Tyrosinemia type 2 (ORPHA:28378)
A rare inborn error of tyrosine metabolism characterized by hypertyrosinemia with oculocutaneous manifestations and, in some cases, intellectual deficit.
Epidemiology
Prevalence is unknown but less than 150 cases have been reported in the literature so far. The disease appears to be more common in Arab and Mediterranean populations.
Clinical description
Skin lesions occur in 80% of cases, ocular involvement in 75% of cases and neurologic findings and some degree of intellectual deficit in up to 60% of cases. Onset is variable but the ocular symptoms (redness, photophobia, excessive tearing and pain) usually develop in the first year of life. Ocular signs include corneal clouding with bilateral dendritiform corneal lesions (pseudodendritic keratitis), neovascularization, corneal ulceration and scarring, which may lead to decreased visual acuity. Cutaneous manifestations usually begin after the first year of life but may develop at the same time as the ocular symptoms. The skin lesions consist of nonpruritic, hyperkeratotic papules and plaques principally located on the palms and soles (palmoplantar hyperkeratosis). These lesions are painful and progressive and are often associated with hyperhidrosis. Central nervous system (CNS) involvement is highly variable with intellectual deficit (ranging from mild to severe) being the most common manifestation. Other signs of CNS involvement include behavioral problems, nystagmus, tremor, ataxia, and convulsions.
Etiology
Tyrosinemia type 2 is caused by mutations in the TAT gene (16q22.2) encoding tyrosine aminotransferase (TAT). The elevated levels of tyrosine caused by TAT deficiency appear to result in deposition of tyrosine crystals leading to an inflammatory response and the oculocutaneous findings. Tyrosine crystals were not found in skin lesions; it was suggested that intracellular tyrosine excess interfere with microtubules and tonofilaments. It has also been suggested that there is a correlation between the extent of the CNS involvement and the levels of tyrosine in the plasma.
Diagnostic methods
Diagnosis is established on the basis of the clinical findings and detection of high levels of plasma and urinary tyrosine, and elevated levels of urinary tyrosine metabolites (such as 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate, 4-hydroxyphenylacetate and N-acetyltyrosine). The confirmation of the diagnosis is done by mutations analysis; TAT assays on liver biopsy samples are usually not necessary. Some patients with tyrosinemia type 2 may be identified through neonatal screening program studies.
Differential diagnosis
As the ocular findings are often the initial manifestations of the disease, the pseudodendritic keratitis is often mistaken for herpes simplex keratitis. Mutilating palmoplantar keratoderma with periorificial keratotic plaques is also part of the differential diagnosis.
Antenatal diagnosis
Antenatal diagnosis is possible with chorionic villus sampling and amnioncentesis when a mutation has been identified in the family.
Genetic counseling
Tyrosinemia type 2 is an autosomal recessive disorder. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them there is a 25% chance of having an affected child at each pregnancy.
Management and treatment
Management revolves around dietary restriction of phenylalanine and tyrosine. Oral retinoids may also be administered for treatment of the skin lesions.
Prognosis
The controlled diet results in lowering of plasma tyrosine levels and rapid resolution of the oculocutaneous manifestations. However, the extent to which this controlled diet prevents the CNS involvement is unclear.

                            Last update: 
                            June 2023


                            - Expert reviewer(s): 
                            Dr Corinne DE LAET | MetabERN*


                                * European Reference Network