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Tyrosinemia Type II: Report of the First Four Cases in Saudi Arabia

1998; King Faisal Specialist Hospital and Research Centre; Volume: 18; Issue: 5 Linguagem: Inglês

10.5144/0256-4947.1998.466

0975-4466

Mohammed Alessa, Masoud Mahdavi Rashed, Pinar T. Ozand,

Diabetes and associated disorders

Brief ReportsTyrosinemia Type II: Report of the First Four Cases in Saudi Arabia M. Al-Essa, MD M. Rashed, and PhD P.T. OzandMD, PhD M. Al-Essa From the Departments of Pediatrics and Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Search for more papers by this author , M. Rashed From the Departments of Pediatrics and Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Search for more papers by this author , and P.T. Ozand Address reprint requests and correspondence to Dr. Ozand: Department of Pediatrics, MBC-58, King Faisal Specialist Hospital and Research Centre, P.O. Box 3354, Riyadh 11211, Saudi Arabia. From the Departments of Pediatrics and Biological and Medical Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Search for more papers by this author Published Online:1 Sep 1998https://doi.org/10.5144/0256-4947.1998.466SectionsPDFCite ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionTyrosinemia type II (oculocutaneous tyrosinemia) is an autosomal recessive disorder due to deficiency of tyrosine aminotransferase, an enzyme involved in the metabolism of tyrosine.1 More than 50 cases have been reported to date. Most of the patients are Italian, German, French, Swedish, Spanish, Norwegian, American, Canadian, Australian, and Turkish Ashkenazi Jews.2–5 Almost half of the patients that have been reported are from Italy.6 Our files contain four patients under clinical follow-up with confirmed biochemical diagnosis for tyrosinemia type II.The aim of this study is to increase the awareness of the scientific and medical community, particularly in the Kingdom of Saudi Arabia, of the clinical progression of this disease, the ability to make a diagnosis through tandem mass spectrometry (MS/MS) and the rewarding clinical response and prevention of complications by use of dietary therapy.PATIENTS AND METHODSThe clinical and biochemical data of four tyrosinemia type II patients were reviewed retrospectively. They were diagnosed by the Inborn Errors of Metabolism section at King Faisal Specialist Hospital and Research Centre (KFSH&RC), a tertiary referral center for metabolic diseases in the Kingdom of Saudi Arabia. All of the patients had the typical clinical presentation, with mild mental retardation, progressive painful nonpruritic and hyperkeratotic plaques on the soles and palms. An experienced physician assessed their IQ, and the eye examination was performed by an ophthalmologist. The diagnosis of the disease was established by the findings of high-plasma tyrosine and normal plasma phenylalanine levels through plasma high-pressure liquid chromatography (HPLC) and tandem mass spectrometry (MS/MS) (Figure l). 7Figure 1. (Top) Electrospray tandem mass spectrometry (ESI-MS/MS) analysis of blood spot from a patient with tyrosinemia type II, showing a high tyrosine level. (Bottom) ESI-MS/MS analysis of blood spot from a control.Download FigureRESULTSThe tyrosinemia type II patients reviewed at KFSH&RC were from the Western part of Saudi Arabia, and came from the same tribe. They included three women aged between 25 and 30 years, and a boy of seven years. They were all mildly mentally retarded and had painful nonpruritic and hyperkeratotic plaques on the soles and palms. No eye signs or symptoms could be demonstrated. The treatment consisted of dietary restriction of tyrosine and phenylalanine to a degree sufficient to achieve a resolution of the clinical symptoms. The patients were compliant with the dietary therapy, and six weeks later, the hyperkeratotic plaques on the soles and palms had completely healed (Figure 2). Before the initiation of therapy, the tyrosine values were above 1000 μmol/L (normal 30-90 μmol/L) in all of the patients. There was a drop of between 15%-20% in the tyrosine levels after the dietary therapy (Figure 3). This drop was accompanied by a parallel improvement in the clinical status of the patients.Figure 2A. A patient with tyrosinemia type II who suffered from painful progressive hyperkeratotic plaques before therapy.Download FigureFigure 2B. The same patient after dietary treatment shows complete healing of the lesions six weeks later.Download FigureFigure 3 Tyrosine levels in the four patients before and after therapy.Download FigureDISCUSSIONTyrosinemia type II (oculocutaneous tyrosinemia) is an autosomal recessive disorder due to deficiency of tyrosine aminotransferase (TAT). Skin, eye, and neurological signs are the cardinal features of this disease. Richner in 1938 8 and Hanhart in 1947 9 independently described this clinical syndrome.Skin manifestation of the disease usually begins after the first year of life, but may begin as early as one month of age. The patients usually suffer from progressive painful, nonpruritic, and hyperkeratotic plaques on the soles and palms. Hypothenar and thenar eminences are areas of predilection. Hyperhidrosis may be associated with hyperkeratosis.10 Leukokeratosis