760
impairment of consciousness. They may be so severe that the patient drops objects or falls, but often are mild and interpreted as clumsiness or tremor. A series of such jerks may herald a generalised tonic-clonic seizure. About one-third of patients experience typical absences, which may antedate myoclonic jerks by several years. Seizure-precipitating factors include sleep deprivation, alcohol, stress, menstruation, and flashing lights. Over 80% of patients are well controlled by treatment with sodium valproate alone with or in combination clonazepam or phenobarbitone, but relapse is the norm on discontinuation of antiepileptic medication even after many years seizure-free.2--7,9,10 Carbamazepine is not effective, even though recommended for generalised tonic-clonic seizures in the British National
Formulary. 11 Grunewald and co-workers,in London, have identified 22 patients with JME among 180 referrals to an epilepsy clinic. None of these had been
diagnosed previously, even by experienced neurologists. The most common misdiagnosis was "complex partial seizures with secondary generalisation" or the unacceptably vague term "epilepsy". Control of seizures was often poor since patients were treated mainly with carbamazepine; on substitution of appropriate medication they improved strikingly. Avoidable morbidity in this group, in addition to the psychological and social effects of poor seizure control, included the loss of driving licence or employment, injury to self or child, inappropriate withdrawal of medication either during pregnancy or when fits were well controlled, and status epilepticus. To elicit the characteristic history of myoclonic jerks is something of an art. It may be necessary physically to demonstrate mild myoclonic jerks confined to the hands, and to inquire about morning tremulousness or clumsiness ("do you spill your morning tea?"). If the patient reports normal hypnogogic jactitations, then the concept has been understood. Diagnostic yield may be improved by emphasising the close relation of jerks to fatigue and sleep deprivation. Unilaterally predominant jerks and those preceding generalised tonic-clonic seizures must not be interpreted as focal epilepsy. Diagnosis of typical absences and their differentiation from complex partial seizures can be equally difficult. The general conception of typical absences (petit mal) is of childhood phenomena associated with severe impairment of consciousness. In contrast, in patients with JME absences tend to be inconspicuous with little disturbance of consciousness.12 They may be described by patients merely as a momentary lapse in concentration and they are not associated with automatisms. Complex partial seizures tend to last longer and are more often associated with experiential phenomena and automatisms. Electroencephalography can help greatly since in most untreated patients it will show generalised discharges of spikes or multiple spikes and
slow waves enhanced by overbreathing.2,12 One-third of patients also show photosensitivity. These abnormalities are most pronounced with sleepdeprived electroencephalography. 30% of patients, however, show additional focal abnonnalities3,4 that may bolster an erroneous clinical diagnosis of complex partial seizures. Physicians should be ever alert to the
possibility of JME. 1. Gram L. Epileptic seizures and syndromes. Lancet 1990; 336: 7-9. 2. Tsuboi T, Christian W. Epilepsy. A clinical, electroencephalographic and statistical study of 466 patients, Berlin: Springer-Verlag, 1976. 3. Obeid T, Panayiotopoulos CP. Juvenile myoclonic epilepsy: a study in Saudi Arabia. Epilepsia 1989; 29: 280-82. 4. Grünewald RA, Chroni E, Panayiotopoulos CP. Delayed diagnosis of juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 1992; 55: 497-99. 5. Delgado-Escueta AV, Enrile-Bacsal FE. Juvenile myoclonic epilepsy of Janz. Neurology 1984; 34: 285-94. 6. Panayiotopoulos CP, Tahan R, Obeid T. Juvenile myoclonic epilepsy: factors of error involved in the diagnosis and treatment. Epilepsia 1991; 32: 672-76. 7. Janz D. Juvenile myoclonic epilepsy: epilepsy with impulsive petit mal. Cleveland Clin J Med 1989; 56: S23-S33. 8. Hopkins A, Garman A, Clarke C. The first seizure in adult life. Lancet 1988; i: 721-26. 9. Obeid T, Panayiotopoulos CP. Clonazepam in juvenile myoclonic epilepsy. Epilepsia 1987; 30: 603-06. 10. Jeavons PM, Clark JE, Maheshwari MC. The treatment of generalised epilepsies of childhood and adolescence with sodium valproate. Dev Med Child Neurol 1977; 19: 9-25. 11. BMA and Royal Pharmaceutical Society. British National Formulary, 23. London: BMA/RPS, 1992. 12. Panayiotopoulos CP, Obeid T, Waheed G. Absences in juvenile myoclonic epilepsy: a clinical and video-electroencephalographic study. Ann Neurol 1989; 25: 391-97.
