Genetics and Neurology

Sarah Bundey, Alan E. H. Emery

• Publisher: Elsevier
• Year: 2014
• Print ISBN: 9780443028182
• eBook ISBN: 9781483281018
• Topic: Medicine
• Subtopic: Diseases & Allergies

Genetics and Neurology focuses on disorders that affect the nervous system, including atrophies, neuropathies, and tumors. The book first examines malformations of the central nervous system, phacomatoses and tumors, and cerebral degenerative disorders of childhood. Topics include malformations of the corpus callosum and neighboring structures; abnormalities of closure of neural tube; spongiform leucodystrophy; and tumors of the nervous system. The text then takes a look at extrapyramidal disorders and dyskinesias and muscle disorders. The publication elaborates on spinal muscular atrophies (SMAs), cerebellar and spinocerebellar ataxias, and hereditary neuropathies. Discussions focus on hereditary motor and sensory neuropathies of infancy and early childhood; peripheral neuropathies and lipid disorders; and congenital cerebellar ataxias. The book also discusses spastic paraplegias and multifactorial inheritance and neurological diseases. The text is a valuable reference for readers interested in genetics and neurology.

1

Malformations of the central nervous system

Publisher Summary

This chapter discusses the malformations of the central nervous system. Many malformations of the nervous system carry no recurrence risks. The chapter discusses those conditions where there is a risk of the same malformation occurring again in relatives, such as abnormalities of closure of neural tube, abnormalities of cleavage, malformations of the corpus callosum and neighboring structures, malformations of structures in posterior fossa, and abnormalities of gyri formation. Abnormalities of closure of neural tube malformations include anencephaly, iniencephaly, encephalocoele, myelomeningocoele, and meningocoele but not isolated hydrocephalus. They arise as a result of failure of the neural groove to form a tube and close at each end, a procedure which normally occurs between 18 and 26 days after ovulation. Abnormalities of cleavage form a heterogenous group of malformations where the common factor is failure of cleavage of the forebrain. Malformations of the corpus callosum consist of partial or complete agenesis and are frequently associated with malformations of neighboring structures such as the absence of anterior or hippocampal commissures, agenesis of the septum lucidum, porencephaly or hydrocephalus. Abnormalities of gyri formation are schizencephaly, macrogyria, and micropolygyria.

Introduction

Malformations of the central nervous system are relatively common, occurring in 3 to 4 % of early spontaneous abortuses (Creasy & Alberman 1976) and in about 0.6% of births in the U.K. (Leck 1974). Congenital malformations of the brain are found at autopsy in between 20 and 30% of mentally retarded patients (Freytag & Lindenberg 1967).

The gross malformations have started to appear by the end of the third month of gestation and must therefore be caused by factors acting early in pregnancy. The first embryological landmark is the development and then the closure of the neural tube which occurs between 18 and 28 days after ovulation. Posterior defects in the neural tube give rise to anencephaly, spina bifida and related malformations; while anterior defects produce the holotelencephaly group of malformations. The cerebral and optic vesicles and the choroid plexus start to form at four to five weeks’ gestation and soon afterwards the primordia of the cerebellum appear. The ventricles are well formed by about eight weeks and the corpus callosum develops at about 10 weeks. From about five to 25 weeks’ gestation there is cellular migration and proliferation; abnormalities in these processes lead to the formation of abnormal gyri, to ectopic positioning of nervous tissue (cortical and cerebellar heterotopias) and to the development of phakomas and other cerebral tumours. From 25 weeks of gestation until one to two years of postnatal life, there is cellular maturation, the formation of synapses, the development of specific cellular patterns in different parts of the brain, and myelination. Noxious influences at this time produce defects in cellular architecture and in myelination, and from about seven to nine months of gestation will cause destructive or degenerative changes rather than developmental abnormalities. For reviews of the embryology of the nervous system see Hamilton et al (1972) and Gabriel (1974).

