In vivo confocal microscopic features of corneal pseudodendritic lesions in tyrosinemia type II.

PURPOSE: To report the clinical and in vivo confocal microscopic (IVCM) findings of corneal deposits in a patient with tyrosinemia type II. METHODS: The pretreatment and 1-month posttreatment slit-lamp examination and IVCM findings of a patient with tyrosinemia type II are described. RESULTS: A 12-year-old girl diagnosed with tyrosinemia type II was evaluated for photophobia and bilateral ocular discomfort of 1-year duration. The patient had been placed on topical acyclovir treatment with the diagnosis of recurrent bilateral herpetic keratitis during the previous 12 months. Slit-lamp examination revealed bilateral dendritiform epithelial lesions in the central cornea, which stained poorly with fluorescein. IVCM highlighted multiple hyperreflective linear crystalline deposits at the level of superficial epithelium. One month after discontinuation of acyclovir treatment and initiation of a protein-restricted diet therapy, improvement in the patient's symptoms and regression of corneal epithelial lesions was noted. Reduction in the extent of corneal deposits was also confirmed with IVCM. CONCLUSIONS: Corneal involvement, secondary to hereditary tyrosinemia type II, is characterized by pseudodendritic epithelial lesions on slit-lamp examination and hyperreflective linear deposits in the superficial epithelium using IVCM. These lesions may regress expeditiously with a low-protein diet. IVCM may be a useful tool in the differential diagnosis of this disorder by highlighting the crystalline structures in the superficial epithelial layers and also in evaluating the response to the treatment in patients with tyrosinemia type II.

Tyrosinemia type II (Richner-Hanhart syndrome): a new mutation in the TAT gene.

In the present study we report the clinical features and the molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in a young girl from Croatia with Richner-Hanhart syndrome, mainly suffering from photophobia, hyperkeratosis of the palmes and soles and slight neurological abnormalities. Sequencing analysis of the TAT gene revealed a novel homozygous missense mutation c.1250G>A (p.R417Q) in exon 12, and herewith confirmed the clinical diagnosis. Showing the first symptoms in babyhood, at the age of 8 years it was for the first time clinically diagnosed that the patient suffers from tyrosinemia type II and a therapy with tyrosine and phenylalanine reduced diet has been started successfully. All symptoms disappeared within 2-4 weeks. Since that time, we have been following the girl until today for more than ten years. She is in a good condition, and attends the normal high school program.

Gene therapy for liver enzyme deficiencies: what have we learned from models for Crigler-Najjar and tyrosinemia?

The liver is the site of numerous metabolic inherited diseases. It has unique features that make it compliant to various gene therapy approaches. Many vector types and gene delivery strategies have been evaluated during the past 20 years in a number of animal models of metabolic liver diseases. However, the complete cure of inherited liver deficiencies by gene therapy in relevant animal models were only reported recently. These successes were achieved thanks to major advances in vector technology. In this review, we will focus on Crigler-Najjar disease and hereditary tyrosinemia, two paradigmatic examples of the two categories of enzymatic liver deficiencies: type I, in which the genetic defect does not affect liver histology; and type II, in which liver lesions are present.

The narrow substrate specificity of human tyrosine aminotransferase--the enzyme deficient in tyrosinemia type II.

Human tyrosine aminotransferase (hTATase) is the pyridoxal phosphate-dependent enzyme that catalyzes the reversible transamination of tyrosine to p-hydrophenylpyruvate, an important step in tyrosine metabolism. hTATase deficiency is implicated in the rare metabolic disorder, tyrosinemia type II. This enzyme is a member of the poorly characterized Igamma subfamily of the family I aminotransferases. The full length and truncated forms of recombinant hTATase were expressed in Escherichia coli, and purified to homogeneity. The pH-dependent titration of wild-type reveals a spectrum characteristic of family I aminotransferases with an aldimine pK(a) of 7.22. I249A mutant hTATase exhibits an unusual spectrum with a similar aldimine pK(a) (6.85). hTATase has very narrow substrate specificity with the highest enzymatic activity for the Tyr/alpha-ketoglutarate substrate pair, which gives a steady state k(cat) value of 83 s(-1). In contrast there is no detectable transamination of aspartate or other cosubstrates. The present findings show that hTATase is the only known aminotransferase that discriminates significantly between Tyr and Phe: the k(cat)/K(m) value for Tyr is about four orders of magnitude greater than that for Phe. A comparison of substrate specificities of representative Ialpha and Igamma aminotransferases is described along with the physiological significance of the discrimination between Tyr and Phe by hTATase as applied to the understanding of the molecular basis of phenylketonuria.

