Epilepsy & Encephalopathies — Genetic Workup

Genetic testing is now standard in unexplained early-onset epilepsy and developmental and epileptic encephalopathies (DEEs). The NSGC evidence-based practice guideline for the unexplained epilepsies — endorsed by the American Epilepsy Society — supports early use of exome / genome sequencing or an appropriately broad multi-gene panel, with explicit treatment relevance for Dravet (avoid sodium-channel blockers), GLUT1 deficiency (ketogenic diet), tuberous sclerosis (mTOR inhibitors), pyridoxine-dependent epilepsy (pyridoxine + lysine restriction), and others.

When to Order Genetic Testing for Epilepsy

• Early-onset epilepsy (<2 years) without clear acquired cause.
• Developmental and epileptic encephalopathy (DEE).
• Refractory epilepsy failing >2 appropriate ASMs.
• Epilepsy + developmental delay / intellectual disability / autism.
• Epilepsy + dysmorphic features / multiorgan involvement.
• Family history of unexplained epilepsy.
• Specific syndrome suspicion (Dravet, Lennox-Gastaut, infantile spasms with abnormal MRI, progressive myoclonic epilepsy).

Test Choice: Panel vs. WES

• Epilepsy NGS panel (~150–500 genes): faster turnaround, cheaper, simpler counseling. Good first-line in classical syndromes.
• Trio WES: higher yield in non-specific or atypical phenotypes; better for novel gene discovery; covers larger differential (metabolic, neuromuscular).
• Increasing trend: trio WES as first-line in DEE; panels still used when budget / turnaround / counseling constraints dominate.
• Reflex strategy: panel negative → trio WES; WES negative → trio WGS / mitochondrial / chromosomal microarray.
• Don’t forget chromosomal microarray (CMA): catches CNVs (15q11–13 dup, 16p13 del/dup) missed by panel/WES.

Dravet Syndrome (SCN1A)

• First-line test: SCN1A sequencing + deletion/duplication analysis (MLPA).
• Yield: ~80% have SCN1A mutations (~75% point mutations, ~5% deletions).
• Other causes: PCDH19 (girls), GABRA1, STXBP1, SCN1B, SCN2A.
• Clinical clues: prolonged febrile + afebrile hemiclonic seizures starting in infancy; later myoclonic, atypical absence, atonic seizures; intellectual disability; gait ataxia.
• Treatment relevance — CRITICAL:
  • AVOID sodium-channel blockers: carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, lamotrigine — paradoxically worsen seizures in Dravet (Na-channel loss-of-function pathology).
  • First-line: valproate, clobazam.
  • Add-on: stiripentol (Diacomit), cannabidiol (Epidiolex), fenfluramine (Fintepla).
  • Avoid hyperthermia: aggressive fever management.

GLUT1 Deficiency (SLC2A1)

• First-line test (functional): lumbar puncture → CSF glucose, with simultaneous serum glucose.
  • Low CSF glucose (<40 mg/dL).
  • CSF/serum glucose ratio <0.45 (most specific).
  • Normal CSF cell count + protein (no infection).
  • Low CSF lactate (helps distinguish from mitochondrial).
• Confirmation: SLC2A1 sequencing.
• Clinical clues: infantile-onset seizures unresponsive to ASMs, paroxysmal exercise-induced dyskinesia (PED), intellectual disability, microcephaly, ataxia.
• Treatment — TREATABLE: ketogenic diet provides ketone bodies as alternative brain fuel; dramatic response.

Tuberous Sclerosis Complex (TSC)

• First-line test: TSC1 + TSC2 sequencing + deletion/duplication analysis.
• Yield: ~85% (TSC2 ~70% of mutations, TSC1 ~30%; deletions in ~5%).
• Mosaic mutations: ~10% — deep sequencing required to detect low-level mosaicism; if blood negative + clinical TSC, test affected tissue (e.g., resected cortex).
• Clinical diagnosis: still possible by major/minor clinical criteria (cortical tubers, subependymal nodules, SEGA, facial angiofibroma, ungual fibroma, ash leaf spots, etc.).
• Treatment:
  • Vigabatrin: first-line for infantile spasms in TSC.
  • mTOR inhibitors (everolimus): SEGA, refractory seizures, renal angiomyolipomas.
  • Epilepsy surgery for tuber-driven focal epilepsy.

Pyridoxine-Dependent Epilepsy

• First-line test (biochemical): urine α-aminoadipic semialdehyde (α-AASA) elevated; plasma pipecolic acid elevated.
• Confirmation: ALDH7A1 sequencing.
• Therapeutic trial: IV pyridoxine (100 mg) at the bedside for refractory neonatal seizures — dramatic response within minutes is diagnostic.
• Other vitamin-responsive epilepsies:
  • Pyridoxal phosphate-dependent epilepsy (PNPO): give pyridoxal-5-phosphate (PLP).
  • Folinic-acid-responsive seizures: same as ALDH7A1; respond to folinic acid.
  • Biotinidase deficiency (BTD): biotin replacement.
  • Cerebral folate deficiency (FOLR1): folinic acid.
• Treatment: lifelong pyridoxine + lysine-restricted diet improves neurodevelopmental outcome.

Progressive Myoclonic Epilepsies (PME)

• First-line test: PME NGS panel covering all major PME genes.
• Major PMEs:
  • Unverricht-Lundborg (EPM1): CSTB dodecamer repeat expansion — requires repeat-primed PCR (NGS misses!). Commonest PME in adolescents.
  • Lafora disease (EPM2): EPM2A or NHLRC1 sequencing. Rapidly progressive; childhood onset; PAS-positive Lafora bodies on skin biopsy.
  • MERRF: m.8344A>G — see Mitochondrial page.
  • Sialidosis (type I cherry-red spot myoclonus): NEU1.
  • Action myoclonus-renal failure (EPM4): SCARB2.
  • Neuronal ceroid lipofuscinoses (NCL): see below.
  • DRPLA: ATN1 CAG repeat expansion (see Movement page).
  • GOSR2, KCNC1, ASAH1, others.