Developmental biology: impact on medicine For most doctors, the first and last encounter with the science of developmental biology is when they study human embryology during their undergraduate years. After that, it is usually sufficient to know whether something is or is not an embryological defect and to act accordingly. However, in the past ten years there has been a revolution in our understanding of animal development that cannot fail ultimately to have a profound impact on human medicine. This breakthrough has arisen from a fusion of classic experimental embryology with modern molecular biology and developmental genetics.1 The first animal to have been "solved" is the humble fruit fly, Drosophila, success depending crucially on the relative ease of experimental genetics with this organism. Drosophila has a short life cycle, so it is possible to handle and examine huge numbers of flies and hence to detect rare mutational events. In the late 1970s researchers came to realise that mutations in the genes that controlled early development would probably be lethal, and therefore have been missed in previous genetic work in which only adult flies had been studied. Screens were carried out to identify all the genes that, when mutated, would give rise to dead larvae with some identifiable anatomical abnonnality-for example, missing segments or
761
conversion of one type of segment into another. Most of these genes have now been cloned and we know in which regions and at what developmental stages of the embryo they are expressed. An important initial insight into their functions was provided by the mutant phenotypes, and further information was obtained by studying how the absence of one gene affects the expression of others. The result of all this effort is something approaching a gene-by-gene account of how Drosophila develops from the newly laid egg to a larva, which, although it may look simple, is actually a complex animal with many differentiated tissues and body parts.33 Surprising though it may seem, the higher animals, including man, contain genes with a considerable degree of evolutionary conservation to many of the developmentally significant genes in Drosophila. When the embryonic expression patterns of the vertebrate genes have been studied, a remarkable proportion look as though they, too, have important functions in controlling embryonic development. Some were already known from different lines of work--eg, as oncogenes or growth factors-whereas many others are novel. They probably could not have been found by direct genetic methods because screens for recessive lethal mutations are very laborious and expensive for vertebrates, and saturation of the genome could not easily be achieved. Thus the Drosophila work has an impact far beyond understanding the development of one small insect, because it has enabled us to identify many important genes in vertebrates that would have been difficult or impossible to find by other methods. Moreover, we know that the expression patterns for now
developmentally important genes are virtually identical in the early embryos of all vertebrates from fish to mouse and, although there have been few studies in human beings, this fact provides us with a virtual guarantee that man will prove to be the same. It is interesting to compare the results of the breakthrough with previous speculations of experimental embryologists about how animals develop.4,s Three important predictions have been borne out. First there is an important class of gene-homoeotic or selector genes-whose function is to code for parts of the body rather than for specific tissues or cell types. For example, one such gene might normally be expressed in the anterior but not in the posterior half of the body. If it were inactivated by mutation, the body plan would accordingly become changed to double posterior; if it were ectopically expressed in the posterior half then those parts would become anterior in character. Homoeotic genes code for transcription factors whose function is to regulate the expression of other genes and they lie near the top of a hierarchy of gene regulation whose final branches lead to the familiar cell-type-specific enzymes and structural proteins. Second, the body plan is specified by concentration gradients of inducing factors or morphogens. In Drosophila these are themselves
