Volume 68 - 2005 - Fasc.4 - Symposium
Introduction : liver and liver cell transplantation for inborn errors of liver metabolism
Inborn errors of metabolism affect around 1/900 life births. Most of these conditions are rare, but any physi- cian will face patients affected by one or another of these diseases.
Management of patients with inborn errors of metab- olism is often complex and includes orphan medica- tions, very specific diets, special education. Beside life threatening conditions, a main concern is that long term intellectual prognosis of certain patients may be im- paired, especially for diseases such as urea cycle disor- ders, organic aciduria and amino acidopathies.
Quality of life is often poor, due to anorexia, naso gastric feeding, poor variability of the diet and severe diet restriction, social eviction, special education re- quirements, frequent hospitalisations.
Liver transplantation has now become a very success- ful procedure, and more than 90% of the children sur- vive on the long term. It remains however an heavy and radical procedure, and doctors and patients may be reluctant to undergo this operation for non vital indica- tions. In addition, new hopes and perspectives such as emerging cell therapy and prospects of gene therapy are now being considered in the decision making pro- cess (1;2) (3).
Long-term complications of immunosuppression in pediatric liver recipients
Liver transplantation (LT) today constitutes a well-standard- ized and efficient therapy for children with acute and chronic hepatic failure. Appropriate pre-transplant management, organ preservation, adequate surgical techniques, and the progressive introduction of new immunosuppressive regimens have con- tributed to significantly improve, over the years, the general out- come after LT. Consequently, these good overall results has allowed the constitution of a growing cohort of children, adoles- cents and young adults submitted to chronic immunosuppression. The long-term complications of immunosuppression administered to transplant recipients include the adverse effects secondary to the depression of the immune system, the toxicities specifically related to the individual immunosuppressive drugs, and the sense of lack of rehabilitation for the transplant patient, with, secondar- ily, the question of non-adherence to the medications. This review will essentially focus on these three issues in the particular context of pediatric liver transplantation (Acta gastroenterol. belg., 2005, 68, 453-456).
Introduction : liver and liver cell transplantation for inborn errors of liver metabolism
Inborn errors of metabolism affect around 1/900 life births. Most of these conditions are rare, but any physi- cian will face patients affected by one or another of these diseases.
Management of patients with inborn errors of metab- olism is often complex and includes orphan medica- tions, very specific diets, special education. Beside life threatening conditions, a main concern is that long term intellectual prognosis of certain patients may be im- paired, especially for diseases such as urea cycle disor- ders, organic aciduria and amino acidopathies.
Quality of life is often poor, due to anorexia, naso gastric feeding, poor variability of the diet and severe diet restriction, social eviction, special education re- quirements, frequent hospitalisations.
Liver transplantation has now become a very success- ful procedure, and more than 90% of the children sur- vive on the long term. It remains however an heavy and radical procedure, and doctors and patients may be reluctant to undergo this operation for non vital indica- tions. In addition, new hopes and perspectives such as emerging cell therapy and prospects of gene therapy are now being considered in the decision making pro- cess (1;2) (3).
Hepatocyte transplantation for metabolic disorders, experience at King's College hospital and review of literature
Hepatocyte transplantation is emerging as a potential treatment for liver based metabolic disorders and acute liver failure. To date, clinical studies have shown that hepatocyte transplantation could be used as a "bridge" to liver transplantation in a few patients with acute liver failure and has changed the phenotype of meta- bolic patients in terms of reducing the severity of illness. For many years, research studies have been carried out to optimise condi- tions for a) hepatocyte isolation in order to obtain the highest pos- sible number of viable hepatocytes isolated from various sources of unused donor liver tissues, and b) cryopreservation and storage of hepatocytes for immediate cell availability in emergency cases. In this review, we summarise the worldwide clinical experience in hepatocyte transplantation for liver based metabolic disorders including the experience of our centre at King's College Hospital, London (United Kingdom). We briefly comment on the possible future developments and improvements needed in this field (Acta gastroenterol. belg., 2005, 68, 457-460).
