Browsing by Author "McDonald, Marie"

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    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 A

    Background

    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.
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    Unraveling non-participation in genomic research: A complex interplay of barriers, facilitators, and sociocultural factors.
    (Journal of genetic counseling, 2023-04) McConkie-Rosell, Allyn; Spillmann, Rebecca C; Schoch, Kelly; Sullivan, Jennifer A; Walley, Nicole; McDonald, Marie; Undiagnosed Diseases Network; Hooper, Stephen R; Shashi, Vandana
    Although genomic research offering next-generation sequencing (NGS) has increased the diagnoses of rare/ultra-rare disorders, populations experiencing health disparities infrequently participate in these studies. The factors underlying non-participation would most reliably be ascertained from individuals who have had the opportunity to participate, but decline. We thus enrolled parents of children and adult probands with undiagnosed disorders who had declined genomic research offering NGS with return of results with undiagnosed disorders (Decliners, n = 21) and compared their data to those who participated (Participants, n = 31). We assessed: (1) practical barriers and facilitators, (2) sociocultural factors-genomic knowledge and distrust, and (3) the value placed upon a diagnosis by those who declined participation. The primary findings were that residence in rural and medically underserved areas (MUA) and higher number of barriers were significantly associated with declining participation in the study. Exploratory analyses revealed multiple co-occurring practical barriers, greater emotional exhaustion and research hesitancy in the parents in the Decliner group compared to the Participants, with both groups identifying a similar number of facilitators. The parents in the Decliner group also had lower genomic knowledge, but distrust of clinical research was not different between the groups. Importantly, despite their non-participation, those in the Decliner group indicated an interest in obtaining a diagnosis and expressed confidence in being able to emotionally manage the ensuing results. Study findings support the concept that some families who decline participation in diagnostic genomic research may be experiencing pile-up with exhaustion of family resources - making participation in the genomic research difficult. This study highlights the complexity of the factors that underlie non-participation in clinically relevant NGS research. Thus, approaches to mitigating barriers to NGS research participation by populations experiencing health disparities need to be multi-pronged and tailored so that they can benefit from state-of -the art genomic technologies.