HEREDITARY TYROSINEMIA

The clinical and biochemical findings in the case of an infant with hereditary tyrosinemia followed from birth have been reported. The child received a low protein diet from birth and a formula diet restricted in phenylalanine and tyrosine when the diagnosis was established at 54 days of age. There was a steady progress of the disease and the baby died from liver failure complicated with septicemia when he was 5½ months old. The clinical course and the biochemical findings as well as the morphological changes were typical of the acute type of the disease. A 6½ year old brother suffers from the same disease of the chronic type and the two types of hereditary tyrosinemia therefore seem to belong to the same genotype. The biochemical data from the patient with hereditary tyrosinemia have been compared with those in a healthy looking baby with longstanding and pronounced transient tyrosinemia of early infancy. The patterns of amino acids in blood and of phenolic acids in urine were similar in the two patients and it is concluded that an early laboratory differential diagnosis between hereditary tyrosinemia and transient tyrosinemia may only be made by observing the biochemical response to a diet restricted in tyrosine and phenylalanine in combination with the results of phenylalanine tolerance tests. The clinical features of hereditary tyrosinemia can apparently not be attributed to a high serum-tyrosine concentration or to the overproduction of phenolic acids; the lack of effect of early restriction in the intake of phenylalanine and tyrosine indicates a more complex pathogenesis of hereditary tyrosinemia than a primary deficiency of p-hydroxyphenylpyruvate hydroxylase.     

Enzyme defect in a case of tyrosinemia type I, acute form

We determined the activities of tyrosine aminotransferase (TAT, EC 2.6.1.5), p-hydroxyphenylpyruvate oxidase (p- HPPA oxidase, EC 1.14.2.2) and fumarylacetoacetate fumarylhydrolase ( FAH , EC 3.7.12) in cytosol of the liver and kidney tissues obtained at autopsy from a case of hereditary tyrosinemia type I. Values were compared with those from a control group of autopsied tissues from three adults and six children, who had died of other causes. In tyrosinemia, these three hepatic enzyme activities were all decreased: TAT showed approximately 35%, p- HPPA oxidase 11%, and FAH 60% of the corresponding control values. On the other hand, kidney enzymes in tyrosinemia revealed that FAH was most significantly decreased to approximately 14% of the control activity. Km values for substrate--determined for p- HPPA oxidase and FAH --were not different between the patient and controls, suggesting no altered properties of these enzymes. We conclude that in the present case of hereditary tyrosinemia type I, the activities of p- HPPA oxidase in liver and FAH in kidney were most strikingly affected. This fact may in part explain the deteriorated metabolism of tyrosine observed in this patient.     

Clinical Course of Hereditary Fructose Intolerance in 56 Patients

The clinical course of hereditary fructose intolerance (HFI) was investigated retrospectively in 56 patients. The most frequently observed features were hepatomegaly, vomiting, diarrhea and failure to thrive. Fructose containing formulae given in the neonatal period lead in about one third of patients to cirrhosis of the liver — regardless of the amount ingested. Among patients receiving small amounts of fructose a mild clinical course was observed five times as often as a severe course. Two out of 12 patients who had developed cirrhosis of the liver, died soon after diagnosis in the early months of life. This stresses the danger of infants receiving fructose very early. Good dietary control brought serum transaminase activity to normal in half the time required with poor control. There was no correlation between dietary control and the duration of hepatomegaly.     

Hereditary fructose intolerance in childhood. Diagnosis, management, and course in 55 patients

The early manifestations of hereditary fructose intolerance are described in a series of 55 patients. Management of this metabolic disorder depends on the severity of liver impairment. When the patients are given a fructose-free diet, the improvement is a dramatic but liver enlargement and fatty vacuolization of liver cells often persist. These hepatic findings were also observed in the five homozygous infants who were given a fructose-free diet from birth; this outcome may support the hypothesis that minimal amounts of fructose are esential for human beings.     

Metabolic studies of transient tyrosinemia in premature infants.

The recently developed technique of gas chromatography-mass spectrometry supported by computer has considerably improved the analysis of physiologic fluids. This study attempted to demonstrate the value of this system in the investigation of metabolite patterns in urine in two metabolic problems of prematurity, transient tyrosinemia and late metabolic acidosis. Serial 24-hr urine specimens were analyzed in 9 infants. Transient tyrosinemia, characterized by 5-10-fold increases over basal excretion of tyrosine, p-hydroxyphenyllactate, and p-hydroxyphenylpyruvate in urine, was noted in five of the infants. Several infants had fluctuating levels of tyrosine metabolites in urine although dietary protein intake remained constant at 3-4 g/kg/24 hr and ascorbic acid at 50 mg/24 hr. Late metabolic acidosis was seen in four infants, but bore no relation to transient tyrosinemia. The ratio of net acid to urea excretion in urine increased with increasing base deficit, implying a nonprotein origin of the metabolic acid. No unique metabolic patterns were characteristic of late metabolic acidosis.     

