An introduction to the genetics of epilepsy — from neonatal-onset epileptic encephalopathies and ion channelopathies to inborn errors of metabolism causing seizures, with a practical focus on genetic diagnosis and treatment implications.
Tags: Neurogenetics · Advanced
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
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
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
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
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
1. 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?
SCN2A genotype-phenotype correlations are strongly influenced by the functional consequence of the variant and the age of seizure onset. Early-onset seizures (<3 months) are predominantly associated with gain-of-function (GoF) SCN2A variants that increase neuronal sodium current, and these respond well to sodium channel blockers. In contrast, later-onset SCN2A epilepsy (>3 months) is more often associated with loss-of-function variants, where sodium channel blockers are contraindicated as they may worsen seizures. While in vitro electrophysiology provides definitive functional characterization, age of onset is a reliable clinical proxy for guiding initial treatment decisions in SCN2A epilepsy.
2. 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?
KCNQ2 encodes the Kv7.2 voltage-gated potassium channel subunit. Loss-of-function (LoF) variants in KCNQ2 cause neonatal epileptic encephalopathy — reduced M-current (Kv7.2/Kv7.3) diminishes the normal brake on neuronal excitability, leading to seizures. Critically, sodium channel blockers (carbamazepine, oxcarbazepine, phenytoin) are highly effective in KCNQ2 LoF encephalopathy and should be prioritized. This is a clear example of precision/genotype-guided therapy in genetic epilepsy.
3. 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?
SCN1A encodes the Nav1.1 sodium channel subunit, preferentially expressed in GABAergic interneurons. Haploinsufficiency (loss of function) reduces inhibitory interneuron firing, causing the net hyperexcitability of Dravet syndrome. Sodium channel blockers (oxcarbazepine, lamotrigine, carbamazepine, phenytoin) further reduce Nav1.1 activity and are contraindicated — they can precipitate status epilepticus in Dravet syndrome. Oxcarbazepine and lamotrigine are particularly important to avoid as they are commonly prescribed AEDs that may be tried before a genetic diagnosis is established. Valproate, clobazam, stiripentol, and levetiracetam are preferred agents.
4. 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?
A CSF/serum glucose ratio <0.4 (normal ≥0.6) in the absence of CNS infection indicates hypoglycorrhachia due to impaired glucose transport across the blood-brain barrier — the hallmark of GLUT1 deficiency syndrome (SLC2A1 haploinsufficiency). The brain is deprived of its primary fuel. The ketogenic diet provides ketone bodies as an alternative brain fuel and is highly effective. GLUT1 deficiency presents with infantile-onset epilepsy, developmental delay, acquired microcephaly, and paroxysmal movement disorder.
5. 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:
Elevated urine AASA is the diagnostic biomarker for pyridoxine-dependent epilepsy caused by ALDH7A1 (antiquitin) deficiency. AASA accumulation leads to inactivation of pyridoxal-5-phosphate (the active form of vitamin B6), causing cerebral PLP deficiency and seizures. Treatment is lifelong pyridoxine supplementation. PNPO deficiency causes a similar phenotype but requires pyridoxal-5-phosphate (not pyridoxine), and AASA is not elevated in PNPO deficiency.
6. A 6-month-old infant presents with epileptic spasms and hypsarrhythmia on EEG. Brain MRI shows multiple cortical tubers and subependymal nodules. The treating neurologist chooses vigabatrin over ACTH for initial treatment. What is the rationale for this choice?
Vigabatrin is the first-line treatment specifically for TSC-associated infantile spasms, with ~90–95% spasm cessation rates — far superior to ACTH in this etiology. Vigabatrin irreversibly inhibits GABA transaminase, increasing brain GABA levels. It does not directly target the mTOR pathway (everolimus does). For non-TSC infantile spasms, ACTH or prednisolone is typically first-line. This is a prime example of precision medicine: the diagnosis of TSC directly changes the treatment algorithm.