Genetic and Metabolic Disease in Pediatrics

Butterworths International Medical Reviews

June K. Lloyd, Charles R. Scriver

• Publisher: Butterworth-Heinemann
• Year: 2014
• Print ISBN:
  9780407023123
• eBook ISBN:
  9781483161013
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

Genetic and Metabolic Disease in Pediatrics is a compendium of papers that discusses the problems of inborn diseases in terms of homeostasis. One paper traces "backward" from the disease phenotype to discover and investigate the gene, as well as moves "forward" from mutation in DNA to discover phenotypes or proteins connected with the disease. Specific genes are assigned to particular places (loci) on chromosomes that can manifest the presence or type of disease. Another paper examines a classical disease—osteogenesis imperfecta—pointing out that the aberrant collagen of osteogenesis imperfecta reflects mutation at chromosomes 7 and 17. Another paper shows that in osteogenesis imperfecta, Mendelian phenotypes lead to genes and their products as being involved in critical aspects of protein traffic in human cells. Several papers examine the inborn errors of metabolism covering the lacticacidemias, urea synthesis, the hyperphenylalaninaemias, and the hyperlipidaemias. Other papers investigate the effects of metabolic dishomeostasis caused by variant maternal genotypes on fetal development, the "androgen pathway, its known Mendelian variants

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Genetic causes of deviant metabolism. What do we know? What can we do?

Charles R. Scriver and June K. Lloyd

Publisher Summary

This chapter discusses the genetic causes of deviant metabolism. Disrupted homeostasis underlies any disease and has proved to be a useful paradigm to interpret the cause, pathogenesis, and manifestations of even that classic genetic but nonmetabolic disease, Down’s syndrome. To appreciate the origins of dishomeostasis in a disease, it is necessary to consider the process of displacement. Homeostasis has metrical parameters; their statistics are the central tendency (mean), the dispersion (standard deviation), and the character of dispersion (skewness and kurtosis). Deviation of a value beyond the normal boundaries of a biological parameter can reflect only two events (mutation or experience); one or other acts predominantly or, as is most often the case, they act together. Displacement, therefore, reflects either an extrinsic experience overwhelming the process or an intrinsic event subverting it or a combination of the two. Health of modern man living in a developed society has resulted largely from ascendency over causes of the first type. When mortality and morbidity were most often the manifestations of extrinsic causes, it was sufficient to control these causes; as a result, collective health and longevity improved.

Claude Bernard (1878) said: ‘Constancy of the milieu interieur is the condition of a free and independent existence’. This idea reflected a new awareness about life on earth. There was form: the awareness that living things on earth have certain limits to form which are their own, reflecting evolutionary processes and physical laws that are not miraculous or supernatural. There were signs: manifestations of specific forms and functions and ways to describe them. And there were mechanisms: explanations of how things work. Homeostasis, the term devised (Cannon, 1932) to fix the idea of adaptive constancy of biological functions in living systems, was perceived as a product of mechanisms serving the integrity of form.

Knowledge of heredity preceded knowledge of its mechanism. The origin of continuity in form, and in the mechanisms that sustain living systems, was mysterious until the discovery of DNA (Schrödinger, 1944). Now that we understand the ‘phenotype paradigm’ (Figure 1.1) and the processes of replication, transcription and translation of information encoded in DNA (Crick, 1970), we perceive that the gene is a relative ‘constant’; it determines species and the persistence of their form (phenotype) in the individual descendants. But life is a process whereby genotype and thus phenotype is undergoing variation, and in the resultant interactions with experience, organisms can fail or succeed. The consequences of variation are measured in biological terms; either individuals reproduce adequately or they do not. Their adaptation and their success reflects homeostasis in the individual members of the species. Humans prefer not to measure their own success merely in biological terms; we see the consequences of selection extended to encompass behaviour and culture (Skinner, 1981). Nevertheless, adaption in any context implies measures of normality. Deviant values indicate dishomeostasis, the cost of which is disadaption or, as we usually call it, disease. We tend to think about obvious physiological and metabolic parameters when we invoke homeostasis. But the idea in its broadest terms, that disrupted homeostasis underlies any disease, has proved to be a useful paradigm to interpret the cause, pathogenesis and manifestations of even that classic genetic but non-metabolic disease, Down’s syndrome (Shapiro, 1983).

