PLAA-related Neurodevelopmental Disorder (NDMSBA; OMIM #617527) is an ultra-rare autosomal recessive condition caused by biallelic loss-of-function variants in the PLAAgene, with only a handful of families reported worldwide. More recently, de novo monoallelic variants have been associated with milder neurodevelopmental phenotypes.
Disease Name and Classification
The condition is formally designated Neurodevelopmental Disorder with Progressive Microcephaly, Spasticity, and Brain Anomalies (NDMSBA). It is classified among the leukoencephalopathies — white matter disorders related to abnormal myelin formation, maintenance, and turnover.
Inheritance
• Classic (severe) form: Autosomal recessive (biallelic variants — homozygous or compound heterozygous).
• Milder form (recently described): De novo heterozygous (monoallelic) missense variants in the PUL domain, presenting with intellectual disability, psychomotor regression, and autism spectrum disorders.
Prevalence
The exact prevalence is unknown. As of 2019, only six families had been reported in the literature. Cases have been identified in Israeli-Arab, British, and Chinese populations, suggesting a pan-ethnic distribution, though the condition remains exceedingly rare.
PLAA