Spotlight on epilepsy

epilepsy

 

Epilepsy is a neurological disorder in which abnormal brain activity results in seizures. Signs and symptoms of seizures are not always easily recognizable, particularly in young children. They can include:

  • Uncontrolled twitching of arms and legs
  • Periods of staring into space, loss of attention or lack of response
  • Periods of momentary confusion
  • Loss of consciousness or awareness
  • Sudden feelings of fear or anxiety
  • Complaints of unusual sensations (sights, sounds, tastes, smells, feelings)

Seizures can be induced by many factors, but some forms of epilepsy are genetic in origin. Even in these cases, obtaining a molecular diagnosis can be difficult due to oftentimes complex patterns of inheritance. The first challenge is that many seizure disorders look clinically very similar. Plus seizures can be a major clinical presentation in other rare genetic disorders. So it can be difficult to distinguish between different epilepsy syndromes and seizures as a symptom of another disorder based on clinical presentation alone. The second challenge is that epilepsy syndromes and other disorders that present with seizures can be inherited through autosomal dominant, autosomal recessive, X-linked and mitochondrial mechanisms with many different genes affected.

The following table provides examples of epilepsy syndromes and rare genetic disorders where seizures are a major clinical presentation:

Type of disorder Disorder Inheritance Gene(s) affected Mutation type(s)
Epilepsy syndrome Generalized epilepsy with febrile seizures plus (GEFS+) Autosomal dominant SCN1A Small nucleotide change
Epilepsy syndrome Dravet syndrome Autosomal dominant SCN1A Small nucleotide change, del/dup, chromosomal rearrangement
Epilepsy syndrome Myoclonus epilepsy and ragged red fibers (MERRF) Mitochondrial MT-TK Mitochondrial small nucleotide change
Other disorder manifesting as epilepsy Fragile X syndrome X-linked FMR1 CGG repeat expansion
Other disorder manifesting as epilepsy Rett syndrome X-linked MECP2 Small nucleotide change, del/dup, chromosomal rearrangement
Metabolic disorder causing seizures Phenylketonuria (PKU) Autosomal recessive PAH Small nucleotide change, del/dup
Metabolic disorder causing seizures Galactosemia Autosomal recessive GALT Small nucleotide change, del/dup
Type of disorder Disorder Inheritance Gene(s) affected Mutation type(s)
Epilepsy syndrome Generalized epilepsy with febrile seizures plus (GEFS+) Autosomal dominant SCN1A Small nucleotide change
Epilepsy syndrome Dravet syndrome Autosomal dominant SCN1A Small nucleotide change, del/dup, chromosomal rearrangement
Epilepsy syndrome Myoclonus epilepsy and ragged red fibers (MERRF) Mitochondrial MT-TK Mitochondrial small nucleotide change
Other disorder manifesting as epilepsy Fragile X syndrome X-linked FMR1 CGG repeat expansion
Other disorder manifesting as epilepsy Rett syndrome X-linked MECP2 Small nucleotide change, del/dup, chromosomal rearrangement
Metabolic disorder causing seizures Phenylketonuria (PKU) Autosomal recessive PAH Small nucleotide change, del/dup
Metabolic disorder causing seizures Galactosemia Autosomal recessive GALT Small nucleotide change, del/dup

Specific gene testing for these and other disorders is available, but broader genetic testing can be helpful in distinguishing between different epilepsy syndromes and other disorders that present with seizures. Using a test such as Genomic Unity™ which sequences the whole genome and identifies small sequence changes, structural variants (including del/dups), mitochondrial variants and short tandem repeat expansions in a single assay can avoid the need for iterative rounds of targeted gene panel testing.

While cures do not exist for most epilepsy disorders, medication can oftentimes help reduce the seizures. Depending on the individual disorder and the area of the brain that the seizures are emanating from, surgery may be an option when medication alone is not sufficient to adequately control the seizures. Alternative therapies include vagus nerve stimulation, deep brain stimulation and following a ketogenic diet.

 

References

1. Epilepsy Foundation
2. NIH Genetics Home Reference
3. HGMD Professional, version 2018.3, Qiagen

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