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Hereditary Tyrosinemia Type I – Causes and Treatment

Hereditary tyrosinemia type I is a rare inherited metabolic disorder affecting the breakdown of the amino acid tyrosine, leading to severe liver and kidney damage if untreated.

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Hereditary tyrosinemia type I is a rare inherited metabolic disorder affecting the breakdown of the amino acid tyrosine, leading to severe liver and kidney damage if untreated.

What is Hereditary Tyrosinemia Type I?

Hereditary tyrosinemia type I (HT-1) is a rare, autosomal recessive metabolic disorder belonging to the group of inborn errors of amino acid metabolism. It affects the catabolic pathway of the amino acid tyrosine. Due to a specific enzyme deficiency, toxic metabolic intermediates accumulate in the body, causing progressive damage to the liver, kidneys, and peripheral nervous system. The condition occurs globally with an incidence of approximately 1 in 100,000 to 120,000 live births, though it is significantly more prevalent in certain regions such as the Saguenay-Lac-Saint-Jean region of Quebec, Canada.

Causes

HT-1 is caused by pathogenic variants in the FAH gene (fumarylacetoacetase), located on chromosome 15q23-q25. This gene encodes the enzyme fumarylacetoacetate hydrolase, which catalyzes the final step of tyrosine catabolism.

When this enzyme is absent or non-functional, toxic metabolites such as succinylacetone, fumarylacetoacetate, and maleylacetoacetate accumulate in tissues and body fluids.
Succinylacetone is the most characteristic and harmful metabolite: it inhibits heme biosynthesis and directly damages hepatocytes and renal tubular cells.
The disorder follows an autosomal recessive inheritance pattern, meaning both parents must carry a mutated copy of the FAH gene for a child to be affected.

Symptoms

The clinical presentation of HT-1 is variable and can manifest in acute, subacute, or chronic forms:

Acute Form

Onset typically within the first months of life
Severe acute liver failure with jaundice, coagulopathy, and ascites
Elevated liver enzymes, hypoglycemia, and hepatomegaly
Potentially fatal within the first two years of life without treatment

Chronic Form

Progressive liver cirrhosis and significantly elevated risk of hepatocellular carcinoma
Renal tubular dysfunction (Fanconi syndrome), leading to phosphate wasting and rickets
Neurological crises resembling acute intermittent porphyria, characterized by severe pain and autonomic dysfunction

Diagnosis

Diagnosis is established through a combination of biochemical, metabolic, and molecular methods:

Newborn screening: HT-1 is included in expanded newborn screening programs in many countries. Elevated succinylacetone levels in dried blood spots are the most specific marker and allow early diagnosis before symptoms appear.
Plasma amino acid analysis: Elevated tyrosine, methionine, and phenylalanine levels.
Urine organic acid analysis: Detection of succinylacetone and related toxic metabolites in urine.
Molecular genetic testing: Confirmation of diagnosis by identifying pathogenic FAH gene variants.
Liver imaging and biopsy: To assess the extent of hepatic involvement and screen for malignant transformation.

Treatment

The management of HT-1 has been transformed by the introduction of pharmacological therapy, dramatically improving patient outcomes.

Nitisinone (NTBC)

Nitisinone (formerly known as NTBC) is the first-line treatment and has revolutionized the management of HT-1. It works by inhibiting the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD), thereby blocking the production of the toxic downstream metabolites fumarylacetoacetate and succinylacetone. When initiated early, nitisinone effectively prevents hepatic failure, renal complications, and neurological crises.

Dosage: individually adjusted, typically 1-2 mg/kg body weight per day
Side effect: elevation of plasma tyrosine levels, making dietary restriction of tyrosine and phenylalanine mandatory

Dietary Therapy

In combination with nitisinone, patients require strict dietary management:

Severely restricted intake of phenylalanine and tyrosine
Use of specialized amino acid formulas free of tyrosine and phenylalanine
Lifelong dietary monitoring with regular blood amino acid level checks

Liver Transplantation

Prior to the availability of nitisinone, liver transplantation was the only curative option for HT-1. Today, it is reserved for exceptional cases such as established hepatocellular carcinoma or failure to respond to nitisinone therapy.

Prognosis

With early diagnosis through newborn screening and prompt initiation of nitisinone therapy combined with dietary management, the prognosis for patients with HT-1 has improved dramatically. Most affected children can lead largely normal lives. However, lifelong medical follow-up is essential, including regular liver surveillance with imaging and alpha-fetoprotein (AFP) levels, as a residual risk of hepatocellular carcinoma persists even during treatment.

References

Russo P.A. et al. - Tyrosinemia: A Review. Pediatric and Developmental Pathology, 2001. PMID: 11572155.
European Medicines Agency (EMA) - Orfadin (nitisinone) Summary of Product Characteristics. EMA, 2023. Available at: https://www.ema.europa.eu
Orphanet - Hereditary Tyrosinemia Type I. Available at: https://www.orpha.net (accessed 2024).

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