Long-term complications of immunosuppression in pediatric liver recipients
Liver transplantation (LT) today constitutes a well-standardized and efficient therapy for children with acute and chronic hepatic failure. Appropriate pre-transplant management, organ preservation, adequate surgical techniques, and the progressive introduction of new immuno- suppressive regimens have contributed to significantly improve, over the years, the general outcome after LT. Consequently, these good overall results has allowed the constitution of a growing cohort of chil- dren, adolescents and young adults submitted to chronic immunosup- pression. The long-term complications of immunosuppression admin- istered to transplant recipients include the adverse effects secondary to the depression of the immune system, the toxicities specifically relat- ed to the individual immunosuppressive drugs, and the sense of lack of rehabilitation for the transplant patient, with, secondarily, the question of non-adherence to the medications. This review will essentially focus on these three issues in the particular context of paediatric liver trans- plantation.
Hepatocyte Transplantation for metabolic disorders, experience at King's College hospital and review of literature
Hepatocyte transplantation is emerging as a potential treatment for liver based metabolic disorders and acute liver failure. To date, clinical studies have shown that hepatocyte transplantation could be used as a "bridge" to liver transplantation in few patients with acute liver failure and has changed the phenotype of metabolic patients in terms of reducing the severity of illness. For many years, research studies have been carried out to optimise condi- tions for a) hepatocyte isolation in order to obtain the highest pos- sible number of viable hepatocytes isolated from various sources of unused donor liver tissues, and b) cryopreservation and storage of hepatocytes for immediately cell availability in emergency cases. In this review, we summarise the worldwide clinical experience in hepatocyte transplantation for liver based metabolic disorders including the experience of our centre at King's College Hospital, London (United Kingdom), and we briefly comment on the possi- ble future developments and improvements needed in this field.
Adult stem cells - perspectives in treatment of metabolic diseases
There is currently great excitement and expectation concern- ing the differential potential of adult stem cells or adult cells with capacity of differentiation. As the body of work concerning trans- differentiation of somatic stem cells and bone marrow derived stem cells grows, the number of critics increases steadily question- ing the reliability of reported findings. So scientists are now chal- lenged more and more to prove that resulting differentiated somatic cells originated from somatic adult stem cell through a transdifferentiation process. Phenomenons such as fusion of cells have to be ruled out and the origin of the differentiated cell has to be determined by specific techniques i.e. in situ hybridisation. Cellular mimicry through uptake of specific factors out of the medium is questioned to be the reason for cells staining positive for Insulin. Some multipotent adult stem cells can cross lineage boundaries and differentiate into somatic cells of other lineages after being relocated. Bone marrow cells have been described to have the greatest plasticity among adult stem cells regenerating damaged liver or myocardium. It has been proposed that the dif- ferentiation of bone marrow derived adult stem cells occurs natu- rally even in healthy organs as a physiologic process of tissue- regeneration. Others believe that organ damage is essential to induce transdifferentiation by release of organ specific microenvi- ronmental factors. We here try to constitute necessary data which should be demonstrated to give substantial evidence for transdif- ferentiation of newly characterized cells including exclusion of fusion, phagocytosis or DNA uptake, description of the outset cell, differentiation into all three germ layers and functional parame- ters. (Acta gastroenterol. belg., 2005, 68, 461-465)
Long-term outcome of urea cycle disorders
Evaluation of long-term outcome of patients with urea cycle diseases (UCD) is needed for medical decisions and counselling. Own data comparing outcome of UCD patients with the old treat- ment limited to protein restriction (i.e. close to the natural history) with that of patients on the modern conservative treatment have shown that gains in survival occur at the cost of more mentally retarded surviving patients. We discuss the possible bias in long- term outcome studies of those rare inheritable disorders where non-predictable environmental factors leading to catabolic crises have a crucial impact on prognosis. A combination of peak or ini- tial ammonia value combined with the duration of coma is dis- cussed as a criterion for prognosis of handicap. The neglect of dietary compensation of branched chain amino acid deficiency worsened by phenylbutyrate treatment in some published proto- cols could well be an additional cause of the non satisfactory long- term results of conservative treatment which - in our view - main- ly aim at bridging optimally the period of late neonatal presenta- tion until liver transplantation in patients with CPS and OTC defi- ciency (except for mild forms) (Acta gastroenterol. belg., 2005, 68, 466-468).