Richner-Hanhart syndrome: importance of early diagnosis and early intervention.

Fewer than 100 cases of Richner-Hanhart syndrome have been reported. We describe two additional patients who have the classic clinical, biochemical, and microscopic features of this syndrome.

Richner-Hanhart syndrome (tyrosinemia type II). Case report and literature review.

Richner-Hanhart syndrome (Tyrosinemia Type II) is an autosomal recessive disorder of amino acid metabolism characterized by ocular changes, painful palmoplantar hyperkeratosis, and mental retardation. Serum tyrosine increases due to tyrosine aminotransferase deficiency resulting in the deposition of tyrosine crystals in the cornea and in corneal inflammation. Patients are often misdiagnosed as having herpes simplex keratitis. We report on a child who presented with bilateral keratitis secondary to Tyrosinemia Type II diagnosed as herpes simplex keratitis.

[The metabolic basis of the hyperphenylalaninemias and tyrosinemia].

The hyperphenylalaninemias are caused by the defect of either phenylalanine hydroxylase (PAH) or tetrahydrobiopterin (BH4) cofactor. The former is diagnosed as phenylketonuria (PKU) or benign hyperphenylalaninemia, based on the serum phenylalanine values. The latter, so called malignant hyperphenylalaninemia, includes three enzyme defects, dihydropteridine reductase (DHPR), 6-pyruvoyl tetrahydropterin synthase (PT PS) and guanosine triphosphate cyclohydrolase (GTP-CH). Excess phenylalanine and its metabolites cause brain damage before 6 years of age. Deficiency of BH4 impairs two other hydroxylases (tyrosine and tryptophan), and severe neurological symptoms develop because of the lack of neurotransmitters. Tyrosinemia I, II, and III are different enzyme defects, fumarylacetoacetate hydrolyase (FAH), hepatic tyrosine aminotransferase (TAT), and 4-hydroxyphenylpyruvate acid oxidase, respectively. Tyrosinemia I is associated with severe involvement of the liver, kidney and central nervous system. Tyrosinemia II has mental retardation, palmar hyperkeratosis and corneal ulcers. Tyrosinemia III has mild mental retardation but no eye or skin manifestations.

Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus.

We describe an Ashkenazi Jewish family in which two adults, offspring of consanguineous parents, have persistent hypertyrosinaemia (770-1110 mumol/L; normal less than 110 mumol/L). The metabolic disorder in this family is apparently due to hepatic cytosolic tyrosine aminotransferase deficiency (hereditary tyrosinaemia, type II; McKusick, 276600), because it is associated with the oculocutaneous manifestations of Richner-Hanhart syndrome. The association of this syndrome with hereditary tyrosinaemia type II is presumed to be constant. It is not in this family. The affected female sib (age 41 years) has hypertyrosinaemia and oculocutaneous signs; the brother (age 39 years) has hypertyrosinemia but no oculocutaneous disease. Both sibs have two children; none has signs of a metabolic fetopathy. Maternal hypertyrosinaemia and maternal hyperphenylalaninaemia evidently constitute different risk factors for the fetus. Paternal hypertyrosinaemia is apparently not a risk to male infertility.

Applications of automated amino acid analysis using 9-fluorenylmethyl chloroformate.

A rapid and sensitive fully automated method for the determination of primary and secondary amino acids in different matrices is described. Amino acids are derivatized with 9-fluorenylmethyl chloroformate using an automated precolumn derivatization technique. Data are presented to show that the technique is both reproducible and highly sensitive. Applications of the technique are presented, including the analysis of peptide and protein hydrolysates and the profiling of free amino acids in physiological fluids.

Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1----q22.3 in a patient with tyrosinemia type II.

Tyrosinemia II is an autosomal-recessively inherited condition caused by deficiency in the liver-specific enzyme tyrosine aminotransferase (TAT; EC 2.6.1.5). We have restudied a patient with typical symptoms of tyrosinemia II who in addition suffers from multiple congenital anomalies including severe mental retardation. Southern blot analysis using a human TAT cDNA probe revealed a complete deletion of both TAT alleles in the patient. Molecular and cytogenetic analysis of the patient and his family showed one deletion to be maternally inherited, extending over at least 27 kb and including the complete TAT structural gene, whereas loss of the second TAT allele results from a small de novo interstitial deletion, del 16 (pter----q22.1::q22.3----qter), in the paternally inherited chromosome 16. Three additional loci previously assigned to 16q22 were studied in our patient: haptoglobin (HP), lecithin: cholesterol acyltransferase (LCAT), and the metallothionein gene cluster MT1,MT2. Of these three markers, only the HP locus was found to be codeleted with the TAT locus on the del(16) chromosome.