Phenylalanine hydroxylase activity jama pediatrics jama. Pku is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine. This deficiency is caused by mutation in the pah gene on chromosome 12 in band 12q23. Differential diagnosis pku should be distinguished from bh4 deficiency.
Phenylalanine is found in all proteins and in some artificial sweeteners. The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. Different phenotypes for phenylalanine hydroxylase deficiency. Four molecules of phenylalanine hydroxylase interact to form a tetramer, which is the functional unit for this enzyme. Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid. Phenylalanine hydroxylase an overview sciencedirect topics. Phenylalanine hydroxylase pah deficiency, traditionally called phenylketonuria pku due to characteristic phenylketones accumulating in the. Phenylalanine hydroxylase pah deficiency, also known as phenylketonuria pku, results in a defect in the metabolism of phenylalanine phe to tyrosine due to mutations of the phenylalanine hydroxylase pah gene with consequent reduced enzyme activity. Without the enzyme necessary to process phenylalanine, a dangerous buildup can.
Phenylalanine hydroxylase deficiency, includes phenylketonuria. Early diagnosis and initiation of treatment through newborn screening has gradually shifted treatment goals from the prevention of disabling complications to the optimization of long term outcomes. Treatment has predominantly been dietary manipulation, and use of low protein and phenylalanine medical foods is likely to remain a major component of therapy for the immediate future. Pharmacological levels of the phenylalanine hydroxylase enzyme cofactor, tetrahydrobiopterin bh4, reduce plasma phenylalanine levels in some patients with phenylketonuria pku, providing the first pharmacological therapy for pku. Phenylketonuria phenylalanine hydroxylase deficiency orphanet. Mutations of the phenylalanine hydroxylase gene in patients with phenylketonuria in shanxi, china yongan zhou1, yunxia ma1, quanbin zhang1, weihua gao2, jianping liu3, jianping yang3, gaixiu zhang4, xiaogang zhang3 and liang yu3 1centre laboratory, taiyuan city centre hospital, taiyuan, shanxi, p. This gene encodes a member of the biopterindependent aromatic amino acid hydroxylase protein family. Pah deficiency is caused by mutations in the pah gene. Phenylalanine is an amino acid, a simple molecule that is part of proteins. Phenylalanine hydroxylase pah deficiency, which has an estimated prevalence of 1 in 10,000 individuals, is a heritable disorder characterized by an inability to break down the essential amino acid phenylalanine phe.
This study presents the clinical findings on seven children from malta population 385 000. Phenylalanine hydroxylase deficiency is an inherited condition that affects the bodys ability to process the amino acid phenylalanine from food. Individuals with phenylalanine hydroxylase deficiency have a defect in the enzyme phenylalanine hydroxylase, which is. Phenylalanine hydroxylase deficiency may be complete classic pku, type i or partial types ii and iii. Phenylalanine hydroxylase deficiency includes phenylketonuria. Patients with either defect have psychomotor retardation, truncal hypotonia with limb hypertonia, seizures and a tendency to hyperthermia. Research on phenylalanine hydroxylase by seymour kaufman led to the discovery of tetrahydrobiopterin as a biological cofactor. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria. Phenylalanine hydroxylase activity jama pediatrics. Jan 10, 2000 phenylalanine hydroxylase pah deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the ratelimiting step in phenylalanine catabolism. Phenylalanine hydroxylase pah deficiency results in intolerance to the dietary intake of the essential amino acid phenylalanine and produces a spectrum of disorders.
Phenylalanine hydroxylase pah deficiency results in intolerance to the. Abnormalities related to the hydroxylation of phenylalanine to tyrosine are. Acmg position statement on prenatalpreconception expanded carrier screening. Phenylketonuria is a genetic disorder inherited from a persons parents. There are three different categories of phenylalanine hydroxylase deficiency based on their severity. There are two main categories of phenylalanine hydroxylase deficiency, pku and nonpku, based on levels of phenylalanine found in the blood. Treatment of pah deficiency to decrease blood phe levels. Lower levels or absence of the phenylalanine hydroxylase enzyme underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain. Oct 10, 20 pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase and others. Pah deficiency encompasses a spectrum of biochemical phenotypes from classic pku severe pah deficiency to mild hyperphenylalaninemia with varying degrees of residual pah activity.
