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Rework of cause and diagnosis sections. Added specific genes affected, pathophysiology, and detection method for each disorder, as well as significant sourcing.
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{{Refimprove|date=December 2007}}

{{Infobox disease
{{Infobox disease
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|Name = Tyrosinemia
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'''Tyrosinemia''' [[American and British English spelling differences#ae and oe|or]] '''tyrosinaemia''' is an error of [[metabolism]], usually [[inborn error of metabolism|inborn]], in which the body cannot effectively break down the amino acid [[tyrosine]]. Symptoms include [[liver]] and [[kidney]] disturbances and [[intellectual disability]]. Untreated, tyrosinemia can be fatal.{{citation needed|date=January 2017}}Most inborn forms of tyrosinemia produce hypertyrosinemia (high levels of tyrosine).<ref>
'''Tyrosinemia''' [[American and British English spelling differences#ae and oe|or]] '''tyrosinaemia''' is an error of [[metabolism]], usually [[inborn error of metabolism|inborn]], in which the body cannot effectively break down the amino acid [[tyrosine]]. Symptoms include [[liver]] and [[kidney]] disturbances and [[intellectual disability]]. Untreated, tyrosinemia can be fatal.<ref>{{Cite book|title=Fleisher & Ludwig's Textbook of Pediatric Emergency Medicine|last=Shaw|first=Kathy|last2=Bachur|first2=Richard|publisher=Wolters Kluwer|year=2016|isbn=978-1451193954|location=|pages=}}</ref> Most inborn forms of tyrosinemia produce hypertyrosinemia (high levels of tyrosine).<ref>
[[Charles Scriver]], Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (Accessed 2007). [http://www.ommbid.com/OMMBID/the_online_metabolic_and_molecular_bases_of_inherited_disease/b/abstract/part8/ch79 The Online Metabolic and Molecular Bases of Inherited Disease.] Chapter 79. New York: McGraw-Hill.</ref>
[[Charles Scriver]], Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (Accessed 2007). [http://www.ommbid.com/OMMBID/the_online_metabolic_and_molecular_bases_of_inherited_disease/b/abstract/part8/ch79 The Online Metabolic and Molecular Bases of Inherited Disease.] Chapter 79. New York: McGraw-Hill.</ref>
==Cause==
==Cause==
[[Image:autorecessive.svg|thumb|left|140 px|Tyrosinemia is inherited in an [[autosomal recessive]] pattern.]]
[[Image:autorecessive.svg|thumb|left|140 px|Tyrosinemia is inherited in an [[autosomal recessive]] pattern.]]
All tyrosinemias result from dysfunction of various genes in the phenylalanine and tyrosine catabolic pathway and are inherited in an autosomal recessive pattern.<ref name=":0">{{Cite web|url=https://www.uptodate.com/contents/disorders-of-tyrosine-metabolism|title=Disorders of Tyrosine Metabolism|last=Grompe|first=Markus|date=2016-12-20|website=www.uptodate.com|access-date=2018-02-23}}</ref>
Mutations in the FAH, TAT, or HPD gene cause a decrease in the activity of one of the enzymes in the breakdown of tyrosine.


[[Type I tyrosinemia]] results from a mutation in the ''FAH'' gene, which encodes the enzyme fumarylacetoacetase.<ref name=":1">{{Cite book|title=Lehninger Principles of Biochemistry|last=Nelson|first=David|last2=Cox|first2=Michael|publisher=WH Freeman and Co.|year=2013|isbn=978-1-4292-3414-6|edition=6th ed.|location=New York|pages=719}}</ref> As a result of ''FAH'' deficiency the substrate [[fumarylacetoacetate]] can accumulate in [[Proximal tubule|proximal renal tubular cells]] and [[Hepatocyte|hepatocytes]], resulting in damage to the kidney and liver, respectively.<ref name=":0" />
As a result, tyrosine and its byproducts accumulate to toxic levels, which can cause damage and death to cells in the liver, kidneys, nervous system, and other organs.{{citation needed|date=December 2017}}

{{clear}}
[[Tyrosinemia type II|Type II tyrosinemia]] results from a mutation in the ''TAT'' gene, which encodes the enzyme [[tyrosine aminotransferase]].<ref name=":1" /> As a result of ''TAT'' deficiency the substrate tyrosine accumulates, causing ophthalmologic and dermatologic abnormalities.<ref name=":0" />

