Biomedical subjects
A E Emery
Publications and source records attributed to A E Emery.
Developments in the new genetics.
The advent of recombinant DNA has introduced novel ways of diagnosing genetic disorders. The application of these techniques in affected families, coupled with genetic counselling, should help prevent the recurrence of a proportion of cases, and thereby reduce a considerable amount of suffering, and in some cases the expense of caring for a severely affected individual. However, such aims may be achieved only when the importance of such services is more widely recognized and they become more generally available. Counselling and prenatal diagnostic services have been available in University Centres of Medical Genetics for at least the last 20 years yet still only a proportion of the population at risk avail themselves of these services. The role of Health Departments in ensuring that those at risk are aware of and then use these facilities is clear. Health education must play an important role in this regard. Furthermore, there is a real need for financial support to employ adequately trained medical and technical staff in such centres. Currently, these problems are being debated by such bodies as the Clinical Genetics Society and the Royal College of Physicians. With the co-operation, help and support of Public Health Departments in the future, these exciting developments will not remain within the confines of research laboratories but will be extended to the community at large. In this way all those at risk in the population can benefit.
Emery-Dreifuss muscular dystrophy and other related disorders.
There are some 30 or so different forms of muscular dystrophy which are conveniently classified according to the mode of inheritance. Emery-Dreifuss X-linked muscular dystrophy is characterized by the triad of: (1) early contractures of the elbows, Achilles tendons and postcervical muscles; (2) slowly progressive muscle wasting and weakness with a humero-peroneal distribution in the early stages; and (3) a cardiomyopathy usually presenting as heart-block. The insertion of a cardiac pace-maker can be life saving and therefore the recognition of the condition is essential. The responsible gene has been localized to Xq28. The autosomal recessive dystrophies are classified into congenital forms (the Fukuyama type is particularly common in Japan); a childhood form (similar to Duchenne) which occurs frequently in certain inbred communities; and adult onset limb girdle dystrophy. The autosomal dominant dystrophies are classified on the distribution of predominant muscle weakness into facioscapulohumeral, scapuloperoneal (with or without early contractures and cardiomyopathy), proximal, distal and ocular forms. The basic biochemical defects and the localizations of the responsible genes are as yet unknown in any of the autosomal recessive or autosomal dominant dystrophies.
Emery-Dreifuss syndrome.
Emery-Dreifuss muscular dystrophy is characterised by the triad of (1) early contractures of the elbows, Achilles tendons, and postcervical muscles; (2) slowly progressive muscle wasting and weakness with a humeroperoneal distribution in the early stages; and (3) a cardiomyopathy usually presenting as heart block. The early recognition of the condition is essential because the insertion of a cardiac pacemaker can be life saving. The disorder is usually inherited as an X linked recessive trait (linked to DNA markers around Xq28). However, occasionally it can be inherited as an autosomal dominant trait and there is an indication that this and the X linked form may in some cases have a neurogenic basis. For these reasons it has recently been proposed that the appellation 'Emery-Dreifuss syndrome' be used for this triad of symptoms and signs.
Joseph Adams (1756-1818).
Joseph Adams was eclectic in his interests and wrote on a variety of medical subjects. His last book published in 1814 was on hereditary disease and based on a lifetime's careful clinical observations. In it he distinguished between what would now be defined as dominant and recessive disorders; defined the term congenital; emphasised the role of inbreeding in producing clustering of certain inherited disorders; introduced concepts now known as founder effect, incomplete penetrance, and variable age at onset; emphasised the importance of environmental factors in precipitating disease in certain genetic disorders; and, finally, recommended the establishment of registers for the purpose of preventing genetic disease. But because he proposed no scientific explanation for these various ideas, they were largely ignored by his contemporaries. Nevertheless, it would seem right to regard Joseph Adams as perhaps the first clinical geneticist.
Clinical and molecular studies in Duchenne muscular dystrophy.
X-linked DMD is a serious condition characterized by progressive muscle wasting and weakness and death ensues in the late teens or early twenties. There is considerable clinical variability even within families and some suggestions of genetic heterogeneity. Though skeletal muscle is primarily involved, other tissues are also affected including cardiac and smooth muscle. Other abnormalities include mental retardation, thymus hyperplasia and possibly certain endocrinological changes. The responsible locus is at Xp21 and the gene product is a very large protein (dystrophin) which is normally localised to muscle cell membranes. It is hypothesised that its absence in DMD may result in instability of the muscle cell membrane with resultant ingress of calcium, an increase in intracellular calcium, and cell death. An understanding of this pathway is important in devising an effective treatment.
John Dalton (1766-1844).
There is no doubt that John Dalton ranks among the great names in science, a position which rests on his enunciation of the Atomic Theory. However, his very first scientific paper in 1798 was concerned with his own affliction of colour blindness and was in fact the first clear description of the disorder. This publication stimulated much subsequent research into the pathophysiology and genetics of the condition. His recorded observations on colour blindness are detailed and precise and betoken the approach which was to characterise all his later research in chemistry.
Pierre Louis Moreau de Maupertuis (1698-1759).
