Neurogenetics and genetic and genomic testing

Jacinda B Sampson MD PhD (Dr. Sampson of Columbia University Medical Center is the principal investigator for clinical trials sponsored by GlaxoSmithKline, PTC, and Sarepta.)
Jill Goldman MS MPhil CGC (Jill Goldman of Columbia University Medical School has no relevant financial relationships to disclose.)
Sarah Teed (Sarah Teed of Columbia University Medical School has no relevant financial relationships to disclose.)
Salvatore DiMauro MD, editor. (Dr. DiMauro, Director Emeritus of H Houston Merritt Clinical Center for the Study of Muscular Dystrophy and Related Diseases at Columbia University, has no relevant financial relationships to disclose.)
Originally released September 27, 2013; last updated September 23, 2015; expires September 23, 2018

Overview

Neurogenetics encompasses heritable disorders in all the subspecialties of neurology and is an ever-growing field. New technologies such as next-generation sequencing (including whole exome or whole genome sequencing) are expanding testing options, discovering new mutations, and creating challenges in counseling, interpreting, and reporting results to the patient for the ordering neurologist. Yet, next-generation sequencing does not detect many neurogenetic disorders. The types of genetic tests currently available and resources for choosing appropriate and economical testing are discussed.

Key points

 

• Deciding on the genetic tests to order can be simplified by narrowing the differential diagnosis and defining the patient's phenotype.

 

• Next-generation sequencing of the whole exome is useful for testing for multiple candidate genes simultaneously or for discovering new, rare disorders.

 

• Whole exome sequencing is not suitable for detecting polynucleotide repeat disorders or large insertion/deletions.

 

• Genetic counseling, informed consent, and insurance preauthorization must be obtained before performing genetic testing.

Historical note and terminology

Genetic disorders affecting the nervous system typically present first to the general neurologist, and can present at any point in the lifespan. Neurogenetic disorders are a component of every neurologic subspecialty. The heritable nature of certain neurogenetic disorders was appreciated well before the discovery of DNA. Diagnosis by biochemical assays for metabolic and enzymatic defects, or histologic changes on muscle biopsy well preceded the description of DNA. Indeed, the precedent for treatment of neurogenetic disorders with metabolic defects began before clinical genetic tests became available.

Table 1. Timeline of Therapies of Neurogenetic Disorders

Year

Disease

Symptom

Intervention

1930a

Phenylketonuria

Cognitive decline

Dietary restriction, phenylalanine (Alonso-Fernandez and Colon 2009)

1965

Porphyria

Episodic neurologic symptoms-including seizure

Avoidance of precipitating medications (Granick 1966)

1972

Wilson disease

Neurodegeneration, liver failure

Chelation therapy (Walshe 1973)

1982

Metachromatic leukodystrophy

Cognitive decline, neuropathy

Bone marrow transplant (Bayever and Ladisch 1985)

1994

Duchenne muscular dystrophy

Delay, loss of ambulation

Corticosteroids (Karpati and Acsadi 1994)

1998

Fabry disease

Recurrent stroke

Enzyme replacement (Schiffmann et al 2001)

1999

Pompe disease

Respiratory failure from muscular dystrophy

Enzyme replacement (Amalfitano et al 2001)

2001

Friedreich ataxia

Cardiomyopathy

Idebenone (Hausse et al 2002)

2015

Nonsense-mediated Duchenne muscular dystrophy

Slow decline in walking speed

Ataluren (Bushby et al 2014; Haas et al 2015)

The content you are trying to view is available only to logged in, current MedLink Neurology subscribers.

If you are a subscriber, please log in.

If you are a former subscriber or have registered before, please log in first and then click select a Service Plan or contact Subscriber Services. Site license users, click the Site License Acces link on the Homepage at an authorized computer.

If you have never registered before, click Learn More about MedLink Neurology  or view available Service Plans.