D-DEMØ, a distinct phenotype caused by ATP1A3 mutations

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• The ATP1A3 gene encodes a critical component of the sodium-potassium pump, essential for neuronal function.
• Mutations in ATP1A3 are associated with various neurological disorders, including rapid-onset dystonia-parkinsonism and alternating hemiplegia of childhood.

Purpose of the Study:

• To delineate a distinct clinical phenotype associated with ATP1A3 mutations.
• To identify the genetic basis of a specific neurodevelopmental disorder characterized by dystonia, facial dysmorphism, encephalopathy, and cerebellar hypoplasia.

Main Methods:

• Comprehensive review and analysis of clinical data from affected individuals.
• Whole-exome sequencing to identify genetic variants in the ATP1A3 gene.
• Correlation of identified mutations with observed clinical and neuroimaging findings.

Main Results:

• Four patients presented with a consistent phenotype: dystonia, facial dysmorphism, encephalopathy with developmental delay, and cerebellar hypoplasia (D-DEMØ), with neonatal onset.
• Whole-exome sequencing revealed de novo, predicted pathogenic variants in the ATP1A3 gene in all patients.
• Specific mutations identified include c.1079C>G (p.Thr360Arg), c.420G>T (p.Gln140His), c.974G>A (Gly325Asp), and c.971A>G (p.Glu324Gly), all located in critical functional regions of the protein.

Conclusions:

• D-DEMØ is a recognizable phenotype caused by ATP1A3 mutations, warranting genetic investigation.
• The distinct phenotypes associated with ATP1A3 mutations suggest varying pathomechanisms underlying different neurological presentations.
• Further research is needed to elucidate the precise molecular mechanisms driving these diverse ATP1A3-related disorders.