Miller-Dieker Syndrome

Miller-Dieker syndrome is a contiguous gene deletion disorder of chromosome 17p13.3 that includes PAFAH1B1 (LIS1) and YWHAE, with classical lissencephaly, characteristic facies, severe developmental disability and early mortality. Most deletions are de novo, though a parental balanced rearrangement is found in a minority.

Pathophysiology. PAFAH1B1 is needed for neuronal migration, and its loss leaves a smooth brain surface with a thick, four layered cortex. Loss of YWHAE, which lies next to it, adds growth restriction and facial dysmorphism.

Isolated PAFAH1B1 variants cause lissencephaly without the full syndrome.

The extent of the deletion determines severity, and aspiration and seizures drive early mortality.

• Lissencephaly (agyria pachygyria) with posterior predominance
• Prominent forehead, bitemporal narrowing, short nose with upturned nares, thick upper lip, small jaw
• Severe intellectual disability and hypotonia, later spasticity
• Seizures, usually infantile spasms from the first year, then multiple seizure types
• Feeding difficulty, reflux and aspiration
• Congenital heart disease, renal anomalies, omphalocele and cryptorchidism
• Poor growth and microcephaly
• Most children die in early childhood, with some surviving into adolescence

• Chromosomal microarray showing a deletion at 17p13.3 including PAFAH1B1 and YWHAE.
• Brain MRI: lissencephaly with a thick cortex and a posterior to anterior gradient.
• FISH or MLPA targeted to the 17p13.3 region when microarray is not available.
• Parental karyotype and FISH to detect a balanced rearrangement.
• EEG: hypsarrhythmia in infantile spasms.
• Echocardiography, renal ultrasound and swallow assessment to define complications.

Differential diagnosis.

• Isolated lissencephaly (PAFAH1B1, DCX, TUBA1A, RELN and other genes)
• Walker-Warburg syndrome and other dystroglycanopathies
• Zellweger spectrum disorder
• Other contiguous deletion syndromes with seizures
• Smith-Lemli-Opitz syndrome
• Congenital cytomegalovirus infection

• Infantile spasms: vigabatrin 50 mg/kg orally daily in two doses, increasing over several days to 100 to 150 mg/kg daily, or prednisolone 40 to 60 mg daily for 14 days with taper, or ACTH, in a paediatric neurology unit. Monitor vigabatrin with visual field or electroretinography assessment where feasible.
• Other seizures: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, and add valproate, clobazam or topiramate by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for seizures lasting more than 5 minutes.
• Feeding and aspiration: speech and language swallow assessment, nasogastric feeding, then gastrostomy with or without fundoplication. Treat reflux with omeprazole 0.7 to 1 mg/kg daily.
• Respiratory care: chest physiotherapy, vaccination, prompt treatment of pneumonia, and sleep assessment.
• Spasticity and orthopaedics: physiotherapy, baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg), hip surveillance and scoliosis care.
• Cardiac and renal care: repair of significant defects when compatible with goals of care.
• Palliative care: discuss prognosis early, set goals of care, plan for symptom control and an emergency plan.
• Genetic counselling: de novo deletions carry a low recurrence risk, while a parental translocation carries a higher risk and calls for prenatal testing options.

Special groups.

• Infants with spasms: early treatment within days of onset improves developmental outcome in most epilepsies, though in lissencephaly benefit is limited.

Monitoring. Seizure control, feeding, weight and chest status at every visit (every 3 months in early childhood). Hip radiograph every 12 months. Echocardiography as cardiology advises.

Referral and escalation. Refer to clinical genetics, paediatric neurology and palliative care. Emergency for prolonged seizures, aspiration, respiratory distress or dehydration.