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Tyrosinemia type III(TYRSN3)

MedGen UID:
78694
Concept ID:
C0268623
Disease or Syndrome
Synonyms: 4-alpha hydroxyphenylpyruvate dioxygenase deficiency; 4-alpha hydroxyphenylpyruvic acid oxidase deficiency; 4-Hydroxyphenylpyruvate dioxygenase deficiency; 4-HYDROXYPHENYLPYRUVIC ACID OXIDASE DEFICIENCY; Tyrosinemia type 3
SNOMED CT: 4-Hydroxyphenylpyruvate dioxygenase deficiency (413356003); Tyrosinemia type III (415764005); 4-Hydroxyphenylpyruvate hydroxylase deficiency (413356003); Tyrosinemia type 3 (415764005)
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).
 
Gene (location): HPD (12q24.31)
 
Monarch Initiative: MONDO:0010162
OMIM®: 276710
Orphanet: ORPHA69723

Definition

Tyrosinemia type III (TYRSN3), an autosomal recessive disorder caused by a deficiency in the activity of 4-hydroxyphenylpyruvate dioxygenase (HPD), is characterized by elevated levels of blood tyrosine and massive excretion of its derivatives into urine. Patients with this disorder have mildly impaired intellectual development and/or convulsions, with the absence of liver damage (summary by Tomoeda et al., 2000). [from OMIM]

Additional description

From MedlinePlus Genetics
Tyrosinemia is a genetic disorder characterized by problems breaking down the amino acid tyrosine, which is a building block of most proteins. If the condition is untreated, tyrosine and its byproducts build up in tissues and organs, which can lead to serious health problems.

There are three types of tyrosinemia, distinguished by their symptoms and genetic cause. Tyrosinemia type I is the most severe form of this disorder and usually begins in the first few months of life. Affected infants do not gain weight and grow at the expected rate (failure to thrive) because eating high-protein foods leads to diarrhea and vomiting. Affected infants may also have yellowing of the skin and whites of the eyes (jaundice), a cabbage-like odor, and an increased tendency to bleed (particularly nosebleeds). 

In addition, tyrosinemia type I can lead to liver and kidney failure, softening and weakening of the bones (rickets), and an increased risk of liver cancer (hepatocellular carcinoma). Some affected children have repeated neurologic crises that consist of changes in their mental state, reduced sensation in the arms and legs (peripheral neuropathy), abdominal pain, and serious breathing problems (respiratory failure). These crises can last from 1 to 7 days. Without treatment, children with tyrosinemia type I often do not survive past the age of 10. With early diagnosis and treatment, though, affected individuals can live into adulthood.

About 1 in 10 of all newborns have temporarily elevated levels of tyrosine (transient tyrosinemia). These cases are not genetic. The most likely causes are vitamin C deficiency or an immature liver due to premature birth.

Tyrosinemia type II often begins in early childhood and affects the eyes, skin, and mental development. Signs and symptoms include eye pain and redness, excessive tearing, abnormal sensitivity to light (photophobia), and thick, painful skin on the palms of the hands and soles of the feet (palmoplantar hyperkeratosis). About half of individuals with tyrosinemia type II have some degree of intellectual disability.

Tyrosinemia type III is the rarest of the three types. The characteristic features of this type include intellectual disabilities, seizures, and periodic loss of balance and coordination (intermittent ataxia). Liver problems do not occur in types II and III.  https://medlineplus.gov/genetics/condition/tyrosinemia

Clinical features

From HPO
4-Hydroxyphenylpyruvic aciduria
MedGen UID:
376416
Concept ID:
C1848678
Finding
Increased relative concentration of 4-hydroxyphenylpyruvic acid in the urine.
4-hydroxyphenylacetic aciduria
MedGen UID:
376417
Concept ID:
C1848680
Finding
Increased concentration of 4-hydroxyphenylacetic acid in the urine.
Intellectual disability, mild
MedGen UID:
10044
Concept ID:
C0026106
Mental or Behavioral Dysfunction
Mild intellectual disability is defined as an intelligence quotient (IQ) in the range of 50-69.
Seizure
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
A seizure is an intermittent abnormality of nervous system physiology characterized by a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.
Intellectual disability, severe
MedGen UID:
48638
Concept ID:
C0036857
Mental or Behavioral Dysfunction
Severe mental retardation is defined as an intelligence quotient (IQ) in the range of 20-34.
Global developmental delay
MedGen UID:
107838
Concept ID:
C0557874
Finding
A delay in the achievement of motor or mental milestones in the domains of development of a child, including motor skills, speech and language, cognitive skills, and social and emotional skills. This term should only be used to describe children younger than five years of age.
Elevated circulating hepatic transaminase concentration
MedGen UID:
338525
Concept ID:
C1848701
Finding
Elevations of the levels of SGOT and SGPT in the serum. SGOT (serum glutamic oxaloacetic transaminase) and SGPT (serum glutamic pyruvic transaminase) are transaminases primarily found in the liver and heart and are released into the bloodstream as the result of liver or heart damage. SGOT and SGPT are used clinically mainly as markers of liver damage.
Hypertyrosinemia
MedGen UID:
742296
Concept ID:
C1879362
Disease or Syndrome
An increased concentration of tyrosine in the blood.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVTyrosinemia type III
Follow this link to review classifications for Tyrosinemia type III in Orphanet.

