The topic of this review is hepatorenal tyrosinemia (hereditary tyrosinemia type 1 [HT1], or fumarylacetoacetate hydrolase deficiency; OMIM# 276700). HT1 is the most serious and common of the genetic defects in tyrosine degradation. In addition, this disorder has importance as a model of spontaneous self-correction of liver disease, as a model of liver repopulation by transplanted cells and gene therapy, and as a genetic cause of hepatocarcinoma. However, other forms of hypertyrosinemia exist; hence, the differential diagnosis also will be described briefly. Recent years have seen much progress in our understanding of the molecular basis, the pathophysiology, and especially the treatment of HT1. The current intervention with 2-(2-nitro-4-trifluoro-methylbenzyol)-1,3 cyclohexanedione (NTBC) therapy has improved the outcome of this once devastating disorder. The successful repopulation of the HT1 liver with transplanted cells and positive results in the use of gene therapy in animal models may someday lead to therapy in humans that will obviate the need for life-long dietary and pharmacological therapy.

The pathophysiology and treatment of hereditary tyrosinemia type 1.

Lysosomal free sialic acid–storage diseases include the allelic disorders Salla disease (SD) and infantile sialic acid–storage disease (ISSD). The defective gene, SLC17A5, coding for the lysosomal free sialic acid transporter was recently isolated by positional cloning. In the present study, we have identified a large number of mutations in SLC17A5 in patients presenting with either Salla disease or the ISSD phenotype. We also report for the first time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n=80) had a missense mutation changing a highly conserved arginine to cysteine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one allele, presented with a more severe phenotype than did the homozygote patients. The same R39C mutation was also found both in most of the Swedish patients with SD and in a heterozygous form in five patients from central Europe who presented with an unusually severe (intermediate) SD phenotype. Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes. Our results indicate some genotype-phenotype correlation in free sialic acid–storage diseases, suggesting that the phenotype associated with the homozygote R39C mutation is milder than that associated with other mutations.

https://www.cell.com/ajhg/pdf/S0002-9297(07)63277-7.pdf

The Spectrum of SLC17A5-Gene Mutations Resulting in Free Sialic Acid–Storage Diseases Indicates Some Genotype-Phenotype Correlation

Metabolic and Nutritional Disorders

Tyrosinemia type II: nine cases of ocular signs and symptoms

Infantile free sialic acid storage disease (ISSD) is a rare autosomal recessive metabolic disorder caused by a lysosomal membrane transport defect, resulting in accumulation of free sialic acid within lysosomes. Only a few cases have been described. We report on three new cases of ISSD with different modes of presentation: an infant with nephrotic syndrome, a case of fetal and neonatal ascites with heart failure, and a case of fetal ascites with esophageal atresia type III. From these patients and a review of the literature (27 cases total) we draw the following conclusions. 1) “Coarse facies,” fair complexion, hepatosplenomegaly, and severe psychomotor retardation are constant findings in this disorder. 2) Nephrotic syndrome occurred in most cases (four in seven) in which renal evaluation was performed. Therefore, ISSD is an important cause of nephrosis in infants with a storage disorder phenotype. 3) Fetal/neonatal ascites or hydrops was the mode of presentation in 13 (60%) of 21 cases. Thus, ISSD enters in the differential diagnosis of hydrops fetalis with a storage disease phenotype. 4) Cardiomegaly was evident in nine cases. 5) Corneae were always clear, and albinoid fundi were reported in five cases. 6) Dysostosis multiplex was not prominent. 7) Bone marrow aspiration could be negative. 8) Death ensued in early infancy with a mean age of 13.1 months. All reported deaths were caused by respiratory infections. Am. J. Med. Genet. 82:385–391, 1999. © 1999 Wiley-Liss, Inc.

Clinical spectrum of infantile free sialic acid storage disease.