Adult stem cells - perspectives in treatment of metabolic diseases
There is currently great excitement and expectation concern- ing the differential potential of adult stem cells or adult cells with capacity of differentiation. As the body of work concerning trans- differentiation of somatic stem cells and bone marrow derived stem cells grows, the number of critics increases steadily question- ing the reliability of reported findings. So scientists are now chal- lenged more and more to prove that resulting differentiated somatic cells originated from somatic adult stem cell through a transdifferentiation process. Phenomenons such as fusion of cells have to be ruled out and the origin of the differentiated cell has to be determined by specific techniques i.e. in situ hybridisation. Cellular mimicry through uptake of specific factors out of the medium is questioned to be the reason for cells staining positive for Insulin. Some multipotent adult stem cells can cross lineage boundaries and differentiate into somatic cells of other lineages after being relocated. Bone marrow cells have been described to have the greatest plasticity among adult stem cells regenerating damaged liver or myocardium. It has been proposed that the dif- ferentiation of bone marrow derived adult stem cells occurs natu- rally even in healthy organs as a physiologic process of tissue- regeneration. Others believe that organ damage is essential to induce transdifferentiation by release of organ specific microenvi- ronmental factors. We here try to constitute necessary data which should be demonstrated to give substantial evidence for transdif- ferentiation of newly characterized cells including exclusion of fusion, phagocytosis or DNA uptake, description of the outset cell, differentiation into all three germ layers and functional parame- ters.
Long-term Outcome of Urea Cycle Disorders
Evaluation of long-term outcome of patients with urea cycle diseases (UCD) is needed for medical decisions and counselling. Own data comparing outcome of UCD patients with the old treat- ment limited to protein restriction (i.e. close to the natural history) with that of patients on the modern conservative treatment have shown that gains in survival occur at the cost of more mentally retarded surviving patients. We discuss the possible bias in long- term outcome studies of those rare inheritable disorders where non-predictable environmental factors leading to catabolic crises have a crucial impact on prognosis. A combination of peak or ini- tial ammonia value combined with the duration of coma is dis- cussed as a criterion for prognosis of handicap. The neglect of dietary compensation of branched chain amino acid deficiency worsened by phenylbutyrate treatment in some published proto- cols could well be an additional cause of the non satisfactory long- term results of conservative treatment which - in our view - main- ly aim at bridging optimally the period of late neonatal presenta- tion until liver transplantation in patients with CPS and OTC defi- ciency (except for mild forms).
Evaluation of long-term outcome of patients with urea cycle diseases (UCD) is needed for medical decisions and counselling. Own data comparing outcome of UCD patients with the old treat- ment limited to protein restriction (i.e. close to the natural history) with that of patients on the modern conservative treatment have shown that gains in survival occur at the cost of more mentally retarded surviving patients. We discuss the possible bias in long- term outcome studies of those rare inheritable disorders where non-predictable environmental factors leading to catabolic crises have a crucial impact on prognosis. A combination of peak or ini- tial ammonia value combined with the duration of coma is dis- cussed as a criterion for prognosis of handicap. The neglect of dietary compensation of branched chain amino acid deficiency worsened by phenylbutyrate treatment in some published proto- cols could well be an additional cause of the non satisfactory long- term results of conservative treatment which - in our view - main- ly aim at bridging optimally the period of late neonatal presenta- tion until liver transplantation in patients with CPS and OTC defi- ciency (except for mild forms).
Liver and liver cell transplantation for glycogen storage disease type IA
Glycogen storage disease type Ia (GSDIa) is an inherited disorder of glucose metabolism, due to the selective deficiency of the hepat- ic enzyme glucose-6-phosphatase. Clinical manifestations include severe hypoglycaemia three to four hours post-prandially, increased production of lactic acid, triglycerides and uric acid, hepatic glycogen storage disease with development of multiple adenomas and kidney disease with proteinuria. Liver transplanta- tion is frequently performed in order to achieve metabolic control and when malignant transformation of adenomas is suspected. Long term outcome following transplantation is good, but immunosuppressive therapy can worsen the progression of associ- ated kidney disease. Hepatocyte transplantation could be consid- ered as a less invasive procedure in such patients. Our experience with hepatocyte transplantation in a 47 year-old woman affected by glycogen storage disease type Ia and suffering of severe fasting hypoglycaemia indicates that the procedure can partially correct some metabolic abnormalities and improve the quality of life in this disease. However, the metabolic improvement was reduced and finally abolished during long term follow-up, probably due to rejection or to senescence of transplanted cells. Moreover, the por- tal and pulmonary hypertension associated with the disease need to be evaluated for their possible influence on haemodynamic changes associated with cell infusion. Finally, hepatic adenomas need careful monitoring because of the possible risk of malignant transformation (Acta gastroenterol. belg., 2005, 68, 469-472).