Throughout this document, pah deficiency is used instead of the older nomenclature of phenylketonuria, in order to reflect the spectrum of pah deficiency and in accordance with the terminology established. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase and others under development. Phenylalanine hydroxylase pah deficiency is one of 31 targeted inherited metabolic diseases imd for the canadian inherited metabolic diseases research network cimdrn. As a result of this metabolic block, abnormally high levels of phenylalanine accumulate in the blood, cerebrospinal fluid, and urine. The enzyme is also interesting from a human health perspective because mutations in pah, the encoding gene, can lead to phenylketonuria, a severe metabolic disorder. Untreated, pah deficiency is characterized by elevated phenylalanine phe. Nutritional management of phenylalanine hydroxylase pah. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Deficiency of this enzyme produces a spectrum of disorders including classic. This causes phenylalanine to build up in the blood to harmful levels and can lead to brain damage and impair normal development. Strategies for successful longterm engagement of adults.
Phenylalanine hydroxylase deficiency is a condition in which the body cannot process phenylalanine, an amino acid found in dietary proteins, because an enzyme called phenylalanine hydroxylase is lacking. Phenylalanine hydroxylase deficiency is an autosomal recessive disease caused by mutations in the pah gene. Ten phenylketonuric patients and two parents were studied. Testing for tetrahydrobiopterin responsiveness in patients. Phenylalanine hydroxylase deficiency is an inherited condition. Many mutations of the phenylalanine hydroxylase gene. Depending on the severity of the pah enzymatic defect, phenylalanine levels may exceed a critical threshold that leads to permanent cognitive defects. Pdf phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood. Phenylketonuria fenulkeytoenureeuh, also called pku, is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. The lack of ascertainment by way of newborn screening and increasingly broad phenotypic spectrum makes these disorders as a group much more challenging to recognize. Article information, pdf download for different phenotypes for phenylalanine. Phenylketonuria pku symptoms and causes mayo clinic. Since the appearance of universal newborn screening, symp tomatic classic pku is infrequently seen in the developed world.
This enzyme is responsible for the first step in processing phenylalanine, which is a building block of proteins an amino acid obtained through the diet. Click here pdf for more information on the proposed mechanism of. Phenylalanine hydroxylase deficiency pah deficiency, also called phenylketonuria pku, is an inherited disease in which the body cannot properly process the amino acid phenylalanine due to a deficient enzyme called phenylalanine hydroxylase. Each molecule in the tetramer is organized into three domains. Phenylalanine hydroxylase deficiency american college of. Pdf biopterin responsive phenylalanine hydroxylase. The risk of adverse outcome varies based on the degree of pah deficiency. The minimum requirements for the normal reaction, which occurs in both liver and kidney in human subjects, are phenylalanine hydroxylase enzyme a monooxygenase, ec 1. Phenylketonuria pku is an autosomal recessive disorder caused by a deficiency in phenylalanine hydroxylase, required to convert phenylalanine to tyrosine, which is essential to make dopamine. The pah enzyme is encoded by the pah gene, which is located on chromosome 12 at band q23. Informed written consents for genetic studies were obtained from 25 families of pah deficiency. The influence of mutations of enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency. What are the symptoms of phenylalanine hydroxylase deficiency and what treatment is available.
Decreased pah activity results in accumulation of phenylalanine and a decreased amount of tyrosine and other metabolites. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. It is due to mutations in the pah gene, which results in low levels of the enzyme phenylalanine hydroxylase. However, the treatment regime is complex, costly, and often difficult to maintain for the long term. Other articles where phenylalanine hydroxylase is discussed. An individual who inherits two mutations in this gene, one from each parent, is.
Management of women with phenylalanine hydroxylase deficiency. The effectiveness of a phenylalanine restricted diet to improve the outcome of individuals with phenylalanine hydroxylase deficiency omim no. Classical phenylketonuria pku is the most severe form. The authors have analyzed the loading tests currently in use in. The pah gene provides instructions for making an enzyme called phenylalanine hydroxylase. Responsiveness to this therapy must be determined empirically through a bh4 loading test or trial.
Pah is one of three members of the biopterindependent aromatic amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin bh 4, a pteridine cofactor and a nonheme iron for catalysis. Many mutations of the phenylalanine hydroxylase gene have been identified missense, nonsense, insertions, deletions, and duplications leading to pku or nonpku hyperphenylalaninemia. Previous studies have suggested that the highly variable metabolic phenotypes of pah deficiency correlate with pah genotypes. Diagnostic methods the disorder is usually diagnosed through neonatal screening programs. Mutations of the phenylalanine hydroxylase gene in patients. Phenylalanine hydroxylase deficiency is an autosomal recessive disorder caused by pathogenic variants in the gene pah. This enzyme converts the amino acid phenylalanine to other important compounds in the body. While it is found in many different ethnicities, it is particularly prevalent in sephardic jewish, sicilian, irish, and turkish individuals, as well as caucasians. Different phenotypes for phenylalanine hydroxylase deficiency f. This results in the buildup of dietary phenylalanine to potentially toxic levels. We identified both causative mutations in 686 patients from seven european centers.
