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Clinical therapeutics for phenylketonuria

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Abstract

Phenylketonuria was amongst the first of the metabolic disorders to be characterised, exhibiting an inborn error in phenylalanine metabolism due to a functional deficit of the enzyme phenylalanine hydroxylase. It affects around 700,000 people around the globe. Mutations in the gene coding for hepatic phenylalanine hydroxylase cause this deficiency resulting in elevated plasma phenylalanine concentrations, leading to cognitive impairment, neuromotor disorders and related behavioural symptoms. Inception of low phenylalanine diet in the 1950s marked a revolution in the management of phenylketonuria and has since been a vital element of all therapeutic regimens. However, compliance to dietary therapy has been found difficult and newer supplement approaches are being examined. The current development of gene therapy and enzyme replacement therapeutics may offer promising alternatives for the management of phenylketonuria. This review outlines the pathological basis of phenylketonuria, various treatment regimes, their associated challenges and the future prospects of each approach. Briefly, novel drug delivery systems which can potentially deliver therapeutic strategies in phenylketonuria have been discussed.

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Abbreviations

BH4:

Tetrahydrobiopterin

DHPR:

Dihydropteridine reductase

DNA:

Deoxyribonucleic acid

EC:

Enzyme Commission

EMEA:

European Medicines Agency

ENU:

Ethylnitrosourea

ERT:

Enzyme Replacement Therapy

FDA:

Food and Drug Administration

GMP:

Glycomacropeptide

GTPCH:

Guanosine triphosphate cyclohydrolase

HPA:

Hyperphenylalaninemia

IQ:

Intelligence quotient

LNAA:

Large neutral amino acid

OMIM:

Online Mendelian Inheritance in Man

PAH:

Phenylalanine hydroxylase

PAL:

Phenylalanine ammonia lyase

PCD:

Pterin-4a-carbinolamine dehydratase

PEG:

Polyethylene glycol

Phe:

Phenylalanine

PKU:

Phenylketonuria

qDHB:

Quinonoid dihydrobiopterin

t-CA:

Trans-cinnamic acid

Tyr:

Tyrosine

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  1. Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Block S4 Level 2, Singapore, Singapore, 117543

    Jaspreet Singh Kochhar, Sui Yung Chan, Pei Shi Ong & Lifeng Kang

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Kochhar, J.S., Chan, S.Y., Ong, P.S. et al. Clinical therapeutics for phenylketonuria. Drug Deliv. and Transl. Res. 2, 223–237 (2012). https://doi.org/10.1007/s13346-012-0067-1

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