What is Jordan syndrome (PPP2R5D-related intellectual disability)?

Jordan Syndrome (PPP2R5D-Related Intellectual Disability)

Jordan syndrome is a rare autosomal dominant neurodevelopmental disorder caused by de novo pathogenic missense variants in the PPP2R5D gene, characterized by global developmental delay, intellectual disability, macrocephaly, hypotonia, epilepsy, autism spectrum disorder, and behavioral challenges. 1, 2

Core Clinical Features

The disorder presents with a constellation of neurodevelopmental and physical manifestations:

Neurological Manifestations

• Global developmental delay and intellectual disability (present in 100% of cases) - ranging from mild to severe, though generally milder than other PP2A-related syndromes 2, 3
• Macrocephaly or relative macrocephaly (approximately 75-80% of cases) - head circumferences consistently above average 1, 4
• Epilepsy/seizures (variable penetrance, approximately 40-50% of affected individuals) 1, 4
• Hypotonia - commonly observed in infancy and early childhood 2
• Autism spectrum disorder and behavioral challenges - including attention disorders, social difficulties, and sensory processing issues 2, 3

Additional Features

• Ophthalmological abnormalities - most common non-neurological manifestation 2, 4
• Speech and language delays 2
• Sleep disturbances and feeding difficulties 2
• Dysmorphic facial features - typically mild and non-specific, may include prominent forehead 1, 3
• Skeletal, endocrine, cardiac, and genital malformations - variable presentation 5

Emerging Adult Phenotype

Progressive parkinsonism in early adulthood is an increasingly recognized feature that neurologists must be aware of, as the clinical triad of macrocephaly, intellectual disability, and early-onset parkinsonism is highly specific for this condition 6. This presents with mixed-tremor parkinsonism and confirmed presynaptic nigrostriatal dysfunction on dopamine transporter imaging 6.

Genetic Basis

The disorder results from heterozygous de novo missense variants in PPP2R5D, which encodes the B56δ regulatory subunit of protein phosphatase 2A (PP2A) 1, 5.

Most Common Variant

The c.598G>A (p.Glu200Lys) mutation accounts for approximately 40% of all reported cases and represents one of the most frequently reported pathogenic variants 1, 2. The alternative nomenclature c.592G>A (p.E198K) refers to the same variant 4, 6.

Pathogenic Mechanism

These variants act through a dominant-negative mechanism, disrupting PP2A-mediated dephosphorylation rather than simple loss of function 5, 7. The mutations affect substrate binding, catalytic subunit binding, or both, leading to deficient PP2A activity particularly in neuronal tissues 5, 8.

Diagnostic Approach

When to Suspect Jordan Syndrome

Consider PPP2R5D testing in patients presenting with:

• Developmental delay + macrocephaly + autism/behavioral abnormalities
• Developmental delay + epilepsy + macrocephaly without clear etiology
• The specific triad of macrocephaly + intellectual disability + early-onset parkinsonism in adults 6, 3

Diagnostic Testing

• Whole-exome sequencing (WES) or targeted gene panel including PPP2R5D is the diagnostic method of choice 1, 3
• Confirm variants are de novo through parental testing 1
• Classify variants according to ACMG guidelines 1

Supportive Investigations

• Brain MRI - often shows abnormalities, though non-specific 1
• EEG - may show persistent abnormalities even with antiepileptic treatment in those with seizures 1
• Dopamine transporter imaging - in adults with parkinsonian features 6

Clinical Management

Early diagnosis through genetic testing and multidisciplinary management is essential to optimize outcomes 1. While no specific disease-modifying therapies are currently standard of care, clinical trials are underway 6.

Surveillance and Intervention

Based on the clinical care guidelines derived from 100+ reported individuals 2:

• Neurodevelopmental support: Early intervention services, special education, speech and occupational therapy
• Seizure management: Standard antiepileptic medications as indicated; note that EEG abnormalities may persist despite treatment 1
• Behavioral and psychiatric support: Management of autism spectrum features, attention disorders, and behavioral challenges
• Ophthalmological screening: Regular eye examinations given high frequency of abnormalities
• Growth monitoring: Serial head circumference measurements
• Adult surveillance: Monitor for emergence of parkinsonian features in early adulthood 6

Emerging Therapeutic Considerations

Research suggests mTORC1 pathway dysregulation with RPS6 hyperphosphorylation across PPP2R5D variants, raising the possibility that rapamycin or p70S6K inhibitors may have therapeutic potential, though this requires further investigation 8.

Important Clinical Pitfalls

• Do not dismiss macrocephaly as benign familial macrocephaly when accompanied by developmental concerns - pursue genetic testing 3
• In adults with longstanding neurodevelopmental disorder diagnoses, the emergence of parkinsonism should prompt PPP2R5D testing even if not previously considered 6
• Novel phenotypes continue to emerge: persistent unexplained fever in early infancy has been reported and may represent an underrecognized feature 1
• Developmental and epileptic encephalopathy (DEE) phenotype may be the presenting feature and is likely underreported 4

Genotype-Phenotype Correlations

While there is phenotypic variability even among individuals with the same variant, the p.Glu200Lys (E198K) variant consistently associates with developmental delay, high frequency of macrocephaly (73%), and epilepsy (40%) 1, 4. The degree of intellectual disability and presence of additional features varies considerably between individuals, suggesting modifier genes or environmental factors influence phenotypic expression 2, 5.