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remedial therapy or psychological procedures, are sometimes dismissed as spontaneous changes unrelated to the intervention. Use of the single-case study design9 with independent assessors of any treatment being evaluated may help clarify this issue. Nevertheless, rehabilitation does not have to justify itself on grounds of promoting intrinsic recovery alone any more than other branches of medicine are judged "cure rates". Prevention of secondary on complications in physical, psychological, and social terms and assistance given to patients and their families to adapt and come to terms with residual disabilities and maximise their functional abilities are often more realistic. The need to address the longer term cognitive, emotional, and behavioural consequences of brain injury is essentialS and explains the great emphasis on cognitive remediation and behaviour modification techniques. Most people with persisting memory, attentional, perceptual, and other cognitive problems are probably best managed with intensive day-care

involving clinical psychologists, occupational therapists, and other disciplines such as nursing and speech therapy.4,7,10 Although there is growing evidence that some cognitive remediation programmes are accompanied by improvement in neuropsychological test scores, the effectiveness of various components has not been clearly established. programmes

The critical issue is whether such interventions are effective in the real life-home, school, or workplace.lo An outpatient approach to behavioural disorders, personality change, and emotional distress can also be effective,11 but there is still a need for inpatient units for those with severe behavioural disorders. 3,4 The ultimate goal of rehabilitation for the great majority of those who survive head injury should be return to work. The use of specifically trained vocational rehabilitationists, who oversee this aspect from the early stages of recovery through to actual advocacy in the workplace, combined with intensive holistic rehabilitation programmes has been shown to get people back to work with a consequent reduction in family stress.12 In the UK, patients often fall between the separate responsibilities of health, social, and employment agencies and have no recourse to informed advice about retaining or finding new employment after head injury. If support and resources are not invested in health service and university departments for critical appraisal and development of new techriiques and training of personnel, patients with head injuries will remain very poorly served. 1.

Jefferson G. Discussion

on rehabilitation after injuries to the central system. Proc R Soc Med 1941; 35: 295-99. Pentland B, Boake C, McKinlay WW. Scottish head injury rehabilitation: an historical account. Scot Med J 1989; 34: 411-12. Scottish Home and Health Department. Medical rehabilitation: the pattern for the future. Edinburgh: HM Stationery Office, 1972. Medical Research Council. Research aspects of rehabilitation after acute brain damage in adults. Lancet 1982; ii: 1034-36. Royal College of Physicians. Physical disability in 1986 and beyond. J R Coll Physicians Lond 1986; 20: 161-94. nervous

2. 3. 4. 5.

6. Medical Disability Society. The management of traumatic brain injury. London: Development Trust for the Young Disabled, 1988. 7. Oddy M, Bonham E, McMillan T, Stroud A, Rickard S. A comprehensive service for the rehabilitation and long-term care of head injury survivors. Clin Rehabil 1989; 3: 253-59. 8. Radar MN, Alston JB, Ellis DW. Sensory stimulation of severely brain injured patients. Brain Injury 1989; 3: 141-47. 9. Wilson B. Single-case experimental designs in neuropsychological rehabilitation. J Clin Exp Neuropsychol 1987; 9: 527-44. 10. Gordon WA, Hibbard MR, Kreutzer JS. Cognitive remediation: issues in reseach and practice. J Head Trauma Rehabil 1989; 4: 76-84. 11. Prigatano GP, Fordyce DJ, Zeiner HK, Roueche JR, Pepping M, Wood BC. Neuropsychological rehabilitation after brain injury. Baltimore: John Hopkins University Press, 1986. 12. Ben-Yishay Y, Silver SM, Piasetsky E, Rattok J. Relationship between employability and vocational outcome after intensive holistic cognitive rehabilitation. J Head Trauma Rehabil 1987; 2: 35-48.

