Phenylketonuria
Phenylalanine hydroxylase (PAH) performs an enzymatic function during the conversion of phenylalanine (abbreviated Phe), to tyrosine. Existing naturally in several types of foods, for instance breast milk, Phe is an essential α-amino acid and one of the plethora of amino acids used in the formation of proteins. Phenylalanine exists in three forms; L-phenylalanine, D-phenylalanine (mirror image of L-phenylalanine), and DL-phenylalanine which is a typic combination of D and L-phenylalanine, and unlike D and L- phenylalanine, is not found in foods. On the other hand, tyrosine, a part from being a derivative of phenylalanine, is a non-essential amino acid that forms part of the list of amino acids utile during the constitution of proteins. Ordinarily, lack of PAH leads to the accumulation of phenylalanine (phenylalanine in not converted to tyrosine) leading the development of a disease called Phenylketonuria (PKU). This paper presents a relatively detailed overview of Phenylketonuria in terms of its genetic basis, symptoms, diagnosis, treatment and other illustrious features of the disease.
Genetic Basis of Phenylketonuria
Williams, Mamotte, & Burnett (2008) asseverate that there have been more than 500 disease causing mutations of the PAH gene. The human PAH gene exhibits great allelic variation with all its 13 axons having been identified with specific pathogenic mutation (Williams, Mamotte, & Burnett, 2008). With the help of ‘broad range’, denaturing gradient gel electrophoresis (DGGE), the researchers analyzed exons and flanking regions of intron sequences in the PAH gene to institute the types of mutations often experienced by the PAH gene. It is worth noting that not all mutations of the PAH gene are pathogenic- some of the mutations are neutral unlike the pathogenic mutations which causes a disruption of the PAH enzyme structure as well as its function (Williams, Mamotte, & Burnett, 2008). The major types of mutations commonly reported in PKU patients include missence mutation (62% of all PAH allele mutations), small or large deletions (13%), nonsense mutations (5%), insertions (2%), splice site (11%) and silent polymorphisms (6%) (Williams, Mamotte, & Burnett, 2008). Missence mutation essentially entails the substitution of a nucleotide leading to the formation of a wrong amino acid hence formation of a malfunctioning protein. Splice site mutations are yet another set of commonly encountered genetic mutations involving the splicing of the intron sequences. Likewise, inversion mutations are other plausible causes of PKU. Inversion pertains to the change in the orientation of some parts of the gene particularly when a gene breaks at two positions. Deletion mutations involves the excision of a part of the PAH gene.
Inheritance and prevalence of Phenylketonuria
Utilizing audit data from two London based newborn screening laboratories offering screening services to denizens of South East England for their study, Hardelid et al. (2007), report finding out that the number of incidences of PKU among black populations that migrated to South East England is far much lower than their corresponding white counterparts. Citing Donlon et al. (2004), the researchers underscore that the prevalence of PKU among European communities is 1:10000 births; an emphatic declaration that it reinforced by Gu &Wang (2004), Lee et al. (2004), and Song et al.’s (2005) assertions on the same matter (as cited in Hardelid et al., 2007). Further, the prevalence is low in Asian/ Asian British people of Indian sub continental line of descent (Hardelid et al., 2007). However, Hardelid et al., (2007) keenly pinpoint that it is arduous to ascertain the exact statistics about the prevalence of PKU in sub-Saharan regions owing to the fact there is a paucity of literature covering it.
In light for the inheritance of its inheritance, PKU, is an autosomal recessive gene that according to Scriver (2007) is imputable to its increased frequency of consanguinity among parents of its victims. Every single human being has two Phenylalanine hydroxylase genes normally found on the chromosome 12. Usually, a child gains one PAH gene from each parent. In the case that both parents have one mutated PAH gene, there are 25% chance that the parents might give birth to PKU child. In the event that one parent is suffering from PKU, and the other has one mutant gene, there is 50% chance that they will bear a child suffering from PKU.
