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Genomics and Medicine
Published in Danielle Laraque-Arena, Lauren J. Germain, Virginia Young, Rivers Laraque-Ho, Leadership at the Intersection of Gender and Race in Healthcare and Science, 2022
Newborn screening, carried out on all newborns in the first few days of life, detects genetic conditions and metabolic diseases early in life, before symptoms have developed. Instituting steps such as dietary restriction or supplementation is an early intervention that dramatically improves the course of a person's life. Phenylalanine hydroxylase (PAH) deficiency, formerly known as phenylketonuria or PKU, is one of the earliest conditions routinely screened for in newborns, beginning in the 1960s. The condition has no gender predilection and countless individuals have experienced enormous health improvements and avoided severe neurodevelopmental manifestations throughout their lives due to newborn screening and early intervention. Of note, due to the success of newborn screening and early intervention, people with PAH deficiency that are identified as newborns and treated throughout their childhood and adolescence are poised to have healthy pregnancies and families and no longer need to be limited by their condition (ACOG, 2020).
Nutrition Therapy of Inborn Errors of Metabolism
Published in Fima Lifshitz, Childhood Nutrition, 2020
Kimberlee Michals-Matalon, Reuben Matalon
The biochemical findings on patients with untreated PKU include elevated levels of phenylalanine in blood, urine, and spinal fluid. A normal concentration of blood phenylalanine is 1–2 mg/dl. Patients with untreated PKU have levels of phenylalanine that often exceed 20 mg/dl. Once an infant with an elevated phenylalanine blood level is identified by newborn screening, confirmatory diagnostic studies must be completed. Blood should be analyzed for quantitative amino acids to document that the phenylalanine is indeed greater than 6 mg/dl and that the tyrosine blood level is normal. The urine should show elevated phenylalanine and phenylalanine metabolites. Phenylalanine hydroxylase requires the cofactor te-trahydrobiopterin (BH4) for the conversion of phenylalanine to tyrosine. The co-factor, BH4, is also utilized in the hydroxylation of tyrosine to dopamine and tryptophan to serotonin. Approximately 2% of infants with hyperphenylalani-nemia have BH4 deficiency. Therefore, this must be ruled out since the treatment for BH4 deficiency is totally different than that for PKU.7
Phenylketonuria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Restriction enzyme polymorphism permitted heterozygote detection and prenatal diagnosis in the approximately 75 percent of families in which relevant polymorphism was identified [18]. Affected fetuses have been diagnosed prenatally in this way. Restriction fragment length polymorphism (RFLP) exists in or near the phenylalanine hydroxylase gene that permits assessment of the transmission of alleles within a family. A composite family of RFLPs on an allele is referred to as an “RFLP haplotype”. Some 50 haplotypes have been described for the phenylalanine hydroxylase locus. Once the mutation in the phenylalanine hydroxylase gene is known, mutational analysis may be used for prenatal diagnosis and for heterozygote detection. This provides a practical argument for seeking the precise molecular diagnosis. In the best studied Northern European population, eight mutations have resulted in 64 percent of the mutant phenylalanine hydroxylase chromosomes [4, 5]. Two mutations, in each of which there was zero enzyme activity and cross-reacting material (CRM), accounted for 46 percent; these were an arginine to tryptophan change in amino acid residue 408 (R408W) of exon 12 and a splicing mutation of intron 12. A number of the abnormal alleles identified have involved cytosine-phosphate-guanine (CpG) dinucleotides, which are known to be highly mutable.
Preclinical and clinical developments in enzyme-loaded red blood cells: an update
Published in Expert Opinion on Drug Delivery, 2023
Marzia Bianchi, Luigia Rossi, Francesca Pierigè, Sara Biagiotti, Alessandro Bregalda, Filippo Tasini, Mauro Magnani
Phenylketonuria (PKU) is an inborn metabolic disease caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene resulting in increased blood phenylalanine (Phe) concentrations which are neurotoxic and lead to severe intellectual disability, autistic behavior, seizures, and epilepsy [57]. The management of PKU has been extensively covered in the literature and recent reviews highlight emerging therapies, which could improve patient health, compliance, and quality of life [58,59]. Among these, the enzyme replacement therapy based on recombinant phenylalanine ammonia lyase (rAvPAL) from Anabaena variabilis, catalyzing the deamination of Phe to the nontoxic product trans-cinnamate, plays a leading role. Indeed, pegvaliase (Palynziq®, BioMarin Pharmaceutical Inc., USAA), a PEGylated recombinant PAL, has been approved by FDA (2018) and EMA (2019) for treatment of adult patients.
Phenylalanine 4-monooxygenase: the “sulfoxidation polymorphism”
Published in Xenobiotica, 2020
Stephen C. Mitchell, Glyn B. Steventon
Phenylalanine 4-monoxygenase (PAH, phenylalanine hydroxylase, phenylalaninase, E.C. 1.14.16.1) is a non-haem iron-dependent enzyme that catalyses the hydroxylation of l-phenylalanine to l-tyrosine, a reaction which is the rate limiting step in phenylalanine catabolism. It proceeds via the heterolytic cleavage of molecular oxygen transferring one atom to the phenylalanine moiety whilst the other is reduced to water using tetrahydrobiopterin as the reductant. Inefficiency in the functioning of the enzyme may lead to hyperphenylalaninaemia and precipitate the clinical condition of phenylketonuria (PKU). However, owing to a copious built-in redundancy, as little as 10% of maximum activity is sufficient to maintain acceptable metabolic balance and prevent clinical consequence (Bartholomé et al., 1975; Friedman et al., 1972, 1973). Some even quote a value lower than this; “in classical PKU enzyme activity is <1% of normal” (Carr, 2009). Interestingly, it has been stated that the activity of rat liver phenylalanine 4-monoxygenase displayed circadian rhythmicity (Castells & Shirali, 1971; Kaufman & Fisher, 1974) and perhaps this phenomenon may be involved in diurnal variations seen in plasma phenylalanine levels in humans. However, without doubt many other factors in addition to food intake certainly contribute to this and may be the causation, such as protein catabolism predominating over protein anabolism during the fasting (night-time) period (Cleary et al., 2013).
Tryptophan hydroxylase 2 as a therapeutic target for psychiatric disorders: focus on animal models
Published in Expert Opinion on Therapeutic Targets, 2019
Elizabeth A. Kulikova, Alexander V. Kulikov
The mutations affecting the structure of the human TPH2 molecule are rare and poorly studied [27]. Some of these mutations, such as R441H in the hTph2 gene or R439H and P447R in the mTph2 gene seem to result in the enzyme misfolding and their negative effects on the TPH2 activity can be reduced by pharmacological chaperone treatment. The BH4 cofactor is a natural pharmacological chaperone for all tetrahydropterin-dependent L-aromatic amino acid hydroxylases. It corrects the activity of mutant phenylalanine hydroxylase and effectively reduces phenylketonuria in 60% of patients [127,128]. Moreover, therapy with BH4 has several advantages over other existing (antidepressants) or potential (Tph2 AAV vectors, artificial 5-HT neurons, etc.) kinds of treatments, since BH4 is a natural product of an organism, easily delivered with food and selectively corrects only misfolded TPH2 and does not affect ‘healthy’ TPH1. Therefore, BH4 and other chemical chaperones are the most promising and safe pharmacological means for treatment of hereditary psychiatric disorders caused by loss-of-function of the TPH2 molecule (Figure 4). Lines of mice with R439H (Tph2KI) [51] and P447R (Balb/c, DBA2) [60,61] mutations are promising models for preclinical studies of new and effective pharmacological chaperons to correct the TPH2 activity.