Conference Coverage

Research Illuminates Genetic Forms of Epilepsy



WASHINGTON, DC—Familial genetic studies suggest that GLUT1 deficiency may be more common among patients with epilepsy than previously understood, according to Ingrid Scheffer, MBBS, PhD, Professor of Pediatric Neurology at the University of Melbourne and Florey Institute of Neuroscience and Mental Health in Melbourne, Australia. Study of gene mutations in families is also helping identify mechanisms for other forms of epilepsy.

Ingrid Scheffer, MBBS, PhD

At the 67th Annual Meeting of the American Academy of Neurology, Dr. Scheffer shared research that helps shed new light on what she referred to as “the complex puzzle of epilepsy.” Epilepsies generally have been regarded as a group of disorders of unknown etiology, she continued, that entail either generalized seizures, which involve bilateral corticothalamic circuitry, or focal seizures, which begin in one region of the brain and spread to other regions.

“Historically, generalized seizures have been thought of as genetic, and the focal seizures as acquired, and we tend to think of them being associated with structural lesions, such as hippocampal sclerosis,” Dr. Scheffer explained.

GLUT1 Deficiency
First described by Darryl De Vivo, MD, in 1991 as a metabolic encephalopathy resulting from abnormal glucose transport across the blood–brain barrier, the epileptology of GLUT1 deficiency had not been well characterized. GLUT1 encephalopathy involves progressive intellectual disability, movement disorder, and microcephaly.

GLUT1 deficiency is treatable, however, with the ketogenic diet. The hallmark of GLUT1 deficiency is hypoglychorhacchia with a low fasting plasma glucose (ie, < 2.2 mmol/L) and a low CSF:plasma glucose ratio (ie, < 0.45). The milder forms of GLUT1 deficiency may include epilepsy syndromes that respond to the ketogenic diet.

GLUT1 deficiency in epilepsy may not be as rare as originally presumed. Dr. Scheffer and Italian collaborators examined adults and children with epilepsy with myoclonic–atonic seizures and found that 5% had GLUT1 deficiency. GLUT1 deficiency is found in a significant proportion of patients presenting with early-onset absence epilepsy. Children with early-onset absence epilepsy have normal intellect or mild intellectual disability and may later develop other seizure types. “In two studies, we showed that 10% of children with this disorder may have GLUT1 deficiency, their mutations may be de novo or inherited, and family studies show a pattern of predominantly generalized and some focal epilepsies,” said Dr. Scheffer.

DEPDC5 Mutation
Dr. Scheffer and her colleagues also have been investigating a mutation in DEP domain-containing protein 5 gene (DEPDC5), which encodes a repressor of the mTORC1 signaling pathway. Mutations in this gene appear to be a significant factor in familial focal epilepsy. Focal epilepsies account for 60% of all patients with epilepsy, and many patients do not have a structural cause identified. Yet most clinicians still do not believe that nonlesional focal epilepsies are likely to have a genetic basis. Eight families with the rare syndrome of familial focal epilepsy with variable foci have been reported in the literature, seven of which have been identified as having a DEPDC5 mutation with a relatively low penetrance of 66%. “This [finding] means that the families do not always have a clearly genetic flavor when you look at them,” said Dr. Scheffer.

In small families with two or more affected individuals, Dr. Scheffer’s group found that 10 out of 82 probands had DEPDC5 mutations, most of which were truncation mutations. Of 95 affected individuals with DEPDC5 mutations, 70% had frontal or temporal lobe epilepsy, 12% had exclusively nocturnal frontal lobe epilepsy, and a few individuals had posterior epilepsies.

“We’ve gone from a whole exome study in a single family to showing that DEPDC5 is the gene causing this disease—familial focal epilepsy with variable foci—but more importantly, to showing that it is relevant to 12% of small focal families,” Dr. Scheffer said.

Linda Peckel

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