Browsing by Author "Mueller, David M"
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Item Open Access D-DEMØ, a distinct phenotype caused by ATP1A3 mutations.(Neurology. Genetics, 2020-10) Prange, Lyndsey; Pratt, Milton; Herman, Kristin; Schiffmann, Raphael; Mueller, David M; McLean, Melissa; Mendez, Mary Moya; Walley, Nicole; Heinzen, Erin L; Goldstein, David; Shashi, Vandana; Hunanyan, Arsen; Pagadala, Vijay; Mikati, Mohamad AObjective:To describe a phenotype caused by ATP1A3 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. Methods:Review and analysis of clinical and genetic data. Results:Patients shared the above traits and had whole-exome sequencing that showed de novo variants of the ATP1A3 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. Conclusions:D-DEMØ represents an ATP1A3-related phenotype, the observation of which should trigger investigation for ATP1A3 mutations. Our findings, and the presence of multiple distinct ATP1A3-related phenotypes, support the possibility that there are differences in the underlying mechanisms.Item Open Access Early onset severe ATP1A2 epileptic encephalopathy: Clinical characteristics and underlying mutations.(Epilepsy & behavior : E&B, 2021-01-22) Moya-Mendez, Mary E; Mueller, David M; Pratt, Milton; Bonner, Melanie; Elliott, Courtney; Hunanyan, Arsen; Kucera, Gary; Bock, Cheryl; Prange, Lyndsey; Jasien, Joan; Keough, Karen; Shashi, Vandana; McDonald, Marie; Mikati, Mohamad ABackground
ATP1A2 mutations cause hemiplegic migraine with or without epilepsy or acute reversible encephalopathy. Typical onset is in adulthood or older childhood without subsequent severe long-term developmental impairments.Aim
We aimed to describe the manifestations of early onset severe ATP1A2-related epileptic encephalopathy and its underlying mutations in a cohort of seven patients.Methods
A retrospective chart review of a cohort of seven patients was conducted. Response to open-label memantine therapy, used off-label due to its NMDA receptor antagonist effects, was assessed by the Global Rating Scale of Change (GRSC) and Clinical Global Impression Scale of Improvement (CGI-I) methodologies. Molecular modeling was performed using PyMol program.Results
Patients (age 2.5-20 years) had symptom onset at an early age (6 days-1 year). Seizures were either focal or generalized. Common features were: drug resistance, recurrent status epilepticus, etc., severe developmental delay with episodes of acute severe encephalopathy often with headaches, dystonias, hemiplegias, seizures, and developmental regression. All had variants predicted to be disease causing (p.Ile293Met, p.Glu1000Lys, c.1017+5G>A, p.Leu809Arg, and 3 patients with p.Met813Lys). Modeling revealed that mutations interfered with ATP1A2 ion binding and translocation sites. Memantine, given to five, was tolerated in all (mean treatment: 2.3 years, range 6 weeks-4.8 years) with some improvements reported in all five.Conclusions
Our observations describe a distinctive clinical profile of seven unrelated probands with early onset severe ATP1A2-related epileptic encephalopathy, provide insights into structure-function relationships of ATP1A2 mutations, and support further studies of NMDAR antagonist therapy in ATP1A2-encephalopathy.