ORIGINS OF GENETIC DISEASE Most genetic disorders are maintained in the population not only by the progeny of those already carrying the defective gene but also by a steady input of new mutations. The latter contribution is likely to be especially important in disorders that adversely affect reproductive fitness. Estimates of the rates of such new mutations are derived from a formula that takes account of the incidence of the disease in the population and the reproductive potential of affected individuals. Some idea of their accuracy can be obtained by analysing the structure of affected families, essentially asking the question "how often can a new ’founder’ (ie, an affected individual whose forbears had no evidence of the disease) be identified?"1 Now that diagnostic techniques can confirm both disease classification and family relationships, these estimates have become much more firm and in some instances are remarkably high. Thus achondroplasia, an autosomal dominant condition, affects about one in ten thousand newborn babies and in almost all cases the disorder is due to a new mutation.2 As a rule the mutation itself takes place not in the affected individual but in one of his or her parents during gametogenesis (formation of the sperm or egg). Since mother and father contribute twenty-three chromosomes each to the zygote, one might expect the origins of new mutations to be equally distributed between the sexes. With the mapping of the chromosomal locations for more and more single-gene defects it has become practicable to trace their inheritance by linkage to flanking markers (if not by direct analysis of the genes themselves) and also to identify the parental origin of the mutation in a founder. Somewhat surprisingly, for many disorders there is a pronounced bias towards one or other sex as the source of new mutations. For example, most achondroplasia mutations arise during spermatogenesis in the male,12 whereas most chromosome imbalance disorders (trisomy 21 being a prime example) originate in the mother. 3,4 There are several possible explanations for these observations. The mutation might be lethal or debilitating to sperm or to egg but not to both. This possibility can be ruled out when subsequent transmission is shown to occur equally through both sexes, as is the case for most genetic disorders. Mutations usually arise during cell division, when the DNA is replicating, so the total number of replicative cycles preceding formation of the germ cell is a highly relevant factor. In this respect spermatogenesis differs profoundly from oogenesis since the former process goes on continuously during the fertile life span of the male whereas the

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full complement of ova in the female is already established at birth.1,4 Moreover, there are vastly more sperm than ova to be produced so that, on average, a human sperm is the end result of several hundred more divisions than is an egg. That the actual number of divisions partly depends on the age of the man accords with the finding that for disorders with an excess of paternally derived new mutations there is often a positive association between mutation frequency and paternal age. Well-known examples of such conditions are achondroplasia and haemophilia A. 1,2 A different explanation is required for the link between maternal age and certain chromosome disorders, notably Down syndrome. Some ingenious hypotheses, including late fertilisation due to infrequent intercourse, have been proposed but none is completely satisfactory. It remains uncertain whether the ova that reach maturity towards the end of a woman’s reproductive life are inherently more prone to non-disjunction during meiosis or whether the putative mechanisms for detecting and eliminating such faulty ova are impaired with advancing age.3 Important questions also remain unanswered about disorders with an excess of paternally derived new mutations in the absence of a clear paternal age effect. The issue has lately been raised in connection with retinoblastoma and with neurofibromatosis type I (NF-1, Von Recklinghausen’s disease).5 In Von Recklinghausen’s disease there is a very high mutation rate, arising mainly during spermatogenesis. Meiotic interchange between the chromosome 17 pair in the vicinity of the NF-gene can be detected by genetic recombination of flanking markers but has been found to occur more frequently in the female, so this event is almost certainly not the source of most NF-II mutations.6 It seems that at some late stage in the development of the sperm certain regions of the DNA are in a much more vulnerable state with respect to induction of mutations than are the correspnding regions in the ovum. There is nothing heretical in such a concept. Passage of certain genes through male rather than female gametogenesis can determine whether they are to be expressed after fertilisation and indeed throughout the subsequent lifetime of the offspring.7 This process of "imprinting" implies some differences in the condition of the DNA in sperm and egg without violating the principle that the actual base sequences (the genetic code) remain the same. Differential methylation of the DNA is a probable mechanism but, bearing in mind that sperm differ from other tissues in the composition of their chromosomal structural proteins,8 the macromolecular organisation of chromatin (ie, the degree of supercoiling of the DNA and its interaction with nuclear proteins) could also be important. This is largely uncharted territory for human genetics although considerable progress is being made in understanding the details of DNA fine structure (and how that affects function) in lower organisms.9 As part of the greater equation relating environmental mutagens to genetic damage, determinants of DNA vulnerability in the developing sperm and egg deserve close attention. 1. 2. 3. 4. 5.