Many malformations of the nervous system carry no recurrence risks. Attention will primarily be given in this chapter to those conditions where there is a risk of the same malformation occurring again in relatives. For more comprehensive reviews on congenital malformations see Warkany et al (1981) and Bergsma (1973). Multiple malformation syndromes will not be covered in this section, for they also have been adequately reviewed elsewhere (Holmes et al 1972; Smith 1982).

ABNORMALITIES OF CLOSURE OF NEURAL TUBE

These malformations include anencephaly, iniencephaly, encephalocoele, myelomeningocoele and meningocoele but not isolated hydrocephalus. They arise as a result of failure of the neural groove to form a tube and close at each end, a procedure which normally occurs between 18 and 26 days after ovulation (Hamilton et al 1972). Thus, any teratogens which may cause neural tube malformations must act during this short period. Epidemiological and genetic studies have shown that the malformations are aetiologically related, in that an increased incidence of one is accompanied by a similar increase in the others, and that the increased risk that occurs for relatives of patients with one of these malformations is for any of the other malformations as well as for the same one. Therefore they are usually grouped together as neural tube defects, or NTD.

It has been shown that spinal dysraphism (Carter et al 1976) and multiple congenital vertebral anomalies (Wynne-Davies 1975) should also be included as neural tube defects, since the incidence of anencephaly and spina bifida in first degree relatives is as high in these conditions as if the index patient had anencephaly or spina bifida. However, they have not been included in earlier epidemiological studies.

The incidence of neural tube defects varies from one area to another and also from one race to another (Table 1.1). It is interesting that on migration, races tend to keep the incidence of their country of origin.

Table 1.1

Some incidences of neural tube malformations per 1000 Births

South-East England (London)	2.9
Wales	7.6
Northern Ireland	8.9
Northern India	6.0
Egypt (Alexandria)	5.4
Africa	<1.0
Japan	<1.0
English in Birmingham	3.7
Irish in Birmingham	5.6
Indians in Birmingham	4.3
Negroes in Birmingham	1.0
Whites in U.S.A cities	2.4
Blacks in U.S.A. cities	0.9

(data from Carter et al 1968; Leck 1972; Carter and Evans 1973)

Genetics

The pattern of recurrence of neural tube defects in the families of index patients demonstrates that this group of malformations is polygenically inherited (Carter et al 1968; Carter & Evans 1973). For example, in South-East England (Table 1.2) the incidence in first-degree relatives is about 1 in 22, that is, about 15 times the population incidence; the incidence in second-degree relatives is about five times the population incidence and the incidence in third-degree relatives is about twice that of the population.

Table 1.2

Incidences of neural tube malformations in relatives

Full sibs	1 in 22
Half sibs	1 in 50
Children	1 in 22
Aunts, uncles, nephews, nieces	1 in 70
Cousins*	1 in 148
Incidence in population from which index patients came	1 in 340

^*in fact, mothers’ sisters’ children

(data from studies in South-East England: Carter & Evans 1973; Carter 1976)

The family studies show that, on average, 60 to 70% of the causation of neural tube defects is genetic, leaving about 20 to 30%, which on average is due to environmental factors. It is now clear that one of the environmental factors that can cause ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Genetics and Neurology
• Inside Front Cover
• Copyright
• Foreword
• Dedication
• Preface
• Acknowledgements
• Chapter 1: Malformations of the central nervous system
• Chapter 2: Phacomatoses and tumours
• Chapter 3: Cerebral degenerative disorders of childhood
• Chapter 4: Extrapyramidal disorders and dyskinesias
• Chapter 5: Muscle disorders I
• Chapter 6: Muscle disorders II
• Chapter 7: Spinal muscular atrophies (SMAs)
• Chapter 8: Hereditary neuropathies
• Chapter 9: Cerebellar and spinocerebellar ataxias
• Chapter 10: Spastic paraplegias
• Chapter 11: Neurological diseases in which there are defects in DNA repair or synthesis
• Chapter 12: Multifactorial inheritance and neurological diseases
• Chapter 13: Dementia, epilepsy and miscellaneous disorders
• Appendix 1
• Appendix 2
• Appendix 3
• Index