Abstract book
In the early years because of the high risk of mortality and morbidity, liver transplantation was only used for those that were terminally ill. As the outlook for liver transplantation in childhood has improved so the indications for trans- plantation for metabolic disorders in childhood have expanded (1).
Liver transplantation is used to treat inborn errors for two major indications; firstly because of irreversible liver disease, usually cirrhosis, and secondly for enzyme replacement. The management may be made more complicated by the involvement of other organs by the metabolic disease.
The indications for transplantation for isolated liver failure are the same as those for any other cause. The most frequent disorders are progressive familial intrahepatic cholestasis (PFIC), Wilson's disease, a1- antitrypsin deficiency and tyrosinaemia type 1. In glycogen storage disease (GSD) IV, cystic fibrosis, respiratory chain disorders, and cholesterol ester storage disease liver may be also diseased but other organs are often involved (heart, lung, etc) and may complicate transplantation.
Liver and liver cell transplantation for glycogen storage disease type IA
Glycogen storage disease type Ia (GSDIa) is an inherited disorder of glucose metabolism, due to the selective deficiency of the hepat- ic enzyme glucose-6-phosphatase. Clinical manifestations include severe hypoglycaemia three to four hours post-prandially, increased production of lactic acid, triglycerides and uric acid, hepatic glycogen storage disease with development of multiple adenomas and kidney disease with proteinuria. Liver transplanta- tion is frequently performed in order to achieve metabolic control and when malignant transformation of adenomas is suspected. Long term outcome following transplantation is good, but immunosuppressive therapy can worsen the progression of associ- ated kidney disease. Hepatocyte transplantation could be consid- ered as a less invasive procedure in such patients. Our experience with hepatocyte transplantation in a 47 year-old woman affected by glycogen storage disease type Ia and suffering of severe fasting hypoglycaemia indicates that the procedure can partially correct some metabolic abnormalities and improve the quality of life in this disease. However, the metabolic improvement was reduced and finally abolished during long term follow-up, probably due to rejection or to senescence of transplanted cells. Moreover, the por- tal and pulmonary hypertension associated with the disease need to be evaluated for their possible influence on haemodynamic changes associated with cell infusion. Finally, hepatic adenomas need careful monitoring because of the possible risk of malignant transformation.
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Despite the introduction of NTBC into the treatment of tyrosinaemia type I (TTI) hepatocellular carcinoma (HCC) does occur in affected patients. Serial total a-Fetoprotein (AFP) levels are used to evaluate the individual risk to develop malignant changes. Lectin-reactive a-Fetoprotein is a recently described marker for early recognition of HCC in adult liver disease.
Aim : To investigate if the analysis for Lectin-reactive a-Fetoprotein could lead to earlier detection of HCC compared to a judgement based on the evolution of total AFP alone.
Patients : We report the analysis of AFP data from 41 patients with TTI. 12 patients had TTI and histologically proven HCC.
Methods : AFP electrophoresis in a lectin containing agarose gel leads to separation of lectin-reactive and non-lectin- reactive AFP fractions. A proportion of more than 15% of lectin-reactive AFP is suspicious for the development of HCC in adult cirrhotic patients.
Results : AFP subfractions could be identified in all 41 patients. In the patients with TTI and HCC in 6 patients the lectin reactive AFP was elevated before total AFP became abnormal, in 3 patients the rise in lectin reactive-AFP was consistant with the rise of the total AFP and in 3 patients the lectin reactive-AFP was raised after the total AFP or did not increase at all.
Discussion : We were able to identify 6 out of 12 patients with HCC who had an early rise of lectin reactive AFP before they developed a change in total AFP levels.
Conclusions : Analysis for lectin reactive AFP may allow early diagnosis of HCC in patients with TTI and thus facili- tate liver transplantation before the onset of metastasis. We suggest the further evaluation of lectin-reactive AFP in TTI.
Medical progress and pitfalls of the treatment of inborn errors involving the liver
In the early years because of the high risk of mortali- ty and morbidity, liver transplantation was only used for those that were terminally ill. As the outlook for liver transplantation in childhood has improved so the indica- tions for transplantation for metabolic disorders in child- hood have expanded (1).