transcription factors, because the early insect embryo is a multinucleate syncytium and so proteins can diffuse directly from one nucleus to another. In vertebrates, where the embryo is at all times multicellular, there is good evidence that the inducing factors are growth factors, especially those of the transforming growth factor P and fibroblast growth factor families.6Third, the stability of gene expression depends in at least some cases on a positive feedback, whereby a gene product is responsible for keeping its active state.7 The Drosophila work has also shown that the mechanisms are far more complex than was formerly supposed, and that apparently similar processes may be carried out by quite different sorts of molecule. But despite the complexity, the essence of early development is simple. The egg always contains some asymmetry that can initiate the formation of the first morphogen gradient. The gradient leads to activation of one or more homoeotic genes in particular parts of the embryo, depending on concentration. These gene products turn on other genes that produce sources and sinks for further morphogen gradients, which activate further combinations of homoeotic genes. Each small multicellular region of the embryo soon becomes uniquely specified by the activation of a particular combination or "coding" of homoeotic genes. Once set up, the stability of these codings can be maintained by positive feedback and the gradients become superfluous. In later development each coding will cause activation of genes involved in the terminal differentiation of the appropriate organs and tissues. own
gene in
an
Although understanding embryonic development is an important intellectual goal in its own right, it also promises deeper insights into the working of the human body. We shall come to know not only what the body is made of and how its parts work, but also how it was built. To see the importance of this approach, consider the fact that two houses may look the same but behave differently under stress because in one case the load is borne by brick walls and in the other by a frame of timber. In human beings components tend to fail not during embryonic life but in old age, when we experience cancer, heart disease, arthritis, or neurodegeneration. Thus, knowledge of the building blocks during embryonic development will tell us something both about the causation of embryological abnormalities and, even more important, about the degenerative diseases of later life. JMW. From egg to embryo: regional specification in early development. Cambridge: Cambridge University Press, 1991. 2. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795-801. 3. Lawrence PA. The making of a fly. Oxford: Blackwell, 1992. 4. Waddington CH. New patterns in genetics and development. New York: Columbia University Press, 1962. 5. Wolpert L. Positional information and the spatial pattern of cellular differentiation. J Theor Biol 1969; 25: 1-47. 6. Jessell TM, Melton DA. Diffusible factors in vertebrate embryonic 1. Slack
induction. Cell 1992; 68: 257-70. 7. Kuziora MA, McGinnis W. Autoregulation of selector gene. Cell 1989; 55: 477-85.
a
Drosophila homeotic
impairment of consciousness. They may be so severe that the patient drops objects or falls, but often are mild and interpreted as clumsiness or tremor. A series of such jerks may herald a generalised tonic-clonic seizure. About one-third of patients experience typical absences, which may antedate myoclonic jerks by several years. Seizure-precipitating factors include sleep deprivation, alcohol, stress, menstruation, and flashing lights. Over 80% of patients are well controlled by treatment with sodium valproate alone with or in combination clonazepam or phenobarbitone, but relapse is the norm on discontinuation of antiepileptic medication even after many years seizure-free.2--7,9,10 Carbamazepine is not effective, even though recommended for generalised tonic-clonic seizures in the British National
Formulary. 11 Grunewald and co-workers,in London, have identified 22 patients with JME among 180 referrals to an epilepsy clinic. None of these had been
diagnosed previously, even by experienced neurologists. The most common misdiagnosis was "complex partial seizures with secondary generalisation" or the unacceptably vague term "epilepsy". Control of seizures was often poor since patients were treated mainly with carbamazepine; on substitution of appropriate medication they improved strikingly. Avoidable morbidity in this group, in addition to the psychological and social effects of poor seizure control, included the loss of driving licence or employment, injury to self or child, inappropriate withdrawal of medication either during pregnancy or when fits were well controlled, and status epilepticus. To elicit the characteristic history of myoclonic jerks is something of an art. It may be necessary physically to demonstrate mild myoclonic jerks confined to the hands, and to inquire about morning tremulousness or clumsiness ("do you spill your morning tea?"). If the patient reports normal hypnogogic jactitations, then the concept has been understood. Diagnostic yield may be improved by emphasising the close relation of jerks to fatigue and sleep deprivation. Unilaterally predominant jerks and those preceding generalised tonic-clonic seizures must not be interpreted as focal epilepsy. Diagnosis of typical absences and their differentiation from complex partial seizures can be equally difficult. The general conception of typical absences (petit mal) is of childhood phenomena associated with severe impairment of consciousness. In contrast, in patients with JME absences tend to be inconspicuous with little disturbance of consciousness.12 They may be described by patients merely as a momentary lapse in concentration and they are not associated with automatisms. Complex partial seizures tend to last longer and are more often associated with experiential phenomena and automatisms. Electroencephalography can help greatly since in most untreated patients it will show generalised discharges of spikes or multiple spikes and