Figure 1.1 The ‘central dogma’ of biology (Crick, 1970) is also the ‘phenotype paradigm’. The diagram indicates pathways of information transfer: DNA→DNA (replication); DNA→RNA (transcription); RNA→protein (translation). Solid arrows indicate conventional transfers; interrupted arrows represent special (e.g. reverse transcription) or unidentified transfers. The vectorial relations (direction of arrow) imply that mutation in DNA influences phenotype (protein) but that perturbations in phenotype (e.g. disrupted homeostasis by extrinsic events) cannot alter genotype

The medical model of disease is both universal and simple (WHO, 1980). Manifestations of disease (impairment, disability or handicap, either permanent or temporary) reflect a process (pathogenesis) which has a cause. Medicine is largely concerned with the biological and social manifestations of disease and with process.

The biological consequences (manifestations) of disease can be categorized. They affect longevity, reproductive capability, development (somatic, intellectual and behavioural), and viability, and it is even possible to measure systematically the consequences of a genetic disease in these simple terms (Costa, Scriver and Childs, 1985). For example, Tay-Sachs disease, which impairs postnatal development and kills the individual before reproductive life has begun, is clearly catastrophic; on the other hand, a disorder with primary cosmetic significance and little biological cost such as the Treacher Collins-Franceschetti’s syndrome, can influence social interaction and exert costs in access to schooling and work. Accordingly, behavioural costs which may put an individual on the social ‘side-line’ are a consequence of disease that will concern physicians. Whilst the social consequences of genetic and metabolic diseases are very important (Raine, 1977), they are not the principal focus of this volume, which concentrates on the biological manifestations of some genetic diseases, and offers some explanations for them.

Manifestations are the stuff of medical practice – and curricula. But the processes behind their appearance are of equal importance since they will determine treatment. Mechanisms of disease involve the processes of disadaptation which are often not as well understood as the manifestations. For example, we apparently know almost all there is to know about the manifestations of phenylketonuria; we still do not understand the mechanism(s) of its major manifestation – the mental retardation. The cause of disease must be our ultimate concern. To know the cause enhances prediction and treatment and may even enable prevention.

To appreciate the origins of dishomeostasis in a disease it is necessary to consider the process of displacement. Homeostasis has metrical parameters (Figure 1.2); their statistics are the central tendency (mean), the dispersion (standard deviation), and the character of dispersion (skewness and kurtosis). Deviation of a value beyond the ‘normal’ boundaries of a biological parameter can reflect only two events (mutation or experience); one or other acts predominantly or, as is most often the case, they act together. Displacement therefore reflects either an extrinsic experience overwhelming the process or an intrinsic event subverting it, or a combination of the two.

Figure 1.2 Frequency distributions of a metrical phenotype. Left: the quantitative parameter (abscissa) has both central tendency and dispersion; they are described by conventional statistics: mean value (central tendency); and standard deviation, skewness, and kurtosis (dispersions). If genotype ‘proposes’ the phenotype, and gene products which have been selected as adaptive for homeostasis are centripetal in their effects on the dispersion of values, then experiences (various environmental forces) can be said to ‘dispose’ the normal phenotype with centrifugal effects. Right (top): dispersion of phenotypic values can be altered by a deviant experience (E_v) which overwhelms homeostasis. (Bottom): dispersion altered by mutation (G_v) which modifies the gene products maintaining homeostasis; the modified phenotype may then be skewed (quasi-continuous variation) or bimodal (discontinuous variation). Inborn errors, in their fully expressed forms, tend to confer discontinuous variation

Health of modern man living in a developed society has resulted largely from ascendency over causes of the first type. When mortality and morbidity were most often the manifestations of extrinsic causes it was sufficient to control these causes; as a result collective health and longevity improved. This is the story of public health, the improvement in environment, the discovery of vaccines and immunization procedures, and the awareness of vitamins and other nutritional requirements. Even so, disease and premature death have not disappeared. If a ‘specific disease’ continues to occur, albeit at a lower frequency (and incidence) in the population, we must ask: ‘Why is this so’? The eternal question in medicine – ‘Why does this person have this disease at this time’? – is still and always will be pertinent (King, 1982). It must follow that if the disease persists, yet its causes due to environmental events are less, then causes of intrinsic origin must now be relatively more important. That is to say heritability of the phenotype (or disease, or dishomeostasis) has increased. That is why the content of paediatric disease in modern referral hospitals has such a high genetic component (Hall et al., 1978) and why we must be interested in the genetic causes of disease.

