particularly cerebral), which is referred to as [[Myelin#Dysmyelination|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 sensorineural degeneration that leads to a progressive loss of hearing and vision.<ref name="pmid17055079" />

==Family of peroxisomal diseases==

Very long chain fatty acids are generally found in the [[central nervous system]] ([[brain]] and [[spinal cord]]) and the [[peroxisome]]s of these cells can not import the necessary [[degrative protein]]s for [[B-oxidation]] to occur.

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 fontanelle), [[hepatomegaly]] (enlarged liver), [[chondrodysplasia punctata]] (punctate calcification of the cartilage in specific regions of the body), eye abnormalities, and [[renal cyst]]s.<ref name="pmid17055079" /> Newborns may present with profound [[hypotonia]] (low muscle tone), seizures, apnea, and an inability to eat.<ref name="pmid17055079" /><ref name="doi10.1007/978-0-387-30378-9_26"/>

Zellweger syndrome is one of a group of [[genetic disorder]]s called [[peroxisomal diseases]] that affect [[brain development]] and the growth of the [[myelin]] sheath, the fatty covering&mdash;which acts as an insulator&mdash;on nerve fibers in the brain.

==Presentation Cause ==

[[File:Cerebro-Hepato-Renal Syndrome 1.jpg|thumb|Same Infant with Zellweger syndrome.]]

The most common features of Zellweger syndrome include an [[hepatomegaly|enlarged liver]], high levels of iron and copper in the blood stream, and vision disturbances. Some affected infants may show prenatal growth failure. Symptoms at birth may include a lack of [[muscle tone]], an inability to move and [[glaucoma]]. Other symptoms may include unusual facial characteristics, [[mental retardation]], seizures, and an inability to suck and/or swallow. [[Jaundice]] and [[gastrointestinal bleeding]] may also occur.

Zellweger syndrome is an [[autosomal recessive]] disorder caused by mutations in genes that encode [[peroxin]]s, 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.<ref>{{OMIM|214100|Zellweger syndrome; ZS|accessdate=2007-07-11}}</ref> 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|date=October 2020}}

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 acid]]s (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|date=October 2020}} [[Bile acid]] synthesis is defective due to lack of side chain modifications; for example, the last steps in the synthesis of [[chenodeoxycholic acid]] and [[cholic acid]] involve [[beta-oxidation]] of the branched side chains of dihydroxycholestanoic acid or trihydroxycholestanoic acid, respectively, by peroxisomal enzymes.<ref>{{Cite journal |vauthors=Sundaram SS, Bove KE, Lovell MA, Sokol RJ |year=2008 |title=Mechanisms of Disease: inborn errors of bile acid synthesis |journal=Nature Reviews Gastroenterology & Hepatology |volume=5 |issue=8 |pages=456–468 |doi=10.1038/ncpgasthep1179 |pmc=3888787 |pmid=18577977}}</ref>

==Prognosis==

There is no cure for Zellweger syndrome, 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. The [[prognosis]] for individuals with Zellweger syndrome is poor. Death usually occurs by 6 months of age, and may be caused by respiratory distress, gastrointestinal bleeding, or [[liver failure]].

==References Diagnosis ==

In addition to genetic tests involving the sequencing of ''PEX'' genes,<ref name="pmid15542397">{{Cite journal |last=Steinberg |first=S. |last2=Chen |first2=L. |last3=Wei |first3=L. |last4=Moser |first4=A. |last5=Moser |first5=H. |last6=Cutting |first6=G. |last7=Braverman |first7=N. |year=2004 |title=The PEX Gene Screen: molecular diagnosis of peroxisome biogenesis disorders in the Zellweger syndrome spectrum |journal=Molecular Genetics and Metabolism |volume=83 |issue=3 |pages=252–263 |doi=10.1016/j.ymgme.2004.08.008 |pmid=15542397}}</ref><ref name="pmid19105186">{{Cite journal |last=Yik |first=W. Y. |last2=Steinberg |first2=S. J. |last3=Moser |first3=A. B. |last4=Moser |first4=H. W. |last5=Hacia |first5=J. G. |year=2009 |title=Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders |journal=Human Mutation |volume=30 |issue=3 |pages=E467–E480 |doi=10.1002/humu.20932 |pmc=2649967 |pmid=19105186}}</ref> 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.<ref name="pmid17055079" />

<references/>

*''Based on http://www.ninds.nih.gov/disorders/zellweger/zellweger.htm''

