Biopterin responsive phenylalanine hydroxylase deficiency. 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. Article information, pdf download for different phenotypes for phenylalanine. Phenylalanine hydroxylase deficiency is an autosomal recessive disorder caused by pathogenic variants in the gene pah. Dopamine is essential for prefrontal pyramidal neurons involved with. Phenylalanine hydroxylase deficiency is an autosomal recessive disease caused by mutations in the pah gene. Pdf phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood. Previous studies have suggested that the highly variable metabolic phenotypes of pah deficiency correlate with pah genotypes. Phenylalanine hydroxylase deficiency, includes phenylketonuria. Phenylalanine hydroxylase activity jama pediatrics. Management of women with phenylalanine hydroxylase. What are the symptoms of phenylalanine hydroxylase deficiency and what treatment is available. Carrier screening to help detect the risk of having a baby with a specific inherited disorder, such as cystic fibrosis.
Excessive phenylalanine can be metabolized into phenylketones through the minor route, a transaminase pathway with glutamate. As a result of this metabolic block, abnormally high levels of phenylalanine accumulate in the blood, cerebrospinal fluid, and urine. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed effectively. Phenotypes patients were assigned to our phenotype categories according to the pretreatment plasma phenylalanine levelsf normal, 30 to 120 m and phenylalanine tolerance. Phenylalanine hydroxylase is the ratelimiting enzyme of the metabolic pathway that degrades excess phenylalanine. However, the treatment regime is complex, costly, and often difficult to maintain for the long term. 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. Classical phenylketonuria pku is the most severe form. Phenylalanine is found in all proteins and in some artificial sweeteners. Phenylalanine is an amino acid, a simple molecule that is part of proteins. A deficiency in phenylalanine hydroxylase pah, the first enzyme of phenylalanine processing, leads to accumulation of the amino acid in body fluids.
Mutations of the phenylalanine hydroxylase gene in patients. 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. Informed written consents for genetic studies were obtained from 25 families of pah deficiency. The hpas are disorders of phenylalanine hydroxylation. 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. The authors have analyzed the loading tests currently in use in.
Strategies for successful longterm engagement of adults with. Ptps deficiency is one in 118,010, and for pah deficiency is one in 55,071. Strategies for successful longterm engagement of adults. All of them had early motor delay and a significant degr. Phenylalanine hydroxylase deficiency request pdf researchgate. Molecular characterization of phenylalanine hydroxylase deficiency in chile. 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. It is due to mutations in the pah gene, which results in low levels of the enzyme phenylalanine hydroxylase. Untreated, pah deficiency is characterized by elevated phenylalanine phe. 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. Bh 4 synthesis include gtp cyclohydrolase deficiency and 6pyruvoyltetrahydrobiopterin synthase deficiency. 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.
The pah gene provides instructions for making an enzyme called phenylalanine hydroxylase. The enzyme phenylalanine hydroxylase normally converts the amino acid phenylalanine into the amino acid tyrosine. Different phenotypes for phenylalanine hydroxylase deficiency f. Phenylketonuria pku symptoms and causes mayo clinic. Decreased pah activity results in accumulation of phenylalanine and a decreased amount of tyrosine and other metabolites. Click here pdf for more information on the proposed mechanism of. This causes phenylalanine to build up in the blood to harmful levels and can lead to brain damage and impair normal development. All offspring of women with pah deficiency will minimally be obligate carriers. There are two main categories of phenylalanine hydroxylase deficiency, pku and nonpku, based on levels of phenylalanine found in the blood. 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. A european multicenter study of phenylalanine hydroxylase. Differential diagnosis pku should be distinguished from bh4 deficiency. The inherited inability to process the amino acid phenylalanine normally, due to deficiency of the enzyme phenylalanine hydroxylase.
Other articles where phenylalanine hydroxylase is discussed. Pku is caused by a defect in the gene that helps create the enzyme needed to break down phenylalanine. 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. Phenylalanine hydroxylase deficiency is a disease with variable severity, even within families. Without effective therapy, most individuals with severe pah deficiency, known as classic pku, develop profound and irreversible intellectual disability. Diagnostic methods the disorder is usually diagnosed through neonatal screening programs. The pah enzyme is encoded by the pah gene, which is located on chromosome 12 at band q23. Phenylalanine hydroxylase deficiency is an inherited disease of variable severity. Patients with either defect have psychomotor retardation, truncal hypotonia with limb hypertonia, seizures and a tendency to hyperthermia. Without the enzyme necessary to process phenylalanine, a dangerous buildup can. Phenylalanine hydroxylase deficiency genetics in medicine. Since the appearance of universal newborn screening, symp tomatic classic pku is infrequently seen in the developed world. We identified both causative mutations in 686 patients from seven european centers.
Phenylketonuria is a genetic disorder inherited from a persons parents. Pdf phenylalanine hydroxylase deficiency, traditionally known as phenylketonuria, results in the accumulation of phenylalanine in the blood of. 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. Phenylketonuria pku and mild hyperphenylalaninemia mhp are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase pah. Phenylketonuria fenulkeytoenureeuh, also called pku, is a rare inherited disorder that causes an amino acid called phenylalanine to build up in the body. Recommendations for the nutrition management of phenylalanine hydroxylase deficiency. The influence of mutations of enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency. Acmg position statement on prenatalpreconception expanded carrier screening. Phenylalanine hydroxylase an overview sciencedirect topics. Molecular characterization of phenylalanine hydroxylase. Treatment of pah deficiency to decrease blood phe levels. Management of women with phenylalanine hydroxylase deficiency. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the ratelimiting step in phenylalanine catabolism. Mutation spectrum in taiwanese patients with phenylalanine.