It is noteworthy that PKU, unlike some genetic disorders like hemophilia does not have a preference to male or female students. Moreover, if the patients refrain from eating foods containing phenylalanine particularly during childhood, the victims can have a normal life like expectancy as other normal people.
Symptoms
According to Williams, Mamotte, & Burnett (2008) the effect of PAH mutation on the phenotype is variable hence warranting that the concentration of Phenylalanine in the body. This differing concentration of Phenylalanine in the body overly shapes the clinical manifestation of PKU in an individual. Symptoms of PKU principally encompass; mental retardation, seizures, and microcephaly (Madden, 2008; Williams, Mamotte, & Burnett, 2008). Untreated PKU is believed to cause monstrous brain, which might culminate to epilepsy and stunt growth.
Diagnosis
PKU can be diagnosed using the Guthrie Card Screening, also known as Guthrie’s biochemical assay (Williams, Mamotte, & Burnett, 2008). The procedure, mostly carried out on newborns and famous for their howling success rate, involves the collection of blood from the newborn by a heel prick onto a filter paper. Phe concentration is the determined. On the same note, PKU mutation analysis, is yet another common diagnostic procedure that is utile in the detection of PKU (Williams, Mamotte, & Burnett, 2008). This procedure underscores that the causation of PKU is also attributable to mutations of the PAH gene. Detection of mutations through PKU mutation analysis is done through sequencing and multiplex ligation probe amplification (Williams, Mamotte, & Burnett, 2008).
Treatment of Phenylketonuria
There a quite a number of amelioration models used in the treatment of Phenylketonuria. Dietary treatment is one of such proven models. In dietary treatment model involves the intake of foods low in Phe concentrations in a bid to keep the homeostatic level of Phe in the blood low. Williams, Mamotte, & Burnett (2008), in their article, emphasize the need to start the dietary treatment as early as one of birth though to childhood. This is because the period between birth and childhood presents a time when neural development is at its uttermost. Enzyme Replacement Therapy is applicable in cases where other treatment methods such as the use of tetrahydrobiopterin (BH4) are inapplicable; BH4 is commonly to reduce Phe levels in mild cases of PKU. Gene Therapy can also be used to meliorate PKU conditions is situations where dietary therapy cannot be used (Kim et al., 2004).
Concisely, PKU is a condition resulting from the accumulation of Phe in the body as a result of mutational changes in the structure of PAH which served with the function on catalyzing the conversion of Phe to tyrosine. PKU is diagnosable through Guthrie Card Screening and PKU mutation analysis and can be treated through dietary therapy and gene replacement therapy among other therapeutic methods.
References
Hardelid, P., Cortina-Borja, M., Munro, A. Jones, H., Cleary, M., Champion, M. P., Foo. Y.
Kim, W.,1,2 Erlandsen, H. Surendran, S.,4 Stevens, R. C., Gamez,A., Michols-Matalon, K., Tyring, S. K., & Matalon, R. Trends in Enzyme Therapy for Phenylketonuria. Molecular Therapy, 10(2), 220-224.
Madden, M. (2007). Phenylketonuria: Defects in Amino Acid Metabolism. South Carolina Journal of Molecular Medicine, 5, 57–61.
Scriver, C. R. & Dezateux, C. The Birth Prevalence of PKU in Populations of European, South Asian and Sub-Saharan African Ancestry Living in South East England. Annals of Human 71,1–7. doi: 10.1111/j.1469-1809.2007.00389.x
Scriver, C. R. (2007). The PAH Gene, Phenylketonuria, and a Paradigm Shift. Human Mutation 28(9), 831-845. doi: 10.1002/humu.20526
Williams, R. A.,1,2 Mamotte, C. D. S. & Burnett, J. R. (2008). Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. Clin Biochem Rev, 29, 31-41. doi:10.1016/j.ymthe.2004.05.001
