Type 1 Tyrosinemia, also known as hepatorenal tyrosinemia, is the most severe form of tyrosinemia. It is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase

Fumarylacetoacetate hydrolase

Fumarylacetoacetase is an enzyme that in humans is encoded by the FAH gene.Fumarylacetoacetate hydrolase is an enzyme which catalyzes the hydrolysis of 4-fumarylacetoacetate into fumarate and acetoacetate.-External links:* -Further reading:...

 .

Genetics

Type 1 tyrosinemia is inherited in an autosomal recessive pattern. Worldwide, type I tyrosinemia affects about 1 person in 100,000. This type of tyrosinemia is much more common in Quebec, Canada. The overall incidence in Quebec

Quebec

Quebec or is a province in east-central Canada. It is the only Canadian province with a predominantly French-speaking population and the only one whose sole official language is French at the provincial level....

 is about 1 in 16,000 individuals. In the Saguenay-Lac-Saint-Jean

Saguenay-Lac-Saint-Jean

Saguenay–Lac-Saint-Jean is a region in Quebec, Canada. It contains the Saguenay Fjord, the estuary of the Saguenay River, stretching through much of the region...

 region of Quebec, type 1 tyrosinemia affects 1 person in 1,846. The carrier

Genetic carrier

A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...

 rate has been estimated to be between 1 in 20 and 1 in 31.

Pathophysiology

Fumarylacetoacetate hydrolase catalyzes the final step in the degradation of tyrosine - fumarylacetoacetate to fumarate, acetoacetate and succinate. Fumarylacetoacetate accumulates in hepatocytes and proximal renal tubal cells and causes oxidative damage and DNA damage leading to cell death and dysfunctional gene expression which alters metabolic processes like protein synthesis and gluconeogenesis

Gluconeogenesis

Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....

. The increase in fumarylacetoacetate inhibits previous steps in tyrosine degradation leading to an accumulation of tyrosine in the body. Tyrosine is not directly toxic to the liver or kidneys but causes dermatologic and neurodevelopmental problems.

Signs and symptoms

Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly

Hepatomegaly

Hepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...

. The primary effects are progressive liver and kidney dysfunction. The liver disease causes cirrhosis, conjugated hyperbilirubinemia, elevated AFP, hypoglycemia and coagulation abnormalities. This can lead to jaundice

Jaundice

Jaundice is a yellowish pigmentation of the skin, the conjunctival membranes over the sclerae , and other mucous membranes caused by hyperbilirubinemia . This hyperbilirubinemia subsequently causes increased levels of bilirubin in the extracellular fluid...

, ascites

Ascites

Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...

 and hemorrhage. There is also an increased risk of hepatocellular carcinoma

Hepatocellular carcinoma

Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...

.
The kidney dysfunction presents as Fanconi syndrome

Fanconi syndrome

Falconi syndrome is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid...

: Renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible.

Treatment

The primary treatment for type 1 tyrosinemia is Nitisinone (Orfadin). Nitisinone inhibits the conversion of 4-OH phenylpyruvate to homogentisic acid by 4-OH phenylpyruvate dioxygenase, the second step in tyrosine degradation. By inhibiting this enzyme, the accumulation of the fumarylacetoacetate is prevented. Previously, liver transplantation was the primary treatment option and is still used in patients in whom nitisinone fails.