Fructose 1,6-diphosphatase deficiency in 2 sisters]

The discovery of a fructose-1,6-diphosphatase deficiency in two sisters leads to the discussion of the various loading tests which are required for the diagnosis. The diagnosis may be discussed clinically with type I glycogenosis, and biologically with hereditary fructose intolerance. The specific characteristics of these disorders are analyzed as well as the problem of fructose induced hypoglucosemia. The failure of the treatment with folic acid in one of the cases leads to emphasize the suppression of prolonged fast in order to avoid acute accidents.     

HEREDITARY FRUCTOSE INTOLERANCE IN FOUR SWEDISH FAMILIES

A brief review is given of hereditary fructose intolerance. Seven adult cases of the disease from four families, two of which are distantly related, are reported. Among their relations at least two more persons have shown symptoms of fructose intolerance. The first symptoms appeared in infancy on weaning, when sweetened formulas or fruit juice supplements were given, and consisted of retching, vomiting, and sweating. All the subjects quickly developed strong aversion to foods containing fructose. None had dental caries. All were physically and mentally normal. The characteristic hypoglycaemia and hypophosphataemia were observed in all cases in intravenous fructose tolerance tests. The plasma FFA showed an initial fall after injection of fructose, followed by a sharp rise. The initial fall probably supports the view that fructose is readily metabolized in adipose tissue in subjects with HFI. The subsequent rise may be due to lipolysis. The urinary excretion of adrenaline was examined in one case, and raised values were recorded during the fructose tolerance tests; the significance of this is discussed.     

Hereditary porphyria and acquired porphyria in the child. Five case reports]

Two cases of inherited porphyrinopathies and three cases of acquired porphyrinopathies are described. The two inherited cases were cutaneous porphyrias with 50% reduction of enzyme activities: one case of erythropoietic protoporphyria in a 2 year-old male and one case of familial cutaneous porphyria in a 7 year-old boy. The three cases of acquired porphyrinopathy included one case of lead poisoning in a 3 year-old boy and 2 cases of hereditary tyrosinemia in 1 and 2 year-old infants. Urinary and erythrocytes porphyrins and precursors (5 aminolevulinic acid and porphobilinogen) levels were used for diagnosis and to follow the response to treatment.     

HEREDITARY FRUCTOSE INTOLERANCE: REPORT OF A CASE AND COMMENTS ON THE HAZARDS OF FRUCTOSE INFUSION

A 3 year old child with hereditary fructose intolerance had been recognised by her parents as unable to metabolise cane sugar and fruit sugar, and had been reared very successally without professional aid. She developed appendicitis with pelvic peritonitis, and the unfortunate use of fructose infusion caused hepato-renal failure and death. The diagnosis was confirmed by postmortem assay of hepatic fructose-1-phosphate aldolase. A plea is made for care in the use of fructose infusion in all patients, especially in the newborn, and in those with liver disease. 3 other illustrative case histories are presented to support a claim that fructose infusion is potentially harmful and must be carefully monitored.     

Dietary fructose in the management of intractable diarrhea of infancy

Carbohydrate digestion/absorption was evaluated in 11 infants with intractable diarrhea while they were receiving a carbohydrate-free soy-isolate formula. Seven patients were fed within 48 h of admission. Enteral feedings were initiated in the remainder after they had gained 1 kg while receiving parenteral nutrition. All feedings were initially administered by continuous nasogastric infusion. Nine patients were initially fed formula with polymeric glucose; two received fructose as the carbohydrate source, based on a documented history of polymeric glucose intolerance. Five of the nine developed watery, acidic stools while receiving polymeric glucose. All were switched to fructose, which resulted in improvement in stool pH and consistency. Glucose tolerance was normal 1 month after discharge in all seven fructose-requiring infants. Three of six infants have shown a persistent inability to hydrolyze sucrose. Several putative mechanisms of polymeric glucose intolerance are discussed, as well as the apparent association with primary sucrase-isomaltase deficiency in three of the patients. Fructose is an effective alternative carbohydrate source in infants unable to tolerate polymeric glucose, and early initiation of fructose may obviate the need for total parenteral nutrition and prolonged bowel rest.     

Effect of dietary treatment on the renal tubular function in a patient with hereditary tyrosinemia

In a 1 1/2-month-old girl with hereditary tyrosinemia, renal tubular function studies were done. The effect of a low tyrosine and phenylalanine formula on renal tubular functions was also studied. The tubular handling of phosphorus, uric acid, beta 2-microglobulin, and amino acids was disturbed. Low urinary osmolality was also seen. Creatinine clearance was increased during a period of the standard formula. Although treatment with the low tyrosine and phenylalanine diet produces dramatic improvement in plasma tyrosine and tyrosyluria, all tubular symptoms did not revert to normal. It is possible that tubular dysfunction of hereditary tyrosinemia may be irreversible changes.     

