Phenylketonuria is an autosomal recessive disorder and a common metabolic cause of mental retardation. This inborn error of metabolism is characterized by a deficiency in phenylalanine (Phe) hydroxylase activity, due to mutations in the Phe hydroxylase (PAH) gene. Phenylalanine hydroxylase is responsible for converting Phe to Tyr and requires the cofactor tetrahydrobiopterin (BH4), molecular oxygen, and iron for its action (Blau et al., 2010). The reductant, BH4 is maintained in the reduced state by the NADH-dependent enzyme dihydropteridine reductase. Decreased PAH activity results in elevated Phe concentrations in blood and body tissue. As a result, approximately 75% of untreated patients experience severe neurological dysfunction (Brumm and Grant, 2010).
Phe is a large neutral amino acid that competes for transport across the blood brain barrier via the L-type amino acid carrier. Excessive levels of Phe in the blood saturates these transporters and subsequently cause a decrease in transportation of other large neutral amino acids into the brain which is required for protein and neurotransmitter synthesis (Blau et al., 2010). Neurological dysfunction is a result of elevated Phe levels that disrupt the transportation of Tyr, a neurotransmitter precursor, across the blood brain barrier and cause a reduction in dopamine and other neurotransmitters (Brum and Grant, 2010). Myelination of axons is also compromised by elevated Phe and decreased Tyr levels which further disrupt neurological function (Dyer, 1999). Neurological dysfunction is observed through progressive intellectual impairment, accompanied by the following symptoms, autism, seizures, rash, and motor deficits (Blau et al., 2010). CHANGES IN MOLECULAR GENETICS The PAH gene consists of 13 exons and their accompanied introns (Woo et al., 1983) and according to the early work of Ledley et al. (1985) only about 10% enzyme activity is necessary for normal Phe metabolism in mice. Phenotypic observation of phenylketonuria requires mutations in both alleles of the PAH gene. Mutations in the gene could occur in the exons, promoter or any other unidentified regions, and possibly in the splice junctions of the intervening introns (Blau et al., 2010). According to the Human PAH Mutation Knowledgebase, a total of 548 separate mutations in the gene is possible of which about 50% are missense mutations (Scriver, 2007) which leads to synthesis of a not functional protein (PAH). Missense mutation are point mutations within a gene that result in a codon that codes for a different amino acid and consequently lead to the synthesis of a protein with an altered amino acid sequence. Splice junction mutations accounts for 10% of mutations observed in phenylketonuria, and the position and nature of the mutation ultimately determine the effect on enzyme activity (Blau et al., 2010). Mutations could lead to little or no enzyme activity which result in the classic phenylketonuria phenotype, but could also be evident in partial inhibition of enzyme activity and result in mild phenylketonuria. Approximately 1 to 2% of hyperphenylalanine cases are a result of genetic mutations in the genes encoding for the synthesis and regeneration of BH4, the cofactor for PAH (Thony and Blau, 2006). NEUROPHYSIOLOGICAL PATHOLOGY Phenylalanine metabolism occurs predominantly in the liver where, PAH and the enzymes responsible for the biosynthesis and regeneration of BH4 are found in active hepatocytes (Spronsen and Enns, 2010). …show more content…
Defects in the synthesis or recycling of BH4 could lead to phenotypical characteristics of phenylketonuria. During the hydroxylation of Phe by PAH in the presence of molecular oxygen and iron, BH4 is oxidized to a 4a-hydroxy-BH4 intermediate, which in turn is converted to q-dihydrobiopterin by cabinolamine-4a-dehydratase (Blau et al., 2010). Which is subsequently regenerated back to BH4 by the NADH dependent enzyme, dihydropteridine reductase. Mutations in any of the genes coding for the above mentioned enzymes involved, result in decreased BH4 levels and consequently phenylketonuria due to the elevated plasma Phe concentrations. Neurological dysfunction requires the movement of Phe into the brain as mediated by the large neutral amino acid carrier L-aminoacid transporter 1 (LAT1; Surtees and Blau, 2000). There are several mechanisms described in current literature on how elevated Phe levels in the brain cause neurological dysfunction. The exact mechanism by which myelination of brain white matter (axons) are affected by elevated blood Phe and reduced blood Tyr levels are not well understood. However, both Dyer (1999) and Pearsen et al. (1990) showed a relation