slow waves enhanced by overbreathing.2,12 One-third of patients also show photosensitivity. These abnormalities are most pronounced with sleepdeprived electroencephalography. 30% of patients, however, show additional focal abnonnalities3,4 that may bolster an erroneous clinical diagnosis of complex partial seizures. Physicians should be ever alert to the
possibility of JME. 1. Gram L. Epileptic seizures and syndromes. Lancet 1990; 336: 7-9. 2. Tsuboi T, Christian W. Epilepsy. A clinical, electroencephalographic and statistical study of 466 patients, Berlin: Springer-Verlag, 1976. 3. Obeid T, Panayiotopoulos CP. Juvenile myoclonic epilepsy: a study in Saudi Arabia. Epilepsia 1989; 29: 280-82. 4. Grünewald RA, Chroni E, Panayiotopoulos CP. Delayed diagnosis of juvenile myoclonic epilepsy. J Neurol Neurosurg Psychiatry 1992; 55: 497-99. 5. Delgado-Escueta AV, Enrile-Bacsal FE. Juvenile myoclonic epilepsy of Janz. Neurology 1984; 34: 285-94. 6. Panayiotopoulos CP, Tahan R, Obeid T. Juvenile myoclonic epilepsy: factors of error involved in the diagnosis and treatment. Epilepsia 1991; 32: 672-76. 7. Janz D. Juvenile myoclonic epilepsy: epilepsy with impulsive petit mal. Cleveland Clin J Med 1989; 56: S23-S33. 8. Hopkins A, Garman A, Clarke C. The first seizure in adult life. Lancet 1988; i: 721-26. 9. Obeid T, Panayiotopoulos CP. Clonazepam in juvenile myoclonic epilepsy. Epilepsia 1987; 30: 603-06. 10. Jeavons PM, Clark JE, Maheshwari MC. The treatment of generalised epilepsies of childhood and adolescence with sodium valproate. Dev Med Child Neurol 1977; 19: 9-25. 11. BMA and Royal Pharmaceutical Society. British National Formulary, 23. London: BMA/RPS, 1992. 12. Panayiotopoulos CP, Obeid T, Waheed G. Absences in juvenile myoclonic epilepsy: a clinical and video-electroencephalographic study. Ann Neurol 1989; 25: 391-97.
Developmental biology: impact on medicine For most doctors, the first and last encounter with the science of developmental biology is when they study human embryology during their undergraduate years. After that, it is usually sufficient to know whether something is or is not an embryological defect and to act accordingly. However, in the past ten years there has been a revolution in our understanding of animal development that cannot fail ultimately to have a profound impact on human medicine. This breakthrough has arisen from a fusion of classic experimental embryology with modern molecular biology and developmental genetics.1 The first animal to have been "solved" is the humble fruit fly, Drosophila, success depending crucially on the relative ease of experimental genetics with this organism. Drosophila has a short life cycle, so it is possible to handle and examine huge numbers of flies and hence to detect rare mutational events. In the late 1970s researchers came to realise that mutations in the genes that controlled early development would probably be lethal, and therefore have been missed in previous genetic work in which only adult flies had been studied. Screens were carried out to identify all the genes that, when mutated, would give rise to dead larvae with some identifiable anatomical abnonnality-for example, missing segments or
761
conversion of one type of segment into another. Most of these genes have now been cloned and we know in which regions and at what developmental stages of the embryo they are expressed. An important initial insight into their functions was provided by the mutant phenotypes, and further information was obtained by studying how the absence of one gene affects the expression of others. The result of all this effort is something approaching a gene-by-gene account of how Drosophila develops from the newly laid egg to a larva, which, although it may look simple, is actually a complex animal with many differentiated tissues and body parts.33 Surprising though it may seem, the higher animals, including man, contain genes with a considerable degree of evolutionary conservation to many of the developmentally significant genes in Drosophila. When the embryonic expression patterns of the vertebrate genes have been studied, a remarkable proportion look as though they, too, have important functions in controlling embryonic development. Some were already known from different lines of work--eg, as oncogenes or growth factors-whereas many others are novel. They probably could not have been found by direct genetic methods because screens for recessive lethal mutations are very laborious and expensive for vertebrates, and saturation of the genome could not easily be achieved. Thus the Drosophila work has an impact far beyond understanding the development of one small insect, because it has enabled us to identify many important genes in vertebrates that would have been difficult or impossible to find by other methods. Moreover, we know that the expression patterns for now