Liver transplantation is used to treat inborn errors for two major indications; firstly because of irreversible liver disease, usually cirrhosis, and secondly for enzyme replacement. The management may be made more com- plicated by the involvement of other organs by the meta- bolic disease.
The indications for transplantation for isolated liver failure are the same as those for any other cause. The most frequent disorders are progressive familial intra- hepatic cholestasis (PFIC), Wilson's disease, a1- anti- trypsin deficiency and tyrosinaemia type 1. In glycogen storage disease (GSD) IV, cystic fibrosis, respiratory chain disorders, and cholesterol ester storage disease liver may be also diseased but other organs are often involved (heart, lung, etc) and may complicate trans- plantation.
Liver transplantation for inherited metabolic disease
Liver Transplantation is indicated for children with inherited metabolic disease because of a primary hepatic enzyme deficiency, which leads to liver failure and/or hepatic cancer, or severe extra hepatic disease. The selection and timing depends on the rate of progression of disease, the success of medical therapy and the extent of reversible extra hepatic disease. Transplant techniques include orthotopic, living related and auxiliary liver transplanta- tion or combined liver and kidney transplantation.
Liver transplantation effectively treats structural metabolic hepatic disease with a phenonotypic and functional cure in alpha1 antitrypsin deficiency, Wilson's disease, PFIC and neonatal haemochromatosis. There is only a partial cure in Tyrosinaemia Type 1 as abnormal metabolites are still produced by the kidney, but a complete cure in primary oxalosis and urea cycle defects. Outcome for organic acidaemias remains poor due to technical and metabolic challenges.
Medical versus surgical management of progressive familial intrahepatic cholestasis - PFIC
Pharmacological methods used so far for treating PFIC have not proved clear efficacy. Clinical and bio- chemical improvement was observed only in a few chil- dren treated with ursodeoxycholic acid (UDCA).
In the last decade partial external biliary diversion (PEBD) became standard procedure performed on PFIC children with no response to medical treatment. There is still a group of patients who cannot benefit from this procedure because of technical conditions (earlier per- formed cholecystectomy) or postoperative complica- tions like dyselectrolytaemia due to the excessive amount of bile. In 1998 Holland et al. described ileal bypass (IB) as promising in PFIC children after chole- cystectomy. The only treatment for children with PFIC and hepatic cirrhosis remains liver transplantation.
The aim of our study was a retrospective evaluation of different methods of treatment in children with PFIC: pharmacological therapy with phenobarbital, cholestyra- mine and UDCA, as well as surgical methods, PEBD, IB, as alternative methods to liver transplantation
In vitro tissue expansion perspectives
Besides orthotopic liver transplantation, therapies currently developed to treat liver diseases include trans- plantation of isolated mature adult hepatocytes by their infusion into blood stream, implantation of liver tissue substitutes and perfusion of blood through an extracor- poreal bioartificial device containing liver cells.
With respect to liver cell transplantation (LCT), the success of the procedure closely depends on the viabili- ty and the stability of liver-specific functions of the infused liver cells. The number of needed hepatocytes is also another limiting factor because of donor organ shortage.
Progrees and pifalls in organic aciduria
Organic acidurias comprise many various disorders. Methylmalonic and propionic acidurias are the most fre- quent diseases and the two organic acidurias for which we have the most important view on the long term out- come.
Patients affected with these disorders mostly present in the neonatal period with a neurological distress of the intoxication type with ketoacidosis and mild to moder- ate hyperammonaemia. As neonates they most often require emergency treatment with supportive care, toxin removal procedures, high energy and free-protein nutri- tion. The mainstay of the long term management is a low-protein high-energy diet that is most often supple- mented with amino acids omitting the propiogenic ones. This diet must be completed with sufficient vitamins, minerals and micronutrients. Feeding problems are extremely common and these patients most often require enteral nutrition to maintain a good nutritional state. Specific additional therapies are usually used. L-carni- tine supplementation prevents from deficiency due to acyl-carnitine excretion. Metronidazole reduces propi- onate production in the gut. Sodium benzoate has been proposed to correct both chronic hyperammonaemia and hyperglycinemia.