Professional guidelines

PubMed

Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein MP, Coakley K, Scott CR
Genet Med 2017 Dec;19(12) Epub 2017 Aug 3 doi: 10.1038/gim.2017.101. PMID: 28771246Free PMC Article
Giguère Y, Berthier MT
Adv Exp Med Biol 2017;959:139-146. doi: 10.1007/978-3-319-55780-9_13. PMID: 28755192
Nakamura K, Matsumoto S, Mitsubuchi H, Endo F
Pediatr Int 2015;57(1):37-40. doi: 10.1111/ped.12550. PMID: 25443793

Curated

American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Increased Tyrosine, Tyrosinemia, 2022

American College of Medical Genetics and Genomics, Algorithm, Tyrosine Elevated, Succinylacetone Normal, 2022

American College of Medical Genetics and Genomics, Algorithm, Tyrosine Normal/Elevated, Succinylacetone Elevated, 2022

Recent clinical studies

Etiology

Cerone R, Holme E, Schiaffino MC, Caruso U, Maritano L, Romano C
Acta Paediatr 1997 Sep;86(9):1013-5. doi: 10.1111/j.1651-2227.1997.tb15192.x. PMID: 9343288

Diagnosis

Han D, Wang L, Zhao C, Li J, Huang C, Song W, Wang H, Li X, Tao Y
Mol Genet Genomic Med 2024 Jan;12(1):e2298. Epub 2023 Oct 10 doi: 10.1002/mgg3.2298. PMID: 37817461Free PMC Article
Barroso F, Correia J, Bandeira A, Carmona C, Vilarinho L, Almeida M, Rocha JC, Martins E
Rev Paul Pediatr 2020;38:e2018158. Epub 2020 Jun 5 doi: 10.1590/1984-0462/2020/38/2018158. PMID: 32520295Free PMC Article
Zhao D, Tian Y, Li X, Ni M, Zhu X, Jia L
J Pediatr Endocrinol Metab 2020 Apr 28;33(4):563-567. doi: 10.1515/jpem-2019-0498. PMID: 32109208
Blundell J, Frisson S, Chakrapani A, Kearney S, Vijay S, MacDonald A, Gissen P, Hendriksz C, Olson A
Cogn Neuropsychol 2018 May-Jun;35(3-4):120-147. doi: 10.1080/02643294.2018.1443913. PMID: 29741470
Scott CR
Am J Med Genet C Semin Med Genet 2006 May 15;142C(2):121-6. doi: 10.1002/ajmg.c.30092. PMID: 16602095

Therapy

Cerone R, Holme E, Schiaffino MC, Caruso U, Maritano L, Romano C
Acta Paediatr 1997 Sep;86(9):1013-5. doi: 10.1111/j.1651-2227.1997.tb15192.x. PMID: 9343288

Prognosis

D'Eufemia P, Finocchiaro R, Celli M, Raccio I, Properzi E, Zicari A
Biomed Pharmacother 2009 Jun;63(5):359-61. Epub 2008 Jul 9 doi: 10.1016/j.biopha.2008.06.030. PMID: 18657947
Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, Boneh A, Scott CR, Danks DM, Endo F
Mol Genet Metab 2000 Nov;71(3):506-10. doi: 10.1006/mgme.2000.3085. PMID: 11073718
Cerone R, Holme E, Schiaffino MC, Caruso U, Maritano L, Romano C
Acta Paediatr 1997 Sep;86(9):1013-5. doi: 10.1111/j.1651-2227.1997.tb15192.x. PMID: 9343288

Clinical prediction guides

Scott CR
Am J Med Genet C Semin Med Genet 2006 May 15;142C(2):121-6. doi: 10.1002/ajmg.c.30092. PMID: 16602095
Tomoeda K, Awata H, Matsuura T, Matsuda I, Ploechl E, Milovac T, Boneh A, Scott CR, Danks DM, Endo F
Mol Genet Metab 2000 Nov;71(3):506-10. doi: 10.1006/mgme.2000.3085. PMID: 11073718

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.
    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • ACMG ACT, 2022
      American College of Medical Genetics and Genomics, Newborn Screening ACT Sheet, Increased Tyrosine, Tyrosinemia, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Tyrosine Elevated, Succinylacetone Normal, 2022
    • ACMG Algorithm, 2022
      American College of Medical Genetics and Genomics, Algorithm, Tyrosine Normal/Elevated, Succinylacetone Elevated, 2022

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