Hereditary type II tyrosinaemia (McKusick 27660) is an autosomal recessive disorder characterized by hypertyrosinaemia and tyrosyluria, without signs of hepatic and renal damage. The patients have a dendritic keratopathy, painful hyperkeratosis of the palms and soles and sometimes mental retardation. Hypertyrosinaemia with values ranging from 14 to 62mgdl−1, tyrosinuria and tyrosyluria are found. A defect of hepatic tyrosine aminotransferase (EC 2.6.1.5) in the cytosol is considered to be the molecular abnormality (Kennaway and Buist, 1971; Goldsmith et al., 1979).

Presentation of the data of the Italian registry for oculocutaneous tyrosinaemia

Increased amounts of free sialic acid were found in cultured fibroblasts and urine of a 4-year-7-month-old Italian boy with mental retardation, hypotonia, failure to thrive, coarse facial features, convergent strabismus, pale skin and fair hair. Ultramicroscopic examination of conjunctival and skin tissues showed a number of membrane-bound vacuoles containing low-density granular material in the cytoplasm of the fibroblasts. The clinical, biochemical and ultrastructural findings are similar to those described in Salla disease. Neuraminidase activity is normal.

Free sialic acid storage disease. A new Italian case.

Two cases of tyrosinaemia with eye and skin lesions typical of the Richner-Hanhart syndrome are described. The patients are a 29- and 26-year-old brother and sister. They do not show neurological abnormalities or mental retardation. Parents are not consanguineous and family history is negative for similar conditions. The diagnosis of type II tyrosinaemia was based upon an increase of blood tyrosine (14-16mg/100 ml), tyrosinuria and absence of liver and kidney abnormalities. The treatment with a low tyrosine phenylalanine diet has resulted in a disappearence of the ocular manifestations while the cutaneous lesions are much improved.

Familial Tyrosinaemia with Eye and Skin Lesions

A screening program for congenital hypothyroidism has been starting in Siena since November, 1977 with the Guthrie's test for PKU. According to the recommendations of the Committee of the European Thyroid Association the program were performed on capillary blood samples collected between the fourth and sixth days after birth on an adsorbent paper. The screening began with the measurement of T4 RIA (up to May, 1980), and T4 and TSH RIA (from may, 1980, to december, 1981). At december, 1981, 23.693 newborns have been screened. The recall rate was 2,5% up to may, 1980, and 0,11% from may, 1980 to december, 1981. Ten newborns with congenital hypothyroidism have been detected; the incidence is one in 2.400 live births. There were no cases of transient hypothyroidism and no cases of TBG deficiency. All patients are treated before the age of one month. The diagnosis is confirmed in seven cases at one year of life after stopterapy for one month. Our program confirm the high incidence of congenital hypothyroidism. Clinical control, based on physical and psychomotor development testing in seven patients treated confirmed that all infants are normal.

Results of a screening project for congenital hypothyroidism in 4 years of experience

Gyrate atrophy of the choroid and retina is a tapetoretinal dystrophy in which Simell and Takki (1973) observed an increase in plasma ornithine. The disease seems to be more frequent in Finland (Sipila et al., 1979) and the acronym HOGA, hyperornithinaemia-gyrate-atrophy, (McKusick 25887)has been suggested. A defect of ornithine-ketoacid aminotransferase (EC 2.6.1.13) has been demonstrated in transformed lymphocytes (Valle et al1977), and in fibroblasts (Trijbels et al., 1977), which do not convert L-ornithine to proline (O’Donnell et al., 1978). The inheritance of this condition is autosomal recessive (Takki and Simel, 1974).

P. Borgogni

Papers

Presentation of the data of the Italian registry for oculocutaneous tyrosinaemia

Free sialic acid storage disease. A new Italian case.

Familial Tyrosinaemia with Eye and Skin Lesions

Results of a screening project for congenital hypothyroidism in 4 years of experience

Gyrate Atrophy of the Choroid and Retina: 3 Cases in One Italian Family