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Tyrosinemia type I(TYRSN1)

MedGen UID:
75688
Concept ID:
C0268490
Disease or Syndrome
Synonyms: Deficiency of fumarylacetoacetase; FAH deficiency; Fumarylacetoacetase deficiency; Hepatorenal tyrosinemia; Tyrosinemia type 1; TYRSN1
SNOMED CT: Deficiency of beta-diketonase (124536006); Deficiency of fumarylacetoacetase (124536006); Tyrosinemia type I (410056006)
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): FAH (15q25.1)
 
Monarch Initiative: MONDO:0010161
OMIM®: 276700
Orphanet: ORPHA882

Disease characteristics

Excerpted from the GeneReview: Tyrosinemia Type I
Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets. [from GeneReviews]
Authors:
Lisa Sniderman King  |  Cristine Trahms  |  C Ronald Scott   view full author information

Additional descriptions

From OMIM
Hereditary tyrosinemia type I (TYRSN1) is an autosomal recessive disorder caused by deficiency of fumarylacetoacetase (FAH), the last enzyme of tyrosine degradation. The disorder is characterized by progressive liver disease and a secondary renal tubular dysfunction leading to hypophosphatemic rickets. Onset varies from infancy to adolescence. In the most acute form patients present with severe liver failure within weeks after birth, whereas rickets may be the major symptom in chronic tyrosinemia. Untreated, patients die from cirrhosis or hepatocellular carcinoma at a young age (summary by Bliksrud et al., 2005). Genetic Heterogeneity of Hereditary Tyrosinemia Tyrosinemia type II (TYRSN2; 276600), also known as Richner-Hanhart syndrome, is caused by mutation in the TAT gene (613018) on chromosome 16q22. Tyrosinemia type III (TYRNS3; 276710) is caused by mutation in the HPD gene (609695) on chromosome 12q24.  http://www.omim.org/entry/276700
From MedlinePlus Genetics
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.

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.

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.

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). 

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.  https://medlineplus.gov/genetics/condition/tyrosinemia