Phenylalanine hydroxylase is the ratelimiting enzyme of the metabolic pathway that degrades excess phenylalanine. Neurotransmitter deficiency disorders with normal blood phenylalanine levels span an increasingly complex spectrum of clinical phenotypes, ranging from ataxia and mental retardation to spastic diplegia to exerciseinduced dystonia. There are two main categories of phenylalanine hydroxylase deficiency based on levels of phenylalanine phe found in the blood and the subsequent risk for mental retardation. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. Without effective therapy, most individuals with severe pah deficiency, known as classic pku, develop profound and irreversible intellectual disability.
Treatment of phenylalanine hydroxylase deficiency wiley online. Pah enu1 is a mouse model for tetrahydrobiopterinresponsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo an exon skippingassociated nonsense mutation in the dystrophin gene uncovers a complex interplay between multiple antagonistic splicing elements. It is autosomal recessive, meaning that both copies of the gene must be mutated. Needle liver biopsies were carried out on patients with phenylketonuria pku to establish a diagnosis either of partial or complete phenylalanine hydroxylase ph deficiency. Biopterin responsive phenylalanine hydroxylase deficiency. The most severe, classic form of pah deficiency is called pku. In the article, diagnosis of phenylalanine hydroxylase deficiency phenylketonuria journal 1982. Han3en abnormalities related to the hydroxylation of phenylalanine to tyrosine are classifiedinto three phenotypes based on the amount of dietary phenylalanine tolerated to keep serum phenylalanine. The inherited inability to process the amino acid phenylalanine normally, due to deficiency of the enzyme phenylalanine hydroxylase. Phenylalanine hydroxylase deficiency is a disease with variable severity, even within families. Mutation spectrum in taiwanese patients with phenylalanine. The hpas are disorders of phenylalanine hydroxylation. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medica.
Dopamine is essential for prefrontal pyramidal neurons involved with. Nine of the ten patients had completed a threeday oral. Ptps deficiency is one in 118,010, and for pah deficiency is one in 55,071. This enzyme is not active in individuals who have phenylketonuria. Strategies for successful longterm engagement of adults with.
Phenylalanine hydroxylase deficiency genetics in medicine. Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. Hundreds of different diseasecausing mutations have been found in the pah gene. Keywords phenylalanine hydroxylase deficiency, phenylketonuria, metabolic clinic, patient outcomes, management, rare disease. Phenylalanine hydroxylase pah deficiency including. Phenylalanine hydroxylase deficiency request pdf researchgate. Phenylalanine hydroxylase deficiency is an inherited disease of variable severity. All offspring of women with pah deficiency will minimally be obligate carriers. Phenylalanine hydroxylase pah deficiency is an autosomal recessive disorder of phenylalanine metabolism that is characterized by insufficient activity of pah, a hepatic enzyme. All of them had early motor delay and a significant degr. Proteins are formed by a very long chain of amino acids, which bind as the pearls of a necklace, in. Phenotypes patients were assigned to our phenotype categories according to the pretreatment plasma phenylalanine levelsf normal, 30 to 120 m and phenylalanine tolerance.
Bh 4 synthesis include gtp cyclohydrolase deficiency and 6pyruvoyltetrahydrobiopterin synthase deficiency. Phenylketonuria pku and mild hyperphenylalaninemia mhp are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase pah. Molecular characterization of phenylalanine hydroxylase deficiency in chile. Carrier screening to help detect the risk of having a baby with a specific inherited disorder, such as cystic fibrosis. Phenylalanine hydroxylase deficiency nxgen mdx accurate. A european multicenter study of phenylalanine hydroxylase. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed. Pharmacotherapy for phenylalanine hydroxylase deficiency is in early stages with one approved medication sapropterin, a derivative of the natural cofactor of phenylalanine hydroxylase and others. Molecular characterization of phenylalanine hydroxylase. Molecular epidemiology and predictable bh4responsiveness in south portugal pku patients. Phenylalanine hydroxylase deficiency is an autosomal recessive disorder and the carrier frequency for pah deficiency depends on ethnicity but is approximately 1 in 50 in those of northern european descent 9. A deficiency in phenylalanine hydroxylase pah, the first enzyme of phenylalanine processing, leads to accumulation of the amino acid in body fluids.
Management of women with phenylalanine hydroxylase. Pdf recommendations for the nutrition management of. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively. Pdf phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of. Significant evidence gaps remain in our understanding of the optimum therapies for phenylalanine hydroxylase deficiency, nonphenylalanine effects of these therapies, and longterm sequelae of even welltreated disease in children and adults.
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