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Early observations of genetic diseases

1999; Elsevier BV; Volume: 354; Linguagem: Inglês

10.1016/s0140-6736(99)90364-1

1474-547X

Maik Urban,

Science, Research, and Medicine

Maik Urban was born in Hoyerswerda, East Germany. A scholarship at the Studien-stiftung des deutschen Voikes allowed him to study medicine. Now he works at the Institute of Medical Genetics of the Charite, Berlin, where he is currently researching the history of medical genetics. In 1902 Archibald E Garrod published an epidemiological study in The Lancet in which he proposed that alcaptonuria had a recessive mode of transmission that followed Gregor Mendel's principles. With this milestone, the connection had been made between a human disease and the laws of inheritance published by Mendel in 1865. Since then our knowledge of genetically determined diseases has increased explosively. Victor McKusick's catalogue Mendelian Inheritance in Man contains over 10 000 entries about monogenic signs and diseases. Mendel's statistical discoveries, developed with green peas, which had such fundamental importance for biology, were made at a time when a lone researcher could discover laws of universal significance. The history of genetic diseases did not start with the rediscovery of Mendel's laws at the beginning of the 20th century. Early paintings, drawings, and sculptures show patients with genetic disorders such as achondroplasia, Robert's syndrome, hermaphroditism, or neurofibromatosis. Even the X-linked bleeding disorder in Queen Victoria's family had been known for a long time. The disease was also mentioned in the Talmud. In the Middle Ages it was called "passio flux sanguinis". It was only in the 19th century that J L Schónlein named it "haemorrhophilia"; a term later turned into the current meaningless "haemophilia". Valuable clinical observations existed before the advent of Mendel's era. For example, in 1866 the British physician J Langdon Down published a classification of mental retardation, which he subdivided into racial types: the caucasian, the ethiopian, the malaysian, and the mongolian. The former three types were not nosologically convincing and rapidly fell into oblivion. By contrast, Down's mongoloid idiot-ism, nowadays known as Down's syndrome, proved to be a well defined disorder. 93 years after Down's paper, in 1959, Lejeune and colleagues found the cause of Down's syndrome: a small extra chromosome (chromosome 21). Tjio and Levan had made this finding possible 3 years earlier with their discovery that human beings normally have 46 chromosomes. The recurrence of specific signs in successive generations in a given family had been observed by naturalists and physicians long before Mendel's time. Pierre Louis Moreau de Maupertuis; who under Frederick the Great was president of the Berlin Academy, published in 1752 the pedigree of a family in which isolated hexadactyly occurred in four generations. He also showed that this minor malformation could be transmitted to their children by either parent. But the i~nechanism of inheritance remained a mystery for doctors until 1900. Between 1895 and 1898, the Berlin Anthropological Society, chaired by the pathologist Rudolf Virchow, struggled with this issue when it repeatedly addressed the case of Alice Vance (the "bear woman", figure). It is retrospectively possible to speculate that the Society was describing in Alice Vance a case of autosomal dominant Nievergelt syndrome and that Virchow's 1898 lecture The Phocomelias and the Bear-Woman described a typical case of autosomal recessive Roberts' syndrome. The description of this syndrome was however inadvertent. Despite the fact that Virchow did not fail to appreciate the various degrees which malformations of the extremities could have, he did not attempt to describe and distinguish between them as different syndromes. He rejected, for example, Isidore Geoffroy St Hilaire's classification of reductive malformations of the extremities that distinguished: (i) ektromelia (missing extremity), (ii) hemimelia (incomplete extremity consisting only of a stump), and (iii) phocomelia (an extremity consisting only of a hand or of a foot). Virchow grouped all these malformations (including Vance's) and called them the phocomelias. He explained this approach with the remark that reductive malformations formed "such a continuum, that the classification of each single case is almost impossible". He added "experience teaches that usually the accumulation of special eponyms leads to confusion rather than to clarity". Virchow instead looked for common pathogenesis among various isolated observations. Alice Vance's mother had similar malformations, but not her son. This led to the question why this malformation was sometimes inherited and sometimes not. Virchow and the other members of the Anthropological Society in Berlin came to no conclusion, however simple the explanation of this pedigree may nowadays seem. The ignorance of a fundamental principle such as Mendel's laws cannot be usefully replaced by any amout of experience or good clinical skills.