Neurogenetics

Neurogenetics

Introduction

Individual genetic disorders are rare but there are many of them so that together their cumulative morbidity is significant. Some are particularly important as they are treatable. In recent years, new insights have been made into these diseases and this field is changing rapidly. This section will describe some aspects of clinical neurogenetics, and discuss the principal patterns of inheritance and some of the clinical problems posed by the more common neurological conditions.

Molecular genetic techniques have enabled identification of genes for inherited conditions, which allows:

identification of gene products, enhancing understanding of pathophysiology and potentially allowing the development of treatments

increased understanding of the relationships between phenotype and genotype

improved diagnosis for the affected patient and for patients at risk. This has improved both preconceptual and antenatal advice.

In this section we will explore the clinical approach to patients with genetic or suspected genetic disease and consider the ways in which the newer genetic tests are used.

Clues to diagnosis

Family history of neurological disease

The pedigree helps to define the pattern of inheritance. However, in some situations a positive family history may be lacking (e.g. autosomal recessive and X-linked recessive illnesses, and dominant illnesses with partial penetrance).

Parental consanguinity (marriage between relatives)

This makes autosomal recessive disorders more likely. Certain small racial groups have particularly high rates of autosomal recessive disease, for example Tay–Sachs disease in Askenazi Jews.

Mildly affected relatives

Dominant illnesses may have variable penetrance (variable disease expression) such that some affected members never come to medical attention, for example tuberous sclerosis. They may have to be seen to establish whether they are affected.

Evidence of longstanding disease

Inherited neurological illnesses usually cause a slowly progressive neurological deficit, with a variable age of onset. There may be a history of delayed developmental milestones, even if the patient only comes to medical attention in adult life.

Multiple system involvement

Dominantly inherited conditions especially tend to affect several systems, for example myotonic dystrophy or tuberous sclerosis.

Patient with unusual appearance

Unusual facial appearance is a common indicator of genetic abnormality, for example Down’s syndrome. An excessively large or small head points to abnormal CNS development and other skeletal abnormalities may suggest failure of neural guidance of development, for example small stature or pes cavus. These could also represent congenital disease or sometimes an insult in early postnatal life. Retinitis pigmentosa is virtually always due to inherited disease and some conditions are associated with typical skin lesions such as tuberous sclerosis and neurofibromatosis.

Disease definition and genetic testing

The clinical definition of inherited diseases is crucial in the identification of their underlying defects. However, as genes underlying diseases are being identified, it is becoming apparent that the link between phenotype and genotype is less clear cut than had been anticipated. The phenotype of the same gene defect may be very different in different individuals, presumably because of other constitutional and environmental factors. This means that although a diagnosis can be made, it is sometimes difficult to give a prognosis, making it difficult to give clear advice. Equally the same clinical syndrome may be due to several gene defects, some unidentified, and a genetic diagnosis can only be made in a proportion of similarly affected individuals. For example, in Charcot–Marie–Tooth (hereditary sensory and motor neuropathy) type I disease, only 80% of patients have identified mutations. Thus a normal genetic test does not exclude the diagnosis. In any one family, however, the genetic defect should be in the same locus in all affected individuals.

Tags: Neurology An Illustrated Colour Text

Jun 10, 2016 | Posted by admin in NEUROLOGY | Comments Off

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