Studies on rare genetic diseases: a good use of funds?

Studies on rare genetic diseases: a good use of funds? n April, Abhimanyu Garg’s group phies are a window of opportunity (University of Texas Southwestern that should not be ignored”, he says. Medical Center, Dallas, TX, USA) Indeed, the genetics of rare disorwas awarded US$1·6 million by the ders are often easier to tackle than National Institute of Diabetes and those of common multigenic disorDigestive and Kidney ders and it is generally Diseases to study rare accepted that variant inherited forms of alleles of some of the lipodystrophy that affect genes mutated in rare about one person in 25 disorders will contribute million. As often hapto common diseases. pens when a grant is Nevertheless, scientists given to study a rare whose work is directly disease, those involved related to common stressed how the work multigenic diseases would provide insights often attract greater into the mechanisms public sympathy and underlying more comfind it easier to obtain mon diseases—in this funding, says Mulligan, case, obesity and dia- Pinpointing rare defects who works on the rare betes. But how often are inherited cancer synclaims like these just a way to keep drome multiple endocrine neoplasia grant-awarding bodies happy? type 2 (MEN 2). “The focus tends to Garg admits to being under be towards awarding research money pressure to justify his work on rare for more common diseases, particudiseases, as does Lois Mulligan larly by the smaller charities that rely (Queen’s University, Kingston, on public donations.” Her collaboraCanada) who comments that “phartor, Charis Eng (Ohio State Univmaceutical companies tend to favour ersity, Columbus, OH, USA), agrees research that will lead to new drugs and says that the problem in the USA for many patients, rather than a is compounded by a generally negahandful”. But, although emphasising tive attitude towards projects that that the wider perspectives of involve medical and human genetics. research on rare syndromes can help Yet Mulligan and Eng’s work illuswhen it comes to securing funding, trates how understanding a rare Garg is adamant that “the primary disease can have wide applications. In aim should be to help people affected 1993, Mulligan, Eng, and others by rare diseases”. identified mutations in the RET In the case of the rare lipodystroproto-oncogene associated with phies, knowing more about the genes MEN 2 and the congenital abnorinvolved should “enable patients to mality Hirschsprung’s disease adjust their lifestyle to compensate (HSCR). In MEN 2, the mutations for their condition”, says Garg. But are specific, affecting only about ten how can his work help obese people RET codons and they occur in most or those with diabetes? Garg explains families with the disease. “Knowing that although patients with familial this enabled us to develop direct partial lipodystrophy (Dunnigan mutation detection that is now done type) lose all subcutaneous fat from routinely”, says Mulligan. Thus, the the limbs after puberty, they have condition can be detected presympmany of the same complications as tomatically in young children and if a obese people. One possibility, says mutation is found, prophylactic Garg, is that the product of the gene thyroidectomy can be done followed responsible for familial partial lipoby annual surveillance for phaeochrodystrophy may interact with steroid mocytoma and hyperparathyroidism. hormones. Garg and co-workers have “This is life-saving”, stresses Eng. also localised a gene for congenital In addition, research into HSCR generalised lipodystrophy, a disorder has provided some early clues that in which there is a lack of body fat RET is important to neural cell types at birth and, suggests Garg, further that do not have a neuroendocrine characterisation of these genes and function, says Mulligan. The ligands their products may lead to targeted for RET, a receptor tyrosine kinase, therapies, both for lipodystrophy and have now been recognised as a family for obesity. “We can never be sure of neurotropic factors “and the whole that this work will lead on to a treatRET system has been targeted as a ment for common forms of obesity, potential intervention point in neurobut the rare single-gene lipodystrodegenerative diseases and in nerve

injury, both of which affect many patients”. Eng cites other examples where work on rare cancer syndromes has had a wide impact. “The obvious three are retinoblastoma, Cowden syndrome, and Li-Fraumeni syndrome. Studies on these diseases led to the discovery of tumour suppressors that are ubiquitously involved in the pathogenesis of many sporadic common cancers”, she says. Other fields have also benefited from the study of rare syndromes. Michael Brownstein (National Institutes of Health, Bethesda, MD, USA) pinpoints Parkinson’s disease. “Our understanding of the aetiology and molecular basis of Parkinson’s disease and other neurodegenerative diseases has been boosted by the study of rare familial forms”, he says. The a-synuclein gene was identified in 1997 as a result of research into the rare autosomal dominant Parkinson’s disease. a-synuclein turns out to be a major component of Lewy bodies, “a major neuropathological feature of almost all forms of the disorder”, says Brownstein. Gordon Plant (National Hospital of Neurology and Neurosurgery, London, UK) also believes that studying rare neurological diseases can tell us more about common ones. Plant and co-workers have shown that British familial dementia is due to a mutation that eliminates the stop codon of the BRI gene. Affected individuals produce an over-long protein that tangles up and produces amyloid deposits. Plant believes that studying BRI and its product will help us understand other neurodegenerative disorders in which there is amyloid deposition. Indeed, just this month, Sangram Sisodia (University of Chicago, IL, USA) and colleagues published further information on how fibrillogenic peptides are generated from mutant BRI (Nat Neurosci 1999: 2: 984–88). The study of rare genetic diseases may often be justifiable, but funding priorities have to be set, admits Brownstein. “It is undoubtably easier to get funding for projects that focus on rare inheritable forms of common diseases. Some projects—research into the molecular mechanisms that result in an auditory system capable of perfect pitch is the best example I can think of—are very difficult to fund. People don’t die from perfect pitch, do they?”, he concludes wryly.

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THE LANCET • Vol 354 • November 20, 1999

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Kathryn Senior