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Tyrosinemia

Tyrosinemia



Overview

In tyrosinemia, the body doesn't have an enzyme it needs [called fumarylacetoacetate hydrolase (FAH)] to metabolize tyrosine. Metabolism is a process in which our bodies break down substances as we use them for energy; in this case tyrosine. Tyrosine is an amino acid that is found in most proteins. When people with tyrosinemia break down protein, abnormal toxic break down products of tyrosine build up in their bodies. This causes progressive damage to the liver and kidneys, but mainly the liver. This is because the liver is normally the primary place tyrosine is metabolized.

Tyrosinemia is hereditary; in order to have the disease, a child must get a mutation in the gene for tyrosinemia from each parent. In families where both parents carry a mutation, there is a one in four risk that a child will have tyrosinemia. There is now a genetic test available, so that couples at high risk of being carriers can determine their risk of having a child with tyrosinemia. This is a very rare disease; only about one person in 100,000 has it.

Symptoms

Tyrosinemia Type I Symptoms (Severe/Acute)

Liver Dysfunction: Jaundice, enlarged liver and spleen (hepatomegaly), abdominal fluid accumulation, and increased tendency to bleed (e.g., nosebleeds).

Kidney/Bone Issues: Renal tubular dysfunction and rickets (softening/weakening of bones).

Growth/Development: Severe failure to thrive and inability to gain weight.

Neurologic Crises: Changes in mental state, severe abdominal pain, peripheral neuropathy (reduced sensation in limbs), and respiratory failure.

Odor: Characteristic cabbage-like or fishy smell in urine. 

Tyrosinemia Type II Symptoms (Oculocutaneous) 

Eye Issues: Excessive tearing (lacrimation), pain, redness, photophobia (light sensitivity), and corneal clouding/lesions.

Skin Issues: Painful, thick, hyperkeratotic plaques on the palms and soles of the feet.

Cognitive: Potential intellectual disability or behavioral problems. 

Tyrosinemia Type III Symptoms (Rare) 

This form is rare but can include intellectual disability, seizures, and periodic lack of balance (ataxia). 

Causes and Types

Tyrosinemia Type I (Hepatorenal): Caused by mutations in the FAH gene (fumarylacetoacetate hydrolase deficiency), leading to severe liver damage, renal failure, and, if untreated, high risk of liver cancer.

Tyrosinemia Type II (Oculocutaneous): Caused by mutations in the TAT gene (tyrosine aminotransferase deficiency), affecting the eyes, skin, and sometimes causing intellectual disability.

Tyrosinemia Type III: Caused by mutations in the HPD gene (4-hydroxyphenylpyruvate dioxygenase deficiency), which is rare and can cause neurological issues.

Transient Tyrosinemia of the Newborn: A common, non-genetic, temporary form often caused by an immature liver or Vitamin C deficiency.

 Risk Factors

Autosomal Recessive Inheritance: If both parents are carriers, there is a 25% (1 in 4) chance that their child will inherit the condition.

Family History: A sibling with the disease is a major risk factor.

Genetic Ancestry (Founder Effect): The disease is much more common in specific populations due to a founder effect:


Complications of Tyrosinemia Type 1

Liver: Severe liver dysfunction, cirrhosis, enlarged liver/spleen (hepatomegaly), and a high risk of liver cancer (hepatocellular carcinoma).

Kidney: Renal tubular dysfunction (Fanconi syndrome), leading to kidney damage and rickets (weakened bones).

Neurological: "Neurologic crises" manifesting as extreme pain in the limbs/abdomen, peripheral neuropathy, vomiting, paralysis, and respiratory failure.

Systemic: Failure to thrive, severe growth failure, jaundice, and an odor similar to cabbage.

Long-term: Even with treatment, some patients may face neurocognitive impairments

Complications of Other Tyrosinemia Types

Type II: Affects the eyes (corneal ulcers, pain, redness) and skin (thickened skin on palms and soles).

Type III: Rare, but can lead to intellectual disability and neurological symptoms.

Diagnosis

Newborn Screening: Most US states screen for Type 1 by detecting elevated succinylacetone in dried blood spots.

Biochemical Testing: Elevated succinylacetone in urine or blood is the definitive diagnostic marker for Type 1.

Genetic Testing: Molecular genetic testing for mutations in the FAH gene confirms Type 1.

Imaging & Lab Work: Ultrasound is used for surveillance of liver/kidneys. Lab tests often show abnormal liver function, low albumin, and high alpha-fetoprotein (AFP).

Prenatal Diagnosis: Possible by measuring succinylacetone in amniotic fluid or testing for DNA mutations

Treatment

Nitisinone (Orfadin/NTBC): The primary drug for Type 1, which blocks the production of toxic metabolites. It stops the metabolic pathway that leads to liver and kidney failure.

Dietary Restriction: An extremely strict, lifelong diet low in protein—specifically restricting tyrosine and phenylalanine—is required. This involves avoiding meat, dairy, nuts, and beans.

Specialized Formula: Patients must consume special formula that provides essential nutrients while remaining free of tyrosine and phenylalanine.

Monitoring: Regular, precise monitoring of blood levels of tyrosine and succinylacetone is crucial.

Liver Transplant: If treatment with nitisinone fails or if hepatocellular carcinoma (liver cancer) is present, a liver transplant is necessary.

Supportive Care: Supportive care is necessary to manage acute liver failure, and sometimes requires vitamin and mineral supplements. 

Type of Doctor Department : A pediatric hepatologist ,nephrologist 

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