Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.
Eyes front and ears open. Class is now in session.
The disease that we will be learning about today is:
Hereditary Tyrosinemia Type 1
Sometimes just called tyrosinemia type 1 or fumarylacetoacetase deficiency.
What is Hereditary Tyrosinemia Type 1?
- Hereditary tyrosinemia type 1 (HT-1) is a type of tyrosinemia
- Tyrosinemia is a genetic disorder in which the breakdown of tyrosine is impaired causing elevated blood levels of tyrosine
- Tyrosine is one of 20 amino acids present in all proteins
- Tyrosine is important in the synthesis of thyroid hormones, catecholamines, and melanin
- If HT-1 is untreated, tyrosine and its byproducts build up in tissues and organs, which leads to serious medical problems
- There are three types of tyrosinemia, Type I, Type II and Type III
- Type I (HT-1)
- Most severe form
- Caused by a shortage of the enzyme fumarylacetoacetate hydrolase
- Type II
- Caused by a deficiency of the enzyme tyrosine aminotransferase
- About 50 percent of individuals with type II tyrosinemia have some degree of intellectual disability
- Type III
- Caused by a deficiency of the enzyme 4-hydroxyphenylpyruvate dioxygenase
- Typically causes intellectual disabilities, seizures, and periodic loss of balance and coordination
- Type I (HT-1)
- HT-1 is a rare metabolic disease
- Of the three types of tyrosinemia, HT-1 is the most serious and common
- Caused by a shortage of the enzyme fumarylacetoacetate hydrolase
- The lack of fumarylacetoacetate hydrolase prevents the body from breaking down tyrosine and its metabolites
- The accumulation of tyrosine can damage tissue and organs
- Can lead to liver and kidney failure, problems affecting the nervous system, and an increased risk of liver cancer
- If not recognized and promptly treated, tyrosinemia type I is usually fatal before the age of 10
- There are three subtypes of HT-1
- Acute
- Symptoms start in the first few months of life
- Most severe
- Sub acute
- Symptoms start in the 2nd half of the 1st year of life
- Similar to acute but less severe
- Chronic
- Symptoms develop after the 1st year of life
- Acute
How Do You Get It?
- Genetic disorder
- Caused by an absence of the enzyme fumarylacetoacetate hydrolase (FAH)
- Caused by a mutation in the gene for the FAH enzyme needed to break down tyrosine
- An autosomal recessive trait – must inherit the same defective gene from each parent for the condition to occur
- The risk of transmitting the disease to a child if both parents are carriers is 25%
- 50% of the children of two parent carriers risk being carriers of the disease
- Protein from food that is eaten is broken down into smaller parts called amino acids
- Special enzymes make changes to the amino acids so they can be used by the body
- HT-1 occurs when an enzyme, called fumarylacetoacetase (FAH), is either missing or not working properly
- When FAH is not working, it cannot break down tyrosine
- Tyrosine and other harmful substances then build up in the blood. One of these substances is called succinylacetone.
- The build-up of succinylacetone causes serious liver and kidney damage. It may also cause episodes of weakness or pain.
- US incidence is 1 case per 100,000 live births
- Males and females are affected equally
- One region in Quebec, Canada has a higher incidence with HT-1 occurring in 1 case per 1,850 births and 1 in 14 being genetic carriers
- According to CenterWatch, there are less than 100 children in the United States with HT-1
What Are The Symptoms?
- Symptoms in acute HT-1 include:
- Poor weight gain
- Enlarged liver and spleen
- Distended abdomen
- Swelling of the legs
- Increased tendency to bleeding/GI bleeding, nosebleeds
- Jaundice
- Lethargy
- Symptoms in sub-acute HT-1 include:
- Enlargement of the liver and spleen
- Distended abdomen
- Frequent vomiting and diarrhea
- “Boiled cabbage” or “rotten mushroom” odor to the body and urine
- Rickets
- Growth failure
- Symptoms in chronic HT-1 include:
- Renal disease
- Rickets
- Cardiomyopathy
- Cirrhosis
- Developmental delays
How Is It Treated?
- HT-1 is managed by controlling:
- Serum tyrosine levels – less than 500 µmol/L are ideal
- Serum and urine succinylacetone levels – below detectable levels
- Once newborn children reach recommended levels, a serum tyrosine level is recommended every month for the first 6 months, and every 3 months thereafter
- Treated with a combination of medication and diet
- Medication
- Approved therapies – Orfadin® (nitisinone)
- Orfadin® (nitisinone) is the only FDA approved treatment for HT-1
- Orfadin® is started as soon as possible after diagnosis
- Orfadin is used to prevent liver and kidney damage and stop neurologic crises
- Orfadin is taken orally
- The recommended dose is 1-2 mg/kg/day in two divided doses
- Patients may also be given Vitamin D supplementation to strengthen bones
- Nityr (nitisinone)
- Biosimilar of Orfadin
- Offers advantages such as lower price, better stability, and smaller size
- Diet
- The goal of dietary treatment is to restrict tyrosine and phenylalanine
- High protein foods, which are also high in tyrosine and phenylalanine, need to be eliminated from the diet
- Moderate protein foods need to be limited
- A low-tyrosine, low-phenylalanine food pattern is necessary to maintain safe serum tyrosine levels and to prevent the formation of crystals in the cornea of the eye
- Typically a special formula or medical food is prescribed to make sure that nutritional needs are met at the same time that appropriate serum tyrosine levels are maintained
- Low Protein diet
- Liver Transplant
- Required in cases that fail to respond to medical therapy, have evidence of liver cancer or develop end-stage liver failure
- HCP’s and clinics treating HT-1 include:
- Metabolic disease specialists
- Metabolic Clinics
- Clinical Biochemical genetics specialists
- Genetic clinics
- Dieticians
- Genetics counselor
- Clinic psychologists
- Clinic social workers
- Without treatment, death secondary to liver failure usually occurs by 2 years of age
- The biggest risk for those with HT-1 is progression to cirrhosis, liver failure and liver cancer
- With medical and dietary management, childhood activity does not require restriction and most patients can survive in good health
- It is unknown if treatment with Orfadin® will prevent liver and kidney disease in the long-term
- Gene therapy is a treatment that might help those with HT-1 in the future
Where Can I Learn More???
- Check out our cornerstone on this disease here.
- Learn more about this disease from the Network of Tyrosinemia Advocates.
