Metabolic abnormalities detected in a survey of mentally backward individuals in Northern Ireland.

In 1908, Sir Archibald Garrod in his Croonian lectures coined the name 'inborn errors of metabolism' to describe a group of rare metabolic disorders which appeared to be genetically determined. In 1923, he described six such conditions in a monograph-alcaptonuria, pentosuria, cystinuria, albinism, pancreatic steatorrhoea and porphyria. He predicted that a biochemical reason would be found for these disorders and that they probably resulted from a block at some point in metabolism due to the congenital deficiency of a specific enzyme. The development of chromatographic and enzymatic techniques over the past 15 years has led to the elucidation of many metabolic pathways and provided the scientific proof of his brilliant induction. Garrod thought that in alcaptonuria, the accumulation of homogentisic acid was evidence that this substance was a normal metabolite in the breakdown of tyrosine and that its increase was due to a failure of oxidation of homogentisic acid. Now, a half century later, Garrod's hypothesis has been proved by demonstration of the absence of homogentisic acid oxidase activity in the liver of a patient with alcaptonuria (La Du, Zannoni, Laster and Seegmiller, 1958). In the past decade many abnormalities in the excretion of aminQ acids have been noted in association with hereditary biochemical disorders and mental retardation. Among these may be noted maple syrup urine disease (Dancis, Levitz, Miller and Westall, 1959), in which there is a metabolic block in the degradative pathway of the branched chain amino acids isoleucine, leucine and valine; this is associated with mental retardation, muscular hypertonicity and a maple syrup odour to the urine. Hartnup disease was first described by Baron, Dent, Harris, Hart and Jepson in 1956; this is characterized by a pellagra-like, light-sensitive skin rash, cerebellar ataxia and emotional instability. A constant feature of the disease is a generalized aminoaciduria related to an intermittent upset in tryptophane metabolism (Milne, Crawford, Girao and Loughridge, 1960). Harris, Penrose and Thomas (1959) described cystathionuria in an elderly mentally-retarded patient. Glycinuria has recently been described by Childs, Nyhan, Borden, Bard and Cooke (1961) where mental retardation and microcephaly were accompanied by excess glycine in urine and blood. Metabolic errors in carbohydrate metabolism have been known for many years; pentosuria as cited by Garrod in 1908 was first described in 1892 by Salkowski and Jastrowitz. Galactosaemia was also first noted in 1908 by Reuss-although the mechanism of its occurrence was only described in 1956 by Schwarz, Golberg, Komrower and Holzel in England and Isselbacher, Anderson, Kurahashi and Kalckar in America. Gargoylism was recognized in 1917 by Hunter, but it is only within recent years that it has been discovered to be due to deviations in the metabolism of mucopolysaccharides (Dorfman and Lorincz, 1957; Meyer, Hoffman and Linker, 1957). All these conditions are rare and there are, as yet, few specific instances in which a chemical disturbance results in mental retardation; less than 5% of the mentally defective population are of this type. With the exception of Hartnup disease, these metabolic disturbances are responsible for the more severe degrees of mental retardation. Some are amenable to treatment especially when diagnosed and treated from an early age, e.g. phenylketonuria, galactosaemia, maple syrup urine, but in them the actual cause of the brain damage is still unknown. With the increased interest in these metabolic errors in recent years it was considered desirable to determine their incidence in Northern Ireland. With special reference to phenylketonuria it was felt that the registration of all phenylketonuric families would allow the condition to be anticipated in any new siblings so that treatment could be started at an early age when success would be more sure.