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SCN1A Testing: A Companion Diagnostic for the Treatment of Dravet Syndrome

A Health Care Professional and Mother’s Perspective

Michelle Welborn, PharmD

My visit to Athena Diagnostics in May of 2009 was surreal. After all, this was the company that genetically confirmed that my daughter Lilly has Dravet Syndrome.

As Founder and President of the Intractable Childhood Epilepsy (Ion Channel Epilepsy) Alliance or ICE*, I met with Athena Diagnostics to discuss ways we could improve the world’s understanding and importance of genetic testing and early diagnosis of the disease that had altered my family’s life.

Lilly suffered her first seizure at 5 months old; the episode was a 20 minute, non-febrile, non-convulsive status epilepticus. When I explained to the pediatrician on call about her staring and unresponsiveness lasting 20 minutes, he suggested that Lilly had experienced a “spell”. When I explained that the “spell” looked like a prolonged absence seizure, he assured me that a 5 month-old developing infant does not typically have absence seizures.

We counted each minute of seizure activity during status epilepticus, knowing that at some point Lilly was losing brain cells and was closer to intubation and sedation. By the time she was 11 months old, the severity and duration of her seizures led to the placement of a port-a-cath for the next time she required IV drugs to stop her seizures. This surgical intervention was a turning point for my husband and me as well as her medical team. The SCN1A test was ordered.

In January 2006, my husband Tim and I were called to our neurologist’s office at a major medical center in Northwestern NC to discuss Lilly’s SCN1A test results. While every neurologist that saw Lilly told us it was improbable that she had a catastrophic neuro-developmental disorder such as Dravet Syndrome, we desperately wanted an explanation of why our “normal” baby had suddenly developed intractable epilepsy.

While it is true we are still in the dark ages of fully understanding the relationship between genetic polymorphisms and disease, Dravet Syndrome is a condition in which there are more than 800 known disease-causing SCN1A mutations. The understanding of a genetic variant that contributes to more than 80% of Dravet Syndrome cases is a breakthrough in understanding epilepsy.

Sometimes, an SCN1A mutation will be detected and reported as a “Variant of Unknown Significance” (VUS) which means the mutation is not confirmed to be disease-causing based on review and comparison of reported variants. Furthermore, misinterpretation of the significance of a VUS has led to mismanagement of the syndrome, increased morbidity, and poor outcome.

In the following months, Lilly presented with a fairly textbook case of Dravet Syndrome with prolonged febrile and non-febrile alternating hemi-clonic seizures, heat sensitivity to modestly warm outdoor or bath temperature, atypical absence seizures, and GTC seizures, all of which were drug resistant. Her EEG was normal aside from episodes of febrile status epilepticus and cyclonic jerks, as was her MRI and other blood and spinal fluid tests that ruled out many progressive or catastrophic epilepsy syndromes.

I recently learned that Athena Diagnostics reclassified approximately 90 variants of unknown significance in 2010. Fifty three mutations were classified as benign, while 37 (41%) were classified as pathogenic with a definitive diagnosis through Athena’s Variant Investigation Process. As a parent advocate and health care professional, I am pleased to know that through this process, Athena’s geneticist team comprehensively reviews internal and external data for each VUS to provide clinicians with the most reliable genetic diagnostic guidance. One-on-one guidance by experienced geneticists and counselors is available to doctors to ensure they are confident in the test report and comfortable with how to relay the results to the patient or parent. Athena’s genetic counselors are also available for patient and parent consultations.

As a medical consultant, I know Athena is on the cutting edge of modern day medicine. Drug discovery and development over the next ten years will be based on “companion diagnostics” – the pharmaco-diagnostic tools such as genetic, proteomic or gene expression markers that predict whether a drug will work. Companion diagnostics defines personalized medicine. The SCN1A test holds a strong clinical case for the use of companion diagnostics as we know which drugs are likely to increase seizures in SCN1A positive patients and which drugs have proven effective.

And the good news for Lilly is that the understanding of the SCN1A haplo-insufficient mutation recently led to the development of a compound that may improve or cure Dravet Syndrome by increasing protein expression of the “good” copy of the SCN1A gene – personalized medicine here and now. The prognosis for Lilly is no longer grim as it was when we first heard her diagnosis five years ago. Her SCN1A companion diagnostic may very well lead to her cure.

*ICE Epilepsy Alliance advocates that an SCN1A test is warranted in an infant less than 12 months of age on a second prolonged (> 5 minute) febrile seizure or after the first prolonged seizure if myoclonic jerks or unprovoked seizures such as absence or atypical absence appear. Often, the first seizure is associated with 6 month vaccinations. Alternating hemi-clonic seizures are a very common seizure type in infancy, as are seizures that are provoked by warm bath water. Seizures are not always prolonged. Further, ICE Epilepsy Alliance advocates for SCN1A confirmation of patients of any age with an undiagnosed seizure disorder or diagnosis of Lennox-Gastaut Syndrome in which seizures began before age 12 months and past medical history reveals symptoms consistent to Dravet Syndrome. Pharmacologic management of seizures and quality of life of the patient can be improved with correct diagnosis of Dravet Syndrome at any age. Should a cure become available, genetic confirmation will be essential. For more information, please view our website at www.ICE-epilepsy.org

About the Author

Michelle Welborn, PharmD is the Founder and President of the Intractable Childhood Epilepsy (Ion Channel Epilepsy) Alliance or ICE, a 501(c)(3) organization dedicated to improving lives of children affected by drug resistant epilepsy through evidence-based information, advocacy for appropriate medical treatment including compassionate and Orphan drug products, promotion of drug development, development of patient registries, and funding of research that will lead to a cure for ion channel epilepsies beginning with Dravet syndrome. Michelle is also a regulatory consultant and owner of M. Welborn Group, a Limited Liability Corporation that provides consultant services to pharmaceutical companies internationally who are seeking Orphan Designation for products for rare diseases.

She is President and CEO of Bravo Pharma, a start up Biotech Company seeking to license products for rare diseases and epilepsy

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