HNRNPU-Related Neurodevelopmental Disorder

HNRNPU-related neurodevelopmental disorder (developmental and epileptic encephalopathy 54) is caused by haploinsufficiency of HNRNPU (1q44), with severe intellectual disability, absent speech, early onset epilepsy and hypotonia. Variants and deletions are usually de novo.

Pathophysiology. HNRNPU encodes a heterogeneous nuclear ribonucleoprotein that regulates RNA processing, chromatin structure and transcription. Loss of function disrupts neuronal development and excitability.

Epilepsy begins in the first year in most patients and is often difficult to treat.

Larger 1q44 deletions that include AKT3 and ZBTB18 also cause microcephaly and corpus callosum anomalies.

• Severe intellectual disability, with absent or very limited speech
• Early onset epilepsy (infantile spasms, myoclonic, focal and generalised seizures), often triggered by fever
• Hypotonia, ataxia and delayed walking
• Microcephaly in many
• Corpus callosum hypoplasia and ventriculomegaly
• Feeding difficulty, reflux and constipation
• Congenital heart disease, renal anomalies, and cryptorchidism
• Autism features, stereotypies and sleep disturbance
• Strabismus, visual impairment and hearing loss in some
• Mild dysmorphism: broad forehead, wide set eyes, and a thin upper lip

• HNRNPU sequencing with deletion and duplication analysis, or exome sequencing; chromosomal microarray for 1q44 deletions.
• EEG and brain MRI, with corpus callosum and ventricular assessment.
• Developmental assessment.
• Echocardiography and renal ultrasound.
• Hearing and vision assessment.
• Parental testing to confirm de novo origin.

• Infantile spasms: vigabatrin 50 mg/kg orally daily increasing to 100 to 150 mg/kg daily, or prednisolone 40 to 60 mg daily for 14 days.
• Epilepsy: 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, clobazam 0.25 mg/kg daily increasing to 1 mg/kg daily (maximum 40 mg), and a ketogenic diet (3:1 to 4:1 ratio) in refractory epilepsy under specialist care. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes. Treat fever promptly with paracetamol 15 mg/kg every 6 hours (maximum 60 mg/kg daily) to limit febrile triggers.
• Feeding and gastrointestinal care: feeding therapy, gastrostomy for unsafe swallow, omeprazole 0.7 to 1 mg/kg daily for reflux, and macrogol 0.4 to 0.8 g/kg daily for constipation.
• Development and communication: early intervention, physiotherapy, augmentative communication and special education.
• Sleep: sleep hygiene and melatonin 2 to 5 mg orally 30 to 60 minutes before bed (up to 10 mg if needed).
• Cardiac, renal, hearing and vision care: treat anomalies and review yearly.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue epilepsy and nutrition care, and plan transition to adult services and supported living.

Monitoring. Seizures and development every 3 to 6 months. Growth, head circumference and feeding at each visit, and vision and hearing yearly.

Referral and escalation. Refer to clinical genetics, paediatric neurology and epilepsy services. Emergency for status epilepticus or prolonged febrile seizures.