DNA is the ultimate constant in living systems. Of course, the message in the nucleotide code is not constant throughout all living species, and that fact explains differences among species and individuals. Mutations at specific loci are sudden, one-time-only events in lineages; but once they occur, they will persist if they are not genetic lethals. The mutations will descend in their lineages, and they will spread in the population. The ubiquity of mutations, their allelic heterogeneity, and the phenomenon of genetic polymorphism are now widely appreciated (Vogel and Motulsky, 1979). Of major concern, in this book, is the phenotypic significance of the genetic diversity which is characteristic of man.

ILLUSTRATIONS OF THEMES

This book reflects the organizational intentions of the editors; the authors provide the substance to fulfil those intentions. To know an address is one thing; to get there and back is another. Pembrey describes the journey in Chapter 2. If the central dogma or sequence paradigm (DNA→mRNA→protein) is the basis of biology, then methods that reveal the links between DNA and phenotype are of great interest to physicians. The recent development of molecular genetics is the technical domain which permits us to move ‘backward’ from disease phenotype to discover and read the gene; it is also the technique that will help us to move ‘forward’ from mutation in DNA to discover phenotypes (proteins) presently unidentified but known to be associated with disease. For example, the aberrant cellular mechanisms of Duchenne muscular dystrophy, Huntington’s disease, and cystic fibrosis may soon be discovered by identifying the relevant DNA sequences and interpreting their products. Molecular genetics can now predict causes of certain diseases and, with suitable options, their manifestations can be prevented.

Next, Sparkes describes an important development in modern human genetics: the assignment of specific genes to particular places (loci) on chromosomes. Vesalius gave us modern human anatomy and every physician has had to learn it; the emerging map of human gene loci constitutes a ‘neoVesalian anatomy’ of importance equal to its namesake of earlier times. There is even now an emerging genetic morbid anatomy (McKusick, 1983), specifying the chromosomal loci, and DNA sequences, at which particular diseases find their causes in mutation. These developments represent a new form in medicine whose signs may be daunting to the uninitiated. The purpose of Sparkes’ chapter is to familiarize the signs. Their relevance to manifestations of disease needs no further defence.

Genes specify polypeptide products; the latter are the true primary phenotype. Form determines the function of polypeptides. Deviation from the normal form initiates the process of disease. Two chapters in the book deal with new ideas about form; their authors are as responsible as anyone for a refined understanding about the process of disease. In Chapter 4, Byers and Bonadio nominally discuss osteogenesis imperfecta – a ‘classical’ disease with a long and interesting history – but the actual focus of their chapter is a major protein – collagen, its form, and its synthesis. They make it clear that the aberrant collagen of osteogenesis imperfecta reflects mutation at speci...

Table of contents

• Cover image
• Title page
• Table of Contents
• Butterworths International Medical Reviews
• Copyright
• Preface
• Contributors
• Chapter 1: Genetic causes of deviant metabolism. What do we know? What can we do?
• Chapter 2: Genes
• Chapter 3: The human gene map
• Chapter 4: The molecular basis of clinical heterogeneity in osteogenesis imperfecta: Mutations in type I collagen genes have different effects on collagen processing
• Chapter 5: The I-Cell model: the molecular basis for abnormal lysosomal enzyme transport in mucolipidosis II and mucolipidosis III
• Chapter 6: The lacticacidemias
• Chapter 7: Inborn errors of urea synthesis
• Chapter 8: The hyperphenylalaninaemias
• Chapter 9: The hyperlipidaemias
• Chapter 10: Effect of mutation on maternal–fetal metabolic homeostasis: general concepts
• Chapter 11: Effect of mutation on maternal–fetal metabolic homeostasis: maternal aminoacidopathies
• Chapter 12: The androgen-response system in developmental health and disease
• Index