What is the approach to evaluating and managing seizures in pediatric and neonatal patients with genetic and metabolic disorders?

Genetic and Metabolic Disorders Causing Seizures in Pediatrics and Neonates

Genetic and metabolic disorders account for approximately 10-12% of all neonatal seizures, and prompt identification is critical for implementing specific treatments that can significantly improve outcomes in terms of mortality, morbidity, and quality of life.

Etiology and Epidemiology

Seizures occur in 1-5 per 1,000 live births, with genetic and metabolic causes accounting for approximately 10-12% of all neonatal seizures 1. These disorders can be categorized into:

• Disorders of neurotransmitter metabolism
• Disorders of energy production
• Synthetic or catabolic disorders associated with brain dysfunction
• Channelopathies
• Disorders affecting neuronal development

Perinatal ischemic stroke, which occurs in approximately 1 per 4,000 live births, is also a significant cause of seizures in the neonatal period 2.

Pathophysiology

The pathophysiological mechanisms underlying seizures in genetic and metabolic disorders include:

1. Disruption of neurotransmitter balance: Abnormal metabolism of inhibitory (GABA) or excitatory (glutamate) neurotransmitters
2. Energy failure: Inadequate ATP production in mitochondrial disorders
3. Accumulation of toxic metabolites: Leading to neuronal dysfunction and hyperexcitability
4. Ion channel dysfunction: Altered membrane excitability in channelopathies
5. Abnormal brain development: Structural abnormalities predisposing to seizure activity

History and Physical Examination

Key elements to assess include:

• Timing of seizure onset: Many metabolic disorders present in the neonatal period
• Seizure characteristics: Type, duration, frequency, and triggers
• Family history: Consanguinity, previous unexplained infant deaths, or neurological disorders
• Pregnancy and birth history: Maternal illness, medications, complications
• Developmental history: Regression or delay
• Feeding patterns: Poor feeding, vomiting, failure to thrive

Physical examination should focus on:

• Dysmorphic features: May indicate a syndromic diagnosis
• Neurological examination: Hypotonia/hypertonia, abnormal reflexes, focal deficits
• Hepatosplenomegaly: Suggests storage disorders
• Skin findings: Café-au-lait macules (>6 spots >0.5cm), hypopigmented lesions
• Unusual odors: Characteristic of certain metabolic disorders

Evaluation

A systematic approach to diagnosis includes:

1. First-line investigations:

   • Complete blood count, electrolytes, glucose, calcium, magnesium
   • Liver and renal function tests
   • Blood gas analysis
   • Ammonia and lactate levels
   • Urine organic acids and plasma amino acids
   • Neuroimaging (MRI preferred over CT)
   • EEG (standard recommendation for all infants with seizures) 3

2. Second-line investigations (based on clinical suspicion):

   • CSF analysis (including neurotransmitter metabolites)
   • Specific metabolic testing (e.g., very long chain fatty acids, acylcarnitine profile)
   • Genetic testing (targeted gene panels or whole exome/genome sequencing)

The American Academy of Neurology recommends EEG as part of the standard neurodiagnostic evaluation of children with first unprovoked seizures 3. MRI is the preferred neuroimaging modality when indicated 3.

Treatment and Management

Treatment should follow a two-pronged approach:

1. Acute Seizure Management:

• First-line antiepileptic drugs: Levetiracetam is often preferred due to its efficacy and safety profile 4
• Avoid valproic acid in suspected metabolic disorders until mitochondrial disease is excluded
• Correct metabolic derangements: Glucose, electrolytes, calcium, magnesium

2. Disorder-Specific Treatments:

Vitamin-Responsive Epilepsies:

• Pyridoxine-dependent epilepsy: Pyridoxine (vitamin B6) 100mg IV trial
• Pyridoxal phosphate-responsive epilepsy: Pyridoxal-5-phosphate 30mg/kg/day
• Folinic acid-responsive seizures: Folinic acid 3-5mg/kg/day
• Biotinidase deficiency: Biotin 5-20mg/day
• GLUT-1 deficiency: Ketogenic diet

Other Treatable Metabolic Epilepsies:

• Serine biosynthesis defects: L-serine supplementation
• Creatine disorders: Creatine monohydrate
• Molybdenum cofactor deficiency: Cyclic pyranopterin monophosphate
• MTHFR mutations: Folate and B vitamins to normalize homocysteine levels 2

Channelopathies:

• KCNQ2 encephalopathy: Sodium channel blockers (carbamazepine, phenytoin)
• SCN2A encephalopathy: Sodium channel blockers or levetiracetam

Differential Diagnosis

The differential diagnosis for neonatal and infant seizures includes:

1. Acquired causes:

   • Hypoxic-ischemic encephalopathy
   • Intracranial hemorrhage
   • Infection (meningitis, encephalitis)
   • Stroke (perinatal stroke accounts for ~10% of seizures in term neonates) 2

2. Metabolic derangements:

   • Hypoglycemia
   • Electrolyte disturbances (hyponatremia, hypocalcemia)
   • Kernicterus

3. Genetic disorders:

   • Channelopathies (KCNQ2, SCN2A, SCN8A)
   • Developmental and epileptic encephalopathies (CDKL5, STXBP1)
   • Chromosomal disorders

4. Inborn errors of metabolism:

   • Amino acid disorders
   • Organic acidemias
   • Urea cycle disorders
   • Mitochondrial disorders
   • Peroxisomal disorders

Prognosis

Prognosis varies widely depending on:

• Type of disorder: Some vitamin-responsive epilepsies have excellent outcomes if treated early
• Timing of diagnosis and treatment: Early intervention is critical
• Presence of brain malformations or damage: Structural abnormalities may limit improvement
• Specific genetic mutation: Some mutations have milder phenotypes

For perinatal stroke, lesions involving the cortex, basal ganglia, and internal capsule are more likely to cause hemiplegia than strokes involving only one of these regions 2. Cognitive impairment after perinatal arterial ischemic stroke ranges from 0% to 55%, and language delay occurs in approximately 25% of children 2.

Complications

Potential complications include:

• Developmental delay/intellectual disability
• Cerebral palsy
• Refractory epilepsy
• Metabolic crises during illness
• Organ damage (liver, heart, kidney) in multisystemic disorders
• Feeding difficulties and failure to thrive

Pearls and Pitfalls

Pearls:

• Consider treatable metabolic causes in all neonates and infants with unexplained seizures
• Early diagnosis is crucial for disorders with specific treatments
• Genetic testing has revolutionized diagnosis of these conditions
• Therapeutic trial of vitamin B6 should be considered in refractory neonatal seizures
• Avoid valproate in suspected metabolic disorders until mitochondrial disease is excluded

Pitfalls:

• Misdiagnosing movement disorders as seizures
• Overlooking subtle seizures in neonates (apnea, eye deviation, autonomic changes)
• Delaying specific treatment while awaiting confirmatory tests
• Failing to recognize that normal initial metabolic screening does not exclude all metabolic disorders
• Missing the opportunity for early intervention in treatable disorders

Genetic referral should be considered for any neonate with unexplained seizures, especially when accompanied by dysmorphic features, developmental delay, or a family history of similar disorders 3.