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dioxygenase, but her case remains puzzling and has since been assigned a separate OMIM number. The first typical patient with hepatorenal tyrosinemia was described in 1956 by
Margaret D Baber at Edgware General Hospital in Middlesex, England. Starting the following year, Kiyoshi Sakai and colleagues, at the Jikei University School of Medicine in Tokyo, published 3 reports describing the clinical, biochemical, and pathological findings of a 2-year-old boy with hepatorenal tyrosinemia who was then thought to have an "atypical" case of tyrosinosis. Between 1963 and 1965, Swedish pediatrician Rolf Zetterström and colleagues at the Karolinska Institute in Sweden published the first detailed clinical account of hepatorenal tyrosinemia and its variants. Shortly thereafter, a Canadian group also described the clinical and laboratory findings of hepatorenal tyrosinemia. Both the Scandinavian and Canadian groups suggested that the Japanese patients described earlier by Sakai and colleagues had the same disorder, ie, hepatorenal tyrosinemia. In 1965, doubts emerged that the underlying biochemical cause of hepatorenal tyrosinemia was a defective form of the 4-hydroxyphenylpyruvate dioxygenase enzyme. In 1977, Bengt Lindblad and colleagues at the University of Gothenburg in Sweden demonstrated that the actual defect in causing hepatorenal tyrosinemia involved the fumarylacetoacetate hydrolase enzyme. This was subsequently confirmed using direct enzyme assays.
836:. Patients received amino acid supplements lacking tyrosine and phenylalanine, most often by drinking a specially engineered formula, in order to acquire sufficient protein. It is recommended that tyrosine levels remain below 500 ÎĽmol/L. Phenylalnine is the precursor to tyrosine. The ideology behind maintaining low tyrosine levels is two-fold. Firstly, it prevents the toxic metabolic intermediates from accumulating as a result of the dysfunctional tyrosine metabolic pathway. Prior to the introduction of nitisinone, this was the main treatment measure. Secondly, the mechanism of action of nitisinone is prevention of any tyrosine metabolism, thus it is important to prevent tyrosine from accumulating. Dietary protein consumption while taking nitisinone can also lead to side effects affecting the ocular system, which are easily reversed by removing protein from the diet.
947:
growth of plants and weeds was inhibited under the bottlebrush plant (Callistemon citrinus). It became clear that neither the shade nor the litterfall of these plants was responsible for the suppression of plant and weed growth. Rather, a substance – which was identified as leptospermone – in the soil under the bottlebrush plant was shown to have bleaching activity on the emerging plants. The allelochemical leptospermone was extracted from the bottlebrush plant and chemically characterized. Leptospermone belongs to the triketone family and inhibits chloroplast development due to a lack of plastoquinone secondary to hepatic 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibition; thus, it served as a blueprint for the synthesis of nitisinone.
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752:. Elevated SA levels are not associated with any other known medical condition, so there is minimal risk of misdiagnosis. Quantitation of tyrosine levels is also used as a diagnostic but is less reliable due to high false positive and false negative rates. Newborns are not generally screened for HT1 due to rarity of the condition and lack of apparent symptoms at time of birth. However, prompt assessment upon the manifestation of physical symptoms such as
845:
530:
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Nitisinone was first used to clinically treat tyrosinemia type I in 1991. Nitisinone was approved by the
European Medicine Agency (EMA) under exceptional circumstances in 2005. Originally, nitisinone was developed as a weed-killer by Zeneca Agrochemicals. It was epidemiologically observed that the
897:
Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1. A study regarding the efficacy of treatment with nitisinone and dietary restrictions found that 93% of people survived at two years, four years, and six years indicating
918:
in Quebec is believed to be due to reduced genetic heterogeneity within the original founder population for the
Saguenay-Lac Saint-Jean region. The initial settlement of Saguenay Lac-Saint-Jean (SLSJ) occurred between 1838 and 1911. From a total of 28,656 settlers, 75 percent originated from the
880:
in dose increments of 2 mg, 5 mg, 10 mg, or 20 mg or 4 mg/mL respectively. The starting dose is 1 mg/kg one time daily or 2 mg/kg one time daily for 48 hours if the patient is experiencing acute liver failure. Patient responsiveness to nitisinone is assessed by
488:
Many patients display impaired kidney function and neurological symptoms. In addition to liver cells, kidney cell expression involves expression of the gene for FAH. Kidney failure is a potential result of impaired kidney function, but the most common symptom associated with renal dysfunction is
206:
are associated with the clinical presentation of the disease. If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of
954:
first described "a new disorder of tyrosine metabolism," She coined the condition "tyrosinosis" after observing 4-hydroxyphenylpyruvate in the urine of a 49-year-old man with myasthenia gravis. She proposed that the metabolic defect in this patient was a deficiency of 4-hydroxyphenylpyruvate
1439:
Lock EA, Ellis MK, Gaskin P, Robinson M, Auton TR, Provan WM, et al. (August 1998). "From toxicological problem to therapeutic use: the discovery of the mode of action of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), its toxicology and development as a drug".
296:) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs. Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1.
613:
Fumarylacetoacetate hydrolase (FAH) is the final enzyme in the tyrosine metabolic pathway. The mutation of FAH enzyme results in nonfunctional FAH in all cells expressing this gene and thus metabolizing tyrosine is impaired. FAH catalyzes the conversion of
871:
as the second enzymatic reaction in the tyrosine catabolic pathway. This prevents the further catabolism of tyrosine. It is recommended that nitisinone treatment begins immediately following a confirmed or suspected case of HT1. It is supplied orally as a
792:, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.
588:. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems.
451:
The liver is the organ affected most by
Tyrosinemia Type I due to the high level of expression of the gene for fumarylacetoacetate hydrolase (FAH) in liver cells. The production of blood coagulation factors by the liver is disrupted, causing
608:
Tyrosine metabolic pathway. Fumarylacetoacetate hydrolase (FAH) is shown to be nonfunctional, leading to the accumulation of maleylacetoacetate (MAA) and succinylacetoacetate (SAA), the later of which is converted to succinylacetone
815:
are used in combination as therapeutic measures that control the disease state if they are continued indefinitely. If not, there is a lack of control over the disease, resulting in continued liver and kidney damage, contributing to
1258:"Clinical Review Report: Nitisinone (Orfadin): (Sobi Canada Inc.): Indication: For the treatment of patients with hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine"
327:. The primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This can lead to
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in these tissues which ultimately results in organ failure. Accumulated SA in liver and kidney cells results in its release into the bloodstream, which leads to secondary effects. SA inhibits the enzyme
419:
The final classification, chronic HT1, is detected with presentations occurring after one year of life. The course of the disease up to this point can lead to different ailments affecting the liver.
1205:
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within 24–48 hours of first dose. Establishment of the long-term dosage will vary from patient to patient. It is recommended that nitisinone levels be maintained at 30-50 μM in the blood stream.
1338:
Thimm E, Richter-Werkle R, Kamp G, Molke B, Herebian D, Klee D, et al. (March 2012). "Neurocognitive outcome in patients with hypertyrosinemia type I after long-term treatment with NTBC".
343:: Renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The urine has an odor of cabbage or rancid butter.
584:
and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and
1014:
As of April 2020, two new clinical trials, are underway in the USA for a Mass
Spectrometry-based biomarker for the early and sensitive diagnosis of Tyrosinemia type 1 from blood plasma.
744:
Beyond the identification of physical clinical symptoms outlined above, the definitive criterion for diagnostic assessment of
Tyrosinemia Type I is elevated succinylacetone (SA) in
906:
Tyrosinemia type I affects males and females in equal numbers. Its prevalence has been estimated to be 1 in 100,000 to 120,000 births worldwide. HT1 is especially prevalent in the
737:
315:. There are five other known types of tyrosinemia, all of which derange the metabolism of tyrosine in the human body. They are distinguished by their symptoms and genetic cause.
1007:
symptom of type 1 tyrosinemia in mice. Since human type 1 tyrosinemia is caused by a similar mutation in the same gene, this finding sets a precedent for further research into
1613:
Yin, Hao; Xue, Wen; Chen, Sidi; Bogorad, Roman L.; Benedetti, Eric; Grompe, Markus; Koteliansky, Victor; Sharp, Phillip A.; Jacks, Tyler; Anderson, Daniel G. (March 2014).
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is prescribed ultimately to reduce the accumulation of toxic metabolic intermediates, such as succinylacetate, which are toxic to cells. It modifies the function of
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damaging cell components. Over time, the combined effect of accumulation of toxic metabolic intermediates and elevated ROS levels in liver and kidney cells leads to
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region. The settling of the
Charlevoix region itself started in 1675 when 599 founders of mostly French descent moved to this region from the Quebec City area.
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Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence in
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824:. In this case, a liver transplant may be required. Levels of SA are monitored throughout treatment in order to assess treatment effectiveness.
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The acute classification typically is presented clinically between birth and 6 months of age. The common presentation in an acute case is
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1946:
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The presentation of symptoms of tyrosinemia type 1 in terms of timing is broken into three categories: acute, sub-acute, and chronic.
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Chakrapani A, Holme E (2006). "Disorders of
Tyrosine Metabolism". In Fernandes J, Saudubray JM, van den Berghe G, Walter JH (eds.).
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is lessened to an extent. Again, synthetic function of the liver in terms of blood coagulation factors is impaired in addition to
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are inherited from both parents. The genetic mutation occurs to the fumarylacetoacetate hydrolase (FAH) enzyme gene, located on
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in areas affected by this scarring of liver tissue. These scars are known as nodules. There is a 37% chance of developing a
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and restriction of tyrosine in the diet. Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by
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prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible.
245:. It is expressed primarily in the liver and kidney. Loss of FAH activity results in the accumulation of certain
2029:
510:
1509:"A single mutation of the fumarylacetoacetate hydrolase gene in French Canadians with hereditary tyrosinemia type I"
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685:, leading to the acute neurological crises experienced by some patients. Additionally. SA can function to inhibit
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712:. Tyrosine is a precursor molecule required for synthesis of several neurotransmitters and hormones, mainly
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may present as a result of chronic liver disease. Additional symptoms common in this classification include
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1951:
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626:. Loss of FAH results in the accumulation of upstream compounds in the catabolic pathway. These include
493:. Neurological manifestations are characterized by acute neurological crises due to overaccumulation of
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501:. They typically follow an infection. Patients can present with a variety of varied symptoms including
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Pathophysiology of metabolic disorders of tyrosine, resulting in elevated levels of tyrosine in blood.
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2504:
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1961:
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de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, et al. (January 2013).