Report of liver transplantation in organic aciduria
The outcome for childrens suffering from severe and early-onset organic acidurias (OA), such as propionic acidemia (PA) and methylmalonic acidemia (MMA), due to the inherited propionyl-Coa carboxylase and methylmalonyl-CoA mutase deficieny, respectively, remains poor. Despite the conventional treatment with low-protein diet, carnitine and metronidazole supple- mentation, the course of severely affected patients who survived to the neonatal ketoacidotic coma is character- ized by recurrent life-threatening episodes of metabolic acidosis, anorexia, vomiting, failure to thrive, develop- mental delay, stroke, extrapyramidal signs, pancreatitis, progressive renal disease and cardiomyopathy. Retrospective studies show a 80% mortality within the first 10 years of life . Alternative treatment such as liver transplantation (OLT) has been considered, but this option is not commonly adopted. The goal of OLT in OA is to provide normal enzyme activity at the liver in order to assure a sufficient clearance of toxic organic, deriv- ing mainly from muscular aminoacid catabolism.
Results of liver cell transplantation in urea cycle disorders
The urea cycle is the final pathway for the metabo- lism of waste nitrogen in humans. As many inborn errors of metabolism, urea cycle disorders are based in the liver, but do not damage the liver itself. Indeed, an anomaly of this pathway leads to an accumulation of ammonia, with several deleterious effects to the brain including neurological damage and cognitive deficits. Management by strict diet protein restriction and use of ammonium scavengers are not always sufficient to con- trol the disease and, eventually, the liver remains the tar- get of curative treatment. Orthotopic liver transplanta- tion (OLT) becomes then the ultimate solution to avoid repeated encephalopathic episodes and irreversible brain damage. Rapid transplantation is however limited by the organ shortage and the waiting time is long, during which irreversible brain damage may occur and jeopar- dize the long-term psychomotor development1 (2).
Preemptive liver transplantation for primary hyperoxaluria type 1
Hyperoxaluria may be either a secondary or a primary disease. Secondary hyperoxaluria is due to oxalate poisoning, i.e., accidental intoxication with precursors such as ethylene glycol, absorptive hyperoxaluria of bowel disease. Two distinct inherited enzyme defects have been related to type 1 and type 2 primary hyperoxalurias (PH), i.e., alanine : glyoxylate aminotransferase (AGT) and glyoxylate reductase/hydroxypyruvate reductase, respectively ; in addition non-PH1 non-PH2 patients have been reported
Liver transplantation for neurologic manifestations of Wilson's disease
Wilson's disease, a copper-overload disease, is an inherited as an autosomal recessive trait. The majority of clinical presentation include hepatic and neurologic manifestations. Hepatic manifestations are represented by end-stage liver cirrhosis or fulminant hepatitis with acute failure. Neurological form is represented by severe motor abnormalities such as ataxia, involuntary move- ments, hypertonia and loss of speech. Sometime these neurological features lead to bedridden states.
Crigler Najjar (CN) disease and liver transplantation
CN disease is caused by an inherited defect of biliru- bin conjugation and biliary secretion resulting in an increase of plasma unconjugated bilirubin (UCB) levels. The prognosis is determined by the occurrence of ker- nicterus caused by toxic levels of free UCB in the brain. In case of complete absence of bilirubin conjugation this condition start at birth, while residual capacity is associ- ated with milder course and later presentation of the dis- ease.
Liver or liver cell transplantation for phenylketonuria
Phenylketonuria (PKU) is an inherited autosomal reces- sive disorder (OMIM 261600). The causes of PKU include mutations in the gene encoding phenylalanine hydroxylase (PAH) enzyme or less frequently defect in the metabolism of tetrahydrobiopterin, the cofactor of PAH. PAH is expressed mainly in the liver. It catalyzes the hydroxylation of phenylalanine to tyrosine. Alter- ation of PAH activity causes an increase in phenylala- nine concentrations in blood and tissues, and reduced tyrosine concentrations. Although there is a considerable variation in genotype and phenotype, the great majority of PKU patients are at risk of intellectual and neurolog- ical impairements and severe disability. Phenylalanine itself is probably the neurotoxic agent but the exact pathophysiological mechanisms are still unknown. Pathogenesis of PKU can be considered from three viewpoints : a putative deficiency of tyrosine in the brain ; the effect of hyperphenylalaninemia on transport and distribution of metabolites in the brain and an effect on neurochemical processes, such as defective brain myelination or perturbed protein synthesis. Risk of brain dysfunction due to transient or chronic hyperphenylala- ninemia persists throughout life, although risk in adult- hood is apparently smaller than in childhood, during brain development.
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