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. Phenylalanine hydroxylase pah deficiency including. Abnormalities related to the hydroxylation of phenylalanine to tyrosine are. Keywords phenylalanine hydroxylase deficiency, phenylketonuria, metabolic clinic, patient outcomes, management, rare disease. Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid phenylalanine. Eventually, treatment of phenylalanine hydroxylase deficiency will be individualized with multiple medica. The most severe, classic form of pah deficiency is called pku. While it is found in many different ethnicities, it is particularly prevalent in sephardic jewish, sicilian, irish, and turkish individuals, as well as caucasians.
It is autosomal recessive, meaning that both copies of the gene must be mutated. Phenylalanine hydroxylase deficiency nxgen mdx accurate. Phenylalanine hydroxylase deficiency is an inherited condition that affects the bodys ability to process the amino acid phenylalanine from food. 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. Deficiency of this enzyme produces a spectrum of disorders including classic. Phenylalanine hydroxylase deficiency may be complete classic pku, type i or partial types ii and iii. Many mutations of the phenylalanine hydroxylase gene. 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. Phenylalanine hydroxylase activity jama pediatrics jama.
Ten phenylketonuric patients and two parents were studied. Phenylalanine hydroxylase deficiency american college of. Hundreds of different diseasecausing mutations have been found in the pah gene. Molecular epidemiology and predictable bh4responsiveness in south portugal pku patients.
Phenylalanine hydroxylase pah deficiency is one of 31 targeted inherited metabolic diseases imd for the canadian inherited metabolic diseases research network cimdrn. Phenylalanine hydroxylase deficiency is an inherited condition. If gene mutations reduce the activity of phenylalanine hydroxylase, phenylalanine from the diet is not processed. 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. Nine of the ten patients had completed a threeday oral.
Individuals with phenylalanine hydroxylase deficiency have a defect in the enzyme phenylalanine hydroxylase, which is. 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. 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. Needle liver biopsies were carried out on patients with phenylketonuria pku to establish a diagnosis either of partial or complete phenylalanine hydroxylase ph deficiency. This enzyme is not active in individuals who have phenylketonuria.
This deficiency is caused by mutation in the pah gene on chromosome 12 in band 12q23. 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. This results in the buildup of dietary phenylalanine to potentially toxic levels. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. Many mutations of the phenylalanine hydroxylase gene have been identified missense, nonsense, insertions, deletions, and duplications leading to pku or nonpku hyperphenylalaninemia. This enzyme converts the amino acid phenylalanine to other important compounds in the body. Responsiveness to this therapy must be determined empirically through a bh4 loading test or trial. 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. Pdf biopterin responsive phenylalanine hydroxylase.
Pah deficiency encompasses a spectrum of biochemical phenotypes from classic pku severe pah deficiency to mild hyperphenylalaninemia with varying degrees of residual pah activity. There are three different categories of phenylalanine hydroxylase deficiency based on their severity. Different phenotypes for phenylalanine hydroxylase deficiency. Each molecule in the tetramer is organized into three domains. Pdf recommendations for the nutrition management of. If this reaction does not take place, phenylalanine accumulates and tyrosine is deficient. Phenylalanine hydroxylase pah deficiency results in intolerance to the. Research on phenylalanine hydroxylase by seymour kaufman led to the discovery of tetrahydrobiopterin as a biological cofactor. 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.
Nutritional management of phenylalanine hydroxylase pah. Phenylalanine hydroxylase deficiency includes phenylketonuria. In the article, diagnosis of phenylalanine hydroxylase deficiency phenylketonuria journal 1982. Testing for tetrahydrobiopterin responsiveness in patients. The effectiveness of a phenylalanine restricted diet to improve the outcome of individuals with phenylalanine hydroxylase deficiency omim no. 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. 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 pah deficiency, traditionally called phenylketonuria pku due to characteristic phenylketones accumulating in the. An individual who inherits two mutations in this gene, one from each parent, is. Proteins are formed by a very long chain of amino acids, which bind as the pearls of a necklace, in.
Pah deficiency is caused by mutations in the pah gene. Phenylketonuria phenylalanine hydroxylase deficiency orphanet. Deficiency of this enzyme produces a spectrum of disorders including classic phenylketonuria. 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. Four molecules of phenylalanine hydroxylase interact to form a tetramer, which is the functional unit for this enzyme. This gene encodes a member of the biopterindependent aromatic amino acid hydroxylase protein family. This study presents the clinical findings on seven children from malta population 385 000. The risk of adverse outcome varies based on the degree of pah deficiency.
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. Phenylalanine hydroxylase deficiency is an autosomal recessive disorder that results in intolerance to the dietary intake of the essential amino acid. Depending on the severity of the pah enzymatic defect, phenylalanine levels may exceed a critical threshold that leads to permanent cognitive defects. 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. Phenylalanine hydroxylase pah deficiency is an autosomal recessive disorder of phenylalanine metabolism that is characterized by insufficient activity of pah, a hepatic enzyme.
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