==External linksTreatment==

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 percent of calories being derived from [[long-chain triglyceride]]s (LCT). However, reducing dietary very long chain fatty acids (VLCFA) has not been shown to reduce blood VLCFA levels,<ref name="pmid6465061">{{Cite journal |last=Van Duyn |first=MA |last2=Moser |first2=AE |last3=Brown FR |first3=3rd |last4=Sacktor |first4=N |last5=Liu |first5=A |last6=Moser |first6=HW |display-authors=3 |date=August 1984 |title=The design of a diet restricted in saturated very long-chain fatty acids: therapeutic application in adrenoleukodystrophy. |journal=The American Journal of Clinical Nutrition |volume=40 |issue=2 |pages=277–84 |doi=10.1093/ajcn/40.2.277 |pmid=6465061 |doi-access=free}}</ref><ref name="pmid7120720">{{Cite journal |last=Brown FR |first=3rd |last2=Van Duyn |first2=MA |last3=Moser |first3=AB |last4=Schulman |first4=JD |last5=Rizzo |first5=WB |last6=Snyder |first6=RD |last7=Murphy |first7=JV |last8=Kamoshita |first8=S |last9=Migeon |first9=CJ |last10=Moser |first10=HW |display-authors=3 |date=October 1982 |title=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. |journal=The Johns Hopkins Medical Journal |volume=151 |issue=4 |pages=164–72 |pmid=7120720}}</ref> 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-[[adrenoleukodystrophy|ALD]] patients.<ref name="pmid2440378">{{Cite journal |last=Moser |first=AB |last2=Borel |first2=J |last3=Odone |first3=A |last4=Naidu |first4=S |last5=Cornblath |first5=D |last6=Sanders |first6=DB |last7=Moser |first7=HW |display-authors=3 |date=March 1987 |title=A new dietary therapy for adrenoleukodystrophy: biochemical and preliminary clinical results in 36 patients. |journal=Annals of Neurology |volume=21 |issue=3 |pages=240–9 |doi=10.1002/ana.410210305 |pmid=2440378 |s2cid=29043456}}</ref> Since docosahexaenoic acid (DHA) synthesis is impaired <ref name="pmid1504825">{{Cite journal |last=Martinez |first=M |date=26 June 1992 |title=Abnormal profiles of polyunsaturated fatty acids in the brain, liver, kidney and retina of patients with peroxisomal disorders. |journal=Brain Research |volume=583 |issue=1–2 |pages=171–82 |doi=10.1016/s0006-8993(10)80021-6 |pmid=1504825 |s2cid=20508763}}</ref> [59], DHA supplementation was recommended, but a placebo-controlled study has since shown no clinical efficacy.<ref name="pmid20805528">{{Cite journal |last=Paker |first=AM |last2=Sunness |first2=JS |last3=Brereton |first3=NH |last4=Speedie |first4=LJ |last5=Albanna |first5=L |last6=Dharmaraj |first6=S |last7=Moser |first7=AB |last8=Jones |first8=RO |last9=Raymond |first9=GV |display-authors=3 |date=31 August 2010 |title=Docosahexaenoic acid therapy in peroxisomal diseases: results of a double-blind, randomized trial. |journal=Neurology |volume=75 |issue=9 |pages=826–30 |doi=10.1212/WNL.0b013e3181f07061 |pmc=3013498 |pmid=20805528}}</ref> Due to defective bile acid synthesis, fat-soluble supplements of vitamins A, D, E, and K are recommended.{{citation needed|date=December 2020}}

* [http://healthlink.mcw.edu/article/921991711.html Health Link] at [[Medical College of Wisconsin]]

==Prognosis==

Currently, no cure for Zellweger syndrome is known, nor is there a standard course of treatment. In November 2023, at five months old, Christopher Donald Miller was the first patient with Zellweger Syndrome in the United States to have a bone marrow transplant. He did pass away at seven months old of [[Hepatic veno-occlusive disease|veno-occlusive disease]].<ref>Missing reference</ref>

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.<ref name="pmid17055079" />

==References==

{{Reflist}}

== External links ==

* {{NINDS|Zellweger-Syndrome}}

* {{Office of Rare Diseases|7917|Zellweger syndrome}}

{{refbegin}}

* {{Cite journal |vauthors=Steinberg SJ, Raymond GV, Braverman NE, et al |date=2020 |title=Zellweger Spectrum Disorder |url=https://www.ncbi.nlm.nih.gov/books/NBK1448/ |journal=GeneReviews® [Internet] |publisher=University of Washington |pmid=20301621 |id=NBK1448 |veditors=Adam MP, Ardinger HH, Pagon RA, et al}}

{{refend}}

{{Medical resources

| DiseasesDB = 14248 |

| ICD10 = {{ICD10|Q|87|8|q|80}}

| ICD9 = {{ICD9|277.86}}, {{ICD9|759.8}} |

| ICDO =

| NameOMIM = {{PAGENAME}} |214100

| MedlinePlus = |

| eMedicineSubj = |

| eMedicineTopic = |

| MeshID = D015211

| Orphanet=912

}}

{{Phakomatoses and other congenital malformations not elsewhere classified}}

{{Peroxisomal disorders}}

{{DEFAULTSORT:Zellweger Syndrome}}

[[Category:Hepatology]]

[[Category:InbornPeroxisomal errors of metabolismdisorders]]

[[Category:Leukodystrophies]]

[[Category:RareUrological diseasesconditions]]

[[Category:UrologySyndromes affecting the nervous system]]

[[Category:Syndromes with craniofacial abnormalities]]

[[Category:Rare syndromes]]

[[de:Zellweger-Syndrom]]

[[es:Síndrome de Zellweger]]

[[fr:Syndrome de Zellweger]]

[[pt:Síndrome de Zellwegger]]

[[fi:Zellwegerin oireyhtymä]]