724:. Excessive synthesis of these molecules due to elevated tyrosine levels can impair physical growth,
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1908:
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itself in the blood stream as a consequence of deficient catabolism can also lead to disruption of
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580:- fumarylacetoacetate to fumarate, acetoacetate and succinate. Fumarylacetoacetate accumulates in
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336:
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12. A second allele is the IVS6-1(G-T) mutation. This mutation results in a nonfunctional enzyme.
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While there is no cure for tyrosinemia type I, management of the disease is possible utilizing
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is utilized indefinitely once a diagnosis is suspected or confirmed. Additionally, the drug
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1390:"Clinical utility of nitisinone for the treatment of hereditary tyrosinemia type-1 (HT-1)"
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456:. Acute liver failure is common, especially in early life. Additionally, the synthesis of
8:
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as their growth is limited by the disease. This growth impairment can manifest itself in
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Sub-acute cases present between 6 months and the first year of life and the severity of
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Mutation of enzyme fumarylacetoacetate hydrolase (FAH) in the tyrosine catabolic pathway
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is one in 1,850 births. The elevated frequency of this disorder within individuals of
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Grompe M, St-Louis M, Demers SI, al-Dhalimy M, Leclerc B, Tanguay RM (August 1994).
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1615:"Genome editing with Cas9 in adult mice corrects a disease mutation and phenotype"
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307:, where the prevalence is 1 in 1,850 births. It is most common among those with
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Fumarylacetoacetate hydrolase catalyzes the final step in the degradation of
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1264:. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health. 2018.
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1206:"Diagnosing Inborn Errors of Metabolism in the Newborn: Clinical Features"
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553:. The most common mutation is IVS12+5(G->A) which is a mutation in the
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Type 1 tyrosinemia typically presents in infancy as failure to thrive and
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in response to this pain. Episodes can last for 1–7 days and can lead to
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The accumulation of MAA, FAA, and SA in cells inhibits the breakdown of
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681:. Consequently, porphyrin deposits form in the bloodstream and cause
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region of Quebec, type 1 tyrosinemia affects 1 person in 1,846. The
656:. This inhibits the antioxidant activity of glutathione, leading to
533:
Tyrosinemia type I has an autosomal recessive pattern of inheritance
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2003:
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Type 1 tyrosinemia is inherited in an autosomal recessive pattern.
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onset of symptoms, earlier being more severe. If diagnosed through
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799:. Nitisinone and dietary restrictions that decrease the amount of
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2007:
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in high concentrations. HT1 is diagnosed when elevated levels of
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Paradis K (October 1996). "Tyrosinemia: the Quebec experience".
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the prognosis of stabilizing the HT1 disease state is positive.
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361:. Patients are prone to infections at this stage accompanied by
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265:(SA), one of the metabolites in this pathway, is detected in
233:. FAH is a metabolic enzyme that catalyzes the conversion of
167:
1337:
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and SA levels in blood and urine. Patients should display a
863:. 4-hydrooxyphenylpyruvate dioxygenase functions to convert
311:
and this frequency of infliction has been attributed to the
75:
Failure to thrive, enlarged liver, fever, vomiting, diarrhea
1058:"Recommendations for the management of tyrosinaemia type 1"
984:
975:
of human type I tyrosinemia. The study found that a single
938:
rate has been estimated to be between 1 in 20 and 1 in 31.
795:
Clinical treatment of HT1 relies on medications and strict
690:
562:
546:
223:
1868:
1550:"Genetic aspects of tyrosinemia in the Chicoutimi region"
483:
1438:
117:
Dietary restrictions, Nitisinone, liver transplantation
1315:"Tyrosine - structure, properties, function, benefits"
649:, leading to post-translational modifications to the
109:
Dried blood spot testing, urinalysis, genetic testing
1727:
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in the liver may be defective, therefore leading to
335:
and hemorrhage. There is also an increased risk of
145:
1 in 1,850 (Saguenay-Lac Saint-Jean region, Quebec)
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299:Tyrosinemia type I is especially prevalent in the
2001:
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1111:
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253:. These compounds are toxic to cells and lead to
2642:
784:The primary treatment for type 1 tyrosinemia is
83:Variable, usually with the first 2 years of life
1942:3-hydroxy-3-methylglutaryl-CoA lyase deficiency
1715:NORD (National Organization for Rare Disorders)
1547:
1488:NORD (National Organization for Rare Disorders)
1141:
1051:
1049:
1047:
776:is critical for improving long term prognosis.
2328:6-Pyruvoyltetrahydropterin synthase deficiency
1100:
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1041:
1039:
1037:
1035:
1033:
1031:
1029:
1027:
1854:
599:
137:93% survival rate at six years with treatment
2212:2-Methylbutyryl-CoA dehydrogenase deficiency
832:The prescribed diet for treatment of HT1 is
2510:Carbamoyl phosphate synthetase I deficiency
1947:3-Methylcrotonyl-CoA carboxylase deficiency
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1203:
1024:
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1383:
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1415:
1405:
1287:"Physician's Guide to Tyrosinemia Type 1"
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963:In March 2014, a study successfully used
930:is about 1 in 16,000 individuals. In the
1294:National Organization for Rare Disorders
843:
735:
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2189:Isobutyryl-CoA dehydrogenase deficiency
1541:
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1242:
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995:cured enough hepatocytes of a FAH gene
166:, resulting in damage primarily to the
14:
2643:
2015:
1548:Laberge C, Dallaire L (October 1967).
