Tyrosinemia

Overview

• Tyrosinemia represents a group of autosomal recessive inborn errors of tyrosine metabolism.
• Disorders are characterized by elevated blood tyrosine levels (hypertyrosinemia) and specific organ damage depending on the exact enzymatic defect.
• Tyrosine is an aromatic amino acid essential for the synthesis of dopamine, norepinephrine, epinephrine, melanin, and thyroxine.

flowchart TD
     Primary Pathway Nodes
    Tyr[Tyrosine]:::orangeNode
    HPPA[4-hydroxyphenylpyruvate]:::orangeNode
    HGA[Homogentisate]:::orangeNode
    MAA[Maleylacetoacetate]:::orangeNode
    FAA[Fumarylacetoacetate]:::orangeNode
    FA[Fumarate + Acetoacetate]:::orangeNode

     Main Tyrosine Degradation Pathway with Blocks
    Tyr -->|Tyrosine aminotransferase| HPPA
    HPPA -->|4-hydroxyphenylpyruvate dioxygenase <br> Blocked by NTBC| HGA
    HGA -->|Homogentisate dioxygenase <br> Blocked in AKU| MAA
    MAA -->|Maleylacetoacetate isomerase| FAA
    FAA -->|Fumarylacetoacetate hydrolase <br> Blocked in HT1| FA

     Downstream effects of Succinylacetoacetate
    SuccAceto --> SuccAcetone
    
    %% Inhibition of ALA to PBG pathway
    ALA -->|Enzyme conversion inhibited by <br> Succinylacetone| PBG
    SuccAcetone -. Inhibits .-> ALA

Classification Of Tyrosinemia

Feature	Tyrosinemia Type I	Tyrosinemia Type II	Tyrosinemia Type III	Transient Tyrosinemia
Alternate Name	Hepatorenal Tyrosinemia	Oculocutaneous Tyrosinemia (Richner-Hanhart)	4-HPPD Deficiency	Transient Tyrosinemia of the Newborn
Enzyme Defect	Fumarylacetoacetate Hydrolase (FAH)	Tyrosine Aminotransferase (TAT)	4-Hydroxyphenylpyruvate Dioxygenase (4-HPPD)	Delayed maturation of 4-HPPD
Gene	FAH (15q25.1)	TAT (16q22.2)	HPD (12q24.31)	None (Maturational delay)
Pathognomonic Marker	Elevated Succinylacetone (SA)	Extreme Hypertyrosinemia (>1,200 µmol/L)	Absent Succinylacetone	High Tyrosine and Phenylalanine
Primary Target Organs	Liver, Kidneys, Peripheral Nerves	Eyes, Skin, Central Nervous System	Central Nervous System	Usually asymptomatic

Tyrosinemia Type I (Hepatorenal Tyrosinemia)

Pathophysiology

• Caused by deficiency of Fumarylacetoacetate Hydrolase (FAH), the final enzyme in the tyrosine catabolic pathway.
• Leads to accumulation of upstream metabolites Fumarylacetoacetate and Maleylacetoacetate, which are reduced to the toxic metabolite Succinylacetone (SA).
• Succinylacetone acts as a mitochondrial toxin that inhibits the Krebs cycle and oxidative phosphorylation.
• Succinylacetone is an alkylating agent causing DNA damage, cell death, and oncogenesis in the liver and kidneys.
• Succinylacetone potently inhibits 5-aminolevulinate dehydratase, causing accumulation of 5-aminolevulinic acid (ALA) and resulting in porphyria-like neurotoxic crises.

Clinical Features

• Acute Infantile Form (<6 months):
  • Acute liver failure, jaundice, coagulopathy with bleeding, and ascites.
  • Sepsis-like presentation with fever, vomiting, and irritability.
  • Characteristic “boiled cabbage” odor due to methionine metabolites.
• Chronic Childhood Form (>6 months):
  • Hepatic: Chronic micronodular cirrhosis, failure to thrive, and high risk of Hepatocellular Carcinoma (HCC).
  • Renal: Renal Fanconi syndrome causing phosphaturia, glycosuria, and aminoaciduria, resulting in Vitamin D-resistant rickets.
  • Neurologic: Porphyria-like crises triggered by infection, manifesting as painful peripheral neuropathy, extensor hypertonia, and respiratory failure requiring ventilation.

Investigations

• Diagnostic Marker: Elevated Succinylacetone in blood or urine is pathognomonic.
• Newborn Screening (NBS): Succinylacetone is the preferred target, as testing tyrosine alone misses cases.
• Biochemistry:
  • Elevated plasma Tyrosine, Methionine, and Phenylalanine.
  • Markedly elevated Alpha-fetoprotein (AFP), often >100,000 ng/mL.
  • Prolonged PT/aPTT indicating coagulopathy.
  • Elevated urinary 5-ALA.

Management

• Pharmacotherapy: Nitisinone (NTBC) at 1–2 mg/kg/day is the mainstay of therapy.
  • Inhibits 4-Hydroxyphenylpyruvate Dioxygenase (4-HPPD) upstream of the defect, preventing formation of toxic Succinylacetone.
  • Causes secondary hypertyrosinemia, requiring dietary management.
• Dietary Modification: Low Phenylalanine and Tyrosine diet using special metabolic formulas to prevent NTBC-induced hypertyrosinemia complications.
• Liver Transplantation: Indicated for acute liver failure refractory to medical therapy, confirmed or suspected Hepatocellular Carcinoma, or poor response to Nitisinone.

Tyrosinemia Type II (Oculocutaneous Tyrosinemia)

Pathophysiology And Clinical Features

• Caused by deficiency of cytosolic Tyrosine Aminotransferase (TAT).
• Extreme hypertyrosinemia (>1,200 µmol/L) leads to tyrosine crystal deposition in ocular and cutaneous tissues.
• Ocular: Presents early (<1 year) with photophobia, tearing, and bilateral herpetiform corneal ulcers that stain poorly with fluorescein.
• Cutaneous: Painful palmoplantar hyperkeratosis on pressure points.
• Neurologic: Mild to moderate intellectual disability in 50% of cases.

Management

• Strict dietary restriction of Phenylalanine and Tyrosine leads to rapid resolution of skin and eye lesions.

Tyrosinemia Type III

Pathophysiology And Clinical Features

• Caused by deficiency of 4-Hydroxyphenylpyruvate Dioxygenase (4-HPPD).
• Exceedingly rare disorder presenting with neurological symptoms including seizures, ataxia, and intellectual disability.
• Characterized by absent Succinylacetone and absence of liver or kidney damage.
• Treated exclusively with dietary restriction of Phenylalanine and Tyrosine.

Transient Tyrosinemia Of The Newborn

Pathophysiology And Management

• Caused by delayed maturation of the 4-HPPD enzyme combined with high protein intake.
• Common in premature infants (up to 30%) and typically asymptomatic, though it may cause lethargy and poor feeding.
• Resolves spontaneously within 2 months.
• Managed with reduced protein intake and Vitamin C supplementation to hasten enzyme maturation.