先天性葡萄糖-半乳糖吸收不良研究进展

先天性葡萄糖-半乳糖吸收不良(CGGM)又称先天性葡萄糖-半乳糖不耐受症,是一种罕见的常染色体隐性遗传性疾病,国内研究与发现者甚少,至今国内未见本病的病例报道.该文就先天性葡萄糖-半乳糖吸收不良的发生机制、临床特点、诊断及治疗作一综述.     

Prenatal diagnosis of hereditary tyrosinemia by determination of fumarylacetoacetase in cultured amniotic fluid cells

Fumarylacetoacetase was assayed in cultured amniotic fluid cells from four pregnancies at risk for hereditary tyrosinemia and in 11 controls. The enzyme activity was normal in three of the pregnancies at risk for tyrosinemia and healthy children were born. In the fourth case the enzyme activity was deficient, indicating an affected fetus. As the pregnancy was very advanced it was continued, and the child has tyrosinemia. One parent in one of the four families is a compound heterozygote for the tyrosinemia gene and the recently reported "pseudodeficiency" gene for fumarylacetoacetase. This has important consequences for prenatal diagnosis in this family.     

Neonatal hemochromatosis: a case report with unique presentation

Acute liver failure (ALF) is a relatively rare condition in neonates, and early diagnosis and treatment are crucial for the treatable conditions. Neonatal hemochromatosis (NH) is a rare clinical condition that is clinically defined as severe neonatal liver disease associated with hepatic and extrahepatic iron deposition in a distribution similar to that seen in hereditary hemochromatosis. Although a few cases have been reported with spontaneous remission, early and aggressive medical treatment is essential for improving the outcome. Despite aggressive treatment, some patients may require liver transplantation. We report a five-day-old male infant with NH and associated Duarte variant galactosemia, renal tubulopathy and hypertyrosinemia, who was successfully treated with combination medical treatment. Combination therapy may reduce the need for liver transplantation in infants with NH. Early diagnosis and aggressive treatment are important as in galactosemia or tyrosinemia for the outcome. Thus, NH may be listed as a treatable cause of ALF in neonates.     

Fructose-induced hyperuricemia: observations in normal children and in patients with hereditary fructose intolerance and galactosemia.

After the infusion of fructose, 0.25 g/kg body wt, the mean peak plasma uric acid level was 5.4 +/- 0.7 (SEM) mg/100 ml in six normal children and was not significantly increased compared with that of the mean basal value of 4.1 +/- 0.5 mg/100 ml. The mean blood inorganic phosphate (Pi) levels were significantly less than the mean fasting value after fructose. Blood glucose, lactic acid, and fructose levels were significantly increased after fructose, but serum magnesium levels did not change. In two patients with hereditary fructose intolerance (HFI) the peak blood uric acid levels were 12.1 and 7.6 mg/100 ml, respectively, after fructose. In both patients the blood glucose concentrations decreased 69 and 26 mg/100 ml below the fasting levels after fructose. The serum Pi level decreased 2.3 and 1.2 mg/100 ml below fasting values, decrements greater than the mean decrement in serum Pi of 0.8 +/- 0.2 mg/100 ml which occurred in six normal children. The mean uric acid excretion, expressed as milligrams per mg urinary creatinine, was 0.6 +/- 0.1 (SEM) before fructose in the normal children and increased significantly to 1.0 +/- mg/mg creatinine after fructose. In two patients with HFI the uric acid excretion increased four- to fivefold after fructose administration; the increased uric acid excretion in HFI exceeded that of normal children. In three patients with galactosemia, increases in blood uric acid levels after galactose ingestion were similar to those in normal children after fructose, but less than those in patients with HFI after fructose. The serum Pi levels decreased less in galactosemic patients after galactose administration than in patients with HFI after fructose infusion. These studies support the hypothesis that fructose-induced hyperuricemia results from degradation of adenosine monophosphate. This effect appears to be specific for fructose. The lack of hyperruricemia in galactosemia patients after galactose ingestion may be explained by the observation that galactose is phosphorylated more slowly than fructose.     

Etiologic diagnosis of hypoglycemia in children

When the etiology of an hypoglycemia is not easily recognizable, the diagnosis can be guided by 2 signs: hepatomegaly and ketosis. If an hepatomegaly is present, an abnormality of glycogen metabolism or neoglucogenesis or an hereditary fructose intolerance may be suspected. A hypoketotic hypoglycemia suggests a hyperinsulinism or an impaired fatty acid oxydation. If the liver is normal and ketosis is normal or increased, an abnormality of branched amino acid metabolism or a ketotic hypoglycemia may be evoked.     