[[Tyrosinemia type III|Type III tyrosinemia]] results from a mutation in the ''HPD'' gene, which encodes the enzyme [[4-Hydroxyphenylpyruvate dioxygenase|4-hydroxyphenylpyruvate dioxygenase]].<ref name=":1" /> Type III tyrosinemia is the rarest of the three conditions, with only a few cases ever reported.<ref>{{Cite journal|last=|first=|date=2012-11-01|title=Tyrosinemia Type III detected via neonatal screening: Management and outcome|url=https://www.sciencedirect.com/science/article/pii/S109671921200340X|journal=Molecular Genetics and Metabolism|language=en|volume=107|issue=3|pages=605–607|doi=10.1016/j.ymgme.2012.09.002|issn=1096-7192|via=Elsevier Science Direct}}</ref> Most of those cases have included intellectual disability and neurologic dysfunction.<ref name=":0" />


==Diagnosis==
==Diagnosis==
===Types===
===Types===
Type I tyrosinemia can be detected via blood tests for the presence of a fumarylacetoacetate metabolite, [[succinylacetone]], which is considered a [[Pathognomonicity|pathognomonic]] indicator for the disease.<ref>{{Cite journal|last=|first=|date=2014-09-01|title=Succinylacetone as primary marker to detect tyrosinemia type I in newborns and its measurement by newborn screening programs|url=https://www.sciencedirect.com/science/article/pii/S1096719214002145|journal=Molecular Genetics and Metabolism|language=en|volume=113|issue=1-2|pages=67–75|doi=10.1016/j.ymgme.2014.07.010|issn=1096-7192|via=Elsevier Science Direct}}</ref>
There are three types of tyrosinemia, each with distinctive symptoms and caused by the deficiency of a different enzyme.

* [[Type I tyrosinemia]]
Type II tyrosinemia can be detected via the presence of significantly elevated plasma tyrosine levels, and the diagnosis can be confirmed by detection of a mutation in ''TAT'' in cultured fibroblasts.
* [[Type II tyrosinemia]]
* [[Type III tyrosinemia]]


Type III tyrosinemia can be diagnosed by detection of a mutation in ''HPD'' in cultured fibroblasts.<ref name=":0" />
[[File:Pathophysiology of metabolic disorders of phenylalanine and tyrosine.png|600px|centre|thumb|Pathophysiology of metabolic disorders of tyrosine, resulting in elevated levels of tyrosine in blood.]]
[[File:Pathophysiology of metabolic disorders of phenylalanine and tyrosine.png|600px|centre|thumb|Pathophysiology of metabolic disorders of tyrosine, resulting in elevated levels of tyrosine in blood.]]


==Treatment==
==Treatment==
Treatment varies depending on the specific type. A [[low protein diet]] may be required in the management of tyrosinemia. Recent experience with [[nitisinone]] has shown it to be effective. It is a 4-hydroxyphenylpyruvate dioxygenase inhibitor indicated for the treatment of [[heredity|hereditary]] tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and [[phenylalanine]].<ref name="accessdata.fda.gov">{{Citation |author=Swedish Orphan Biovitrum AB |authorlink=Swedish Orphan Biovitrum |title=Orfadin [package insert] |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206356s000lbl.pdf |accessdate=2016-07-12}}</ref> [[Liver transplantation|Liver transplant]] is indicated for patients with tyrosinemia type I who do not respond to nitisinone, as well as those with acute liver failure and hepatomas.<ref>{{Cite journal|last=Mieles|first=L.A.|last2=Esquivel|first2=C.O.|last3=Van Thiel|first3=D.H.|last4=Koneru|first4=B.|last5=Makowka|first5=L.|last6=Tzakis|first6=A.G.|last7=Starzl|first7=T.E.|date=January 1990|title=Liver Transplantation for Tyrosinemia|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974306/|journal=Digestive Diseases and Sciences|volume=35|issue=1|pages=153–157|issn=0163-2116|pmc=PMC2974306|pmid=2153069|via=PubMed}}</ref>
Treatment varies depending on the specific type. A [[low protein diet]] may be required in the management of tyrosinemia. Recent experience with [[nitisinone]] has shown it to be effective. It is a [[4-Hydroxyphenylpyruvate dioxygenase|4-hydroxyphenylpyruvate dioxygenase]] inhibitor indicated for
the treatment of [[heredity|hereditary]] tyrosinemia type 1 (HT-1) in combination with
dietary restriction of tyrosine and [[phenylalanine]].<ref name="accessdata.fda.gov">{{Citation |author=Swedish Orphan Biovitrum AB |authorlink=Swedish Orphan Biovitrum |title=Orfadin [package insert] |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206356s000lbl.pdf |accessdate=2016-07-12}}</ref> The most effective treatment in patients with tyrosinemia type I seems to be full or partial [[liver transplantation|liver transplant]].{{citation needed|date=December 2017}}


==See also==
==See also==

Revision as of 16:52, 23 February 2018

Tyrosinemia
SpecialtyMedical genetics Edit this on Wikidata

Tyrosinemia or tyrosinaemia is an error of metabolism, usually inborn, in which the body cannot effectively break down the amino acid tyrosine. Symptoms include liver and kidney disturbances and intellectual disability. Untreated, tyrosinemia can be fatal.[1] Most inborn forms of tyrosinemia produce hypertyrosinemia (high levels of tyrosine).[2]

Cause

Tyrosinemia is inherited in an autosomal recessive pattern.

