In the 1890s, the English
physician Archibald Garrod was called upon to examine Thomas P, a
threemonth-old boy whose urine was a deep reddish-brown. His diagnosis was
alkaptonuria, which is caused by a buildup of homogentisic acid (alkapton), a
compound that the body normally breaks down rapidly. At the time, the
prevailing thought was that alkaptonuria, a rare disorder, was caused by a
bacterial infection; Garrod conceived it to be a disease associated with
chemical reactions. Two subsequent siblings of Thomas were born, each with
alkaptonuria, from parents who were blood relatives. Further investigation
revealed to Garrod that in other families having one or more children with
alkaptonia, in every instance, the parents were first cousins. He published
these findings in 1902.
Based on his appreciation of
Gregor Mendel’s rules of inheritance and his knowledge of chemistry, Garrod
concluded that some diseases might represent inherited disorders of metabolism,
and these he described in his classic 1923 text Inborn Errors of Metabolism.
IEM, also called inherited metabolic diseases, are associated with a single
defective gene, resulting in the absence or production of an abnormal specific
enzyme required to carry out a metabolic reaction. Most abnormal genes are
inherited in an autosomal recessive manner—that is, the child must inherit
copies of the defective from each parent. IEM represent a large group of
disorders in which the body cannot convert food into energy or other essential
compounds. As a consequence, the body builds up substances that are toxic or
interfere with normal body function or that reduce the body’s ability to
synthesize essential compounds. The outcome may range from harmless to severe,
even fatal.
IEM, of which over two
hundred have been identified, are traditionally classified based on the type of
metabolism involved—namely, carbohydrate, amino acid, fats, or complex
molecules. Each IEM is individually rare, but collectively, they occur in
roughly 1 of every 4,000 live births, with the incidence varying among
different ethnic and racial groups: sickle cell anemia, 1:600 of African
descent; cystic fibrosis, 1:1600 of European descent; and Tay-Sachs, 1:3500 of
Ashkenazi Jewish descent.
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