atrophy

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Tropical Medicine, St Mary's Hospital Medical School, and the Department of Infection in the University of. Birmingham, together with the South African Medical.
Genetic basis of adult-onset spinal muscular

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atrophy

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SiR-Brahe and colleagues (Sept 16, p 741) present six patients with proximal spinal muscular atrophy, with ages of onset of between 20 and 32 years, showing a homozygous deletion of the telomeric copy of the survival motor neuron (SMN) gene. Two were affected brothers with their affected father from a pseudodominant family. They concluded that there was genetic homogeneity between childhood and adult-onset autosomal recessive spinal muscular atrophy (SMA). The results of analysis of our material differ in part, and raise doubts as to whether this conclusion is generally

applicable. The age of onset definition of adult SMA in various existing classifications is not clear. Peam et al’ originally included nine patients with onset between 15 and 50 years in their study of adult onset SMA, whereas in Emery’s2 classification adult SMA had an onset of greater than age 30 years. We have defined SMA type III (Kugelberg Welander) in patients with onset before age 30 who managed to walk, whereas SMA IV (adult) has an onset over age 30. In our study,’ 59 of 73 SMA type-III patients (82%), who fulfilled the diagnostic criteria of the International SMA Consortium,4 shared a homozygous deletion of exons 7 and 8 of the telomeric copy of the SMN gene. Seven of our 59 deleted type-III patients had an onset beyond age 15, whereas three typical SMA-111 patients with onset at age 15 and 17 did not have a deletion in the SMN gene.’ However, most type-III patients showed a deletion, which is in accordance with Brahe and colleagues’ findings. The situation, however, is different in those with onset beyond age 30 (SMA type IV). Our four patients belonging to this group showed no homozygous deletion of the exons 7 and 8 of the telomeric copy of the SMN gene. All patients had a negative family history and were followed for 10-20 years after first symptoms of proximal weakness, thus excluding a rapid progressing motor neuron disease (table).

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Table: Patients’ characteristics

Since the diagnosis in our patients is not in doubt the following factors should be considered: locus heterogeneity with a second recessive SMA gene; allelic heterogeneity with different mutations in the SMA gene on chromosome 5q; and spontaneous autosomal dominant mutation at a different gene locus. The exclusion of 5q linkage in autosomal dominant SMA’and our findings in two families with an affected parent and affected children, who do not show a deletion of the SMN gene, could support the latter

hypothesis.3 Our data allow the conclusion that genetic heterogeneity of SMA, especially among those rare cases with adult onset beyond age 30, cannot so far be ruled out. Further insight into the molecular basis of proximal SMA is needed for better understanding.

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The nosology of spinal muscular atrophies. J Med Genet 1971; 8: 481-95. Hahnen E, Forkert R, Marke C, et al. Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals. Hum Mol Genet 1995; 4: 1927-33.

Emery AEH.

The International SMA Consortium. Meeting report. Neuromusc Disord 1992; 2: 423-28. Kausch K, Müller CR, Grimm T, et al. No evidence for linkage of autosomal dominant proximal spinal muscular atrophies to chromosome 5q markers. Hum Genet 1991; 86: 317-18.

The

challenge of tuberculosis

SiR-The Lancet is to be congratulated on its continuing interest in infectious diseases, especially their impact on developing countries. The Lancet conference, The Challenge of Tuberculosis, highlighted many of the difficulties and suggested ways of meeting the challenge. In his Sept 23 commentary, Horton emphasises the magnitude of the problem and discusses four potential impediments retarding progress in tuberculosis research. One of these, he believes, is that there are no financial incentives for pharmaceutical companies to develop new antituberculosis drugs since 95% of cases of tuberculosis occur in poor countries in the developing world. I remind you of your May 13 editorial, Harnessing the profit motive (p 1189), in which you discuss the Action TB Initiative, an international 5-year programme of collaborative research into tuberculosis sponsored by Glaxo (now Glaxo Wellcome). This programme involves three academic centres in the UK-the London School of Hygiene and Tropical Medicine, St Mary’s Hospital Medical School, and the Department of Infection in the University of Birmingham, together with the South African Medical Council, which coordinates a number of leading research groups in several South African universities. Since the launch of the programme in 1993 other research groups in the UK and in Canada have joined the initiative. The scientific objectives of this international partnership include research into the biology of mycobacteria (its genetics, molecular biology, microbiology, and biochemistry) to identify novel targets for antibacterial action and other possible therapeutic interventions. Another objective is to increase understanding of the host response to mycobacteria with the intention of discovering new vaccines and exploring the possibility of immunotherapy. The programme involves basic scientists in all the relevant disciplines and clinicians caring for patients with tuberculosis. Studentships are available to provide training in mycobacterial research. Glaxo Wellcome is providing 10 million for this 5-year programme, in addition to the costs of their own research team. The company has placed no restrictions on the nature of the research carried out in the academic departments and has encouraged close collaboration between the various centres in the UK as well as in Canada and South Africa, where scientists from all collaborating centres met in Cape Town early in October, 1995, to exchange results and plan future research. Alasdair Geddes Department of Infection, University of Birmingham, Birmingham B15 2TT, UK

conference in Washington and the did not include relevant disciplines. A published balanced committee and list of speakers would have included an array of disciplines, such as ecological, environmental, and social sciences. Lack of interdisciplinary expertise at the podium led to wild, naive statements rendered with great authority. One participant asserted that huge population growth will be good because it will result in SiR-The Lancet’s

statements

*Klaus Zerres, Sabine Rudnik-Schöneborn, Randolf Forkert, Brunhilde Wirth Institut für Humangenetik der Universitat Bonn, D-53111 Bonn, Germany

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Pearn J, Hudgson P, Walton JN. A clinical and genetic study of spinal muscular atrophy of adult onset. Brain 1978; 101: 591-606.

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