Phe is a large neutral amino acid that competes for transport across the blood brain barrier via the L-type amino acid carrier. Excessive levels of Phe in the blood saturates these transporters and subsequently cause a decrease in transportation of other large neutral amino acids into the brain which is required for protein and neurotransmitter synthesis (Blau et al., 2010). Neurological dysfunction is a result of elevated Phe levels that disrupt the transportation of Tyr, a neurotransmitter precursor, across the blood brain barrier and cause a reduction in dopamine and other neurotransmitters (Brum and Grant, 2010). Myelination of axons is also compromised by elevated Phe and decreased Tyr levels which further disrupt neurological function (Dyer, 1999). Neurological dysfunction is observed through progressive intellectual impairment, accompanied by the following symptoms, autism, seizures, rash, and motor deficits (Blau et al., 2010). CHANGES IN MOLECULAR GENETICS The PAH gene consists of 13 exons and their accompanied introns (Woo et al., 1983) and according to the early work of Ledley et al. (1985) only about 10% enzyme activity is necessary for normal Phe metabolism in mice. Phenotypic observation of phenylketonuria requires mutations in both alleles of the PAH gene. Mutations in the gene could occur in the exons, promoter or any other unidentified regions, and possibly in the splice junctions of the intervening introns (Blau et al., 2010). According to the Human PAH Mutation Knowledgebase, a total of 548 separate mutations in the gene is possible of which about 50% are missense mutations (Scriver, 2007) which leads to synthesis of a not functional protein (PAH). Missense mutation are point mutations within a gene that result in a codon that codes for a different amino acid and consequently lead to the synthesis of a protein with an altered amino acid sequence. Splice junction mutations accounts for 10% of mutations observed in phenylketonuria, and the position and nature of the mutation ultimately determine the effect on enzyme activity (Blau et al., 2010). Mutations could lead to little or no enzyme activity which result in the classic phenylketonuria phenotype, but could also be evident in partial inhibition of enzyme activity and result in mild phenylketonuria. Approximately 1 to 2% of hyperphenylalanine cases are a result of genetic mutations in the genes encoding for the synthesis and regeneration of BH4, the cofactor for PAH (Thony and Blau, 2006). NEUROPHYSIOLOGICAL PATHOLOGY Phenylalanine metabolism occurs predominantly in the liver where, PAH and the enzymes responsible for the biosynthesis and regeneration of BH4 are found in active hepatocytes (Spronsen and Enns, 2010). …show more content…
Defects in the synthesis or recycling of BH4 could lead to phenotypical characteristics of phenylketonuria. During the hydroxylation of Phe by PAH in the presence of molecular oxygen and iron, BH4 is oxidized to a 4a-hydroxy-BH4 intermediate, which in turn is converted to q-dihydrobiopterin by cabinolamine-4a-dehydratase (Blau et al., 2010). Which is subsequently regenerated back to BH4 by the NADH dependent enzyme, dihydropteridine reductase. Mutations in any of the genes coding for the above mentioned enzymes involved, result in decreased BH4 levels and consequently phenylketonuria due to the elevated plasma Phe concentrations. Neurological dysfunction requires the movement of Phe into the brain as mediated by the large neutral amino acid carrier L-aminoacid transporter 1 (LAT1; Surtees and Blau, 2000). There are several mechanisms described in current literature on how elevated Phe levels in the brain cause neurological dysfunction. The exact mechanism by which myelination of brain white matter (axons) are affected by elevated blood Phe and reduced blood Tyr levels are not well understood. However, both Dyer (1999) and Pearsen et al. (1990) showed a relation