Tyrosinemia type I is a genetic disorder that disrupts the metabolism of the amino acid tyrosine, resulting in damage primarily to the liver along with the kidneys and peripheral nerves. The inability of cells to process tyrosine can lead to chronic liver damage ending in liver failure, as well as renal disease and rickets. Symptoms such as poor growth and enlarged liver are associated with the clinical presentation of the disease. If not detected via newborn screening and management not begun before symptoms appear, clinical manifestation of disease occurs typically within the first two years of life. The severity of the disease is correlated with the timing of onset of symptoms, earlier being more severe. If diagnosed through newborn screening prior to clinical manifestation, and well managed with diet and medication, normal growth and development is possible. Tyrosinemia type I is an autosomal recessive disorder caused by mutations in both copies of the gene encoding the enzyme fumarylacetoacetate hydrolase (FAH). FAH is a metabolic enzyme that catalyzes the conversion of fumarylacetoacetate to fumarate and acetoacetate. It is expressed primarily in the liver and kidney. Loss of FAH activity results in the accumulation of certain metabolic intermediates in the tyrosine catabolic pathway. These compounds are toxic to cells and lead to differential gene expression and apoptosis in high concentrations. HT1 is diagnosed when elevated levels of succinylacetone (SA), one of the metabolites in this pathway, is detected in blood and urine samples. While there is no cure for tyrosinemia type I, management of the disease is possible utilizing dietary restrictions and medications. A diet low in tyrosine and phenylalanine is utilized indefinitely once a diagnosis is suspected or confirmed. Additionally, the drug nitisinone (brand name Orfadin) is prescribed and continued indefinitely in order to combat liver and kidney damage, promoting normal function of these organs. Prior to the development of nitisinone, dietary restrictions and liver transplantation were the only forms of treatment for HT1. Tyrosinemia type I is especially prevalent in the Saguenay-Lac Saint-Jean region of Quebec, where the prevalence is 1 in 1,850 births. It is most common among those with French-Canadian ancestry and this frequency of infliction has been attributed to the founder effect. There are five other known types of tyrosinemia, all of which derange the metabolism of tyrosine in the human body. They are distinguished by their symptoms and genetic cause.
Signs and symptoms Type 1 tyrosinemia typically presents in infancy as failure to thrive and hepatomegaly. 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, ascites and hemorrhage. There is also an increased risk of hepatocellular carcinoma. The kidney dysfunction presents as Fanconi syndrome: Renal tubular acidosis, hypophosphatemia and aminoaciduria. Cardiomyopathy, neurologic and dermatologic manifestations are also possible. The urine has an odor of cabbage or rancid butter. The presentation of symptoms of tyrosinemia type 1 in terms of timing is broken into three categories: acute, sub-acute, and chronic. The acute classification typically is presented clinically between birth and 6 months of age. The common presentation in an acute case is synthetic liver failure, marked by the lack of formation of coagulation factors in blood. Patients are prone to infections at this stage accompanied by fever, vomiting, increased tendency to bleed, and diarrhea along with bloody feces as manifestations of sepsis. Other symptoms include enlarged liver, jaundice, and excess abdominal fluid. Sub-acute cases present between 6 months and the first year of life and the severity of liver disease is lessened to an extent. Again, synthetic function of the liver in terms of blood coagulation factors is impaired in addition to enlargement of the liver and spleen. The infant may also display a failure to thrive as their growth is limited by the disease. This growth impairment can manifest itself in rickets, which is the softening of bones. The final classification, chronic HT1, is detected with presentations occurring after one year of life. The course of the disease up to this point can lead to different ailments affecting the liver. Cirrhosis, liver failure, or cancer of the liver may present as a result of chronic liver disease. Additional symptoms common in this classification include cardiomyopathy, renal disease, and acute neurological crises.
Liver The liver is the organ affected most by Tyrosinemia Type I due to the high level of expression of the gene for fumarylacetoacetate hydrolase (FAH) in liver cells. The production of blood coagulation factors by the liver is disrupted, causing hemophiliac-like symptoms. Acute liver failure is common, especially in early life. Additionally, the synthesis of albumin in the liver may be defective, therefore leading to hypoalbuminemia. As the disease progresses, cirrhosis is common. This can lead to a fatty liver and the development of tumors in areas affected by this scarring of liver tissue. These scars are known as nodules. There is a 37% chance of developing a hepatocellular carcinoma (HCC) for untreated patients.
Renal and neurological manifestations Many patients display impaired kidney function and neurological symptoms. In addition to liver cells, kidney cell expression involves expression of the gene for FAH. Kidney failure is a potential result of impaired kidney function, but the most common symptom associated with renal dysfunction is hypophosphatemic rickets. Neurological manifestations are characterized by acute neurological crises due to overaccumulation of porphyrin. These crises are characterized by porphyria. They typically follow an infection. Patients can present with a variety of varied symptoms including paresthesias, abdominal pain, pain-induced seizures, and can result in self-mutilation in response to this pain. Episodes can last for 1–7 days and can lead to neuropathy.
Genetics
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