1442:Journal of Inherited Metabolic Disease
1340:Journal of Inherited Metabolic Disease
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1279:
958:
2525:Ornithine transcarbamylase deficiency
2520:N-Acetylglutamate synthase deficiency
1842:
1690:
484:Renal and neurological manifestations
353:, marked by the lack of formation of
318:
2442:Dopamine beta hydroxylase deficiency
1554:Canadian Medical Association Journal
1394:The Application of Clinical Genetics
1239:
967:to correct the FAH gene mutation in
857:4-hydrooxyphenylpyruvate dioxygenase
497:. These crises are characterized by
339:.The kidney dysfunction presents as
2278:Methylmalonyl-CoA mutase deficiency
1513:The New England Journal of Medicine
1387:
1276:
1197:
1179:Clinical and Investigative Medicine
790:4-Hydroxyphenylpyruvate dioxygenase
416:, which is the softening of bones.
406:enlargement of the liver and spleen
231:fumarylacetoacetate hydrolase (FAH)
24:
571:
41:Hereditary Tyrosinemia type I, HT1
25:
2672:
2030:Glutathione synthetase deficiency
1684:
1062:Orphanet Journal of Rare Diseases
65:Hepatology, nephrology, neurology
700:The accumulation of unprocessed
408:. The infant may also display a
2651:Amino acid metabolism disorders
1662:
1582:
1500:
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1432:
901:
634:. MAA and FAA are converted to
2333:Tetrahydrobiopterin deficiency
1331:
1307:
1170:
1148:. Springer. pp. 233–243.
555:splice site consensus sequence
478:hepatocellular carcinoma (HCC)
468:is common. This can lead to a
301:Saguenay-Lac Saint-Jean region
13:
1:
2656:Autosomal recessive disorders
2578:Lysinuric protein intolerance
1952:3-Methylglutaconic aciduria 1
1670:"Tyrosinemia Clinical Trials"
1017:
839:
779:
658:reactive oxygen species (ROS)
638:which is then catabolized to
539:autosomal recessive inherited
464:. As the disease progresses,
284:. A diet low in tyrosine and
99:Genetic (autosomal recessive)
2217:Beta-ketothiolase deficiency
1154:10.1007/978-3-540-28785-8_18
892:
731:
255:differential gene expression
178:. The inability of cells to
7:
2620:Ethylmalonic encephalopathy
1526:10.1056/NEJM199408113310603
1204:Enns GM, Packman S (2001).
671:aminolevulinic acid (5-ALA)
524:
10:
2677:
2610:2-Hydroxyglutaric aciduria
2589:Oculocerebrorenal syndrome
1691:Reference, Genetics Home.
941:
883:blood coagulation activity
728:, and speech development.
636:succinylacetoacetate (SAA)
600:Tyrosine metabolic pathway
2615:Aminoacylase 1 deficiency
2602:
2544:
2505:Argininosuccinic aciduria
2474:
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2428:
2414:Hermansky–Pudlak syndrome
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2222:Maple syrup urine disease
2202:
2194:Maple syrup urine disease
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2110:
2082:
2067:
1992:
1970:
1962:Maple syrup urine disease
1932:
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1880:
1812:
1731:
1590:"Hepatorenal Tyrosinemia"
1352:10.1007/s10545-011-9394-5
1262:CADTH Common Drug Reviews
1145:Inborn Metabolic Diseases
632:fumarylacetoacetate (FAA)
537:Tyrosinemia type I is an
454:hemophiliac-like symptoms
441:acute neurological crises
385:. Other symptoms include
214:Tyrosinemia type I is an
141:
131:
121:
113:
103:
95:
87:
79:
69:
59:
54:
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37:
32:
1904:Glutaric acidemia type 1
916:French-Canadian ancestry
760:, increased tendency to
628:maleylacetoacetate (MAA)
561:12, therefore affecting
491:hypophosphatemic rickets
480:for untreated patients.
446:
369:, increased tendency to
337:hepatocellular carcinoma
309:French-Canadian ancestry
2410:Oculocutaneous albinism
1697:Genetics Home Reference
1454:10.1023/a:1005458703363
932:Saguenay-Lac-Saint-Jean
908:Saguenay-Lac Saint-Jean
865:4-hydroxyphenylpyruvate
827:
351:synthetic liver failure
247:metabolic intermediates
2529:translocase deficiency
2273:Methylmalonic acidemia
2055:Glycine encephalopathy
977:hydrodynamic injection
849:
741:
687:renal tubular function
610:
596:
534:
395:excess abdominal fluid
222:in both copies of the
2559:Solute carrier family
1874:amino acid metabolism
1388:Das AM (2017-07-24).
1075:10.1186/1750-1172-8-8
993:ssDNA repair template
861:competitive inhibitor
847:
739:
607:
594:
532:
511:pain-induced seizures
474:development of tumors
381:as manifestations of
182:tyrosine can lead to
2420:Waardenburg syndrome
2370:Tyrosinemia type III
2125:Prolidase deficiency
1711:"Tyrosinemia Type 1"
1619:Nature Biotechnology
1484:"Tyrosinemia Type 1"
1407:10.2147/TACG.S113310
1225:10.1542/neo.2-8-e183
1011:treatments for HT1.
