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What can we learn from the history of Charcot‐Marie‐Tooth disease?

2010; Wiley; Volume: 52; Issue: 5 Linguagem: Inglês

10.1111/j.1469-8749.2010.03675.x

1469-8749

Robert Ouvrier,

History of Medicine Studies

Medical advances have rarely been as simple or even scientific as we like to pretend to students and trainees. Important clinical findings have depended on often imperfect people with enormous insight in some respects and fallibility in others, even to the extent of using their influence to suppress new knowledge. The history of Charcot-Marie-Tooth disease is a beautiful illustration. From the time of Galen, it was known that the nerves conveyed sensation and motility to the extremities. Detailed anatomical knowledge of the course of the nerves was shown in the illustrations of Vesalius (1514–64). Anton van Leeuwenhoek (1632–1723), cloth merchant, amateur biologist, and pioneer microscopist, is thought to have been the first to describe single myelinated nerve fibres. In 1837, Robert Remak (1815–65) observed that nerve fibres were in continuity with the nerve cell. In 1838, he disproved the ancient myth that nerves were hollow tubes. They had previously been thought to carry various spirits and fluids. Theodor Schwann (1810–82) was a German naturalist who, with Matthias Schleiden (1804–81), established that cells were the fundamental units of life. The cells which manufacture myelin and nurture the axons are now known as Schwann cells. Cells which contain unmyelinated fibres (without myelinated fibres) are known as Remak cells. Schwann considered that the long chains of nucleated cells coalesced to form a syncytium with a continuous band of protoplasm down the centre. Schwann’s concept was eventually refuted by the classical studies of Ramon y Cajal in 1913. Described as a wild youth, Ramon y Cajal (1852–1934) should be an inspiration to us all. He was so backward in his studies that his father, a struggling country surgeon, apprenticed him first to a barber and then to a cobbler. He eventually entered medicine, found his niche in neuropathology, and was appointed Extraordinary Professor in the University of Saragossa at the age of 25. He and Camillo Golgi won the Nobel Prize in 1906 for their work on the structure of the nervous system. Jean-Martin Charcot (1825–93) was a medical superstar who was the first Professor of Neurology in France, if not worldwide. He introduced routine temperature recording and was the first to describe ankle clonus. Not surprisingly, as he was Professor of Pathological Anatomy before being appointed to the Chair in Diseases of the Nervous System, one of his most important contributions was to demonstrate the links between pathological and clinical features. Charcot distinguished many disorders including rheumatoid arthritis and gout. He made major contributions to the understanding of multiple sclerosis, and described Charcot joints, motor neuron disease, and mini-aneurysms. He is probably best-known, however, for the description of Charcot-Marie-Tooth (CMT) disease in 1886. Pierre Marie (1854–1940) was Charcot’s heir-apparent. He was wealthy, straight-talking, and very productive. He described hypertrophic osteoarthropathy and numerous neurological conditions. He eventually became the Professor at the Salpétrière. He had had a flair for inciting controversy. Charcot and Marie described five cases of distal weakness. Case 1 had severe atrophy and weakness of the lower limbs, and clawing of the hands by the age of 9 years. Cases 2 and 3, with onset around 3 years were siblings with probably unaffected parents. They had severe distal weakness and wasting by 11 and 7 years. These three cases do not resemble the classic phenotype of autosomal dominant CMT type 1 or 2, which is generally much less severe at the age in question. Case 4 would probably be accepted as a typical case of what is currently designated CMT type 1 or 2. Case 5 was probably an example of hereditary sensory neuropathy, based on the presence of severe lancinating pains and the degree of sensory loss. At the time, there were no nerve conduction studies, spinal imaging, or genetic tests but we can reasonably guess that the first three cases were, quite probably, recessively inherited, with such marked atrophy as to have had major axonal degeneration and were, therefore, very similar to the early-onset axonal degenerative forms of hereditary motor and sensory neuropathy (EOHMSNA) described in the last few decades. This entity is sometimes also referred to as SEOAN. An English neurologist educated at Rugby and Cambridge, Howard Tooth became a physician at Queen Square and St. Bartholomew’s. He served in the Boer War and First World War and rose to the rank of Colonel. He was mentioned in despatches twice and was eventually awarded the Companion of (the Order of) the Bath and of the Order of St Michael and St George. He later became Censor to the Royal College of Physicians. In his spare time, he was a musician and a talented worker in wood and metal. Writing independently in the same year as Charcot and Marie, Tooth described five cases which would now be considered to be typical of CMT disease. Tooth rightly thought that the problem lay in the nerves whereas Charcot and Marie implicated the spinal cord. Variants of CMT disease quickly began to be