Metabolic diseases were known as early as the seventeenth century. In 1649, a physician named Zacutus Lusitanus described a case of what we now call alkaptonuria:
The patient was a boy who passed black urine and who, at the age of fourteen years, was submitted to a drastic course of treatment which had for its aim the subduing of the fiery heat of his viscera, which was supposed to bring about the condition in question by charring and blackening his bile. Among the measures prescribed were bleedings, purgation, baths, a cold and watery diet, and drugs galore. None of these had any obvious effect, and eventually the patient, who tired of the futile and superfluous therapy, resolved to let things take their natural course. None of the predicted evils ensued, he married, begat a large family, and lived a long and healthy life, always passing urine black as ink.
By 1891, it was known that alkaptonurics excrete a substance called homogentisic acid that is colorless by itself, but that reacts with oxygen to form an intensely colored substance.
At the beginning of the twentieth century, Archibald Edward Garrod was a physician at the Hospital for Sick Children at Great Ormond Street in London. He noticed that many alkaptonurics were the children of parents who were blood relatives, but who were not themselves alkaptonurics. (First-cousin marriages were fairly common in England at that time.) Garrod's friend William Bateson pointed out that alkaptonuria fit the pattern that had been described by Gregor Mendel for a recessive trait. This was the first example of recessive inheritance to be positively identified in humans.
Garrod could think of two explanations for alkaptonuria: either (1) an alkaptonuric produces an unusual substance (homogentisic acid) which normal individuals cannot make; or (2) everyone produces homogentisic acid, and healthy persons then break it down through normal metabolic reactions, but an alkaptonuric is unable to destroy this substance.
Experiments soon showed that the latter was true. If an alkaptonic is given homogentisic acid by mouth, more than the usual amount is excreted. But if a normal individual takes homogentisic acid, none appears in the urine.
Chemical reactions in living organisms are catalyzed by proteins called enzymes. Garrod predicted that an alkaptonuric would have all of the same enzymes that a healthy person has, except for the one that degrades homogentisic acid. Fifty years later, LaDue proved that this was true by assaying the enzymes in a liver biopsy.
Archibald Garrod was aware of three other conditions that were similar to alkaptonuria: albinism, cystinuria, and pentosuria. He made four important generalizations about inborn errors of metabolism in his 1909 book by that title:
- each condition is caused by the lack of a specific enzyme;
- each condition is inherited recessively because a person can make adequate quantities of the enzyme as long as he / she possesses one undamaged copy of the gene;
- the conditions are essentially harmless;
- more inborn errors of metabolism would be discovered in the future.
Garrod was certainly right about #4; an estimated 4500 metabolic diseases have been identified, and additional examples are still being discovered. However, Garrod was wrong about #3; most metabolic diseases are harmful, and many are lethal. Nearly all of these diseases involve a specific enzyme, as Garrod predicted. Approximately two-thirds of the diseases are inherited recessively.