640:succinylacetone (SA)
513:, and can result in
278:dietary restrictions
184:chronic liver damage
2625:Fumarase deficiency
2365:Tyrosinemia type II
2025:D-Glyceric acidemia
1980:Hypertryptophanemia
1957:Isovaleric acidemia
1319:aminoacidsguide.com
965:CRISPR gene editing
959:Research directions
616:fumarylacetoacetate
429:cancer of the liver
355:coagulation factors
235:fumarylacetoacetate
218:disorder caused by
216:autosomal recessive
198:. Symptoms such as
2360:Tyrosinemia type I
2283:Propionic acidemia
2250:Hypermethioninemia
1919:Pipecolic acidemia
1813:External resources
850:
807:absorbed from the
797:regulation of diet
742:
706:hormonal signaling
611:
597:
541:condition. Mutant
535:
319:Signs and symptoms
162:of the amino acid
158:that disrupts the
152:Tyrosinemia type I
33:Tyrosinemia type I
2638:
2637:
2630:Trimethylaminuria
2540:
2539:
2536:
2535:
2460:
2459:
2456:
2455:
2291:
2290:
2155:
2154:
2102:Urocanic aciduria
2063:
2062:
1988:
1987:
1836:
1835:
1594:MedLink Neurology
1163:978-3-540-28785-8
887:positive response
710:neurotransmission
691:synthesis of heme
677:, a precursor to
667:5-ALA dehydratase
647:thiol derivatives
410:failure to thrive
251:catabolic pathway
209:newborn screening
176:peripheral nerves
149:
148:
105:Diagnostic method
27:Medical condition
16:(Redirected from
2668:
2585:Fanconi syndrome
2472:
2471:
2448:Brunner syndrome
2316:
2315:
2303:
2302:
2240:Cystathioninuria
2172:
2171:
2080:
2079:
2013:
2012:
1999:
1998:
1891:
1890:
1863:
1856:
1849:
1840:
1839:
1729:
1728:
1724:
1722:
1721:
1706:
1704:
1703:
1678:
1677:
1666:
1660:
1659:
1657:
1655:
1642:
1631:10.1038/nbt.2884
1610:
1604:
1603:
1601:
1600:
1586:
1580:
1579:
1569:
1560:(18): 1099–101.
1545:
1539:
1538:
1528:
1504:
1498:
1497:
1495:
1494:
1480:
1474:
1473:
1436:
1430:
1429:
1419:
1409:
1385:
1372:
1371:
1335:
1329:
1328:
1326:
1325:
1311:
1305:
1304:
1302:
1296:. Archived from
1291:
1283:
1274:
1273:
1254:
1237:
1236:
1219:(8): e183–e191.
1210:
1201:
1195:
1194:
1174:
1168:
1167:
1139:
1098:
1097:
1087:
1077:
1053:
683:neuropathic pain
341:Fanconi syndrome
249:in the tyrosine
156:genetic disorder
50:
30:
29:
21:
2676:
2675:
2671:
2670:
2669:
2667:
2666:
2665:
2641:
2640:
2639:
2634:
2598:
2573:Iminoglycinuria
2568:Hartnup disease
2549:
2532:
2482:
2452:
2424:
2400:Ocular albinism
2378:
2337:
2320:Phenylketonuria
2287:
2254:
2226:
2198:
2165:
2151:
2129:
2120:Hyperprolinemia
2106:
2075:α-ketoglutarate
2073:
2059:
2050:GAMT deficiency
1984:
1966:
1928:
1924:Saccharopinuria
1897:/straight chain
1876:
1867:
1837:
1832:
1831:
1808:
1807:
1740:
1719:
1717:
1709:
1701:
1699:
1687:
1682:
1681:
1674:wcg CenterWatch
1668:
1667:
1663:
1653:
1651:
1611:
1607:
1598:
1596:
1588:
1587:
1583:
1546:
1542:
1505:
1501:
1492:
1490:
1482:
1481:
1477:
1437:
1433:
1386:
1375:
1336:
1332:
1323:
1321:
1313:
1312:
1308:
1300:
1289:
1285:
1284:
1277:
1256:
1255:
1240:
1208:
1202:
1198:
1175:
1171:
1164:
1140:
1101:
1054:
1025:
1020:
991:, along with a
961:
944:
904:
895:
859:by acting as a
842:
830:
811:during protein
782:
734:
675:porphobilinogen
669:which converts
602:
586:gluconeogenesis
574:
572:Pathophysiology
527:
515:self-mutilation
486:
462:hypoalbuminemia
449:
321:
263:succinylacetone
170:along with the
28:
23:
22:
15:
12:
11:
5:
2674:
2664:
2663:
2658:
2653:
2636:
2635:
2633:
2632:
2627:
2622:
2617:
2612:
2606:
2604:
2600:
2599:
2597:
2596:
2591:
2581:
2580:
2575:
2570:
2565:
2555:
2553:
2542:
2541:
2538:
2537:
2534:
2533:
2531:
2522:
2517:
2512:
2507:
2502:
2497:
2495:
2494:
2493:
2480:Hyperammonemia
2469:
2462:
2461:
2458:
2457:
2454:
2453:
2451:
2450:
2444:
2438:
2436:
2434:Norepinephrine
2426:
2425:
2423:
2422:
2417:
2407:
2392:
2390:
2380:
2379:
2377:
2376:
2367:
2362:
2357:
2347:
2345:
2339:
2338:
2336:
2335:
2330:
2324:
2322:
2313:
2300:
2293:
2292:
2289:
2288:
2286:
2285:
2280:
2275:
2269:
2267:
2256:
2255:
2253:
2252:
2247:
2245:Homocystinuria
2242:
2236:
2234:
2228:
2227:
2225:
2224:
2219:
2214:
2208:
2206:
2200:
2199:
2197:
2196:
2191:
2186:
2184:Hypervalinemia
2180:
2178:
2169:
2157:
2156:
2153:
2152:
2150:
2149:
2143:
2141:
2131:
2130:
2128:
2127:
2122:
2116:
2114:
2108:
2107:
2105:
2104:
2099:
2094:
2088:
2086:
2077:
2065:
2064:
2061:
2060:
2058:
2057:
2052:
2038:
2037:
2032:
2027:
2021:
2019:
2010:
1996:
1990:
1989:
1986:
1985:
1983:
1982:
1976:
1974:
1968:
1967:
1965:
1964:
1959:
1954:
1949:
1944:
1938:
1936:
1930:
1929:
1927:
1926:
1921:
1916:
1914:Hyperlysinemia
1911:
1906:
1900:
1898:
1888:
1878:
1877:
1866:
1865:
1858:
1851:
1843:
1834:
1833:
1830:
1829:
1817:
1816:
1814:
1810:
1809:
1806:
1805:
1794:
1783:
1772:
1757:
1741:
1736:
1735:
1733:
1732:Classification
1726:
1725:
1707:
1686:
1685:External links
1683:
1680:
1679:
1661:
1625:(6): 551–553.
