D-DEMØ, a distinct phenotype caused by <i>ATP1A3</i> mutations
Lyndsey Prange, Milton Pratt, Kristin Herman, Raphael Schiffmann, David M. Mueller, Melissa McLean, Mary Moya Mendez, Nicole Walley, Erin L. Heinzen, David B. Goldstein, Vandana Shashi, Arsen Hunanyan, Vijay Pagadala, Mohamad A. Mikati
Abstract
<h3>Objective</h3> To describe a phenotype caused by <i>ATP1A3</i> mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset. <h3>Methods</h3> Review and analysis of clinical and genetic data. <h3>Results</h3> Patients shared the above traits and had whole-exome sequencing that showed de novo variants of the <i>ATP1A3</i> gene, predicted to be disease causing and occurring in regions of the protein critical for pump function. Patient 1 (c.1079C>G, p.Thr360Arg), an 8-year-old girl, presented on day 1 of life with episodic dystonia, complex partial seizures, and facial dysmorphism. MRI of the brain revealed cerebellar hypoplasia. Patient 2 (c.420G>T, p.Gln140His), an 18-year-old man, presented on day 1 of life with hypotonia, tremor, and facial dysmorphism. He later developed dystonia. MRI of the brain revealed cerebellar hypoplasia and, later, further cerebellar volume loss (atrophy). Patient 3 (c.974G>A, Gly325Asp), a 13-year-old girl, presented on day 1 of life with tremor, episodic dystonia, and facial dysmorphism. MRI of the brain showed severe cerebellar hypoplasia. Patient 4 (c.971A>G, p.Glu324Gly), a 14-year-old boy, presented on day 1 of life with tremor, hypotonia, dystonia, nystagmus, facial dysmorphism, and later seizures. MRI of the brain revealed moderate cerebellar hypoplasia. <h3>Conclusions</h3> D-DEMØ represents an <i>ATP1A3</i>-related phenotype, the observation of which should trigger investigation for <i>ATP1A3</i> mutations. Our findings, and the presence of multiple distinct <i>ATP1A3</i>-related phenotypes, support the possibility that there are differences in the underlying mechanisms.