Clinical features

From HPO
Nephrocalcinosis
MedGen UID:
10222
Concept ID:
C0027709
Disease or Syndrome
Nephrocalcinosis is the deposition of calcium salts in renal parenchyma.
Glomerular sclerosis
MedGen UID:
61248
Concept ID:
C0178664
Disease or Syndrome
Accumulation of scar tissue within the glomerulus.
Renal Fanconi syndrome
MedGen UID:
137960
Concept ID:
C0341703
Disease or Syndrome
An inability of the tubules in the kidney to reabsorb small molecules, causing increased urinary loss of electrolytes (sodium, potassium, bicarbonate), minerals, glucose, amino acids, and water.
Enlarged kidney
MedGen UID:
108156
Concept ID:
C0542518
Finding
An abnormal increase in the size of the kidney.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Elevated urinary delta-aminolevulinic acid
MedGen UID:
341286
Concept ID:
C1848702
Finding
An increased concentration of 5-aminolevulinic acid (CHEBI:17549) in the urine.
Elevated urinary succinylacetone level
MedGen UID:
1053324
Concept ID:
CN377430
Finding
Presence in the urine of succinylacetone, which is one of the toic block metabolites formed in tyrosinaemia type 1 because of a defect in the final enzyme of the pathway of the degradation of tyrosine, namely fumarylacetoacetase (FAH, EC 3.7.1.2).
Hypertrophic cardiomyopathy
MedGen UID:
2881
Concept ID:
C0007194
Disease or Syndrome
Hypertrophic cardiomyopathy (HCM) is defined by the presence of increased ventricular wall thickness or mass in the absence of loading conditions (hypertension, valve disease) sufficient to cause the observed abnormality.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Ascites
MedGen UID:
416
Concept ID:
C0003962
Disease or Syndrome
Accumulation of fluid in the peritoneal cavity.
Gastrointestinal hemorrhage
MedGen UID:
8971
Concept ID:
C0017181
Pathologic Function
Hemorrhage affecting the gastrointestinal tract.
Hepatomegaly
MedGen UID:
42428
Concept ID:
C0019209
Finding
Abnormally increased size of the liver.
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Melena
MedGen UID:
7523
Concept ID:
C0025222
Pathologic Function
The passage of blackish, tarry feces associated with gastrointestinal hemorrhage. Melena occurs if the blood remains in the colon long enough for it to be broken down by colonic bacteria. One degradation product, hematin, imbues the stool with a blackish color. Thus, melena generally occurs with bleeding from the upper gastrointestinal tract (e.g., stomach ulcers or duodenal ulcers), since the blood usually remains in the gut for a longer period of time than with lower gastrointestinal bleeding.
Paralytic ileus
MedGen UID:
18293
Concept ID:
C0030446
Disease or Syndrome
An ileus caused by abdominal or pelvic surgery, infections, disorders that affect the muscles and nerves, and medications. Signs and symptoms include those of intestinal obstruction.
Liver failure
MedGen UID:
88444
Concept ID:
C0085605
Disease or Syndrome
A disorder characterized by the inability of the liver to metabolize chemicals in the body. Causes include cirrhosis and drug-induced hepatotoxicity. Signs and symptoms include jaundice and encephalopathy. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic dehydrogenase, and alkaline phosphatase.
Acute liver failure
MedGen UID:
58125
Concept ID:
C0162557
Disease or Syndrome
Hepatic failure refers to the inability of the liver to perform its normal synthetic and metabolic functions, which can result in coagulopathy and alteration in the mental status of a previously healthy individual. Hepatic failure is defined as acute if there is onset of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver.
Pancreatic islet-cell hyperplasia
MedGen UID:
108598
Concept ID:
C0597167
Finding
Hyperplasia of the islets of Langerhans, i.e., of the regions of the pancreas that contain its endocrine cells.
Episodic vomiting
MedGen UID:
333228
Concept ID:
C1838993
Finding
Paroxysmal, recurrent episodes of vomiting.
Hepatocellular carcinoma
MedGen UID:
389187
Concept ID:
C2239176
Neoplastic Process
Hepatocellular carcinoma is the major histologic type of malignant primary liver neoplasm. It is the fifth most common cancer and the third most common cause of death from cancer worldwide. The major risk factors for HCC are chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, prolonged dietary aflatoxin exposure, alcoholic cirrhosis, and cirrhosis due to other causes. Hepatoblastomas comprise 1 to 2% of all malignant neoplasms of childhood, most often occurring in children under 3 years of age. Hepatoblastomas are thought to be derived from undifferentiated hepatocytes (Taniguchi et al., 2002).
Periodic paralysis
MedGen UID:
488958
Concept ID:
C1279412
Disease or Syndrome
Episodes of muscle weakness.
Episodic peripheral neuropathy
MedGen UID:
338523
Concept ID:
C1848695
Finding
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Prolonged partial thromboplastin time
MedGen UID:
66815
Concept ID:
C0240671
Finding
Increased time to coagulation in the partial thromboplastin time (PTT) test, a measure of the intrinsic and common coagulation pathways. Phospholipid, and activator, and calcium are mixed into an anticoagulated plasma sample, and the time is measured until a thrombus forms.
Prolonged prothrombin time
MedGen UID:
208879
Concept ID:
C0853225
Finding
Increased time to coagulation in the prothrombin time test, which is a measure of the extrinsic pathway of coagulation. The results of the prothrombin time test are often expressed in terms of the International normalized ratio (INR), which is calculated as a ratio of the patient's prothrombin time (PT) to a control PT standardized for the potency of the thromboplastin reagent developed by the World Health Organization (WHO) using the formula
Hypophosphatemic rickets
MedGen UID:
309957
Concept ID:
C1704375
Disease or Syndrome
Rickets due to low serum phosphate concentrations, the cause of which can be nutritional or genetic. This condition is characterized by normal parathyroid hormone concentrations, usually caused by renal phosphate wasting occurring in isolation or as part of a renal tubular disorder, and characterized by resistance to treatment with ultraviolet radiation or vitamin D.
Splenomegaly
MedGen UID:
52469
Concept ID:
C0038002
Finding
Abnormal increased size of the spleen.
Fever
MedGen UID:
5169
Concept ID:
C0015967
Sign or Symptom
Body temperature elevated above the normal range.
Hypoglycemia
MedGen UID:
6979
Concept ID:
C0020615
Disease or Syndrome
A decreased concentration of glucose in the blood.
Metabolic acidosis
MedGen UID:
65117
Concept ID:
C0220981
Pathologic Function
Metabolic acidosis (MA) is characterized by a fall in blood pH due to a reduction of serum bicarbonate concentration. This can occur as a result of either the accumulation of acids (high anion gap MA) or the loss of bicarbonate from the gastrointestinal tract or the kidney (hyperchloremic MA). By definition, MA is not due to a respirary cause.
Elevated circulating alpha-fetoprotein concentration
MedGen UID:
65916
Concept ID:
C0235971
Finding
Concentration of alpha-fetoprotein in the blood circulation above the upper limit of normal.
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.
Hypermethioninemia
MedGen UID:
887708
Concept ID:
C4048705
Disease or Syndrome
An increased concentration of methionine in the blood.