1605:
1581:
1540:
1499:
1475:
1448:(5): 498–506.
1431:
1373:
1330:
1306:
1303:on 2014-02-11.
1275:
1238:
1196:
1169:
1162:
1099:
1022:
1021:
1019:
1016:
1001:wild-type gene
960:
957:
943:
940:
903:
900:
894:
891:
841:
838:
834:low in protein
829:
826:
781:
778:
733:
730:
726:motor function
718:norepinephrine
601:
598:
573:
570:
526:
523:
507:abdominal pain
485:
482:
448:
445:
433:cardiomyopathy
387:enlarged liver
320:
317:
313:founder effect
204:enlarged liver
147:
146:
143:
139:
138:
135:
129:
128:
125:
119:
118:
115:
111:
110:
107:
101:
100:
97:
93:
92:
89:
85:
84:
81:
77:
76:
73:
67:
66:
63:
57:
56:
52:
51:
43:
42:
39:
35:
34:
26:
9:
6:
4:
3:
2:
2673:
2662:
2661:Rare diseases
2659:
2657:
2654:
2652:
2649:
2648:
2646:
2631:
2628:
2626:
2623:
2621:
2618:
2616:
2613:
2611:
2608:
2607:
2605:
2601:
2595:
2592:
2590:
2586:
2583:
2582:
2579:
2576:
2574:
2571:
2569:
2566:
2564:
2560:
2557:
2556:
2554:
2552:
2547:
2543:
2530:
2526:
2523:
2521:
2518:
2516:
2515:Citrullinemia
2513:
2511:
2508:
2506:
2503:
2501:
2498:
2496:
2491:
2488:
2487:
2486:
2481:
2477:
2473:
2470:
2468:
2463:
2449:
2445:
2443:
2440:
2439:
2437:
2435:
2431:
2427:
2421:
2418:
2415:
2411:
2408:
2405:
2401:
2397:
2394:
2393:
2391:
2389:
2385:
2381:
2375:
2374:Hawkinsinuria
2371:
2368:
2366:
2363:
2361:
2358:
2356:
2352:
2349:
2348:
2346:
2344:
2340:
2334:
2331:
2329:
2326:
2325:
2323:
2321:
2317:
2314:
2312:
2308:
2307:Phenylalanine
2304:
2301:
2299:
2294:
2284:
2281:
2279:
2276:
2274:
2271:
2270:
2268:
2266:
2262:
2257:
2251:
2248:
2246:
2243:
2241:
2238:
2237:
2235:
2233:
2229:
2223:
2220:
2218:
2215:
2213:
2210:
2209:
2207:
2205:
2201:
2195:
2192:
2190:
2187:
2185:
2182:
2181:
2179:
2177:
2173:
2170:
2168:
2163:
2162:propionyl-CoA
2158:
2148:
2145:
2144:
2142:
2140:
2136:
2132:
2126:
2123:
2121:
2118:
2117:
2115:
2113:
2109:
2103:
2100:
2098:
2095:
2093:
2090:
2089:
2087:
2085:
2081:
2078:
2076:
2071:
2066:
2056:
2053:
2051:
2047:
2043:
2040:
2039:
2036:
2033:
2031:
2028:
2026:
2023:
2022:
2020:
2018:
2014:
2011:
2009:
2005:
2000:
1997:
1995:
1991:
1981:
1978:
1977:
1975:
1973:
1969:
1963:
1960:
1958:
1955:
1953:
1950:
1948:
1945:
1943:
1940:
1939:
1937:
1935:
1931:
1925:
1922:
1920:
1917:
1915:
1912:
1910:
1907:
1905:
1902:
1901:
1899:
1896:
1892:
1889:
1887:
1883:
1879:
1875:
1871:
1864:
1859:
1857:
1852:
1850:
1845:
1844:
1841:
1828:
1824:
1823:
1819:
1818:
1815:
1811:
1804:
1800:
1799:
1795:
1793:
1789:
1788:
1784:
1782:
1778:
1777:
1773:
1771:
1767:
1766:
1762:
1758:
1756:
1752:
1751:
1747:
1743:
1742:
1739:
1734:
1730:
1716:
1712:
1708:
1698:
1694:
1693:"Tyrosinemia"
1689:
1688:
1675:
1671:
1665:
1650:
1646:
1641:
1636:
1632:
1628:
1624:
1620:
1616:
1609:
1595:
1591:
1585:
1577:
1573:
1568:
1563:
1559:
1555:
1551:
1544:
1536:
1532:
1527:
1522:
1518:
1514:
1510:
1503:
1489:
1485:
1479:
1471:
1467:
1463:
1459:
1455:
1451:
1447:
1443:
1435:
1427:
1423:
1418:
1413:
1408:
1403:
1399:
1395:
1391:
1384:
1382:
1380:
1378:
1369:
1365:
1361:
1357:
1353:
1349:
1345:
1341:
1334:
1320:
1316:
1310:
1299:
1295:
1288:
1282:
1280:
1271:
1267:
1263:
1259:
1253:
1251:
1249:
1247:
1245:
1243:
1234:
1230:
1226:
1222:
1218:
1214:
1207:
1200:
1192:
1188:
1184:
1180:
1173:
1165:
1159:
1155:
1151:
1147:
1146:
1138:
1136:
1134:
1132:
1130:
1128:
1126:
1124:
1122:
1120:
1118:
1116:
1114:
1112:
1110:
1108:
1106:
1104:
1095:
1091:
1086:
1081:
1076:
1071:
1067:
1063:
1059:
1052:
