Pyridoxine-dependent epilepsy

Pyridoxine-dependent epilepsy
Synonyms	Pyridoxine-dependent seizure (PDS), vitamin B6 responsive epilepsy
Pronounce	ˌpɪrɪˈdɒksin dɪˈpɛndənt ˈɛpɪlɛpsi
Field	Neurology, Clinical genetics, Pediatrics
Symptoms	Seizures, often neonatal onset; irritability, vomiting, developmental delay
Complications	Developmental delay, intellectual disability, neurocognitive impairment
Onset	Typically within hours to days after birth
Duration	Lifelong
Types	Classical (early onset), late-onset, atypical presentation
Causes	Autosomal recessive mutation in the ALDH7A1 gene
Risks	Family history, consanguinity
Diagnosis	Clinical response to pyridoxine, genetic testing (ALDH7A1), measurement of α-AASA in urine or plasma
Differential diagnosis	Neonatal epilepsy, hypoxic-ischemic encephalopathy, metabolic disorders, other vitamin-responsive epilepsies
Prevention	Genetic counseling for at-risk couples
Treatment	Lifelong supplementation with pyridoxine (vitamin B6)
Medication	Pyridoxine, sometimes adjunct antiseizure medications
Prognosis	Good seizure control with early treatment; neurodevelopmental outcome may vary
Frequency	Rare (1 in 100,000 to 1 in 700,000 live births)
Deaths	Rare with appropriate treatment

Pyridoxine-dependent epilepsy (PDE) is a rare genetic disorder characterized by intractable seizures occurring during the prenatal and neonatal periods. First described in 1954 by Hunt et al., the condition is responsive to treatment with pyridoxine (vitamin B6), but often presents challenges in neurodevelopmental outcomes despite seizure control.

Genetics

Pyridoxine-dependent epilepsy is inherited in an autosomal recessive manner. It is caused by mutations in the ALDH7A1 gene, which encodes the enzyme antiquitin, involved in the degradation pathway of lysine in the brain. The incidence of PDE is estimated to be between 1 in 400,000 to 1 in 700,000 live births. However, a study conducted in Germany reported a higher prevalence of approximately 1 in 20,000 births, suggesting the possibility of underdiagnosis in other populations.

Clinical Features

PDE typically manifests in utero or shortly after birth with refractory seizures that do not respond to standard antiepileptic drugs (AEDs). Other associated symptoms may include:

• Irritability
• Vomiting
• Developmental delay
• Abnormal electroencephalogram (EEG) patterns

Diagnosis

A clinical diagnosis is strongly suspected in neonates with seizure activity that does not respond to conventional AEDs but shows rapid cessation following the administration of intravenous vitamin B6. Diagnosis is confirmed through:

• Genetic testing for ALDH7A1 mutations
• Biochemical markers:
  • Elevated levels of α-aminoadipic semialdehyde (AASA) in plasma and urine
  • Elevated pipecolic acid levels in plasma or cerebrospinal fluid (a non-specific marker)

Treatment

The cornerstone of PDE treatment is lifelong supplementation with pyridoxine. Seizure control is typically achieved within minutes to hours after intravenous administration, and maintenance therapy involves daily oral pyridoxine.

Despite effective seizure control, many patients experience varying degrees of intellectual disability or neurodevelopmental delay. Therefore, early diagnosis and intervention are critical.

An additional treatment strategy involves dietary lysine restriction. Since the ALDH7A1 enzyme is involved in lysine degradation, reducing lysine intake has shown potential benefits in improving biochemical markers and possibly neurodevelopmental outcomes.

Lysine-Restricted Diet

Initial clinical trials using lysine restriction have shown:

• Improved levels of AASA and pipecolic acid
• Potential improvements in developmental and cognitive function

Prescribed lysine intake limits based on age include:

• 70–100 mg/kg/day for infants (<1 year)
• 45–80 mg/kg/day for children (1–7 years)
• 20–45 mg/kg/day for older children (>7 years)

Vitamin B6 therapy remains the primary treatment due to limited long-term data on the safety and effectiveness of lysine restriction.

Monitoring

Monitoring of patients with PDE includes:

• Regular assessment of seizure control
• Developmental evaluations using age-appropriate cognitive and behavioral tests
• Biochemical monitoring of AASA and pipecolic acid levels in plasma and urine

Prognosis

With prompt diagnosis and treatment, seizure control is generally good. However, outcomes related to intellectual development are variable, with many individuals experiencing some level of neurodevelopmental delay.

See also

• Pyridoxine deficiency
• Epilepsy
• Vitamin B6
• Inborn errors of metabolism

External links

• GeneReview: Pyridoxine-Dependent Epilepsy
• Genetics Home Reference – PDE