Genetic epilepsy testing can impact clinical care and practice
by providing diagnostic certainty and suggesting an approach to medical
management, said Annapurna Poduri, MD, MPH, in a lecture at the 69th Annual
Meeting of the American Epilepsy Society.
With a precise genetic diagnosis, neurologists might be able
to give more information about a patient’s prognosis. In addition, a genetic
diagnosis can end a patient’s “diagnostic odyssey,” which can entail the burden
of blood tests, lumbar punctures, and repeated imaging, said Dr. Poduri, Associate
Professor of Neurology at Harvard Medical School in Boston.
“There are a small but growing number of genes associated
with specific treatment recommendations,” she said. “We might be able to move
toward precision medicine in epilepsy.”
Epilepsy genetics is “not a new topic, but it’s one where we
have a lot of new evidence.” Twin studies and family studies helped establish
the role of genetics in epilepsy, and in the 1990s, researchers identified
several genes associated with epilepsy, including SCN1A, SCN1B, CHRNA4, and
GABRB2.
When the human genome was sequenced, large association
studies were not initially revealing about new causes of epilepsy. New sequencing
technologies and the ability to assess copy number variation, however, have led
to further advances. “In 2010, there were three papers showing us the role of
copy number variation in epilepsy that had previously not had an identified
etiology,” Dr. Poduri said. Researchers found that as many as 3% of cases of genetic
generalized epilepsy, formerly called idiopathic generalized epilepsy, might
have deletions in the regions 15q11.2, 15q13.3, or 16p13.11. “You might say …
that’s not a lot of our cases in epilepsy. But in fact, there hadn’t been this
sort of robust evidence for the role of copy number variation in genetic
generalized epilepsy and some of the focal epilepsies until this point,” said
Dr. Poduri. “These were seminal discoveries that paved the way for further
testing.”
The Epi4K Consortium and Epilepsy Phenome/Genome Project,
which involved 26 institutions, undertook one effort that identified additional
epilepsy-related mutations and genes. The project initially looked at
individuals with infantile spasms and Lennox-Gastaut syndrome. Sequencing the
exomes of 264 patients and their parents “allowed us to enlist the power of
having a relatively large group of these otherwise rare disorders,” said Dr.
Poduri. Among the known epilepsy genes identified by the study was SCN1A. “If
we hadn’t already known … that SCN1A is an important gene for epilepsy, this is
the sort of study that could tell us.” The study broadened the phenotype
associated with mutations in STXBP1, which previously had been associated with
Ohtahara syndrome. The investigators also identified a new epilepsy gene: DNM1.
This gene did not achieve genome-wide significance in the initial study, but
when researchers added about a hundred trios from a European cohort,
EuroEPINOMICS, DNM1 rose to significance, said Dr. Poduri. “There were a total
of five cases across these 356 trios, and a robust analysis of all of these
data together through the Epi4K and EuroEPINOMICS Consortia was able to put
this gene robustly on the map.”…
Certain genes are associated with specific phenotypes. The
patients with de novo mutations in DNM1 had infantile spasms, and four of the
five patients developed Lennox-Gastaut syndrome. “All of them had severe to
profound intellectual disability and hypotonia,” said Dr. Poduri. “It gives you
some sense of [the] prognosis.” Likewise, if a patient had a mutation that
“uniformly was associated with a benign course, that might give us some
reassurance that it’s not a progressive disorder,” she said. Findings like this
might help to give physicians and patients’ families some diagnostic certainty.
Some genes suggest specific treatments to pursue or avoid. For example, in treating patients with Dravet syndrome and mutations in SCN1A, “we tend to avoid lamotrigine and phenytoin,” Dr. Poduri said. In general, neurologists avoid these sodium channel agents because they have seen patient worsening, although these recommendations are not universal, she said.
According to recent case reports, patients with SCN2A- and
SCN8A- associated encephalopathies have responded to high-dose phenytoin.
Mutations in SLC2A1 are associated with glucose transporter type 1 deficiency,
which can be treated with the ketogenic diet. Mutations in ALDH7A1 are
associated with pyridoxine deficiency, and mutations in PNPO are associated
with a pyridoxal-5-phosphate deficiency. Rectifying the deficiencies may affect
seizures in some cases, Dr. Poduri said. Pierson et al reported in 2014 the case of a child with a
GRIN2A mutation that changed leucine to methionine at amino acid position 812.
This change increased the potency of the NMDA agonists glutamate and glycine.
Investigators found that, with this mutation, memantine can block the excessive
gain of function response. With adjunctive memantine therapy, the child had a
dramatic reduction in seizures, although not a dramatic improvement in
development, Dr. Poduri said. The child had been receiving treatment with
lacosamide, rufinamide, and valproic acid. After starting memantine, lacosamide
and rufinamide were tapered off.
A precise genetic diagnosis also might influence the
decision between epilepsy surgery and medical treatment. For example, if a
patient with infantile spasms and a mutation in SCN1A has a focal lesion, a
neurologist may consider surgery, but some studies suggest that outcomes are
not always favorable for these patients, Dr. Poduri said.
http://www.neurologyreviews.com/specialty-focus/epilepsy/article/how-genetic-epilepsy-testing-can-impact-clinical-care-and-practice/bf84f802d0bcbfc3aff730b7caea8c36.html
No comments:
Post a Comment