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INTRODUCTION1

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What is the first step before ordering genetic testing?

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Before considering genetic testing, a thorough disease and family history should be taken. It is often recommended that genetic counseling is performed, since both clear results and ambiguous incidental findings have psychological and possibly social consequences for the patient and the family. Other methods of diagnosis are often exhausted first before expensive genetic testing is ordered.

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How is genetic testing used?

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Genetic testing is used in hereditary neurological diseases to help with diagnosis, prognosis, and treatment planning. There are three ways in which genetic testing is performed:

  • Testing for a candidate gene—This is when a clinical presentation approximates a known clinical syndrome that has a known genetic cause.

  • Testing panels of genes—This is an expensive diagnostic exercise where all genes related to a category of presentation, for example myotonia or parkinsonism, are tested.

  • Whole-exome sequencing—This allows the sequencing of all genes that may be individually interrogated using bioinformatics methods. It increases the risk of incidental and ambiguous findings. It is cheaper than panel testing, yet it is often difficult to convince the insurance companies to order this test.

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Where can one find more information on available testing and the laboratories that carry them out?

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http://www.ncbi.nlm.nih.gov/gtr/ is a great resource. It also has links to OMIM and gene reviews, which are references that explain the genetics as well as the clinical presentations of genetic disease.

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What are the modes of inheritance of neurological disease?

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  1. Mendelian modes of inheritance:

    1. Autosomal dominant (AD): The patient requires one copy of the gene to acquire the disease. It is often a gain of function change in the protein coded by the gene. For example, the aberrant protein may be toxic to nervous tissue. Each generation has 50% chance of inheriting the disease regardless of gender if one parent has the candidate gene (eg, GRN for frontotemporal dementia).

    2. Autosomal recessive (AR): The patient requires 2 copies of the gene to acquire the disease. It is often a loss of function of the protein coded by the gene. For example, the physiological activity of a particular enzyme may be reduced. Each generation has 25% chance of having 2 copies of the gene, if the parents are both carriers. Another 50% become carriers (eg, Friedreich ataxia).

    3. No male-to-male transmission, 100% male-to-female transmission, and 50% transmission from the affected mother. The more severe phenotypes are found in males.

    4. X-linked recessive: Sons of female carriers have 50% chance of inheriting the condition. In some cases, the female carriers may exhibit a milder form of the same condition (eg, Fragile-X syndrome).

  2. Non-Mendelian modes of inheritance:

    1. Imprinting: This is the phenomena when the same genetic defect has different phenotypes depending on from which parent the defect originates. The classic example is the fact that Prader–Willi (hypotonia, obesity, and hypogonadism—paternally ...

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