Tyrosinemia type

Leptospermone (34) Nitisinone (35) P Triketone Hereditary tyrosinemia type 1... 

Leptospermone (34), a representative of an important new class of herbicides from the bottlebrush plant, Callistemon citrinus (Curtis) Skeels, has been found to have an inhibitory effect on the enzyme, -hydroxyphenylpyruvate dioxygenase (HPPD), involved in the synthesis of plastoquinone in plants. Nitisinone (35), a synthetic derivative of (34), has recently been introduced to the market for the treatment of hereditary tyrosinemia type 1 (HT-1), a severe genetic disease caused by a deficiency of fumaryl acetoacetate hydrolase (FAH). ... 

Nitisinone is a reversibile inhibitor of 4-hydroxy-phenylpyruvate oxidase, an enzyme that plays a crucial role in the tyrosine catabolic pathway. Nitisinone prevents the accumulation of the toxic metabolites fumaryl acetoacetate, succinyl acetoacetate and succinyl acetone. Nitisinone is used for the treatment of hereditary tyrosinemia type 1. After oral administration bioavailability is 90% and peak levels are reached at 2.5 hours after dosing. The drug is eliminated mainly in the urine but some CYP3A4-mediated metabolism seems to occur. The elimination half-life is 45 hours. Blood dyscrasias are frequently occurring side effects as are eye problems like conjunctivitis, corneal opacity and keratitis. Exfoliative dermatitis, erythematous rash and pruritus... 

Nitisinone is an inhibitor of 4-hydroxyphenyIpyruvate dehydrogenase (4-HPPD). Originally studied as a herbicide, it is now marketed to prevent hepatic damage caused by hereditary tyrosinemia type I. This genetic disease is due to the absence in the body of fumarylacetoacetase, which ensures the last step of tyrosine degradation (Figure 8.86). 

Tyrosinemia type 1 p Tyrp, Metp u all AA, -aminolevulinec acid p... 

SAH hydrolase deficiency CBS deficiency Tyrosinemia type 1 Liver disease Severe protein malnutrition... 

Tyrosine Tyrosinemia type 1,2,3 Liver disease Prematurity PKU... 

D.L. Hereditary tyrosinemia type I (chronic form) Pathologic findings in the liver. Hum. Path. 1989 20 149-158... 

Tyrosine derives from the breakdown of dietary or tissue proteins or through the hydroxylation of the essential amino acid phenylalanine. Hepatorenal tyrosinemia (tyrosinemia type I, TYR-I) is an autosomal recessive disease caused by a deficiency of the enzyme fumarylacetoacetase (Figure 55-7),... 

Figure 55-8 Partial urine organic acid profiles 15-23 minute portion of a 33 minute run) of two patients with tyrosinemia type i. A, Acutely III patient with markedly elevated excretion of succiny[acetone, pre-NTBC treatment.The insert shows the selected ion chromatogram of the [M-15] ion of succinylacetone O-TMS-oxime TMS ester, m/z 212 B, Fifteen month old patient, succinylacetone was not detected by either total ion current (orrow) or selected ion chromatogram in three different urine specimens.This patient was later shown to be compound heterozygote for the French Canadian common splice mutation (IVS12+5G>A) and another previously unreported mutation. Peak legend I, Succinylacetone (oxime, peak I) 2, succinylacetone (oxime, peak II) 3, 4-hydroxy phenyllactic acid 4, 4-hydroxy phenylpyruvic add (oxime).The symbol marks the internal standard (pentadecanoic acid), signal abundance is normalized to the intensity of the internal standard peak.

Jakobs C, Dorland L, Wikkerink B, Kok RM, de Jong AP, Wadman SK. Stable isotope dilution analysis of succinyiacetone using electron capture negative ion mass fragmentography an accurate approach to the pre- and neonatal diagnosis of hereditary tyrosinemia type I. CHn Chim Acta 1988 171 223-31. 

Using this isotope labeling approach, metabolites in human plasma have been quantified (38) and altered metabolites have been detected in urine that are due to metabolic disorders such as tyrosinemia type II, argininosuccinic aciduria, homocystinuria, and phenylketonuria (20). Most recently, a smart isotope tag, 15N-cholamine, has been developed for effective detection of the same metabolites using both NMR and MS methods. This approach maximizes the combined strengths of two powerful analytical techniques for a variety of metabolomics applications. 15N-cholamine possesses dual characteristics an NMR-sensitive heteronuclear isotope with good chemical shift dispersion and a permanent charge that improves MS sensitivity (48). 

Hepatic cytosolic tyrosine aminotransferase (tyrosine transaminase) deficiency produces tyrosinemia type II, an autosomal recessive trait marked by hypertyrosine-mia and tyrosinuria. Clinical manifestations may include corneal erosions and plaques, inflammation (from intracellular crystallization of tyrosine), and mental retardation. Low-tyrosine and low-phenylalanine diets are beneficial. 

II or Pompe disease. Tyrosinemia type I, which mainly affects the liver and kidney, also manifests with hypertrophic cardiomyopathy. Conduction defects predisposing to arrhythmia are typically found in disorders of fatty acid oxidation (especially long-chain disorders, CPTII, and camitine-acylcamitine translocase deficiency), Keams-Sayre, and other primary mitochondrial defects. 

Phenylketonuria (PKU) Tyrosinemia type I 3-Methylcrotonylglycinuria Multiple carboxylase deficiency Hypermethioninemia... 

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