developmentally important genes are virtually identical in the early embryos of all vertebrates from fish to mouse and, although there have been few studies in human beings, this fact provides us with a virtual guarantee that man will prove to be the same. It is interesting to compare the results of the breakthrough with previous speculations of experimental embryologists about how animals develop.4,s Three important predictions have been borne out. First there is an important class of gene-homoeotic or selector genes-whose function is to code for parts of the body rather than for specific tissues or cell types. For example, one such gene might normally be expressed in the anterior but not in the posterior half of the body. If it were inactivated by mutation, the body plan would accordingly become changed to double posterior; if it were ectopically expressed in the posterior half then those parts would become anterior in character. Homoeotic genes code for transcription factors whose function is to regulate the expression of other genes and they lie near the top of a hierarchy of gene regulation whose final branches lead to the familiar cell-type-specific enzymes and structural proteins. Second, the body plan is specified by concentration gradients of inducing factors or morphogens. In Drosophila these are themselves
transcription factors, because the early insect embryo is a multinucleate syncytium and so proteins can diffuse directly from one nucleus to another. In vertebrates, where the embryo is at all times multicellular, there is good evidence that the inducing factors are growth factors, especially those of the transforming growth factor P and fibroblast growth factor families.6Third, the stability of gene expression depends in at least some cases on a positive feedback, whereby a gene product is responsible for keeping its active state.7 The Drosophila work has also shown that the mechanisms are far more complex than was formerly supposed, and that apparently similar processes may be carried out by quite different sorts of molecule. But despite the complexity, the essence of early development is simple. The egg always contains some asymmetry that can initiate the formation of the first morphogen gradient. The gradient leads to activation of one or more homoeotic genes in particular parts of the embryo, depending on concentration. These gene products turn on other genes that produce sources and sinks for further morphogen gradients, which activate further combinations of homoeotic genes. Each small multicellular region of the embryo soon becomes uniquely specified by the activation of a particular combination or "coding" of homoeotic genes. Once set up, the stability of these codings can be maintained by positive feedback and the gradients become superfluous. In later development each coding will cause activation of genes involved in the terminal differentiation of the appropriate organs and tissues. own
gene in
an
Although understanding embryonic development is an important intellectual goal in its own right, it also promises deeper insights into the working of the human body. We shall come to know not only what the body is made of and how its parts work, but also how it was built. To see the importance of this approach, consider the fact that two houses may look the same but behave differently under stress because in one case the load is borne by brick walls and in the other by a frame of timber. In human beings components tend to fail not during embryonic life but in old age, when we experience cancer, heart disease, arthritis, or neurodegeneration. Thus, knowledge of the building blocks during embryonic development will tell us something both about the causation of embryological abnormalities and, even more important, about the degenerative diseases of later life. JMW. From egg to embryo: regional specification in early development. Cambridge: Cambridge University Press, 1991. 2. Nüsslein-Volhard C, Wieschaus E. Mutations affecting segment number and polarity in Drosophila. Nature 1980; 287: 795-801. 3. Lawrence PA. The making of a fly. Oxford: Blackwell, 1992. 4. Waddington CH. New patterns in genetics and development. New York: Columbia University Press, 1962. 5. Wolpert L. Positional information and the spatial pattern of cellular differentiation. J Theor Biol 1969; 25: 1-47. 6. Jessell TM, Melton DA. Diffusible factors in vertebrate embryonic 1. Slack
induction. Cell 1992; 68: 257-70. 7. Kuziora MA, McGinnis W. Autoregulation of selector gene. Cell 1989; 55: 477-85.
a
Drosophila homeotic