of the tongue has been reported.11 The pain in the soles may be severe enough to prevent ambulation.The eye symptoms include photophobia, redness, lacrimation and pain. An eye examination usually reveals conjunctivitis and neovascularization. Also, central dendritic corneal erosions are prevalent. If the patient is not treated, these lesions may progress to corneal opacities, cornea plana, stigmatism, strabismus and glaucoma, and thus visual acuity decreases. In our patients (aged 7-30 years), the lack of eye lesions is not unexpected, since some patients may only have their first ophthalmic manifestation in their forties.5 Moreover, the presenting complaint and the manifestations may be confined only to the skin,4,12,13 as in our patients, or to the eyes.14–16The mental retardation may be variable, and occurs in less than 50% of the patients.2,6,17 There is no relationship between age of diagnosis and mental retardation. However, the degree of mental retardation may be related to higher values of plasma tyrosine.6 In rare cases, convulsions, microcephaly6 and behavioral disorders18 have been reported. Their association with TAT deficiency is unclear. The diagnosis can easily be established by high plasma levels of tyrosine, with other plasma amino acid levels being normal.10,17 Tyrosine is the only amino acid increased in the urine of these patients. TAT activity is reduced or absent in supernatant of liver homogenates.19,20 It is rarely necessary to perform a liver biopsy for TAT assay. Preclinical detection and treatment should be possible in areas where neonatal screening for hyper-tyrosenemia is practiced. The treatment consists of dietary restriction of tyrosine and phenylalanine to a degree sufficient to achieve a resolution of the clinical symptoms. There is no consensus on the optimal blood level of tyrosine, or at what age the diet should be started to prevent neurologic impairment. A blood level of tyrosine of 600 μmol/L is thought to be reasonable.Restriction-fragment-length polymorphism has been applied for the human TAT gene,21 and seven pathogenic point mutations have been described.22Tyrosinemia type II is a very labile disease, and from our local experience at KFSH&RC, we have observed that a tyrosine level of 1000 μmol/L is the “biochemical threshold” above which the clinical manifestations start to appear. This probably explains in part why these patients dramatically improved when the tyrosine level was kept below this figure. Commercial low-tyrosine low-phenylalanine formulas are available to optimize growth and meet the nutritional requirements for these patients. The eye and skin lesions, as in our patients, usually resolve after a few weeks of dietary therapy, but recur if the diet is stopped. Oral retinoids can improve skin lesions without changing the tyrosine level.18 Since there is risk of mental retardation in TAT-deficient patients, careful dietary control of maternal plasma tyrosine level should be considered during pregnancy.23 Treatment with systemic steroids should be avoided, as the disease can worsen with this therapy.24In a patient with painful and hyperkeratotic plaques on the soles and palms, the diagnosis of tyrosinemia type II should be suspected, and it can easily be confirmed by the high-plasma tyrosine level through blood tandem MS or amino acids profile. It is rarely necessary to perform a liver biopsy for the enzyme assay. Pre-clinical detection and treatment should be established, especially in areas where neonatal screening programs are practiced. Treatment of tyrosinemia type II is successful with dietary restriction of tyrosine and phenylalanine to a degree sufficient to achieve resolution of eye and skin symptoms. In order to optimize growth and meet the nutritional requirements, commercial low-phenylalanine and low-tyrosine formulas are available for this purpose.ARTICLE REFERENCES:1. Goldsmith LA, Kang E, Bienfang DC, Jimbow K, Gerald P, Baden HP. "Tyrosinemia with plantar and palmer keratosis and keratitis" . J Pediatr. 1973; 83:798–805. Google Scholar2. Goldsmith LA. Tyrosinemia and related disorders. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, Goldstein JL, Brown MS, editors. The metabolic basis of inherited disease. 5.th edition. New York: McGraw-Hill, 1983;287–299. Google Scholar3. Goldsmith LA, Laberge C. 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Mitchell G, Lambert M, Tanguay R. Hypertyrosinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited disease. 7.th edition. New York: McGraw-Hill, 1995:1077–106. Google Scholar24. Sayar RB, von Domarus D, Schäfer HJ, Beckenkamp G. "Clinical picture and problems of keratoplasty in Richner-Hanhart syndrome (tyrosinemia type II)" . Ophthalmologica. 1988; 197:1–6. Google Scholar Previous article Next article FiguresReferencesRelatedDetailsCited byAl-Ratrout J, Al-Muzian M, Al-Nazer M and Ansari N (2005) Plantar keratoderma: a manifestation of tyrosinemia type II (Richner-Hanhart Syndrome), Annals of Saudi Medicine, 25:5, (422-424), Online publication date: 1-Sep-2005. Volume 18, Issue 5September 1998 Metrics History Received18 November 1997Accepted14 June 1998Published online1 September 1998 InformationCopyright © 1998, Annals of Saudi MedicinePDF download