The various types, complexity and clinical symptoms of inborn errors of metabolism present a very big challenge to practicing pediatricians. It is imperative for the physician to be aware of the signs and symptoms of these metabolic errors for early diagnosis and management of these disorders (Burton, 1998). Among the various congenital metabolic errors, phenylketonuria (PKU) is a commonly found disorder occurring in infants.
Mechanism of PKU
Phenylketonuria (PKU) is one among the hereditary biochemical disorders arising from a mutation in the gene responsible for production of phenylalanine hydroxylase (PAH) or its cofactor, both of which are required for degradation of phenylalanine, an essential amino acid, into tyrosine, a non-essential amino acid synthesized in the body (Brough et al, 2004). Genetically, PKU is an autosomal recessive disorder resulting from a mutation in the PAH gene that is made up of 13 exons and is located on chromosome 12 (Lidsky et al, 1985). The incidence of PKU varies across different countries and regions, and in Europe is given as 1/15,000 in the general population. In human beings, phenylalanine is oxidized by PAH to form tyrosine, another amino acid that plays a role in the biosynthesis of various hormones, melanin etc (Phenylketonuria, UIC, 2006). Due to lack of the PAH enzyme, the phenylalanine undergoes either transamination or decarboxylation to produce phenylethylamine or phenylpyruvate and phenylacetate (Williams et al, 2008). This phenylpyruvate is usually responsible for the ‘musty’ odour seen in several affected infants.
The affected infants appear normal at birth but are usually blonder than siblings, with fair skin and blue eyes, presence of seborrhoeic/eczematoid skin rashes, with simultaneous or chronological hypertonicity and hyperactive deep tendon reflexes leading to seizures, mild to severe vomiting, and gradual development of cognitive impairment (Brough et al, 2004).
In the case study of Baby Ashlie, she was found to be clinically normal at birth, probably due to lack of onset of symptoms immediately after birth. The presence of very blonde hair, fair skin and blue eyes, along with eczema and a musty odour are indicative of classical PKU symptoms as described in the previous section. Seizures and vomiting also indicate that Baby Ashlie was showing classical signs of PKU (Phenylketonuria, UIC, 2006). The diagnosis needs to be confirmed with a biochemical test involving EEG and by checking the levels of urinary phenylpyruvate and blood phenylalanine. A blood level of >1.200 mM of phenylalanine confirms the signs of classical PKU (Williams et al, 2008).
Baby Ashlie’s biochemical profile shows that the EEG was abnormal pointing to a inherent neuropathology. Since the urine phenylpyruvate was initially within normal limits at 3 days, but rose 7-10 times above normal (15 mg/24h) at 8 days, it accounted for a lack of the musty odour initially, but which led to such a musty odour later when the levels of phenylalanine rose and resulted in production of phenylpyruvate due to lack of PAH. The high levels of blood phenylalanine (1.2 mM) suggested that phenylalanine was not metabolized by the body and further confirmed the diagnosis of PKU in Baby Ashlie. All these laboratory findings point out without any doubt that Baby Ashlie was afflicted with the classical form of PKU and needs to be monitored and treated if she has to survive this congenital inherited disorder.
Treatment and Prognosis
The management of PKU usually involves a lifelong phenylalanine-free diet to maintain the blood phenylalanine levels below 0.8 mM. The levels need to be monitored 2-3 times a week at initial onset and every week after 1 year of birth (Brough et al, 2004). This diet should be started very early at onset to have a better prognosis. The prognosis of Baby Ashlie surviving and having normal cognitive development is excellent if the dietary treatment is started at 2-3 weeks of age. If the treatment is delayed by a few months, then moderate to severe brain damage may occur, leading to lowered IQ and cognitive impairment (Williams et al, 2008; Brough et al, 2004).
Clinical Biochemistry and Its Role in PKU
As seen in the sections discussed above, clinical biochemistry has a major role to play in the diagnosis and treatment of PKU. Since an understanding of the biochemical pathway of phenylalanine metabolism is important in diagnosing PKU, it shows the importance of the role played by various biochemistry researchers starting from the discoverer of PKU (Folling, 1934) to modern day scientists in elaborating the mechanism, diagnosis, and treatment for PKU. All the screening and diagnostic tests for detection and confirmation of PKU are completely based on the biochemical profile of the infant/patient. But it is essential that the clinician and personnel involved in the screening and prognosis are well-informed of the immediacy of proper diagnosis ruling out other disorders, so that the treatment regime can be started at the earliest.
As seen in this case study, classical PKU is now quite easy to recognize, thanks to the pioneering efforts of Folling (1934), Jervis (1953), and Guthrie (1963). No, thanks to present-day genomic technology, PKU can be diagnosed by mutation analysis of the PAH locus to identify PKU with much greater accuracy. This is especially relevant for prenatal diagnosis of PKU carriers so that the newborn can be monitored for likely affliction with PKU (Williams et al, 2008). Treatment regimes such as the cofactor, BH4, treatment, enzyme replacement therapy and gene therapy are new realms of treatment that hold promise for the future treatment of PKU and its subtypes (Williams et al, 2008).
Even though quite a bit is known about the diagnosis and treatment of PKU, very little is known about the exact mechanism of PKU and its role in impairment of the cognitive mechanism in infants and adults (Williams et al, 2008). Therefore, more light needs to be shed on this aspect of the disease so that future treatments for this disorder are able to address the symptoms of PKU in a more holistic manner.
In this case study, Baby Ashlie was found to have symptoms of classical PKU that were very clear and pointed to a metabolic disorder. Thus, the physician treating such an infant should recognize the symptoms immediately and follow the protocol for diagnosis and treatment at the earliest to avoid any neurological impairment so that the infant can lead a very healthy and productive life in its childhood and adulthood (Brough et al, 2004). As such, PKU is not a deadly disorder and can be easily treated if the physician and clinician involved in the healthcare process understand and follow the process of timely diagnosis and treatment appropriately.