1050:
1048:
1046:
1044:
1042:
1040:
1038:
1036:
1034:
1032:
1030:
1028:
1023:
1015:
1012:
1010:
1006:
1002:
998:
994:
990:
986:
982:
978:
974:
970:
966:
956:
953:
948:
939:
937:
933:
929:
924:
922:
917:
913:
909:
899:
890:
888:
884:
879:
875:
870:
869:homogentisate
866:
862:
858:
854:
846:
837:
835:
825:
823:
819:
818:organ failure
814:
810:
806:
802:
798:
793:
791:
787:
777:
775:
771:
767:
763:
759:
755:
751:
747:
738:
729:
727:
723:
719:
715:
711:
707:
703:
698:
696:
695:immune system
692:
688:
684:
680:
676:
672:
668:
663:
659:
655:
652:
648:
643:
641:
637:
633:
629:
625:
621:
617:
606:
593:
589:
587:
583:
579:
569:
566:
564:
560:
556:
552:
551:chromosome 15
548:
544:
540:
531:
522:
520:
516:
512:
508:
504:
500:
496:
492:
481:
479:
475:
471:
467:
463:
459:
455:
444:
442:
438:
437:renal disease
434:
430:
426:
425:liver failure
422:
417:
415:
411:
407:
403:
402:liver disease
398:
396:
392:
388:
384:
380:
376:
372:
368:
364:
360:
356:
352:
347:
344:
342:
338:
334:
330:
326:
316:
314:
310:
306:
302:
297:
295:
291:
287:
286:phenylalanine
283:
279:
274:
272:
271:urine samples
268:
264:
260:
256:
252:
248:
244:
240:
236:
232:
229:
226:encoding the
225:
221:
217:
212:
210:
205:
201:
197:
193:
192:renal disease
190:, as well as
189:
188:liver failure
185:
181:
177:
173:
169:
165:
161:
157:
153:
144:
140:
136:
134:
130:
126:
124:
120:
116:
112:
108:
106:
102:
98:
94:
90:
86:
82:
78:
74:
72:
68:
64:
62:
58:
53:
49:
44:
40:
36:
31:
19:
2467:oxaloacetate
2359:
2351:Alkaptonuria
2167:succinyl-CoA
2097:Histidinemia
2092:Carnosinemia
2035:Sarcosinemia
1870:Inborn error
1820:
1796:
1785:
1774:
1759:
1744:
1718:. Retrieved
1714:
1700:. Retrieved
1696:
1673:
1664:
1652:. Retrieved
1640:1721.1/97197
1622:
1618:
1608:
1597:. Retrieved
1593:
1584:
1557:
1553:
1543:
1519:(6): 353–7.
1516:
1512:
1502:
1491:. Retrieved
1487:
1478:
1445:
1441:
1434:
1397:
1393:
1346:(2): 263–8.
1343:
1339:
1333:
1322:. Retrieved
1318:
1309:
1298:the original
1293:
1261:
1216:
1212:
1199:
1185:(5): 311–6.
1182:
1178:
1172:
1144:
1065:
1061:
1013:
1009:gene editing
1003:to cure the
962:
949:
945:
925:
919:neighboring
905:
902:Epidemiology
896:
851:
831:
805:phenylalaine
794:
783:
770:bloody feces
743:
699:
644:
624:acetoacetate
612:
575:
567:
536:
503:paresthesias
487:
450:
418:
399:
379:bloody feces
348:
345:
325:hepatomegaly
322:
298:
292:(brand name
275:
243:acetoacetate
213:
151:
150:
2500:Argininemia
2343:Tyrosinemia
1005:weight-loss
983:, encoding
981:DNA plasmid
973:mouse model
969:hepatocytes
952:Grace Medes
768:along with
654:glutathione
651:antioxidant
582:hepatocytes
470:fatty liver
377:along with
282:medications
200:poor growth
80:Usual onset
38:Other names
18:Tyrosinosis
2645:Categories
2594:Cystinosis
2563:Cystinuria
2476:Urea cycle
2355:Ochronosis
2232:Methionine
2204:Isoleucine
1972:Tryptophan
1886:acetyl-CoA
1798:DiseasesDB
1720:2020-05-01
1702:2020-05-01
1599:2020-05-01
1493:2020-05-01
1324:2020-05-02
1213:NeoReviews
1018:References
921:Charlevoix
910:region of
881:measuring
878:suspension
853:Nitisinone
848:Nitisinone
840:Medication
786:nitisinone
780:Management
693:, and the
519:neuropathy
290:nitisinone
186:ending in
160:metabolism
127:Nitisinone
123:Medication
2551:IE of RTT
2546:Transport
2490:aspartate
2446:reverse:
2139:glutamine
2135:Glutamate
2084:Histidine
2070:glutamate
1822:eMedicine
1654:3 October
1649:1546-1696
1400:: 43–48.
