PPP2R5D-Related Neurodevelopmental Disorder

PPP2R5D-related neurodevelopmental disorder (Jordan syndrome) is caused by de novo heterozygous missense variants in PPP2R5D, with macrocephaly, hypotonia, intellectual disability, autism and, in a subset, seizures and early parkinsonism. A small number of recurrent variants account for most cases, and p.Glu198Lys is the commonest.

Pathophysiology. PPP2R5D encodes a regulatory subunit of protein phosphatase 2A, which controls dephosphorylation in cell signalling including the mTOR, AKT and tau systems. Pathogenic missense variants are thought to act through a dominant negative effect on the phosphatase complex.

Variants cluster in an acidic loop of the protein.

The condition is lifelong, and movement disorders can appear in the second decade or later.

• Macrocephaly in most, with a broad forehead
• Hypotonia and delayed motor milestones
• Intellectual disability from mild to severe, and speech delay
• Autism spectrum disorder and attention problems
• Seizures in a minority, with various types
• Ataxia, tremor and dystonia; levodopa responsive parkinsonism has been reported from adolescence
• Feeding difficulty, reflux and constipation in infancy
• Eye problems: strabismus, hypermetropia, cortical visual impairment
• Sleep disturbance
• Brain MRI: ventriculomegaly, thin corpus callosum, delayed myelination
• Congenital heart disease or endocrine problems in some

• PPP2R5D sequencing, within a macrocephaly or intellectual disability panel or exome sequencing. Single nucleotide variants in the acidic loop are typical.
• Parental testing to confirm de novo origin.
• Brain MRI and EEG when seizures or regression occur.
• Developmental and autism assessment.
• Ophthalmology and audiology assessment.
• Echocardiography.

• Development and education: early intervention, speech and communication therapy, occupational therapy and special education.
• Epilepsy: levetiracetam 10 mg/kg twice daily increasing to 30 mg/kg twice daily, with valproate 10 mg/kg twice daily increasing to 20 mg/kg twice daily or other agents by seizure type. Provide a rescue plan: buccal midazolam 0.3 mg/kg (maximum 10 mg) for a seizure lasting over 5 minutes.
• Parkinsonism in adolescents and adults: a course of levodopa with carbidopa (50/12.5 mg three times daily increasing to 100/25 mg three times daily) under specialist care. Response varies, and dyskinesia can follow.
• Behaviour and mental health: behavioural support, sertraline 25 to 50 mg daily increasing to a maximum of 200 mg daily for anxiety, and methylphenidate 5 mg once or twice daily increasing weekly by 5 to 10 mg to a usual maximum of 60 mg daily after cardiac review for ADHD.
• Sleep: sleep hygiene and melatonin 2 to 5 mg 30 to 60 minutes before bed (up to 10 mg if needed).
• Gastrointestinal care: omeprazole 0.7 to 1 mg/kg daily for reflux and macrogol 0.4 to 0.8 g/kg daily (adults 1 to 3 sachets) for constipation.
• Eye and hearing care: spectacles, strabismus treatment, and yearly review.
• Genetic counselling: de novo variants carry low recurrence risk, with a small risk of germline mosaicism.

Special groups.

• Adults: ask about tremor, rigidity, slowness and falls at each visit, because early parkinsonism is treatable.

Monitoring. Development, seizures and behaviour every 6 to 12 months. Movement examination yearly from adolescence, and vision and hearing yearly.

Referral and escalation. Refer to clinical genetics, paediatric neurology and, for parkinsonism, a movement disorder service. Urgent for regression, prolonged seizures or loss of mobility.