Vogel F, Rathenberg R. Spontaneous mutations in man. Adv Hum Genet 1975; 5: 223-318. Vogel F, Motulsky AG. Human genetics: problems and approaches. 2nd ed. Berlin: Springer, 1986. Hassold TJ, Jacobs PA. Trisomy in man. Ann Rev Genet 1984; 18: 69-97. Chandley AC. Meiosis in man. Trends Genet 1988; 4: 79-84. Jadayel D, Fain P, Upadhyaya MA, et al. Paternal origin of new mutations in Von Recklinghausen neurofibromatosis. Nature 1990; 343: 558-59.

6. Fain PM, Goldgar DE, Wallace MR, et al. Refined physical mapping of the NFI region on chromosome 17. Am J Hum Genet 1989; 45: 721-28. 7. Sapienza C, Peterson AC, Rossant J, Balling R. Degree of methylation of transgenes is dependent on gamete of origin. Nature 1987; 328: 251-54. 8. Hecht NB. Molecular biology of structural chromosomal proteins of the mammalian testis. In: Adolph KW, ed. Molecular biology of chromosome function. New York: Springer, 1989: 396-420. 9. Maclean N, Hall BK. Cell commitment and differentiation. Cambridge: Cambridge Univ Press, 1987.

DECLINING MORTALITY FROM DOWN SYNDROME—NO CAUSE FOR COMPLACENCY The life expectancy of babies born with Down syndrome has improved dramatically over the past half-century. Record and Smith,l who analysed data on Down syndrome births in Birmingham between 1942 and 1952, reported that less than half survived the first year and only about 40% were alive at five years. Fryers2 contrasted these figures with the results of several subsequent studies from around the world, including his own Salford series of 1961-80 Down syndrome births of whom 81 % survived the first year and 71 % were alive at five years. He concluded that the decline in mortality over that period had been "very impressive". Other studies3.4 have confirmed the improvement in life expectancy, which may now have reached a plateau, with about 90% surviving to five years. The commonest causes of death in Down syndrome are respiratory infection and complications of congenital heart disease ;5 the improving survival is presumably attributable to more effective treatment of these conditions. The precise contribution of a more interventionist therapeutic approach, which has arisen as a result of changing ethical perceptions of Down syndrome, is difficult to quantify. Even within the past decade, there may have been a substantial shift in attitudes to the neonatal care of such infants.4,6 The most direct consequence of the lengthening lifespan of Down syndrome individuals is the anticipated increase in the number of affected people, children and adults, in the population. This outcome is likely despite the decline in birth frequency of Down syndrome that has been observed in many communities largely because of the lower fertility of older (higher risk) women.2 Down syndrome therefore illustrates the sometimes paradoxical relation between incidence, prevalence, and survival, in which a declining incidence may be more than offset by improved survival resulting in an increased prevalence. There are several important implications for service providers. First, because intellectually impaired children and their families experience substantial physical, emotional, and social difficulties/-9 the burden on health, educational, and social services is liable to increase. Second, couples receiving genetic counselling after Down syndrome pregnancy can now be told that there is a nine in ten chance of a similarly affected subsequent child surviving early childhood.’ Third, planners need to take account of the changing cost-benefit ratios associated with prenatal screening, in view of the proportionately greater potential savings generated by the avoidance of a Down syndrome birth. Finally, we require more detailed information about the quality of life of Down syndrome survivors and their families in the 1990s. Extending life expectancy can scarcely be regarded as a medical triumph if the effect is merely to prolong the time-scale of suffering, handicap, and dependency. Until we are more sure that the birth of a child with Down syndrome heralds a lifetime of joy and sorrow in