Genetic Epilepsies
5 sections · 30 min
Overview of Genetic Epilepsy
Epilepsy affects approximately 1–2% of the population, and genetic factors are implicated in up to 70% of all epilepsy. The International League Against Epilepsy (ILAE) 2017 classification recognizes 'genetic' as one of the primary epilepsy etiologies — defined as epilepsy resulting directly from a known or presumed genetic cause. The genetic architecture ranges from rare, highly penetrant single-gene disorders (causing severe early-onset epileptic encephalopathies) to common polygenic forms of epilepsy influenced by many variants of small effect.
Key Points
- Genetic epilepsies are clinically classified by seizure type, age of onset, EEG pattern, and associated features (developmental delay, regression, focal neurological deficits)
- ~30% of pediatric-onset epilepsies have an identifiable genetic cause; yield increases to ~50–60% for epileptic encephalopathies (see the [[diagnostic-yields|Diagnostic Yields]] module for testing yields across neurogenetic conditions)
- De novo variants account for the majority of severe early-onset epileptic encephalopathies (Ohtahara, West, Dravet syndromes) — sporadic occurrence does not exclude genetic etiology
- Genetic diagnosis has direct treatment implications: SCN1A (avoid sodium channel blockers — especially oxcarbazepine and lamotrigine), KCNQ2 (sodium channel blockers beneficial), ALDH7A1 (pyridoxine), GLUT1 (ketogenic diet), SLC6A1 (avoid vigabatrin). See the [[pharmacogenetics|Pharmacogenetics]] module for more on drug-gene interactions in neurology
✦ Check Your Understanding
A 4-year-old boy with drug-resistant epilepsy undergoes trio exome sequencing. A de novo missense variant in SCN2A is identified and classified as pathogenic. His seizures began at 2 months of age. Based on the age of onset, what is the predicted functional consequence of the variant and the most appropriate pharmacological strategy?
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Neonatal and Infantile-Onset Epileptic Encephalopathies
The neonatal and early infantile period is associated with a distinct and often devastating set of epileptic encephalopathies. The genetic differential for neonatal seizures is broad and includes ion channelopathies, cortical malformation genes, inborn errors of metabolism, and imprinting disorders. Identifying the genetic cause is urgent because several conditions respond to specific treatments.
Key Points
- KCNQ2/KCNQ3: Most common cause of genetic neonatal seizures; KCNQ2 encephalopathy presents on day 1–3 with tonic seizures and burst-suppression EEG; responds to sodium channel blockers (carbamazepine, phenytoin); phenobarbital (a GABA-A receptor potentiator) is also used; self-limited familial neonatal epilepsy (milder phenotype) also caused by KCNQ2/3
- SCN2A: Highly variable — early-onset (<3 months) SCN2A gain-of-function variants cause epileptic encephalopathy (responds to Na-channel blockers); late-onset SCN2A loss-of-function variants cause epilepsy/autism that does NOT respond to Na-channel blockers (which should be avoided in LOF cases)
- KCNT1: Sodium-activated potassium channel; causes epilepsy of infancy with migrating focal seizures (EIMFS); also autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE); quinidine has been used off-label
- Cortical malformations: LIS1 (lissencephaly), DCX (double cortex in females, lissencephaly in males), ARX (X-linked, infantile spasms in males), tubulinopathies (TUBA1A, TUBB2B) — MRI essential for diagnosis
- Inborn errors of metabolism (IEM): Critical to identify — many are treatable; biotinidase deficiency (biotin), pyridoxine-dependent epilepsy (pyridoxine), GLUT1 deficiency (ketogenic diet), molybdenum cofactor deficiency
✦ Check Your Understanding
A 3-day-old term infant presents with tonic seizures, burst-suppression on EEG, and no family history. Metabolic workup is negative. Exome sequencing returns a de novo heterozygous loss-of-function variant in KCNQ2. What is the most appropriate initial anticonvulsant choice?
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Interpreting Genetic Results in Epilepsy
Genetic testing in epilepsy frequently yields variants of uncertain significance (VUS) and results that require careful clinical contextualization. The clinician must integrate variant classification, gene-phenotype fit, inheritance pattern, and functional data to determine whether a genetic finding explains the patient's epilepsy. Understanding common pitfalls prevents both under- and over-interpretation of genetic results.
