Tyrosinemia, Type I , Metabolic Disorder, Amino acid disorder Screening -Infant

Tyrosinemia, Type I , Metabolic Disorder, Amino acid disorder Screening -Infant

Tyrosinemia, Type I , Metabolic Disorder, Amino acid disorder Screening

Summary of Recommendation and Evidence

Population

Recommendation

Grade
(What's This?)

Screening of both genders

The genetic screening for Tyrosinemia, Type I is recommended.

B

Tyrosinemia type I is a rare autosomal recessive genetic metabolic disorder characterized by lack of the enzyme fumarylacetoacetate hydrolase (FAH), which is needed for the final break down of the amino acid tyrosine. Failure to properly break down tyrosine leads to abnormal accumulation of tyrosine and its metabolites in the liver, potentially resulting in severe liver disease. 

OVERVIEW

Tyrosinemia type I is caused by a deficiency of fumarylacetoacetase (FAH), one of the last enzymes in aromatic amino acid metabolism. This results in a mild increase in plasma tyrosine (that can be missed by newborn screening) and the accumulation of succinylacetone (that is specific for this condition) and related compounds that are extremely toxic. These compounds are produced in the liver and kidney resulting in liver failure, cirrhosis and development of liver cancer. Patients can also present with failure to thrive and rickets due to severe renal tubular dysfunction.

SCREENING

Finding

Elevated tyrosine; elevated succinylacetone

Tested By

Tandem mass spectrometry (MS/MS); sensitivity~80% (with tyrosine), >99% with succinylacetone; specificity=99.98%

PREVALENCE

About 1:125,000 live births

INHERITANCE

TYR I is inherited in an autosomal recessive manner. It affects both boys and girls equally.

PRENATAL TESTING

DNA testing, biochemical testing (succinylacetone) by amniocentesis.

CLINICAL CHARACTERISTICS

With treatment>90% survival rate can be expected, along with normal growth, normalization of liver function and prevention of cirrhosis, correction of renal tubular acidosis and resolution of secondary rickets. Early treatment is associated with reduced incidence of hepatic cancer. Treatment consists of a diet low in tyrosine and phenylalanine and use of a drug (nitisone or NTBC) that prevent formation of succinylacetone, the toxic agent responsible for liver and kidney damage. Patients with evidence of cirrhosis or liver cancer require liver transplantation. 

Without treatment, chronic problems ensue, including: liver disease leading to cirrhosis and hepatocellular carcinoma, renal tubular disease (Fanconi syndrome), rickets, failure to thrive, and coagulation disorders. Repeated neurologic crises may occur involving mental status change, abdominal pain, peripheral neuropathy, and/or respiratory failure.These are due to the accumulation of delta amino levulinic acid whose metabolism is inhibited by succinylacetone. Death usually occurs by 10 years of age. 

Initial symptoms may include:

  • Severe liver involvement in the young infant with:
  • Jaundice
  • Ascites
  • Loss of clotting factor synthesis
  • GI bleeding
  • Or development later in the first year of:
  1. Liver dysfunction
  2. Renal involvement
  3. Growth failure
  4. Rickets
  5. "Boiled cabbage" or "rotten mushroom" odor to the body and urine

EARLY SIGNS

There are three types of tyrosinemia (I, II, and III). Tyrosinemia, type I (TYR I) is the most severe of the three forms. Signs of TYR I usually begin in the first few months of life, though some individuals do not begin showing signs until childhood.

Babies with TYR I may show signs such as:

  • Diarrhea
  • Bloody stool
  • Vomiting
  • Poor weight gain
  • Sleeping longer and more often
  • Tiredness
  • Irritability
  • “Cabbage-like” odor
  • Yellowing skin (known as jaundice)
  • Increased bleeding or bruising
  • Swollen legs or abdomen
  • Developmental delays
  • Trouble breathing

Many of these signs may occur when your baby eats foods that his or her body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

CAUSES

When we eat food, enzymes help break it down. Some enzymes help break down proteins into their building blocks, called amino acids. Other enzymes break down these amino acids. In tyrosinemia, type I (TYR I), the enzyme fumarylacetoacetate hydrolase (FAH) is not working correctly.

FAH’s job is to break down the amino acid tyrosine. Babies with TYR I do not make enough FAH. When there is a shortage in FAH, the body cannot break down tyrosine. Tyrosine builds up in the body, which can be toxic.

TYR I is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for TYR I, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with TYR I is rare, when both parents are carriers, they can have more than one child with the condition. 

TREATMENT

Dietary Treatment

Your baby may need to be on a restricted diet to avoid proteins that his or her body cannot break down. A dietician or nutritionist can help you plan the appropriate diet for your child. 

Your baby’s doctor might also recommend special formulas and foods for children with tyrosinemia, type I (TYR I). These formulas will likely need to be continued through adulthood.

Supplements and Medications

Your doctor may prescribe a medication called nitisinone (also called Orfadin or NTBC). This medication helps stop TYR I from affecting the brain, liver, and kidneys. It is important to screen for TYR I at birth because taking this medication early can prevent liver, kidney, and brain damage.

If TYR I is affecting your baby’s bones, your doctor might also prescribe vitamin D supplements. Vitamin D is a natural substance that can help strengthen bones.

EXPECTED OUTCOMES

Early treatment can prevent many of the liver, kidney, and brain effects of tyrosinemia, type I (TYR I). Children who receive treatment can have healthy growth and development.

If treatment is not started soon after birth, children risk some liver and kidney damage.

Without treatment, children are at risk for life-threatening kidney and liver problems.