What causes type I tyrosinemia in Fanconi syndrome?

Updated: Feb 09, 2018
  • Author: Sahar Fathallah-Shaykh, MD; Chief Editor: Craig B Langman, MD  more...
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Tyrosinemia (type I) is the result of a deficiency in fumarylacetoacetate hydrolase activity. The gene is located on chromosome 15. Mutations in this gene result in disturbances of tyrosine metabolism that affect the liver, kidneys, and peripheral nerves. The liver is the organ primarily affected in this disease. Manifestations of hepatic dysfunction can become evident during the first few months of life. Cirrhosis of the liver is the ultimate outcome, sometimes complicated by hepatic carcinoma. Disturbances in renal tubule transport are almost always present, and severe rickets is commonly observed as a result of phosphate losses. Some patients develop nephrocalcinosis and renal insufficiency. Peripheral neuropathy is associated with pain and sometimes paralysis.

Elevations in plasma levels of tyrosine and methionine translate into a specific cabbagelike odor that may lead to the diagnosis. The substance at the origin of Fanconi syndrome is succinylacetone, a compound that is structurally similar to maleic acid. Succinylacetone is derived from maleylacetoacetate and fumarylacetoacetate that accumulate in the tissues of patients with tyrosinemia. Succinylacetone may also account for the peripheral neuropathy through its inhibitory effect on d -aminolevulinic acid dehydratase and the subsequent accumulation of d -aminolevulinic acid, which is neurotoxic.

Treatment with a low tyrosine, low phenylalanine diet results in a prompt and substantial diminution of the renal abnormalities. Its effect on the liver disease is less certain.

2-(2-Nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) has been shown to block p -hydroxyphenylpyruvate dioxygenase (pHPPD) and thus the formation of maleylacetoacetate (MAA) and fumarylacetoacetate (FAA); these compounds are thought to cause harm by reducing the intracellular levels of glutathione and acting as alkylating agents. In patients treated with NTBC, the excretion of succinylacetone and d -aminolevulinic acid is diminished, and renal and hepatic function is improved.

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