In a 28-year-old woman with a family history of tyrosinemia, genetic testing reveals a homozygous mutation in the gene encoding the enzyme that catalyzes the first committed step of tyrosine catabolism. Which of the following is the most common type of hereditary tyrosinemia?

Explanation

## Hereditary Tyrosinemia Classification **Key Point:** Type I (hepatorenal) tyrosinemia due to fumarylacetoacetate hydrolase (FAH) deficiency is the **most common and most severe** form of hereditary tyrosinemia, with an incidence of ~1 in 100,000. ### Comparison Table: Types of Hereditary Tyrosinemia | Feature | Type I (FAH ↓) | Type II (TAT ↓) | Type III (4-HPPD ↓) | Type IV (Transient) | | --- | --- | --- | --- | --- | | **Enzyme Defect** | Fumarylacetoacetate hydrolase | Tyrosine aminotransferase | 4-Hydroxyphenylpyruvate dioxygenase | Hepatic immaturity | | **Plasma Tyrosine** | ↑↑↑ (markedly) | ↑↑↑ (markedly) | ↑ (mild) | ↑ (mild) | | **Urine Succinylacetone** | Present (pathognomonic) | Absent | Absent | Absent | | **Clinical Severity** | **Most severe** | Moderate | Mild | Mild/transient | | **Hepatic Involvement** | Cirrhosis, HCC | Minimal | Minimal | None | | **Ocular Features** | Corneal erosions (late) | **Corneal erosions (early)** | Absent | Absent | | **Renal Involvement** | Tubular dysfunction, Fanconi syndrome | Absent | Absent | Absent | | **Frequency** | Most common | Rare | Very rare | Most common in neonates | ### Type I Tyrosinemia: Pathophysiology **Enzyme:** Fumarylacetoacetate hydrolase (FAH) — final step in tyrosine catabolism **Metabolic Block:** $$\text{Tyrosine} \to \text{...} \to \text{Fumarylacetoacetate} \xrightarrow{\text{FAH}} \text{Fumarate + Acetoacetate}$$ Accumulation of **fumarylacetoacetate** and its precursor **succinylacetone** → hepatotoxicity ### Clinical Features of Type I 1. **Acute form** (infancy): hepatomegaly, jaundice, coagulopathy, renal tubular dysfunction (Fanconi syndrome) 2. **Chronic form** (childhood): progressive cirrhosis, hepatocellular carcinoma (HCC risk ~37% by age 20) 3. **Neurological crises**: hyperammonemia, encephalopathy, seizures 4. **Renal**: tubular dysfunction, hypophosphatemic rickets, hypokalemia ### Diagnostic Hallmark **Succinylacetone in urine** — pathognomonic for Type I; absent in Types II, III, IV **High-Yield:** Type I is the **most common hereditary tyrosinemia** and the **most clinically severe**; nitisinone (NTBC, a tyrosine hydroxylase inhibitor) is now standard therapy and dramatically improves prognosis. **Clinical Pearl:** Nitisinone blocks the step upstream of FAH deficiency, preventing accumulation of toxic metabolites; combined with dietary tyrosine/phenylalanine restriction, it reduces HCC risk and improves survival.