A 28-year-old man from Delhi presents with a 5-year history of brief, explosive nocturnal seizures characterized by bicycling movements, pelvic thrusting, and dystonic posturing lasting 20–40 seconds. Attacks cluster 3–4 times per night during sleep and are stereotyped (identical each time). His father and paternal grandfather had similar seizures. Interictal scalp EEG is normal. During video-EEG polysomnography, the pattern marked **A** in the diagram is captured during stage 2 NREM sleep. Which genetic abnormality is most likely responsible for this patient's condition?

Question

Accepted Answer

D. Mutation in CHRNA4 encoding the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor. ## Why CHRNA4 mutation is correct

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the prototype genetic focal epilepsy, first mapped to chromosome 20q13 by Scheffer and Berkovic. Mutations in CHRNA4 (encoding the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor) account for the majority of ADNFLE families. The receptor abnormality increases acetylcholine sensitivity in frontal cortex and thalamocortical circuits, producing the characteristic bifrontal rhythmic spike-wave discharge (marked **A**) during NREM sleep. The clinical phenotype—brief, stereotyped hypermotor seizures (bicycling, pelvic thrusting, dystonic posturing) clustering in stage 2 sleep, preserved awareness, positive family history with autosomal dominant inheritance, and normal interictal EEG in two-thirds of cases—is pathognomonic for ADNFLE caused by CHRNA4 mutations. The ictal EEG shows bifrontal rhythmic spike-wave or low-voltage fast activity, as depicted in the diagram.

## Why each distractor is wrong

- **PCDH19 mutation**: Causes EFMR (epilepsy and mental retardation restricted to females), an X-linked disorder with a unique inheritance pattern (heterozygous females affected, hemizygous males unaffected). Does not produce nocturnal frontal seizures or bifrontal spike-wave discharges.
- **SLC9A1 mutation**: Causes Angelman-like syndrome with developmental delay and seizures, not a nocturnal focal epilepsy. Not associated with ADNFLE or bifrontal EEG patterns.
- **GABRG2 mutation**: Causes generalized epilepsy and febrile seizures plus (GEFS+), typically with generalized tonic-clonic seizures and 3 Hz spike-wave discharges (marked **B** in the diagram), not focal frontal seizures or bifrontal rhythmic spikes during NREM sleep.

**High-Yield:** ADNFLE = CHRNA4 mutations → nicotinic acetylcholine receptor hyperexcitability → bifrontal spike-wave in NREM sleep → hypermotor seizures (bicycling/pelvic thrusting) → carbamazepine responsive (70% seizure control).

[cite: Harrison's 21e Ch 425; Adams & Victor 12e]

Answer

A. Mutation in GABRG2 encoding the gamma-2 subunit of the GABA-A receptor

Answer

B. Mutation in PCDH19 encoding a calcium-dependent cell adhesion molecule

Answer

C. Mutation in SLC9A1 encoding the Na+/H+ exchanger

Explanation

Why CHRNA4 mutation is correct

Why each distractor is wrong

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