Experience and Problems of Newborn Mass Screening for Inborn Errors of Metabolism in Japan

A program of newborn mass screening for inborn errors of metabolism has since 1977 been conducted by The Ministry of Health and Welfare in Japan with great success in preventing mental and physical handicaps in children and estimating the incidence of these diseases in our country as follows: phenylketonuria (PKU) 1/78,100 maple syrup urine disease (MSUD) 1/281,200 histidinemia 1/10,600 galactosemia 1/156,200 There are some genetic variants of each of these diseases, PKU, MSUD and others. Circumspection is therefore required in making a diagnosis or selecting a particular method of treatment. When MSUD is suspected, it is necessary to make a definite diagnosis promptly and take therapeutic measures including peritoneal dialysis. The efficacy of low histidine diet in histidinemia is not yet ascertained. Close inquiries should be made about the benefit of such a dietary regimen and the long term prognosis therewith. A screening test for homocystinuria by the detection of blood methionine level is difficult. In cases with high blood methionine level during the neonatal period, it is necessary to differentiate the condition from other disease with high blood methionine. Hepatorenal tyrosinemia appears to be unsuitable for mass screening because of the the unefficacy of low phenylalanine tyrosine diet in some of the patient and the difficulty to differentiate from transient tyrosinemia in normal newborn infants. However, mass-screening is recommendable for Richner-Hanhalt type tyrosinemia which responds well to dietary therapy and which is easy to differentiate from the transient tyrosinemia because of the marked elevation of blood tyrosine.     

Contribution of extrahepatic tissues to biochemical abnormalities in hereditary tyrosinemia type I: study of three patients after liver transplantation

Three patients with hereditary tyrosinemia type I were examined before and after liver transplantation to assess the role of extrahepatic tissues in the biochemical disorders of this disease. Before transplantation the three patients excreted excessive amounts of succinylacetoacetate (SAA), succinylacetone (SA), tyrosyl acidic compounds, and 5-aminolevulinate (ALA). The activity of 5-aminolevulinate dehydratase (ALA-D) in red blood cells was markedly inhibited (1% to 5% of control) in the three patients. Successful liver transplantation resulted in decreased excretion of urinary SAA plus SA, tyrosyl acidic compounds, and ALA. Two of the patients continued to excrete significant amounts of SAA plus SA, whereas those compounds were undetectable in the urine of the third patient. Tyrosine loading resulted in increased excretion of SAA plus SA in two patients, but those compounds remained undetectable in the third. All three patients continued to excrete higher than normal amounts of ALA, but the activity of ALA-D in red blood cells returned to normal after transplantation, indicating marked clearance of SA from the blood. Liver transplantation may not totally correct the biochemical abnormalities of hereditary tyrosinemia. It is likely that the kidney is the source of persistent biochemical aberrations in the urine without significant effects on the blood. Our results suggest the existence of heterogeneity for renal involvement in hereditary tyrosinemia.     

Rapid improvement in the renal tubular dysfunction associated with tyrosinemia following hepatic replacement.

The postoperative management of patients with hereditary tyrosinemia type I (McKusick 27670) following liver transplantation is often complicated by the renal tubular dysfunction associated with this disease. To characterize better the temporal course of the improvement in renal excretory activity following hepatic replacement, renal tubular function and metabolite excretion were studied in a 4-year-old girl with hereditary tyrosinemia during the immediate post-transplantation course. Tubular reabsorption of bicarbonate and phosphate were normal 5 days following transplantation, in contrast to glucosuria, hyperaminoaciduria, and tyrosyluria, which persisted for approximately 3 weeks. After hepatic replacement, serum amino acid concentrations returned to normal and succinylacetone was no longer detected in the urine. This is the third tyrosinemia patient reported to achieve complete resolution of urinary abnormalities following transplantation, and the only patient in whom renal tubular function was formally assessed within the first postoperative week.     

Hereditary fructose intolerance with early onset]

Four cases of hereditary fructose intolerance with an early onset are reported. The features of acute liver failure in the neonatal period include a haemorrhagic syndrome, collapse, neurological features, hypoglycaemia, disturbed bleeding and clotting studies and abnormal liver function tests. Investigations into the aetiology include a search for bacterial or viral infection but particularly for a metabolic cause: especially for hereditary fructose intolerance which may be difficult to distinguish from tyrosinosis. Finally, methods of treatment are discussed: continuous glucose infusion, exchange transfusion, assisted ventilation, and dietary measures beginning with protein exclusion. The importance of careful observation is stressed (particularly sequential studies of bloodclotting factors).