Main Clinical Features
Nearly all reported patients with biallelic PLAAmutations share the following core features:
• Progressive microcephaly — head circumference may be normal at birth but falls below −3 SD
• Failure to thrive — severe growth restriction (weight, height, and head circumference all <−3 SD)
• Global developmental delay — severe cognitive and motor impairment; inability to achieve head control
• Central hypotonia with peripheral hypertonia (spastic quadriparesis)
• Seizures/epileptic encephalopathy — reported in ~73% of patients, multifocal spike discharges on EEG
• Feeding difficulties and dysphagia
• Brain MRI abnormalities — leukoencephalopathy, widened subarachnoid spaces
• Additional features may include mildly dysmorphic facies, dystonic posturing, body tremor, pectus carinatum, rocker-bottom feet, and impaired visual responsiveness
Age of Onset and Prognosis
Symptom onset ranges from birth to 4 months. Prognosis is strongly influenced by mutation location:
• WD40 domain mutations — most severe phenotype with earliest onset, including apnea and polydactyly; often lethal in infancy or early childhood.
• PUL domain mutations (e.g., Leu752Phe) — relatively milder course; some patients survive into their teens or 30s, and seizures are less frequent (3/7 cases in the original cohort).
PLAA