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
Halac U, Dubois J, Mitchell GA
Adv Exp Med Biol 2017;959:75-83. doi: 10.1007/978-3-319-55780-9_6. PMID: 28755185

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

Schultz MJ, Netzel BC, Singh RH, Pino GB, Gavrilov DK, Oglesbee D, Raymond KM, Rinaldo P, Tortorelli S, Smith WE, Matern D
Mol Genet Metab 2020 Aug;130(4):247-254. Epub 2020 Jun 6 doi: 10.1016/j.ymgme.2020.06.001. PMID: 32546364
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
van Ginkel WG, Jahja R, Huijbregts SCJ, van Spronsen FJ
Adv Exp Med Biol 2017;959:111-122. doi: 10.1007/978-3-319-55780-9_10. PMID: 28755189
van Ginkel WG, Pennings JP, van Spronsen FJ
Adv Exp Med Biol 2017;959:101-109. doi: 10.1007/978-3-319-55780-9_9. PMID: 28755188
Halac U, Dubois J, Mitchell GA
Adv Exp Med Biol 2017;959:75-83. doi: 10.1007/978-3-319-55780-9_6. PMID: 28755185

Diagnosis

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
van Spronsen FJ, van Rijn M, Meyer U, Das AM
Adv Exp Med Biol 2017;959:197-204. doi: 10.1007/978-3-319-55780-9_18. PMID: 28755197
Halac U, Dubois J, Mitchell GA
Adv Exp Med Biol 2017;959:75-83. doi: 10.1007/978-3-319-55780-9_6. PMID: 28755185
Nakamura K, Matsumoto S, Mitsubuchi H, Endo F
Pediatr Int 2015;57(1):37-40. doi: 10.1111/ped.12550. PMID: 25443793
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

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
van Spronsen FJ, van Rijn M, Meyer U, Das AM
Adv Exp Med Biol 2017;959:197-204. doi: 10.1007/978-3-319-55780-9_18. PMID: 28755197
van Ginkel WG, Jahja R, Huijbregts SCJ, van Spronsen FJ
Adv Exp Med Biol 2017;959:111-122. doi: 10.1007/978-3-319-55780-9_10. PMID: 28755189
van Ginkel WG, Pennings JP, van Spronsen FJ
Adv Exp Med Biol 2017;959:101-109. doi: 10.1007/978-3-319-55780-9_9. PMID: 28755188
Halac U, Dubois J, Mitchell GA
Adv Exp Med Biol 2017;959:75-83. doi: 10.1007/978-3-319-55780-9_6. PMID: 28755185

Prognosis

Giguère Y, Berthier MT
Adv Exp Med Biol 2017;959:139-146. doi: 10.1007/978-3-319-55780-9_13. PMID: 28755192
van Ginkel WG, Pennings JP, van Spronsen FJ
Adv Exp Med Biol 2017;959:101-109. doi: 10.1007/978-3-319-55780-9_9. PMID: 28755188
Halac U, Dubois J, Mitchell GA
Adv Exp Med Biol 2017;959:75-83. doi: 10.1007/978-3-319-55780-9_6. PMID: 28755185
Nakamura K, Matsumoto S, Mitsubuchi H, Endo F
Pediatr Int 2015;57(1):37-40. doi: 10.1111/ped.12550. PMID: 25443793
Holme E, Lindstedt S
Curr Opin Pediatr 1995 Dec;7(6):726-32. doi: 10.1097/00008480-199512000-00017. PMID: 8776026

Clinical prediction guides

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
Halac U, Dubois J, Mitchell GA
Adv Exp Med Biol 2017;959:75-83. doi: 10.1007/978-3-319-55780-9_6. PMID: 28755185
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
Russo PA, Mitchell GA, Tanguay RM
Pediatr Dev Pathol 2001 May-Jun;4(3):212-21. doi: 10.1007/s100240010146. PMID: 11370259

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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