It is understood that a new PLAAcase has been identified and the goal is to recruit additional cases worldwide to expand the cohort for a collaborative publication. Below is a framework for theresearch project, including aims, methods, and expected results, informed by the existing literature and established approaches for ultra-rare disease case aggregation.
Research Aims
1. Expand the global cohort of PLAA-related neurodevelopmental disorder (NDMSBA)
As of the most recent publications, only 6 to 7 families with biallelic PLAAvariants have been reported worldwide (from Israeli-Arab, British, and Chinese populations), plus a small number of de novo monoallelic cases. The primary aim is to identify and recruit additional cases internationally to increase the sample and strengthen genotype-phenotype correlations.
2. Refine the clinical and neuroimaging phenotype — Systematically characterize the full clinical spectrum, including neurological, developmental, growth, and dysmorphic features, as well as longitudinal brain MRI findings across all known and newly identified patients.
3. Establish genotype-phenotype correlations — Determine whether mutation location (WD40domain vs. PUL domain vs. other regions) reliably predicts disease severity, age of onset, seizure burden, and survival, building on preliminary observations that WD40 domain mutations carry amore severe prognosis.
4. Characterize the expanded allelic spectrum — Include both biallelic (autosomal recessive) and de novo monoallelic variants to define the full range of PLAA-associated neurological disease, from severe infantile encephalopathy to milder neurodevelopmental disorders (intellectual disability, autism spectrum disorders).
PLAA