CSNK2B-Related Neurodevelopmental Disorder

CSNK2B-related neurodevelopmental disorder (Poirier-Bienvenu neurodevelopmental syndrome) is caused by heterozygous loss-of-function or missense variants in CSNK2B, with early onset epilepsy, intellectual disability and, in some, mild dysmorphism. Seizures often begin in the first year and are frequently the presenting feature.

Pathophysiology. CSNK2B encodes the regulatory beta subunit of casein kinase 2, a ubiquitous serine and threonine kinase that regulates neuronal development, synaptic function and signalling. Haploinsufficiency and some missense variants disturb the kinase complex.

Most variants are de novo.

Seizure type and age at onset vary widely, and many children have more than one seizure type.

• Seizure onset in infancy or early childhood (generalised tonic clonic, focal, myoclonic, absence, atonic), often triggered by fever
• Seizure clusters and status epilepticus in some
• Intellectual disability from mild to severe, and speech delay
• Hypotonia and motor delay
• Behavioural problems, autism features and attention difficulty
• Dysmorphism in some: a broad forehead, a prominent nose, and a long face
• Skeletal and skin findings (for example spinal curvature, café-au-lait spots) in a minority
• Feeding and gastrointestinal problems
• Normal brain MRI in most

• CSNK2B sequencing with deletion and duplication analysis, within an epilepsy gene panel or exome sequencing.
• EEG, with video monitoring when events are unclear.
• Brain MRI.
• Developmental and behavioural assessment.
• Parental testing to confirm de novo origin.

• Seizure treatment: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily, and clobazam 0.25 mg/kg daily increasing to 1 mg/kg daily (maximum 40 mg). Use lamotrigine, topiramate or other drugs by seizure type, and a ketogenic diet (3:1 to 4:1 ratio) in refractory epilepsy under specialist care.
• Rescue and status epilepticus: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes. If it continues, give lorazepam 0.1 mg/kg intravenously (maximum 4 mg), repeated once after 10 minutes, then levetiracetam 40 mg/kg intravenously (maximum 3 g) over 10 minutes.
• Fever management: paracetamol 15 mg/kg every 6 hours (maximum 60 mg/kg daily) for comfort, and early assessment of intercurrent illness.
• Development and education: early intervention, speech therapy, occupational therapy and special education.
• Behaviour and mental health: behavioural programmes, with methylphenidate or sertraline at the usual doses when needed.
• Sleep: sleep hygiene and melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed).
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Women of child bearing age on valproate need contraception and counselling on foetal risk.

Monitoring. Seizure frequency, drug levels where relevant and side effects at each visit. Development and behaviour every 6 to 12 months, and spinal review yearly.

Referral and escalation. Refer to clinical genetics and paediatric neurology. Emergency for status epilepticus, seizure clusters or a seizure with a fever that does not settle.