Volume 94 Number 6

Brief clinical and laboratory observations

leucine sensitivity. The present report describes two girls with XO karyotype who had fasting hypoglycemia which was aggravated by the administration of leucine. The first patient had nesidioblastosis of the pancreas, which is known to be associated with hyperinsulinism and leucine sensitivity.'-' The second patient had a milder form of idiopathic hyperinsulinism and leucine sensitivity. The presumed defect was transient beta cell hyperfunction, she required only a low-leucine diet to maintain her glucose concentrations in the normal range and because she experienced a spontaneous remission by age 2 years. Unfortunately, dietary management was not instituted early in this patient; consequently, permanent brain damage has resulted from prolonged unrecognized hypoglycemia.

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The occurrence of leucine-sensitive hypoglycemia in these patients with Turner syndrome is reported to document the association of these two disorders. This observation provides further evidence of pancreatic dysfunction in patients with X chromosomal abnormalities. REFERENCES

1. Engel E, and Forbes AP: Cytogenetic and clinical findings in 48 patients with congenitally defective or absent ovaries, Medicine 44:135, 1965. 2. Pagliara AS, Karl IE, Haymond M, and Kipnis DM: Hypoglycemia in infancy and childhood (Parts I and II), J PEDIATR82:365, 558, 1973.

Tyrosine aminotransferase isoenzyme deficiency F. Lemonnier,* C. Charpentier, M. Odievre, M. Larregue, and A. Lemonnier,

Le Kremlin-Bicetre, France

GOLDSMITH 1 recently defined tyrosinemia type II as a distinctive clinical syndrome involving the eyes, skin, and central nervous system. At the present time, seven observations have been described 1 including clinical and biochemical investigations. Fasting blood tyrosine values were increased in all patients, presumably due to a deficiency of cytosol tyrosine aminotransferase isoenzyme, but the enzyme activity was actually measured in only one patient, s' 3 It seems likely that other observations could be included in this syndrome, but clinical and biochemical investigations are often insufficient to establish their accurate classification. We report a new patient with tyrosinemia type II in whom cytosol isoenzyme deficiency is confirmed. This type is different from tyrosinemia type I, in which a pHPPA dioxygenase deficiency, presumably associated with other enzymatic deficiencies, and predominant renal and hepatic involvement are observed. PATIENT AND METHODS A girl, the second child of unrelated parents from the south-western part of France, developed conjunctivitis at From the Unitk de Recherches d'H~patologie Infantile, LN.S.E.R.M. U 56, HOpital d'Enfants, and Facultb des Sciences Pharmaceutiques et Biologiques, Universitk Paris-Sud. *Reprint address: Unit~ de Recherches d'Hbpatologie Infantile, INSERM U 56, HOpitald'Enfants, 94270 Le Kremlin-Bicetre, France.

0022-3476/79/600931 + 02500.20/0 9 1979 The C. V. Mosby Co.

2 weeks of age and bilateral keratitis at 4 months; at that time, she was nearly blind. Skin lesions appeared at 5 months of age and consisted of hyperkeratosis on the toes, fingers, and tongue. She also had severe mental retardation. Liver and kidney function tests were normal. Tyrosinemia type II was confirmed by biochemical investigations at 18 months of age. A phenylalanine-tyrosine-restricted diet (respectively, 58 and 54 mg/kg/day) was then started and resulted in the prompt disappearance of the skin and ocular lesions, with the exception of residual corneal clouding. However, mental development was not improved 14 months later.

Abbreviations used CSF: cerebrospinal fluid tyrosine aminotransferase TAT pHPPA dioxygenase: para hydroxyphenylpyruvate dioxygenase para hydroxyphenylpyruvic acid pHPPA: pHPLA: para hydroxyphenyllactic acid pHPAA: para hydroxyphenylacetic acid

Amino acid concentrations in blood and CSF were measured by ion exchange column chromatography (Technicon AutoAnalyzer). The urinary tyrosine metabolites were determined using gas-liquid chromatography (trimethylsilyl derivatives). The liver TAT activity was assayed in our patient and in two children who were

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Brief clinical and laboratory observations

Table I. Amino acid blood and urine concentrations of tyrosine metabolites

Patient

Blood (mg/dl) Tyrosine Phenylalanine CSF (mg/dl) Tyrosine Phenylalanine Urine (mg/24 hr) Tyrosine pHPPA pHPLA pHPAA

