Nenad Blau (editor) - Physicians Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases

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A new edition for an old subject

The study of inborn errors of metabolism arguably began with Garrods seminal 1902 paper on alkaptonuria (Garrod 1902). At the time, the diagnosis of this disorder was achieved using state-of-the-art technology: visual inspection of recently voided urine. Garrods genius was to use this method to identify and collect a large number of individuals with this rare disorder and to recognize, with input from Bateson, that the familial clustering and distribution of affected individuals (19 affected of 48 individuals in 9 sibships) was consistent with observations made by Gregor Mendel in pea plants some 37 years earlier. An additional feature of alkaptonuria, crucial for Garrods study, is that, at the phenotypic level, it is a relatively mild disorder with minimal, if any, effect on life span. To quote Garrod, an alternative course of metabolism, harmless and usually congenital and lifelong. Thus, it was possible for Garrod to collect affected individuals, many of whom were adults at the time of diagnosis.

From this modest beginning, Garrod not only demonstrated that Mendelism held true in humans, but also suggested that alkaptonuria and a handful of similar disorders (cystinuria, pentosuria, and albinism) were merely extreme examples of variations in chemical behavior which are probably everywhere present in minor degree so that just as no two individuals of a species are absolutely identical in bodily structure neither are their chemical processes carried out on exactly the same lines. First stated in 1902, these ideas lead to Garrods definition in 1931 (Garrod 1931) of chemical individuality as genetically determined biochemical characteristics and capabilities which confer predisposition to and immunities from the various mishaps which are spoken of as diseases. We are only now beginning to put meat on the bones of these prescient predictions.

From Garrods time to the present, progress in identifying specific inborn errors of metabolism has been dependent on technological advances. Thus, in the early 1950s following the development of the first amino acid analyzer, a host of new (really newly recognized) disorders were described on the basis of abnormal patterns of amino acids in plasma and/or urine. Similarly, the development of GC/MS technology leads to the recognition of many organic acidemias, and the development of tissue culture and somatic cell genetic techniques leads to a burst of newly recognized lysosomal storage diseases.

Currently, we are experiencing at least two technologic revolutions: genomic sequencing methods that began with the seminal 2009 paper of Ng et al. (2009) showing that the cause of rare Mendelian disorders could be identified by applying genomic methods to well-phenotyped patients and, more recently, the development of unstructured metabolomic methods that measure thousands of metabolites not previously examined by classical biochemical methods. Application of genomic methods has already had a profound effect on our identification and diagnosis of patients with inborn errors (Posey et al. 2019; Bamshad et al. 2019). Advances and widespread application of metabolomics seems likely to have a similar effect (Burrage et al. 2019; Miller et al. 2015). Moreover, the two technologies are synergistic in their power to identify newly recognized monogenic disorders and to expose their pathophysiology.