PURA Syndrome

PURA syndrome (5q31.3 microdeletion syndrome when a deletion is the cause) is a neurodevelopmental disorder due to haploinsufficiency of PURA, presenting in the newborn period with severe hypotonia, feeding difficulty, hypersomnolence, hypothermia and apnoea. Later features are severe intellectual disability, absent speech and epilepsy. Variants and deletions are usually de novo.

Pathophysiology. PURA encodes a DNA and RNA binding protein (purine rich element binding protein A) that regulates transcription, mRNA transport and neuronal proliferation. Loss of one functional copy impairs neuronal maturation and synapse formation.

Deletions that also remove NRG2 (neuregulin 2) give a similar picture.

Early survival depends on airway, feeding and temperature support.

• Profound neonatal hypotonia with poor suck and weak cry
• Hypersomnolence, excessive sleepiness, and poor feeding needing tube support
• Hypothermia, temperature instability, and hypoglycaemia
• Apnoea (central and obstructive) and respiratory failure in some
• Severe developmental delay, absent or very limited speech, and many patients unable to walk independently
• Epilepsy in about half, including infantile spasms and myoclonic seizures
• Non-epileptic movements: startle like episodes, dystonia and tremor, which can mimic seizures
• Gastrointestinal problems: reflux, constipation, swallowing difficulty
• Eye findings: strabismus, nystagmus, cortical visual impairment
• Congenital heart disease, hip dysplasia, scoliosis, and recurrent infections
• Mild dysmorphism: hypertelorism, a long philtrum and a high arched palate

• PURA sequencing with deletion and duplication analysis, or exome sequencing; chromosomal microarray for 5q31.3 deletions.
• Prolonged video EEG to separate epileptic seizures from non-epileptic movements.
• Brain MRI: delayed myelination and thin corpus callosum in some.
• Metabolic and neuromuscular tests in the newborn with hypotonia (lactate, ammonia, creatine kinase, acylcarnitines) to exclude other causes.
• Echocardiography, hip imaging, swallow and sleep assessment.
• Parental testing to confirm de novo origin.

Differential diagnosis.

• Prader-Willi syndrome and Angelman syndrome
• Congenital myasthenic syndromes and congenital myopathies
• Spinal muscular atrophy
• Hypoxic ischaemic encephalopathy
• Other developmental and epileptic encephalopathies

• Newborn period: temperature control, glucose monitoring, respiratory support, and tube feeding. Treat hypoglycaemia with glucose 2 mL/kg of 10% intravenously and then an infusion of 6 to 8 mg/kg/min titrated to blood glucose.
• Feeding and reflux: feeding therapy, gastrostomy for unsafe swallow, and omeprazole 0.7 to 1 mg/kg daily.
• Apnoea and sleep: sleep study, respiratory support (continuous positive airway pressure) for obstructive or central events, and prompt treatment of chest infection.
• 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, and other agents by seizure type. For infantile spasms give vigabatrin 50 mg/kg daily increasing to 100 to 150 mg/kg daily, or prednisolone 40 to 60 mg daily for 14 days. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Movement disorder: confirm that events are non-epileptic before escalating antiseizure drugs, and use baclofen 0.3 mg/kg daily in divided doses increasing weekly to 2 mg/kg daily (maximum 60 mg) for troublesome spasticity or dystonia.
• Constipation: macrogol 0.4 to 0.8 g/kg daily.
• Eye, cardiac and orthopaedic care: correction of refractive error, treatment of structural heart disease, and yearly hip and spine review.
• Development and communication: early intervention, physiotherapy, augmentative communication and special education.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

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

Monitoring. Growth, feeding and development every 3 to 6 months in childhood. Seizures at each visit, sleep study as symptoms indicate, and eye, hip and spine review yearly.

Referral and escalation. Refer to clinical genetics, paediatric neurology, respiratory medicine and gastroenterology. Emergency for apnoea, aspiration, hypothermia, hypoglycaemia or prolonged seizures.