Normal diet

Restricted diet (2 days)

Control

52 5.3

22 0.36

0.45- 1.1 0.46- 1.2

3.4 Traces

0.05- 0.16 Traces

66.2 12.4 33.8 7.7

3.4 -13.5 0 0 1.05

Table II. Liver aminotransferase activity; the results are expressed by m U / m g protein (one milliunit = nmol of p-hydroxyphenylpyruvate produced per minute and per milligram of protein)

TAT Mitochondrial Control 1 Control 2 Patient

13.2 10.7 23

[

Cytosol 8.5 8.2 Not detected

chronic HBs antigen carriers and were used as control. Informed consent of parents was obtained in all cases. The assay was performed as described by Diamondstone 4 in mitochondrial and cytosol fractions.'-' RESULTS Amino acid concentrations in blood and CSF were normal with the exception of elevated tyrosine and moderately increased phenylalanine values (Table I). Tyrosine metabolites, in particular pHPPA and pHPLA, were excreted in large amounts in the urine. However, N-acetyl tyrosine was not present. Tyrosine aminotransferase activity was not detected in the cytosol but was normal in the mitochondrial fraction and was even more elevated than in either of the two controls (Table II). Blood tyrosine and phenylalanine concentrations decreased within two days When ingesting the restricted diet (Table I). Blood tyrosine concentration was still moderately elevated (between 6 and 8 mg/dl) after 14 months of treatment in spite of a well-controlled diet.

The Journal of Pediatrics June 1979

DISCUSSION The clinical and biochemical data in our patient are in agreement with those data previously reported. 1 This study also confirms the beneficial effect of a restricted diet, with the exception that cerebral damage was not prevented. Previous biochemical studies, thoroughly done in only one patient, 2.3 differed from our results by showing a normal blood phenylalanine concentration, and an increased urine N-acetyl tyrosine excretion. We have no explanation for this last discrepancy in view of the high blood tyrosine levels in our patient. Tyrosine is converted into the corresponding a ketoacid (para hydroxyphenylpyruvic acid) by tyrosine aminotransferase. Two isoenzymes are known: mitochondrial and cytosol TAT. Further catabolism of pHPPA leads to the tricarboxylic acid cycle via homogentisic acid. The enzyme which converts pHPPA to homogentisic acid is pHPPA dioxygenase. The enzyme defect in tyrosinemia type II is at the cytosol TAT step of the metabolic pathway of tyrosine. This defect does not explain the urinary excretion of large amounts of tyrosine metabolites, in particular pHPPA. Several explanations have been proposed. ~. :' Normal mitochondrial TAT activity could lead to increased production of pHPPA that must move back to cytoplasm to be oxidized because there is no pHPPA dioxygenase in mitochondria. Larger amounts of pHPPA and pHPLA in urine could be the consequence of substrate inhibitions of the cytosol pHPPA dioxygenase. Furthermore, tyrosine might also be converted to pHPPA by deamination in the kidney, and then excreted. Our findings concerning enzyme activities are similar to those previously reported 2 and are consistent with these hypotheses. The authors gratefully acknowledge Mrs. M. Couturier for her technical assistance. REFERENCES

1. Goldsmith LA: Molecular biology and molecular pathology of a newly described molecular disease-tyrosinemia type II (The Richner-Hanhart syndrome), Exp Cell Biol 46:96, 1978. 2. Fellman JH, Vanbellinghen PJ, Jones RT, and Koler RD: Soluble and mitochondrial forms of tyrosine aminotransferase. Relationship to human tyrosinemia, Biochemistry 8:615, 1969. 3. Kennaway NG, and Buist NRM: Metabolic studies in a patient with hepatic cytosol tyrosine aminotransferase deficiency, Pediatr Res 5:287, 1971. 4. Diamondstone TI'. Assay of tyrosine transaminase activity by conversion of P-hydroxyphenylpyruvate to P-hydroxybenzaldehyde, Anal Biochem 16:395, 1966.

Tyrosine aminotransferase isoenzyme deficiency.

Volume 94 Number 6 Brief clinical and laboratory observations leucine sensitivity. The present report describes two girls with XO karyotype who had...
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