Tyrosinemia is an inborn error of tyrosine metabolism. There are three types of tyrosinemia (I, II and III), each has distinctive symptoms and is caused by the deficiency of a different enzyme. Tyrosinemia type II or oculocutaneous tyrosinemia is caused by a deficiency of the enzyme tyrosine amniotransferase, and is characterized by hypertyrosinemia with oculocutaneous manifestations and, in some cases, intellectual deficit. The disorder is transmitted as an autosomal recessive trait. To date, less than 150 cases have been reported in the literature. Diagnosis is based on measuring tyrosine aminotransferase (type II) activity in liver and kidney. Patients with Tyrosinemia type II usually have an isolated elevation of tyrosine only.
Patients with this type require dietary restriction of tyrosine and phenylalanine, respond to vitamin A supplementation in clearing of the skin lesions. The controlled diet results in lowering of plasma tyrosine levels and rapid resolution of the oculocutaneous manifestations. Early diagnosis of Tyrosinemia type II and protein-restricted diet are crucial to reduce the risk and the severity of long-term complications of hypertyrosinemia such as intellectual disability.
Rehak et al. (1981) described a family in which four siblings (two males and two females) presented with palmar and plantar keratosis of varying severity. The patients aged in range from 22-years to 10-years. Upon examination, they were all found to have lesions confined mainly to the soles and palms, along with ill-defined hyperkeratosis and lamellar peeling with fissuring. These lesions were tender and often painful. Some of the patients also had a yellow-green discoloration in these sites. All patients were pale and had fair hair as babies. The parents were first cousins. There were no ophthalmological abnormalities. Urine nitrosonaphthol test was positive in all the patients and negative in the parents, providing a suspicion of tyrosinemia. Qualitative amino acid analysis showed elevated tyrosine levels in the serum and urine of all patients. This was confirmed by quantitative tests. A diagnosis of tyrosinemia with the clinical characteristics of Richner-Hanhart syndrome was made, albeit with the absence of ophthalmological involvement. The patients were put on a restricted low tyrosine diet. Follow up over the next 18-months showed considerable improvement in the skin condition, and lowering of serum and urine tyrosine levels.
In a retrospective analysis of IEMs diagnosed over a 12-year period (1998-2010) in a hospital in Lebanon, Karam et al. (2013) found two patients diagnosed with Tyrosinemia Type II. Both patients were detected through newborn screening.
Maydan et al. (2006) investigated TAT gene mutations in nine tyrosinemia II patients from three consanguineous Palestinian kindreds. In two kindreds (seven patients), the only potential abnormality identified after sequencing all 12 exons and exon-intron boundaries was homozygosity for a silent, single-nucleotide transversion c.1224G > T (p.T408T) at the last base of exon 11. Homozygosity for a c.1249C>T (p.R417X) exon 12 nonsense mutation was identified in both patients from the third kindred, enabling successful prenatal diagnosis of an unaffected fetus using chorionic villous tissue.
Tallab (1996) described two Saudi brothers born to consanguineous parents with Tyrosinemia type II. The first patient was a 25-year-old man, who presented with painful skin lesions of the palms and soles associated with increased sweating. He had at the age of 1 year photophobia and recurrent eye pain, redness and tearing began at the age of 8 months. His serum tyrosine level was elevated and an excessive excretion of tyrosine and its metabolites was found in the urine. The second patient was an 11-year-old boy, he also had painful skin lesions of the palms and soles associated with increased sweating. His serum level was elevated and he had an excessive excretion of tyrosine, PHPPA, PHPLA, and PHPAA in the urine. Both patients were placed on a low tyrosine and phenylalanine diet.
Charfeddine et al. (2006) studied three unrelated consanguineous Tunisian families including seven patients with confirmed biochemical diagnosis of tyrosinemia type II. Mutation analyses revealed the presence of two novel missense mutations (p.C151Y and p.L273P) within exons 5 and 8, respectively. Charfeddine et al. (2006) observed phenotypic variability even among individuals sharing the same pathogenic mutation. In a later study, Bouyacoub et al. (2013) studied the clinical features and molecular etiology of the tyrosine aminotransferase (TAT) gene in two young patients, both born to consanguineous unions between first-degree cousins. These two unrelated families originated from Northern and Southern Tunisia. The clinical diagnosis was based on the observation of several complications related to Richner-Hanhart syndrome: recurrent eye redness, tearing and burning pain, photophobia, bilateral pseudodendritic keratitis, an erythematous and painful focal palmo-plantar hyperkeratosis and a mild delay of mental development. Sequencing of the TAT gene revealed the presence of a previously reported missense mutation (c.452G>A, p.Cys151Tyr) in a Tunisian family, and a novel G duplication (c.869dupG, p.Trp291Leufs 6).