DYRK1A Syndrome

DYRK1A syndrome (autosomal dominant intellectual disability type 7) is a neurodevelopmental disorder caused by loss-of-function variants or deletions of DYRK1A (21q22.13), with microcephaly, severe intellectual disability, absent or minimal speech, seizures and feeding difficulty. Most variants are de novo.

Pathophysiology. DYRK1A is a dual specificity kinase that regulates neuronal proliferation and differentiation. Its triplication contributes to Down syndrome, and its haploinsufficiency causes a distinct syndrome.

Presentation is in infancy with feeding difficulty and developmental delay.

Epilepsy, visual problems and growth issues need regular follow up.

• Intellectual disability (moderate to severe) and absent or very limited speech
• Microcephaly, usually postnatal
• Seizures, including febrile seizures and epilepsy (about 60%)
• Feeding difficulty and intrauterine or postnatal growth restriction
• Short stature
• Deep set eyes, broad nasal tip, and a thin upper lip
• Autism spectrum features, stereotypies, an unsteady gait
• Visual problems: hyperopia, strabismus, nystagmus, optic nerve hypoplasia
• Brain MRI abnormalities: ventriculomegaly, thin corpus callosum, delayed myelination
• Congenital anomalies of the heart, kidney and genitalia in some
• Hypotonia, sleep disturbance, constipation and reflux

• DYRK1A sequencing with deletion and duplication analysis, or exome sequencing; chromosomal microarray for 21q22.13 deletions.
• Brain MRI and EEG.
• Developmental and autism assessment.
• Ophthalmology and audiology assessment.
• Echocardiography and renal ultrasound.
• Growth and feeding assessment.
• Parental testing to confirm de novo origin.

• 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, or lamotrigine titrated slowly. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Feeding and growth: feeding therapy, gastrostomy for failure to thrive, and omeprazole 0.7 to 1 mg/kg daily for reflux.
• Gastrointestinal care: macrogol 0.4 to 0.8 g/kg daily (adults 1 to 3 sachets) for constipation.
• Vision and hearing: spectacles, strabismus treatment, and annual review.
• Sleep and behaviour: sleep hygiene and melatonin 2 to 5 mg orally 30 to 60 minutes before bed (up to 10 mg if needed), with behavioural support.
• Development and communication: early intervention, speech therapy with augmentative communication, physiotherapy and special education.
• Cardiac and renal care: treatment of structural anomalies.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: continue epilepsy, nutrition and behavioural care, and plan transition and supported living.

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

Referral and escalation. Refer to clinical genetics, paediatric neurology and ophthalmology. Emergency for prolonged seizures, aspiration or severe dehydration.