A 18-month-old boy presents with recurrent seizures characterized by generalized 2.5–4 Hz spike-wave discharges on EEG, as shown by the pattern marked **A** in the diagram. The seizures are notably worse before meals and improve dramatically after feeding. CSF glucose is found to be 35 mg/dL with a CSF:serum glucose ratio of 0.38, while serum glucose is normal at 95 mg/dL. CSF lactate is normal. Which of the following is the most likely diagnosis?

Question

Accepted Answer

C. GLUT1 deficiency syndrome (De Vivo disease) due to SLC2A1 mutation. ## Why GLUT1 deficiency syndrome (De Vivo disease) is right

The clinical presentation—infantile-onset seizures with the characteristic EEG pattern marked **A** (2.5–4 Hz generalized spike-wave discharges), worsening before meals and improving after feeding—combined with the diagnostic hallmark of **hypoglycorrhachia** (CSF glucose <60 mg/dL, CSF:serum ratio <0.45) with **normal serum glucose** and **normal CSF lactate**, is pathognomonic for GLUT1 deficiency syndrome. This autosomal dominant disorder results from heterozygous loss-of-function mutations in *SLC2A1*, encoding the GLUT1 glucose transporter at the blood–brain barrier. The impaired glucose delivery to the brain creates a cerebral energy crisis manifesting as drug-resistant epilepsy, developmental delay, and movement disorders. The distinctive improvement in seizures and EEG abnormalities in the fed state (postprandial) and with ketosis is a key diagnostic clue exploited clinically (De Vivo DC et al., NEJM 1991; Klepper J et al., Epilepsia Open 2020).

## Why each distractor is wrong

- **Mitochondrial cytopathy**: While mitochondrial disorders also present with seizures and developmental delay, they typically show **elevated CSF lactate** (reflecting impaired oxidative metabolism), not normal lactate. The normal CSF lactate here argues strongly against mitochondrial disease and supports GLUT1-DS.
- **Glycogen storage disease type I**: GSD-I causes fasting hypoglycemia with elevated serum glucose during feeding, but does not produce hypoglycorrhachia or the characteristic EEG pattern marked **A**. CSF glucose would remain normal because the blood–brain barrier transporter is intact.
- **Absence epilepsy with secondary hypoglycorrhachia**: Absence epilepsy is a primary generalized epilepsy that does not cause hypoglycorrhachia. Hypoglycorrhachia is a pathological finding indicating impaired glucose transport into the CNS, not a secondary consequence of seizures. The normal serum glucose excludes systemic hypoglycemia.

**High-Yield:** GLUT1-DS = hypoglycorrhachia (CSF <60, ratio <0.45) + normal serum glucose + normal CSF lactate + seizures worse before meals, better after feeding or on ketogenic diet.

[cite: De Vivo DC et al., NEJM 1991; Klepper J et al., Epilepsia Open 2020]

Answer

A. Glycogen storage disease type I with hepatic glucose output failure

Answer

B. Absence epilepsy with secondary hypoglycorrhachia from prolonged fasting

Answer

D. Mitochondrial cytopathy with impaired oxidative metabolism

Explanation

Why GLUT1 deficiency syndrome (De Vivo disease) is right

Why each distractor is wrong

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