All tyrosinemias result from dysfunction of various genes in the phenylalanine and tyrosine catabolic pathway and are inherited in an autosomal recessive pattern.[3]

Type I tyrosinemia results from a mutation in the FAH gene, which encodes the enzyme fumarylacetoacetase.[4] As a result of FAH deficiency the substrate fumarylacetoacetate can accumulate in proximal renal tubular cells and hepatocytes, resulting in damage to the kidney and liver, respectively.[3]

Type II tyrosinemia results from a mutation in the TAT gene, which encodes the enzyme tyrosine aminotransferase.[4] As a result of TAT deficiency the substrate tyrosine accumulates, causing ophthalmologic and dermatologic abnormalities.[3]

Type III tyrosinemia results from a mutation in the HPD gene, which encodes the enzyme 4-hydroxyphenylpyruvate dioxygenase.[4] Type III tyrosinemia is the rarest of the three conditions, with only a few cases ever reported.[5] Most of those cases have included intellectual disability and neurologic dysfunction.[3]

Diagnosis

Types

Type I tyrosinemia can be detected via blood tests for the presence of a fumarylacetoacetate metabolite, succinylacetone, which is considered a pathognomonic indicator for the disease.[6]

Type II tyrosinemia can be detected via the presence of significantly elevated plasma tyrosine levels, and the diagnosis can be confirmed by detection of a mutation in TAT in cultured fibroblasts.

Type III tyrosinemia can be diagnosed by detection of a mutation in HPD in cultured fibroblasts.[3]

Pathophysiology of metabolic disorders of tyrosine, resulting in elevated levels of tyrosine in blood.

Treatment

Treatment varies depending on the specific type. A low protein diet may be required in the management of tyrosinemia. Recent experience with nitisinone has shown it to be effective. It is a 4-hydroxyphenylpyruvate dioxygenase inhibitor indicated for the treatment of hereditary tyrosinemia type 1 (HT-1) in combination with dietary restriction of tyrosine and phenylalanine.[7] Liver transplant is indicated for patients with tyrosinemia type I who do not respond to nitisinone, as well as those with acute liver failure and hepatomas.[8]

See also

References

  1. ^ Shaw, Kathy; Bachur, Richard (2016). Fleisher & Ludwig's Textbook of Pediatric Emergency Medicine. Wolters Kluwer. ISBN 978-1451193954.
  2. ^ Charles Scriver, Beaudet, A.L., Valle, D., Sly, W.S., Vogelstein, B., Childs, B., Kinzler, K.W. (Accessed 2007). The Online Metabolic and Molecular Bases of Inherited Disease. Chapter 79. New York: McGraw-Hill.
  3. ^ a b c d e Grompe, Markus (2016-12-20). "Disorders of Tyrosine Metabolism". www.uptodate.com. Retrieved 2018-02-23.
  4. ^ a b c Nelson, David; Cox, Michael (2013). Lehninger Principles of Biochemistry (6th ed. ed.). New York: WH Freeman and Co. p. 719. ISBN 978-1-4292-3414-6. {{cite book}}: |edition= has extra text (help)
  5. ^ "Tyrosinemia Type III detected via neonatal screening: Management and outcome". Molecular Genetics and Metabolism. 107 (3): 605–607. 2012-11-01. doi:10.1016/j.ymgme.2012.09.002. ISSN 1096-7192 – via Elsevier Science Direct.
  6. ^ "Succinylacetone as primary marker to detect tyrosinemia type I in newborns and its measurement by newborn screening programs". Molecular Genetics and Metabolism. 113 (1–2): 67–75. 2014-09-01. doi:10.1016/j.ymgme.2014.07.010. ISSN 1096-7192 – via Elsevier Science Direct.
  7. ^ Swedish Orphan Biovitrum AB, Orfadin [package insert] (PDF), retrieved 2016-07-12
  8. ^ Mieles, L.A.; Esquivel, C.O.; Van Thiel, D.H.; Koneru, B.; Makowka, L.; Tzakis, A.G.; Starzl, T.E. (January 1990). "Liver Transplantation for Tyrosinemia". Digestive Diseases and Sciences. 35 (1): 153–157. ISSN 0163-2116. PMC 2974306. PMID 2153069 – via PubMed.{{cite journal}}: CS1 maint: PMC format (link)
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