Key Points
- Match gene to phenotype: A heterozygous SCN1A variant in a patient without Dravet syndrome features (febrile seizures ≥38°C, temperature sensitivity, onset 5–12 months) warrants caution before diagnosing Dravet
- Phase matters in recessive disease: Two heterozygous ALDH7A1 variants must be confirmed in trans (on different alleles) for autosomal recessive PDE — parental testing or long-read phasing is required
- VUS management: ACMG guidelines require that VUS not be used for clinical management decisions; plan reclassification review as new evidence accrues (ClinVar, GeneMatcher, publication)
- Treatment-agnostic genes: Not all genetic epilepsy diagnoses directly inform treatment — but even for 'non-actionable' diagnoses, genetic results guide prognosis, recurrence risk counseling, and avoidance of contraindicated medications
- Reanalysis of non-diagnostic exomes: ~10–15% of previously non-diagnostic exomes yield new diagnoses on reanalysis 1–3 years later as variant/gene knowledge advances — establish a reanalysis schedule
✦ Check Your Understanding
A genetic test returns a heterozygous SCN1A frameshift variant (PVS1 + PM2 + PP4 = Pathogenic) in a 7-month-old with febrile seizures. What medication class should be avoided?
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Inborn Errors of Metabolism Causing Epilepsy
Inborn errors of metabolism (IEM) represent a diverse group of genetic disorders caused by enzyme deficiencies in metabolic pathways. Individually rare, collectively they account for a significant fraction of neonatal and infantile epilepsy — and crucially, many are amenable to specific treatments. A systematic metabolic workup is mandatory for any infant with unexplained early-onset seizures.
Key Points
- Amino acid disorders: MSUD (maple syrup urine disease — elevated leucine; toxicity), glycine encephalopathy (nonketotic hyperglycinemia — elevated CSF/plasma glycine ratio; sodium benzoate), phenylketonuria (PKU — newborn screen detects; phenylalanine-restricted diet)
- Organic acidemias: Propionic acidemia, methylmalonic acidemia — elevated ammonia, metabolic acidosis, elevated organic acids on urine OA; dietary restriction + cofactor supplementation
- Pyridoxine- and pyridoxal-phosphate-responsive epilepsies: ALDH7A1 (pyridoxine-dependent epilepsy), PNPO (pyridoxal-5-phosphate oxidase deficiency — requires P5P not pyridoxine), PLPBP
- GLUT1 deficiency syndrome (SLC2A1): Impaired glucose transport across blood-brain barrier; fasting hypoglycorrhachia (CSF/serum glucose ratio <0.4); ketogenic diet is highly effective
- Sepiapterin reductase deficiency / other BH4 disorders: Irritability, dystonia, and epilepsy; low CSF neurotransmitter metabolites; treat with BH4 + L-DOPA
✦ Check Your Understanding
A toddler is found to have a CSF glucose of 28 mg/dL with a simultaneous serum glucose of 82 mg/dL (CSF/serum ratio 0.34). This pattern suggests which diagnosis and treatment?
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Pyridoxine-Dependent Epilepsy: A Model for Precision Treatment
Pyridoxine-dependent epilepsy (PDE-ALDH7A1) is an autosomal recessive disorder caused by biallelic variants in ALDH7A1, encoding antiquitin — an enzyme in the cerebral lysine degradation pathway. Antiquitin deficiency causes accumulation of alpha-aminoadipic semialdehyde (AASA) and its cyclic form piperideine-6-carboxylate (P6C), which inactivates pyridoxal-5-phosphate (PLP) by forming a Knoevenagel condensation product. The resulting cerebral PLP deficiency causes seizures.
Key Points
- Biochemical diagnosis: Elevated AASA in urine, plasma, and CSF — this biomarker remains elevated even when the patient is already on pyridoxine therapy, making it the preferred diagnostic marker
- Clinical presentation: Early neonatal onset (hours to days of life) with prolonged, refractory focal seizures, often with abnormal fetal movements; characteristic multifocal EEG; may respond incompletely to AEDs before pyridoxine
- Treatment: Lifelong pyridoxine supplementation (15–30 mg/kg/day, max 500 mg/day); doses may be doubled during febrile illness
- Triple therapy for improved neurodevelopmental outcomes: Pyridoxine + lysine-restricted diet + arginine supplementation — reduces AASA accumulation and has improved cognitive outcomes in published case series
- Neurodevelopmental prognosis: Intellectual disability in ~75% of patients even with pyridoxine treatment; early diagnosis and triple therapy improve but do not normalize outcomes — emphasizing the value of newborn screening
✦ Check Your Understanding
An infant with unexplained refractory neonatal seizures is found to have elevated urine alpha-aminoadipic semialdehyde (AASA). The most likely diagnosis and initial treatment are:
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