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Perspective on the paper by Sanderson et al (see 896)
Since Archibald Garrod coined the term “inborn freaks of metabolism” after his classic studies on alkaptonuria, cystinuria and pentosuria a century ago,1 clinicians have believed that these disorders are a rarity. Early progress was hampered by insensitive methods of detection, as well as a lack of awareness within the medical community as a whole. The successive application of chromatographic techniques, mass spectrometry, enzymology and, recently, molecular genetics has increased our ability to detect metabolic perturbations in symptomatic, and in asymptomatic, people. Despite possible diagnosis, nihilism persisted as few therapeutic interventions were available and many of those affected died early in childhood. Even with survival, quality of life was extremely poor.
Phenylketonuria (PKU) is a good example of how the application of new advances, diagnostically and therapeutically, can have a dramatic effect on outcome and therefore on expectations. PKU was first described by Følling in the 1930s. Biochemical diagnosis could be made on urine samples from infants with developmental and neurological problems. Two decades passed before Bickel showed that a phenylalanine-restricted diet could be given safely to affected children, although they remained severely impaired and dependent, with many of them institutionalised for life.2 It required the development, by Robert Guthrie in the 1960s, of a cheap, sensitive and specific screening test that could be applied to large populations before a true effect on outcome could be shown.3 Since then, further technological improvements have provided accurate, quantitative measurements of phenylalanine, and an explosion of phenylalanine-free nutritional products means that a newborn with PKU diagnosed today can expect a near-normal life. Management of PKU is certainly one of the success stories of 20th century medicine.
PKU is well known to paediatricians, but many other inherited metabolic diseases (IMDs) are …