described. Importantly, in 1893, Déjerine and Sottas described two siblings, a male with scoliosis at 4 to 5 years and his sister who did not walk till the age of 3. Autopsy showed a ‘progressive hypertrophic interstitial neuropathy’. Even then, there was controversy as to whether this condition was separate from that which Charcot and Marie reported. Marie, who was a rival of Déjerine’s, did not believe so. Jules Joseph Déjerine (1849–1917) was a ‘provincial’ from Geneva and a boxer in his youth, but managed to scale the heights of Paris and eventually succeeded to Charcot’s Chair before Marie. He married Augusta Klumpke, the Polish-American neurologist who was among the earliest female doctors to graduate from the University of Paris and who went on to describe lower brachial plexus palsy in the neonate. Little is extant about Sottas. Only the initial of his first name appears in the original paper on ‘interstitial neuropathy’. Presentations at la Société de Neurologie were tense and sometimes sarcastic. Déjerine and Marie almost fought a duel on one occasion but Babinski intervened. It is not known whether the dispute leading to this incident concerned peripheral neuropathy! Modern concepts stress the greater frequency of generalized weakness and areflexia, ataxia, enlargement of nerve trunks, and very slow nerve conduction velocities in Déjerine-Sottas syndrome than in ‘classical’ CMT disease. Hypomyelination is the major finding on biopsy. Although Déjerine made sketches of the histopathology, it is not possible to gauge the thickness of the myelin sheath. Controversy still surrounds the separation of this condition from CMT disease but, in the author’s opinion, this variant of the CMT syndromes is distinct, not rare, and the phenotype is highly associated (∼60%) with demonstrable point mutations of myelin-linked genes (MPZ, PMP22, periaxin, and EGR2). The mutations can be either heterozygous or homozygous. Once diagnosed, the Déjerine-Sottas phenotype should ideally be investigated by an orderly search for the known myelin gene mutations. The first cases of an X-linked form of CMT were described by Herringham in 1889. From 1893 on, numerous clinical variants and overlap cases such as scapulo-peroneal neuropathies, the Roussy-Levy syndrome and CMT disease with optic atrophy, retinitis pigmentosa, or deafness were reported. The first major advance in the 20th century was the refinement of histopathological techniques which distinguished axonal from demyelinating pathology and delineated certain characteristic or pathognomonic changes such as changes in the myelin (thickness, variations in inter-period width, the description of giant axons, tomacula, etc.). Electron microscopy, which was refined in the 1930s, was the key contributor to this development. The next major advance was the application of research neurophysiological techniques in the clinical setting by Lambert, Dyck, Gilliatt, Thomas, and others which allowed separation of the axonal and demyelinating types of CMT disease on the basis of nerve conduction studies (1956–1957). The most important development in the field, however, was the extraordinary advance of molecular genetics in the last 30 years. In 1982, linkage was established between one form of CMT disease and the site of the gene for one of the blood groups on chromosome 1. In 1989, Australian and US workers linked CMT type 1A to the short arm of chromosome 17. In 1991, researchers in Belgium and the USA showed that CMT1A was caused by a duplication of the DNA in a region on chromosome 17 which contained the gene for a myelin protein, PMP22. In 1992, it was shown that a point mutation of the gene encoding PMP22 (as opposed to a double dose due to a duplication) could also cause CMT type 1A. This proved that alterations of the PMP22 protein were responsible for causing CMT type 1A. In 1993, Japanese workers showed that the gene that had been linked to the Duffy blood group locus on chromosome 1 encoded a major myelin protein, MPZ, mutations of which caused CMT type 1B and also the Déjerine–Sottas syndrome. Over fifty types of hereditary polyneuropathy with at least forty separate genes have now been described. There is at least one neuropathy gene on every chromosome. There are two genes which have clearly been shown to produce the SEOAN phenotype, MFN (mitofusin)2 and GDAP1. MFN2 mutations are responsible for up to 33% of autosomal dominant CMT type 2. Of seven Sydney SEOAN cases available for DNA testing, five have now been shown to have MFN2 mutations. GDAP1 mutations are a common cause of SEOAN in the North African region but are less frequent in other countries. Comparison of the clinical photographs of case 2 of Charcot and Marie with recently studied MFN2 cases suggests that an MFN2 mutation was probably the cause. I. In conclusion, Charcot, Marie, Tooth, Déjerine, Sottas, and many others described various neuropathies and distinguished between them on clinical grounds. What they are most remembered for (CMT disease and Déjerine–Sottas syndrome) were almost certainly heterogeneous even then. MFN2 mutations were probably the culprit in some of Charcot and Marie’s cases but people continue to duel over the classification. While their eponymous neuropathies show a sometimes unjustified respect for their genius, at least the use of their names reminds us of the people behind medical advances.