Using Genomics in Clinical Practice in Neurology

VBCN - July 2014 Volume 1, No 2

Philadelphia, PA—Molecular subtyping and classification of patients for the selection of appropriate treatment and prognosis can now be used in routine clinical care in neurology, according to Teri Manolio, MD, PhD, Director, Division of Genomic Medicine, National Human Genome Research Institute, Rockville, MD, at the 2014 American Academy of Neurology meeting.

Dr Manolio described Charcot-Marie-Tooth (CMT) disease as a paradigm of molecular subtyping. Almost 80 genes have been identified that are associated with this genetically heterogeneous disease. “One of the neat things about CMT is, given that it’s genetically very heterogeneous, it also has a classification system that was first built on nongenetic things, and then the genetics was added on top,” she said.

For a genetically heterogeneous condition such as CMT disease, whole-exome sequencing can be performed for less than the cost of a multigene panel.

Genetic Elements in CMT Disease
A variety of forms of CMT disease are based on electrophysiology and genetic inheritance. For instance, CMT1 is characterized by abnormalities in myelin, whereas CMT2 is characterized by abnormalities in the axon. CMT4 is autosomal dominant and affects the axon or myelin, and CMTX is caused by mutations in a gene on the X chromosome. Within each type is a subtype distinguished by the specific genes that are altered, which may respond to different treatments.

Approximately 70% of the cases of CMT1 are caused by a duplication in the PMP22 gene in the 17p12 region. “There have been some investigations of silencers of those extra copies, such as ascorbic acid and progesterone antagonists, which haven’t worked well in humans, although they worked in animal models,” said Dr Manolio. Antisense nucleotides, which bind to the messenger RNA to keep it from being expressed, are also under investigation for this purpose.

Another potential strategy is to reduce the amount of neurotoxic aggregates in genes that contribute to CMT disease that cause protein misfolding; curcumin is currently under study. Histone deacetylase inhibitors that target the axonal transport defects in CMT disease are also under investigation.

Stevens-Johnson Syndrome
Genetics can also be used to identify patients who are at high risk for drug adverse effects, as is the case with Stevens-Johnson syndrome (SJS), a severe immune complex–mediated hypersensitivity reaction that causes epidermal blistering and sloughing that can occur in recipients of carbamazepine (Tegretol).

In 2004, the HLA-B*1502 allele was identified in 100% of 44 patients who developed SJS while receiving treatment with carbamazepine compared with 3% of those who were carbamazepine-tolerant and 8.6% of the general population. Other variants have been identified in association with carbamazepine-induced SJS, particularly in patients of European ancestry, said Dr Manolio. “HLA-A*3101 is associated not only with Stevens-Johnson syndrome but some of the milder forms of hypersensitivity,” she said. The presence of this variant increased the odds of having SJS by 26, and the odds of any hypersensitivity reaction by 9, in patients receiving carbamazepine.

More than 90% of patients who have hypersensitivity reactions to carbamazepine will do so within the first few months of treatment. Patients who have been taking carbamazepine for more than a few months are at low risk for carbamazepine-associated SJS.

A 2011 systematic review showed a pooled odds ratio for SJS of 113 for Asian patients with the HLA-B*1502 allele and of 9.5 for all ethnicities with the HLA-A*3101 allele.

The US Food and Drug Administration (FDA) recommends testing all patients of Asian descent for the HLA-B*1502 allele before prescribing carbamazepine. The FDA advises clinicians to determine if a patient has ancestry across broad areas of Asia before prescribing carbamazepine. This requires clinicians to know what Asian ancestry means, and for them to use a consistent, reliable method to figure out which patients have this ancestry.

Dr Manolio said, “We do have a consistent, reliable method to figure out who has this allele, and this is called sequencing for genotype.”

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