Neuronal Ceroid Lipofuscinoses (NCL / Batten Disease)

• First-line test: NCL NGS panel covering CLN1–CLN14 (PPT1, TPP1, CLN3, CLN5, CLN6, CLN8, MFSD8, CTSD, CLN10, others).
• Targeted approach: TPP1 enzyme activity (CLN2) + PPT1 enzyme (CLN1) — quick functional screening.
• Clinical clues: progressive cognitive regression + vision loss + epilepsy + myoclonus. Age of onset narrows differential:
  • Infantile (CLN1).
  • Late-infantile (CLN2).
  • Juvenile (CLN3).
  • Adult (CLN4).
• Treatment — CLN2 is TREATABLE: cerliponase alfa (Brineura) intracerebroventricular enzyme replacement slows progression.

Other Important Epilepsy Genes

• Neonatal/infantile epileptic encephalopathies (early-onset DEE):
  • KCNQ2: benign familial neonatal seizures OR severe EE. Sodium-channel blockers (carbamazepine, oxcarbazepine) can help.
  • SCN2A: gain-of-function → respond to sodium-channel blockers; loss-of-function → avoid.
  • SCN8A: high-dose sodium-channel blockers.
  • STXBP1: West syndrome variant.
  • CDKL5: female-predominant EE.
  • KCNT1: malignant migrating partial seizures of infancy → quinidine trial in some cases.
  • GRIN1, GRIN2A, GRIN2B: NMDA receptor disorders → memantine in some cases.
  • CDH2, PIGA, UBA5, others.
• Rett syndrome: MECP2 sequencing (girls); CDKL5 (early-onset variant); FOXG1 (congenital variant). Trofinetide (Daybue) now FDA-approved for Rett.
• Angelman syndrome: methylation analysis of 15q11–13 (commonest cause: maternal deletion); UBE3A sequencing if methylation negative.
• Familial focal epilepsies:
  • Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE): CHRNA4, CHRNB2, CHRNA2, KCNT1.
  • ADTLE: LGI1, RELN.
  • Familial focal epilepsy with variable foci: DEPDC5, NPRL2, NPRL3.
• Genetic epilepsy with febrile seizures plus (GEFS+): SCN1A, SCN1B, GABRG2.
• Genetic generalized epilepsy (idiopathic GGE — JME, CAE, JAE, GTCS-alone): largely polygenic; GABRA1, GABRG2, CACNA1H, EFHC1 in rare familial forms. Routine single-gene testing usually low yield.

Disease → Test Quick Reference Table

Pitfalls and Pearls

• Lamotrigine in Dravet is a classic error — exacerbates seizures. Always test SCN1A before starting Na-channel blockers in early-onset epilepsy + febrile seizures.
• CSF glucose ratio <0.45 is the diagnostic biomarker for GLUT1 deficiency — order LP early in unexplained refractory infantile seizures or PED.
• TSC mosaicism (~10%) requires deep sequencing; if blood negative + clinical TSC, test affected tissue.
• PME panel must include repeat-primed PCR for CSTB: standard NGS misses the dodecamer repeat in Unverricht-Lundborg.
• NCL (CLN2) is treatable — TPP1 enzyme screening is cheap and fast.
• Trio WES is increasingly first-line over panels for DEE — higher diagnostic yield (30–50% vs 15–25%) and broader differential.
• Chromosomal microarray (CMA) catches CNVs that WES/panels miss; consider in parallel for DEE + dysmorphism / multisystem involvement.
• Mitochondrial epilepsy (POLG, MELAS) shouldn’t be missed — see Mitochondrial page. AVOID valproate in POLG.
• Insurance coverage for epilepsy panel and WES improving but still variable; sponsored programs (e.g., Behind the Seizure) cover many genes free.
• Result delivery: pediatric epilepsy genetic results often arrive via genetic counselor; arrange follow-up to interpret VUS / counsel family.

References

1. Smith L, Malinowski J, Ceulemans S, et al. Genetic testing and counseling for the unexplained epilepsies: an evidence-based practice guideline of the National Society of Genetic Counselors (endorsed by the American Epilepsy Society). J Genet Couns. 2023.
2. Krey I, Platzer K, Esterhuizen A, et al. Current practice in diagnostic genetic testing of the epilepsies. Epileptic Disord. 2022;24(5):765-786.
3. Wirrell EC, Hood V, Knupp KG, et al. International consensus on diagnosis and management of Dravet syndrome. Epilepsia. 2022;63(7):1761-1777.
4. Klepper J, Akman C, Armeno M, et al. Glut1 deficiency syndrome (Glut1DS): state of the art in 2020 and recommendations of the international Glut1DS study group. Epilepsia Open. 2020;5(3):354-365.
5. Northrup H, Aronow ME, Bebin EM, et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr Neurol. 2021;123:50-66.
6. Stockler S, Plecko B, Gospe SM Jr, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics. Mol Genet Metab. 2011;104(1-2):48-60.
7. Schulz A, Ajayi T, Specchio N, et al. Study of intraventricular cerliponase alfa for CLN2 disease. N Engl J Med. 2018;378(20):1898-1907.
8. Symonds JD, Zuberi SM, Stewart K, et al. Incidence and phenotypes of childhood-onset genetic epilepsies. Brain. 2019;142(8):2303-2318.