What is Tyrosinemia?

Tyrosinemia is a rare autosomal recessive genetic metabolic disease. Due to tyrosine degradation, brain, liver, kidney, bone and other organs are damaged. The prognosis is poor, and the mortality and disability rate is very low. high. Different types of patients have different clinical manifestations. Low tyrosine diet and drug treatment are the main intervention methods. If necessary, they need to be treated with liver transplantation.

Basic Information

Causes of Tyrosineemia

There are three types of tyrosinemia based on the defective enzyme:

1. Tyrosinemia type is due to the FAH gene mutation leading to the deficiency of the terminal enzyme fumarate acetoacetate hydrolase in tyrosine metabolism, tyrosine and its metabolites succinylacetone, 4-hydroxyphenyllactic acid and 4 -Hydroxyphenylpyruvate accumulates.

2. Tyrosinemia type is due to tyrosine aminotransferase deficiency caused by tyrosine breakdown disorders.

3. Tyrosinemia type III is a disease caused by lack of 4-hydroxyphenylpyruvate dioxidase.

Clinical manifestations of tyrosineemia

Patients have different conditions and significant individual differences. Untreated patients die before the age of 10, and early detection and prognosis can be greatly improved.

1. Tyrosineemia type I

According to the age of onset are divided into acute, subacute and chronic.

(1) Acute type

Patients develop symptoms within days to weeks after birth. The main clinical manifestations are acute liver failure, jaundice, anorexia, bleeding tendency, vomiting, pale skin, slow growth, hepatomegaly, and rapid disease progression. If not treated, Most died within 1 year of age.

(2) Subacute and chronic

Generally onset from 6 months to 2 years of age, liver, kidney and nerve damage, some children with rickets, angular arch retension, etc., children often cried because of severe pain. Can develop into hepatocellular carcinoma if untreated.

2. Tyrosinemia type II

The child is mainly characterized by ocular symptoms, with tears, photophobia, and conjunctival congestion in the months after birth, followed by corneal ulcers and opacities, nystagmus, and blistering, ulcers, and hyperkeratosis in the palms and soles. Intellectual and developmental disorders after the age.

3. Tyrosinemia type III

Children are generally asymptomatic, and may also experience mild mental retardation, cramps, and ataxia.

Tyrosineemia test

General test

Most patients have anemia, abnormal liver function, hypoglycemia, elevated serum transaminase and bilirubin levels, most of which are accompanied by hypoalbuminemia, and alpha-fetoprotein levels are significantly increased.

Due to reduced synthesis of coagulation factors, abnormal coagulation function is apparent.

In some patients, renal tubular function is impaired, proteinuria, amino aciduria, and hyperphosphatemia occur, and blood phosphorus decreases, leading to renal rickets.

2. Blood amino acid analysis

Increased tyrosine, increased succinylacetone in patients with type I , and increased blood phenylalanine in some patients.

3. Urine organic acid analysis

Urinary 4-hydroxyphenyllactic acid, 4-hydroxyphenylacetic acid, and 4-hydroxyphenylpropionic acid increased, and succinylacetone levels increased in patients with type .

4. Enzymatic inspection

Liver tissue, fibroblasts, or peripheral blood lymphocytes were measured for enzyme activity. Fumarate acetoacetate hydrolase activity was low in patients with tyrosinemia, type tyrosinase deficiency in tyrosinemia type , and tyrosinemia Type 4-hydroxyphenylpyruvate dioxidase deficiency.

5. Genetic testing

Mutations in tyrosinemia-associated genes can help define diagnosis and typing.

Tyrosine diagnosis

1. Basis of diagnosis of tyrosinemia type

(1) Patients often have symptoms and signs of jaundice, ascites, growth retardation and rickets.

(2) Mild or moderate elevations of serum aspartate aminotransferase and plasma alanine aminotransferase, coagulopathy, increased alpha-fetoprotein, increased alkaline phosphatase, and hypophosphatemia are common.

(3) Impaired renal function, such as amino acid urine, phosphate urine, hypophosphatemia, and renal tubular acidosis.

(4) Plasma alpha-fetoprotein levels increased significantly.

(5) Increased blood tyrosine and succinylacetone.

(6) Urine 4-hydroxyphenyllactic acid, 4-hydroxyphenylacetic acid, 4-hydroxyphenylpyruvate and succinylacetone increased. Increased blood or urine succinylacetone is a necessary condition for the diagnosis of tyrosinemia type I.

(7) Pathogenic mutations in FAH alleles, which have diagnostic value.

2. Basis of diagnosis of tyrosinemia type II

(1) Children are mainly characterized by eye symptoms.

(2) The concentrations of tyrosine in urine and 4-hydroxyphenyllactic acid and 4-hydroxyphenylacetic acid in urine increased.

(3) Lack of tyrosine aminotransferase.

(4) Genetic analysis can help confirm the diagnosis.

3. Basis of tyrosineemia type III diagnosis

Tyrosinemia type III symptoms are not typical, and the increased concentration of tyrosine and its metabolites in urine is an important reference for diagnosis.

Differential diagnosis of tyrosineemia

1. Other diseases that cause elevated blood tyrosine levels and other diseases that cause liver damage, such as galactosemia, hereditary fructose intolerance, mitochondrial disease, congenital glycosylation, and infectious diseases.

2. Other diseases that cause kidney damage, such as Lowe syndrome, cystine disease, Fanconi syndrome, etc.

3. Other diseases that cause rickets, such as hypophosphatases, vitamin D-deficient rickets, vitamin D-dependent rickets, and hypophosphatemia.

It can be identified by blood amino acid analysis, urine organic acid spectrum, enzymatic examination, genetic testing, etc.

Tyrosinemia treatment

It is mainly aimed at tyrosinemia type . It can control diseases through diet, medicine or liver transplantation treatment, reduce the level of blood tyrosine and its metabolites, and reduce the damage of tyrosine and its metabolites to the body.

Diet therapy

Low tyrosine and phenylalanine diet.

2. Netisinone

Inhibitor of 4-hydroxyphenylpyruvate dioxygenase is the main drug for the treatment of tyrosinemia type I. It has a fast onset of action and the blood succinylacetone is significantly reduced in most patients.

3. Liver transplantation

For patients with poor diet and medication, liver transplantation should be considered early to improve quality of life.

Prognosis of tyrosinemia

If untreated, patients often die from liver failure and hepatocellular carcinoma before the age of 10. If treated immediately after birth, the prognosis can be greatly improved. Patients with early liver transplantation can survive for a long time and develop better.

Tyrosine prevention

1. Parents and siblings of patients should perform genetic analysis and genetic counseling. Prenatal diagnosis can be performed through fetal gene analysis when parents are reproductive.

2. Newborn screening: Through analysis of heel amino acid and acylcarnitine spectrum analysis, patients with tyrosinemia can be detected in asymptomatic periods or early in the disease, and early intervention can protect the organs.