A 3-day-old neonate is found to have elevated tyrosine and methionine on newborn screening. Succinylacetone is detected in urine. Liver enzymes are markedly elevated. Which enzyme deficiency is the PRIMARY cause of this disorder, and which metabolite is MOST responsible for the hepatotoxicity?

• A Tyrosine aminotransferase; fumarylacetoacetate
• B Homogentisate oxidase; homogentisic acid
• C Fumarylacetoacetase; succinylacetone ✓
• D 4-hydroxyphenylpyruvate dioxygenase; maleylacetoacetate

Explanation

Hereditary tyrosinemia type 1 (HT1) is caused by deficiency of fumarylacetoacetase (FAH gene), the last enzyme in tyrosine catabolism. The resulting accumulation of fumarylacetoacetate and its reduction product succinylacetone causes the primary toxicity — succinylacetone inhibits porphobilinogen synthase (causing porphyria-like crises) and is directly hepatotoxic and nephrotoxic. Succinylacetone in urine is the pathognomonic biomarker. Treatment is nitisinone (NTBC) plus a tyrosine/phenylalanine-restricted diet.

Reference: Ghai Essential Pediatrics, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.