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Hypertyrosinemia Type II – Causes, Symptoms and Treatment

Hypertyrosinemia type II is a rare inherited metabolic disorder characterized by elevated levels of the amino acid tyrosine in the blood, affecting the eyes, skin, and neurological development.

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Things worth knowing about "Hypertyrosinemia Type II"

Hypertyrosinemia type II is a rare inherited metabolic disorder characterized by elevated levels of the amino acid tyrosine in the blood, affecting the eyes, skin, and neurological development.

What is Hypertyrosinemia Type II?

Hypertyrosinemia type II (also known as Richner-Hanhart syndrome or oculocutaneous tyrosinemia) is a rare, autosomal recessive inherited metabolic disorder. It belongs to the group of aminoacidopathies and is characterized by abnormally elevated concentrations of the amino acid tyrosine in the blood and urine. The underlying cause is a deficiency of the hepatic enzyme tyrosine aminotransferase, which impairs the normal breakdown of tyrosine.

Causes

The condition is caused by mutations in the TAT gene (tyrosine aminotransferase gene), located on chromosome 16q22.2. This gene encodes the enzyme tyrosine aminotransferase, which catalyzes the first step in tyrosine catabolism in the liver. When this enzyme is absent or severely reduced in function, tyrosine accumulates in body fluids and tissues. Tyrosine crystals deposit in various organs, triggering local inflammatory reactions.

The disorder follows an autosomal recessive inheritance pattern, meaning that a child must inherit one defective copy of the gene from each parent in order to develop the condition. The exact prevalence is unknown, but the condition is considered extremely rare.

Symptoms

The clinical presentation of hypertyrosinemia type II is characterized by a triad of ocular, cutaneous, and neurological symptoms:

Ocular involvement: Eye symptoms typically appear during the first year of life and include eye pain, photophobia (sensitivity to light), excessive tearing (epiphora), and redness. Dendritic corneal ulcers (branching ulcerations of the cornea) may develop, potentially leading to corneal scarring and impaired vision.
Skin involvement: Painful, hyperkeratotic (thickened, scaly) lesions on the palms and soles (palmoplantar keratoderma) typically appear during the first or second year of life. These lesions can be tender and inflamed.
Neurological and cognitive involvement: Some patients develop intellectual disability of varying severity, delayed motor development, and in some cases seizures. Neurological involvement is variable and does not affect all patients.

Diagnosis

Diagnosis is established through a combination of clinical findings and laboratory investigations:

Plasma amino acid analysis: Detection of markedly elevated tyrosine levels in the blood (typically above 1000 µmol/L; normal values below 100 µmol/L).
Urine analysis: Increased urinary excretion of tyrosine and its metabolites (e.g., 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate).
Molecular genetic testing: Identification of pathogenic variants in the TAT gene to confirm the diagnosis and facilitate genetic counseling.
Newborn screening: In some countries, tandem mass spectrometry-based newborn screening programs can detect elevated tyrosine levels, enabling early diagnosis.
Ophthalmological examination: Slit-lamp examination to assess corneal lesions.
Skin biopsy: May be performed in cases of unclear skin findings to support the diagnosis.

Treatment

Treatment of hypertyrosinemia type II aims to normalize blood tyrosine levels and prevent or limit organ damage.

Dietary Therapy

The cornerstone of treatment is a diet restricted in tyrosine and phenylalanine. Since phenylalanine is metabolically converted to tyrosine in the body, its intake must also be controlled. The diet involves limiting protein-rich foods such as meat, fish, dairy products, and legumes, alongside the use of special amino acid formulas that are free of tyrosine and phenylalanine to meet protein requirements. This dietary regimen should be maintained lifelong.

Medical Treatment

Currently, there is no approved pharmacological therapy that directly corrects the enzyme defect. Dietary management remains the standard of care. Topical eye drops may be used for symptomatic relief of ocular involvement.

Long-Term Monitoring

Regular monitoring of blood tyrosine levels, ophthalmological examinations, and neurodevelopmental assessments are essential. With early and consistent dietary treatment, most organ complications can be prevented or significantly reduced.

Prognosis

With early diagnosis and consistent dietary therapy, the overall prognosis is generally favorable. Ocular symptoms and skin lesions often improve substantially under treatment. Neurological outcomes depend heavily on the timing of treatment initiation: early intervention, ideally within the first weeks of life, minimizes the risk of permanent cognitive impairment.

References

Orphanet: Richner-Hanhart Syndrome (Tyrosinemia Type II) - www.orpha.net (accessed 2024)
Natt E, Kida K, Odievre M et al.: Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II. Proc Natl Acad Sci USA. 1992;89(19):9297-9301.
Maillol A, Vianey-Saban C, Morin G et al.: Tyrosinaemia type II. In: Inborn Metabolic Diseases - Diagnosis and Treatment. Fernandes J, Saudubray J-M, Walter JH, van den Berghe G (eds.), Springer, 5th edition, 2012.

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