Tyrosinemia

Overview

Definition: A group of autosomal recessive inborn errors of tyrosine metabolism characterized by elevated blood tyrosine levels (hypertyrosinemia) and specific organ damage depending on the enzymatic defect.
Metabolic Pathway: Tyrosine is an aromatic amino acid derived from dietary protein or synthesized from phenylalanine. It is a precursor for dopamine, norepinephrine, epinephrine, melanin, and thyroxine.
Catabolism: Excess tyrosine is degraded to fumarate and acetoacetate; defects in this pathway lead to Tyrosinemias (Types I, II, and III).

Most severe and common form.

Enzyme Defect: Deficiency of Fumarylacetoacetate Hydrolase (FAH) (last enzyme in tyrosine catabolic pathway).
Genetics:
- Gene: FAH (Autosomal Recessive).
- Prevalence: High in French Canadians (Saguenay-Lac-Saint-Jean region: 1 in 1,846) due to founder effect; worldwide ~1:100,000.
Mechanism of Toxicity:
- Accumulation of upstream metabolites: Fumarylacetoacetate and Maleylacetoacetate.
- These are reduced to Succinylacetone (SA) and Succinylacetoacetate.
- Succinylacetone (SA):
  - Mitochondrial toxin: Inhibits Krebs cycle and oxidative phosphorylation.
  - Liver/Kidney toxicity: Alkylating agent causing DNA damage, cell death, and oncogenesis.
  - Porphyria-like crisis: Potent inhibitor of 5-aminolevulinate dehydratase (heme synthesis pathway) $\to$ accumulation of 5-aminolevulinic acid (ALA) $\to$ neurotoxicity.

A. Acute Form (Infantile)

Onset: Usually <6 months.
Hepatic Crisis: Acute liver failure, jaundice, ascites, coagulopathy (bleeding), hepatomegaly.
Odor: Characteristic "Boiled Cabbage" odor (due to methionine metabolites).
Sepsis-like picture: Fever, vomiting, irritability.
Mortality: High if untreated (liver failure).

B. Chronic Form (Childhood)

Onset: >6 months.
Hepatic: Chronic cirrhosis, micronodular cirrhosis, failure to thrive. High risk of Hepatocellular Carcinoma (HCC) (often in adolescence/early adulthood).
Renal: Fanconi Syndrome (proximal tubular dysfunction).
- Manifests as: Phosphaturia (hypophosphatemia), glycosuria, aminoaciduria, RTA.
- Result: Vitamin D-resistant Rickets (nephromegaly/nephrocalcinosis seen on USG).
Neurologic (Porphyria-like Crises):
- Triggered by infection/stress.
- Painful peripheral neuropathy (legs), extensor hypertonia, vomiting, paralytic ileus.
- Autonomic instability (HTN, tachycardia).
- Respiratory failure (diaphragmatic paralysis) requiring ventilation.
Cardiac: Hypertrophic cardiomyopathy (rare).

Diagnostic Marker: Elevated Succinylacetone (SA) in urine or blood (Pathognomonic).
Biochemistry:
- Plasma Tyrosine: Elevated (nonspecific, often 6–12 mg/dL).
- Plasma Methionine/Phenylalanine: Often elevated due to liver damage.
- Liver Function: Markedly elevated Alpha-fetoprotein (AFP) (often >100,000 ng/mL), coagulopathy (PT/aPTT prolonged). Transaminases variable.
- Urine: Elevated 5-ALA (due to SA inhibition).
Newborn Screening (NBS): Succinylacetone is the preferred target (tyrosine alone misses many cases).
Molecular Genetics: FAH gene mutation analysis.

1. Pharmacotherapy (Mainstay)

Drug: Nitisinone (NTBC) (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione).
Mechanism: Potent inhibitor of 4-Hydroxyphenylpyruvate Dioxygenase (4-HPPD).
- Blocks the pathway upstream of the defect, preventing formation of toxic Fumarylacetoacetate and Succinylacetone.
Dosing: 1–2 mg/kg/day.
Effect: Rapid normalization of SA and liver function; dramatic reduction in porphyria crises.
Side Effect: Causes marked hypertyrosinemia (must be combined with diet).

2. Dietary Management

Restriction: Low Phenylalanine and Tyrosine diet.
Formula: Special metabolic formula (Phe/Tyr free).
Goal: Keep plasma Tyrosine 200–400 µmol/L (to prevent corneal/skin lesions from NTBC-induced hypertyrosinemia) while ensuring growth.

3. Liver Transplantation

Indications:
- Acute liver failure refractory to medical therapy.
- Suspected or confirmed Hepatocellular Carcinoma (HCC).
- Poor response to NTBC.

Oculocutaneous form.

Enzyme Defect: Cytosolic Tyrosine Aminotransferase (TAT).
Gene: TAT (Autosomal Recessive).
Pathophysiology: Extreme hypertyrosinemia (>1,200 µmol/L) leads to tyrosine crystal deposition in tissues (eye, skin). No toxic metabolites like SA.

Ocular (Early, <1 year):
- Photophobia, excessive tearing, redness.
- Herpetiform corneal ulcers (bilateral, poor staining with fluorescein). Often misdiagnosed as HSV keratitis.
Cutaneous (Later):
- Painful Palmoplantar Hyperkeratosis (thickened skin on pressure points: soles, palms).
Neurologic:
- Mild to moderate Intellectual Disability (50% cases).

Plasma: Markedly elevated Tyrosine (>1,200 µmol/L). Normal Methionine.
Urine: Elevated Tyrosine metabolites (4-hydroxyphenylpyruvate). Absent Succinylacetone.
Genetics: TAT gene.

Diet: Strict Phenylalanine and Tyrosine restriction.
Outcome: Rapid resolution of skin and eye lesions. Neurocognitive outcome depends on early initiation.

Enzyme Defect: 4-Hydroxyphenylpyruvate Dioxygenase (4-HPPD).
Gene: HPD.
Clinical: Very rare. Neurologic symptoms (seizures, ataxia, ID). No liver/kidney damage.
Biochemistry: Moderate hypertyrosinemia; Absent Succinylacetone.
Treatment: Dietary restriction.

Etiology: Delayed maturation of 4-HPPD enzyme + high protein intake.
Epidemiology: Common in premature infants (up to 30%).
Clinical: Usually asymptomatic; may cause lethargy/poor feeding.
Labs: High Tyrosine (up to 3,300 µmol/L), high Phe.
Treatment: Spontaneous resolution (usually <2 months). Reduced protein intake. Vitamin C (cofactor for 4-HPPD) may hasten maturation.