Hereditary Tyrosinaemia Type I

First, what is hereditary tyrosinemia type ITyrosine is a non- essential amino acids the human body , the main sources include dietary intake and phenylalanine (phenylalanine) metabolism of the intermediate product. When elevated plasma tyrosine , can be called high tyrosinemia (hypertyrosinaemia; tyrosinaemia), it causes may be due to an error from the primary metabolism , or by some other reasons caused by the liver caused by . However, due to the high Tyrosinemia cause liver damage , but many of the renewal of liver disease may also cause high Tyrosinemia , not easy to distinguish between the two . Based on past studies indicate that high Tyrosinemia associated with at least three enzymes : tyrosine transaminase ? (Tyrosine aminotrasferase; TAT), ρ- hydroxy - phenyl - Coke grape acid oxidation ? (Ρ- hydroxyphenylpyruvate dioxygenase; 4HPPD) and fumaric acid amide hydrolysis of acetylcholine ? (fumarylacetoacetate hydrolase; FAH), which , TAT lack can cause eye and skin high Tyrosinemia called tyrosinemia type II (Tyrosinaemia type II), also known as Richner-Hanhart syndrome (Richner-Hanhart syndrome), the main features of palms soles horny albinism (palmoplantar keratosis). The lack 4HPPD generates many abnormal metabolites, including the ρ- hydroxy - phenyl - Coke gluconic acid , ρ- hydroxy - phenyl - naphthalene acid and ρ- hydroxy - phenyl - naphthalene acetic acid , this is also known as casein acid aciduria . The lack of FAH will result in liver and kidney disease, known as tyrosinemia type I (Tyrosinaemia type I), also called tyrosine disease (tyrosinosis), can be divided into acute and chronic are two, the present the focus of discussion posts .
Premature newborns often temporary Tyrosinemia (Trainsient neonatal tyrosinaemia), full-term newborns may occasionally be seen . This may be a premature newborn 4HPPD or temporarily lacking , the high amount of phenylalanine and tyrosine intake, or caused by vitamin C deficiency . Such defects as the baby grows , 4HPPD matured and improved , but also by taking vitamin C and quickly corrected.
Biochemical mechanisms :Hereditary tyrosinemia type I is mainly caused because of lack of FAH . Throughout the tyrosine metabolized fumarate (fumarate) and acetoacetic acid (acetoacetate) by a total of five ? Catalyzed reaction steps :

1 by transglutaminase to form ρ- hydroxyphenyl pyruvate (ρ-hydroxyphenylpyruvate).(2) containing three carbon atoms and branched chain transfer the simultaneous oxidation and decarboxylation to form a black acid (homogentisate).3 Connect the black oxidized to maleic acid amide acetylsalicylic acid alone (maleylacetoacetate).4 would maleic acid amide acetoacetate single row into the role of heterogeneous acetoacetic acid amide fumarate (fumarylacetoacetate).5 of fumaric acid amide hydrolysis of acetylcholine fumaric acid and acetylsalicylic acid.FAH in a fifth reaction. When FAH deficiency, the entire tyrosine metabolism will be hindered , making fumaric acid amide will be a substantial accumulation of acetylcholine , maleic acid mono amide acetylsalicylic acid may also be affected and accumulate in the body , causing liver and kidney damage . These metabolites will be restored (reduce) and go carboxyl (decarboxylate) into succinyl acetone (succinylacetone; SA), and gathered in the patient's plasma and urine. Therefore, the concentration of SA in vivo testing patients , the diagnosis can be used as an important basis for high Tyrosinemia . Further, since the metabolic suspension , may also cause ? - Hydroxyphenyl pyruvic acid and its derivatives in vivo accumulation .
FAH gene is located on the human body are known to 15th on the long arm of chromosome (15q23-q25), is autosomal recessive . Liver cells for patients for sequencing DNA sequence analysis showed that 34 point mutations related to lack of FAH .
Second, the clinical featuresI. Acute TyrosinemiaThis baby will have a rapid and fulminant course of the disease , if untreated , the patient will die quickly . Seizures usually 1-6 months old, patients often have loss of appetite , vomiting , diarrhea, bloating , and other symptoms of low blood sugar , will cause growth retardation , anxiety , fever, and hepatomegaly phenomena , while there will be black stools, vomiting blood, urine , and congestion and other hemolytic performance, then cause renal dysfunction (renal tubular dysfunction). Because the liver lesions occur , making the patient began to emerge rickets (rickets), hepatosplenomegaly and other symptoms. Some patients have neurological diseases and low tension phenomenon. These neurological disease may be accompanied by more serious complications , such as acute intermittent sometimes like ? Slightly deposition disease porphyria (acute intermittent porphyria) of symptoms , nerve endings in muscle weakness caused by disease and hypertension . As the disease intensifies, jaundice , edema , abdominal effusion, drowsiness , coma , liver failure , and even death phenomenon will occur .
II. Chronic TyrosinemiaMost of the children with chronic tyrosinemia in a developed symptoms after age . Growth retardation, gastrointestinal symptoms , progressive liver cirrhosis, kidney impairment and multiple clinical manifestations are rickets . Early in the disease may be elevated tyrosine , and later will exhibit methionine (methionine) is increased. Usually die before the age of 10 , autopsies often visible liver tumors.