Maupertuis was one of the most important scientists and original thinkers of the 18th century. He refuted the preformationist theories of the time, and from his study of the inheritance of genetic traits proposed various ideas which forecast the genetic theory of inheritance. He applied the concept of probability to genetic problems and introduced experimental breeding as a means of studying the inheritance of genetic traits in animals. However, he considered his greatest contribution to science to be the 'Principle of Least Action'. Yet paradoxically it was this, through the vitriolic attacks by Voltaire which it engendered, which resulted in his work being largely ignored until recent times.
X-linked muscular dystrophy with early contractures and cardiomyopathy (Emery-Dreifuss type).
The original Virginia family with X-linked muscular dystrophy with early contractures and cardiomyopathy (Emery-Dreifuss type) has been reinvestigated 25 years later. The findings confirm that a cardiomyopathy, presenting most often as atrioventricular block, is a significant feature of the disease, which is characterized by the triad of: 1) slowly progressive muscle wasting and weakness with a humero-peroneal distribution in the early stages; 2) early contractures of the elbows, Achilles tendons, and post-cervical muscles; and 3) a cardiomyopathy usually presenting as heart block (some female carriers may also develop heart block). Other reported families with X-linked Emery-Dreifuss muscular dystrophy as well as a rare autosomal variant are reviewed, and differentiation from scapulo-peroneal muscular dystrophy and the rigid spine syndrome is discussed.
Risk estimation in autosomal dominant disorders with reduced penetrance.
The occurrence in a family of an isolated case of an autosomal dominant disorder with reduced penetrance presents a difficult problem in genetic counselling. It is shown that in such a situation the risk of recurrence in subsequent offspring is given by: (formula; see text) where P is the penetrance (0 less than P less than 1) and f' the relative fitness (0 less than f' less than 1) of affected individuals. In all cases the risks of recurrence will exceed 1 in 20 unless penetrance is high (greater than 0.90) and the relative fitness of affected persons is low (less than 0.6).
Identical twinning and oral contraception.
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A population study of adult onset limb-girdle muscular dystrophy.
Complete ascertainment of adult onset limb-girdle muscular dystrophy in the Lothian Region of Scotland was attempted. Ten index cases were identified giving a prevalence of 1.3 per 100 000 (0.9 per 100 000 for cases where the diagnosis of muscular dystrophy was supported by both electromyographic and muscle biopsy findings). In these 10 sibships there had been 11 affected subjects, significantly less than the 16.5 cases expected for autosomal recessive inheritance. Excluding cases suspected of being Becker muscular dystrophy, the prevalence was 0.7 per 100 000 (0.3 per 100 000 for proven cases of muscular dystrophy) and there remained a significant difference between the number of cases observed (5) and the number expected (9.1) for autosomal recessive inheritance. The prevalence of limb-girdle muscular dystrophy with onset in adult life has apparently declined over the past 30 years, as would be expected with the recognition of other conditions which cause the same pattern of weakness, making this a relatively rare disorder which should only be considered when other diagnoses have been excluded. The possibility that some cases diagnosed as limb-girdle muscular dystrophy may have had Becker muscular dystrophy emphasises the urgent need for a greater understanding of the biochemical basis of these conditions so that such diagnostic and genetic counselling dilemmas can be resolved.
Genetic heterogeneity in Duchenne muscular dystrophy.
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A family study of Paget's disease of bone.
Familial aggregation of Paget's disease of bone occurs occasionally and an exclusively genetic aetiology has been proposed in the past. On the other hand, epidemiological surveys point to an important environmental contribution, and evidence is accumulating to suggest that the disease may be caused by a slow virus infection. Analysis of 407 family history questionnaires completed by patients with Paget's disease confirmed the familial nature of the disease. Overall, the findings were consistent with the hypothesis that Paget's disease is caused by infection with a common and widespread virus superimposed on genetic variation for susceptibility and perhaps severity of the disease.
Human lymphocyte capping and the effect of lanthanum in Duchenne muscular dystrophy.
Capping was studied in lymphocytes obtained from controls and patients with Duchenne muscular dystrophy. Before the induction of capping by anti-Ig antibodies the cells were incubated with increasing concentrations of calcium and lanthanum. It was found that the presence or absence of extracellular calcium had no effect. Lanthanum, which blocks active calcium extrusion, altered the proportion of capping in both controls and Duchenne lymphocytes. These observations are discussed in relation to the possible involvement of free intracellular calcium in normal controls and patients with Duchenne muscular dystrophy.
Antenatal diagnosis--its present status and future prospects.
In the past decade dramatic developments have taken place in antenatal diagnosis. Various techniques are now fully established as routine procedures and these are applicable to several categories of genetic diseases. Transabdominal amniocentesis is currently the most important method for the prenatal diagnosis of chromosomal conditions, neural tube defects and biochemical disorders. Ultrasonography is playing an increasingly important role in the detection of malformations, while fetoscopy is now employed for fetal blood sampling, biopsy and visualization. Recombinant DNA techniques hold great promise for the intra-uterine diagnosis of common and important disorders in which the fundamental defect is unknown.
X chromosome in Duchenne muscular dystrophy.
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