1233:1526-9906
950:In 1932,
893:Prognosis
813:digestion
732:Diagnosis
722:thryoxine
679:porphyrin
662:apoptosis
499:porphyria
495:porphyrin
466:cirrhosis
421:Cirrhosis
259:apoptosis
220:mutations
142:Frequency
133:Prognosis
114:Treatment
61:Specialty
2485:arginine
2430:Tyrosine
2396:Albinism
2384:Tyrosine
2311:tyrosine
2298:fumarate
2259:General
2046:Creatine
2004:pyruvate
1827:ped/2339
1426:28769581
1368:23783926
1360:22069142
1270:30457777
1094:23311542
809:GI tract
801:tyrosine
774:jaundice
766:diarrhea
758:vomiting
740:Tyrosine
714:Dopamine
702:tyrosine
620:fumarate
578:tyrosine
525:Genetics
472:and the
391:jaundice
375:diarrhea
367:vomiting
329:jaundice
239:fumarate
164:tyrosine
91:Lifelong
88:Duration
71:Symptoms
2388:Melanin
2112:Proline
2042:Glycine
2017:Glycine
2008:citrate
1934:Leucine
1792:D020176
1576:6057677
1567:1923580
1535:8028615
1470:6717818
1462:9728330
1417:5533484
1191:8889268
1085:3558375
999:to the
942:History
936:carrier
874:capsule
545:in the
543:alleles
458:albumin
414:rickets
333:ascites
294:Orfadin
196:rickets
180:process
172:kidneys
2176:Valine
2147:SSADHD
1909:type 2
1895:Lysine
1781:276700
1647:
1574:
1564:
1533:
1468:
1460:
1424:
1414:
1366:
1358:
1268:
1231:
1189:
1160:
1092:
1082:
987:and a
928:Quebec
912:Quebec
772:, and
720:, and
689:, the
559:intron
439:, and
393:, and
383:sepsis
373:, and
305:Quebec
228:enzyme
96:Causes
2603:Other
1803:13478
1770:270.2
1755:E70.2
1466:S2CID
1364:S2CID
1301:(PDF)
1290:(PDF)
1209:(PDF)
1068:: 8.
989:sgRNA
979:of a
971:in a
822:death
762:bleed
754:fever
750:urine
746:blood
673:into
609:(SA).
447:Liver
427:, or
371:bleed
363:fever
359:blood
267:blood
168:liver
154:is a
1787:MeSH
1776:OMIM
1765:9-CM
1656:2023
1645:ISSN
1572:PMID
1531:PMID
1458:PMID
1422:PMID
1356:PMID
1266:PMID
1229:ISSN
1187:PMID
1158:ISBN
1090:PMID
985:Cas9
828:Diet
820:and
803:and
748:and
708:and
630:and
622:and
563:exon
547:gene
280:and
269:and
257:and
241:and
224:gene
202:and
194:and
174:and
1872:of
1761:ICD
1746:ICD
1635:hdl
1627:doi
1562:PMC
1521:doi
1517:331
1450:doi
1412:PMC
1402:doi
1348:doi
1221:doi
1150:doi
1080:PMC
1070:doi
997:SNP
876:or
867:to
618:to
557:of
357:in
303:of
237:to
2647::
2587::
2561::
2465:G→
2398::
2296:G→
2265:OA
2261:BC
2160:G→
2068:G→
2048::
2002:G→
1825::
1801::
1790::
1779::
1768::
1753::
1750:10
1713:.
1695:.
1672:.
1643:.
1633:.
1623:32
1621:.
1617:.
1592:.
1570:.
1558:97
1556:.
1552:.
1529:.
1515:.
1511:.
1486:.
1464:.
1456:.
1446:21
1444:.
1420:.
1410:.
1398:10
1396:.
1392:.
1376:^
1362:.
1354:.
1344:35
1342:.
1317:.
1292:.
1278:^
1260:.
1241:^
1227:.
1215:.
1211:.
1183:19
1181:.
1156:.
1102:^
1088:.
1078:.
1064:.
1060:.
1026:^
764:,
756:,
716:,
697:.
642:.
521:.
509:,
505:,
443:.
435:,
423:,
397:.
389:,
365:,
331:,
273:.
2548:/
2527:/
2492:)
2483:(
2478:/
2432:→
2416:)
2412:(
2406:)
2404:1
2402:(
2386:→
2372:/
2353:/
2309:/
2263:/
2164:→
2137:/
2072:→
2044:→
2006:→
1994:G
1884:→
1882:K
1862:e
1855:t
1848:v
1763:-
1748:-
1738:D
1723:.
1705:.
1676:.
1658:.
1637::
1629::
1602:.
1578:.
1537:.
1523::
1496:.
1472:.
1452::
1428:.
1404::
1370:.
1350::
1327:.
1272:.
1235:.
1223::
1217:2
1193:.
1166:.
1152::
1096:.
1072::
1066:8
20:)
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