Third, the clinical diagnosisI. prenatal1 if the parents known to cause high Tyrosinemia point mutations , amniotic fluid cells can be pumped pregnant women , the analysis of gene mutations .(2) can be detected in amniotic fluid concentrations of SA to see if too high.3 Take amniotic fluid cells or chorionic pregnant women , to be multiplication culture . Subject to collect a certain number of cells , the measurement of the activity of intracellular FAH , FAH see if there is a lack of the phenomenon.
II. Blood testHigh Tyrosinemia current test method is the most credible quantitative blood and urine SA and its precursor concentrations. This approach, while sharp, but there is still a small number of patients with low concentration of SA , at this time , it is necessary to detect the FAH activity in cultured cells as a diagnostic aid . Subject variability of genes , cultured cells of a healthy individual may also occur a phenomenon FAH low activity . Similarly , the patient's liver specimen cell culture may also be due to a genetic response (reversed) in the case , so that to obtain a high activity of the illusion of FAH . Therefore , FAH enzyme activity assay is used as a diagnostic reference only , and not as the sole diagnostic credentials.
In addition to the concentration of SA can be used as a diagnostic tool high Tyrosinemia , some biochemical aspects of testing may also apply to general patients . For example: serum tyrosine concentration will increase, but the concentration of methionine were not significantly improved. Urine ρ- hydroxy - phenyl - Coke gluconate , ρ- hydroxy - phenyl - Coke lactic acid and ρ- hydroxy - phenyl - Coke acetic acid concentration will increase . When the renal tubular damage occurs , it will show Fanconi 's syndrome (Fanconi syndrome), which means in the urine with high amounts of amino acids, glucose and phosphate. When the liver cells are destroyed, and affects protein synthesis also occurs when a number of diverse biochemical manifestations, can be used as a basis for diagnosis . For example: vitamin K dependent coagulation factors in patients with acute concentration is quite high , and chronic disease in vivo concentration is not normal . Relative to other liver enzyme activity , the patients in vivo activity of γ-Glutamyltransferase will increase . α-fetoprotein concentration in vivo acute patients has increased significantly , but in chronic patients are showing normal concentrations.
Fourth, clinical treatmentI. NTBC treatment (NTBC treament)NTBC (2 - (2-nitro-4-trifluoro-methylbenzoyl) -1,3-cyclo-hexanedione) is a good 4HPPD inhibitors can prevent ρ- hydroxyphenyl pyruvic acid into black , to reduce the generation of SA , the Last used to treat high Tyrosinemia approach. According to the research report: patient daily oral 0.6 mg / kg of NTBC , in addition to ρ- hydroxyphenyl pyruvic acid and tyrosine concentrations will increase , other biochemical abnormalities will become normal, and the clinical symptoms will play improvement of access . NTBC also be used to treat the neurological aspects of this and similar ? Slightly porphyria deposition disease symptoms. As the concentration of tyrosine as the use NTBC increase, therefore, the control diet are necessary .
Prolonged use of NTBC related research has been discussed , in particular the incidence of liver cancer among NTBC relevance, currently inconclusive. The earlier use of NTBC, is less prone to the more severe abnormalities . So far , NTBC no reports of any side effects .
II. Liver transplant (Liver Transplantation)Stolen goods to the liver transplant to treat first type high Tyrosinemia about 10 years of development schedule , as this type of patients will have the serious liver damage , so when the recipient if the liver has Contributors the normal performance when patients lack an enzyme phenomena can be improved , blood and urine is not normal metabolites will disappear. Get the disease after liver transplant can be a normal diet, does not require special control of tyrosine and phenylalanine intake. Even so , the patient is still in the urine will increase the concentration of SA , presumably due to the kidney caused the problem . Liver transplant kidneys after prolonged prognosis remains unclear.
III. Diet (Dietary treament)Diet control is used to treat high Tyrosinemia first method , which is to limit the concept of tyrosine and phenylalanine intake so low that only needed to provide normal growth . Such foods must come from a special recipe , mainly using protein hydrolyzate or without amino acids tyrosine and phenylalanine mixture , and then add a small amount of natural protein to supplement tyrosine and phenylalanine appropriate . When a patient of tyrosine and phenylalanine , respectively, the daily intake maintained at 15-20 mg / kg , the concentration of SA in vivo is difficult to be detected. With the control diet , because the resulting tubular dysfunction symptoms almost completely back to normal . However, liver disease and malignant tumors can not take this to generate access to treatment and prevention , so when the liver is severely damaged or tumors , such as liver transplants still need to be contacted by other methods such as improved condition .
IV. Supportive treatment (Supportive treament)For acute onset patients, supportive treatment is necessary. Patients often lack potassium and phosphate , therefore, need timely and appropriate supplement. In addition , coagulation factors, calcium , albumin , phosphate , electrolyte and acid-base balance of all need to be carefully monitored and corrected. When the patient is in acute cases, tyrosine and phenylalanine intake must be reduced to a minimum as much as possible . Increase vitamin D used to treat rickets ; patients if infection, infection control and needs to be addressed immediately .