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Allison Brashear - One of the best experts on this subject based on the ideXlab platform.

  • effects of ATP1A3 mutations on brain functional network connectivity 5209
    Neurology, 2020
    Co-Authors: Christopher T Whitlow, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Ihtsham Haq, Jared F. Cook, Mohammad Kawas, Jeongchul Kim, Kiran Kumar Solingapuram Sai, Allison Brashear
    Abstract:

    Objective: The aim of this study was to characterize the effects of ATP1A3 gene mutations of rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) on functional brain network connectivity. We hypothesized that different ATP1A3 gene mutations would be associated with different patterns of brain functional network connectivity compared to controls. Background: ATP1A3 is in the P2 family of ion transport ATPases that establish and maintain electrochemical gradients for Na+ and K+ across the plasma membrane. Little is known about brain functional network connectivity that may underlie ATP1A3 clinical disease phenotypes, including RDP and AHC. Design/Methods: In this IRB-approved study, brain MRI was acquired from all participants, including 10-minutes of resting-state blood oxygen level dependent (BOLD) data. Image pre-processing included file conversion to NIFTI, brain segmentation, head motion correction, and artifact removal from the functional MRI time series data. BOLD data were then co-registered to structural T1-images, and Automated Anatomical Labeling atlas structures used as seeds to map region-to-region connectivity. Group-wise statistical analyses were conducted, with correction for multiple region-to-region comparisons. Results: Compared to controls, RDP was associated with greater connectivity (p Conclusions: ATP1A3 mutations of RDP and AHC are associated with different phenotypes of brain functional network connectivity, suggesting disruption of integrated brain circuitry. Future studies will determine if these differences in ATP1A3-associated functional brain network phenotypes underlie different clinical manifestations of RDP and AHC. Disclosure: Dr. Whitlow has nothing to disclose. Dr. Kawas has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Sai has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Haq has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Boston Scientific. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen and Revance. Dr. Brashear has received research support from Wake Forest.

  • Genotype-structure-phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3.
    Neurology. Genetics, 2019
    Co-Authors: Kathleen J Sweadner, Allison Brashear, Elena Arystarkhova, John T. Penniston, Kathryn J. Swoboda, Laurie J Ozelius
    Abstract:

    Objective We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases ATP1A1 , ATP1A2 , and ATP1A3 . Methods Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology. Results Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of ATP1A3 (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In ATP1A2 (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in ATP1A3 were absent from patient data. The known variants in ATP1A1 fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites. Conclusions Pathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in ATP1A3 that correlates with neurologic outcomes. The absence of “severe” pathogenic variants in ATP1A2 patients predicts that they will manifest either in a different tissue or by death in utero and that new ATP1A1 variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.

  • The Phenotype of ATP1A3+ Rapid-Onset Dystonia-Parkinsonism (RDP) is Broader than Previously Defined. (P5.039)
    Neurology, 2018
    Co-Authors: Ihtsham Haq, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Jared F. Cook, Cynthia K. Suerken, Charlotte E. Miller, Allison Brashear
    Abstract:

    Objective: To update the phenotype of RDP based on a cohort of ATP1A3 mutation+ individuals. Background: RDP is caused by mutations of the ATP1A3 gene, which encodes the α3 subunit of the Na+/K+ ATPase. The published phenotype of RDP is typified by a rostral to caudal gradient of effect, bulbar dysfunction, and abrupt symptom onset. Our group has reexamined the RDP phenotype in a cohort of 53 mutation-positive subjects ( ATP1A3+ ) with 12 distinct mutations. Design/Methods: We analyzed the cohort with respect to mean Unified Parkinson’s Disease Rating motor subscale (UPDRS3) and Burke-Fahn-Marsden Dystonia Rating Scale (BMFDRS) scores, symmetric parkinsonism, and the presence of bulbar symptoms, a rostrocaudal symptom gradient, frontal lobe dysfunction, and cerebellar dysfunction. Results: Rapidity of onset ( ATP1A3 + individuals, but not universal (61%). Bulbar symptoms were present in 81% of ATP1A3 + subjects. ATP1A3 + individuals were dystonic and parkinsonian (mean±SD BMFDRS 47±33 and UPDRS of 44±23). Frontal lobe function measures (trailmaking, verbal fluency) were lower in the ATP1A3+ group than in a control cohort. Neither the presence of a rostrocaudal gradient nor symmetric parkinsonism were typical of the ATP1A3 + cohort. Only 5.8% of ATP1A3+ subjects displayed a rostrocaudal gradient and were about equally likely to have a symmetric or asymmetric parkinsonism (35% symmetric, 48% asymmetric). A subset (n=12) had formal cerebellar function scale assessments, and 17% of these showed cerebellar dysfunction. Conclusions: ATP1A3 + with RDP subjects typically show rapidity of onset, dystonia, parkinsonism, bulbar symptoms, frontal dysfunction, and possibly cerebellar dysfunction. Neither asymmetric parkinsonism nor the lack of a rostrocaudal gradient can be used to exclude a diagnosis of ATP1A3 + RDP. Our results are affected by the nonhomogenous distribution of mutations, which ranged from 1 instance to 16. Future directions include phenotypic analysis within and between mutation types. Study Supported by: This work was supported by R01NS058949 (PI: Allison Brashear) Disclosure: Dr. Haq has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Suerken has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen, Revance, WorldMeds.

  • ATP1A3 Mutation in Adult Rapid-Onset Ataxia.
    PloS one, 2016
    Co-Authors: Kathleen J Sweadner, Beverly M Snively, Laurie J Ozelius, Jared F. Cook, Christopher T Whitlow, Camilo Toro, Thomas C. Markello, Allison Brashear
    Abstract:

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

  • ATP1A3-Related Disorders: A Broadening of the Phenotypic and Genotypic Presentation (P2.141)
    Neurology, 2015
    Co-Authors: Allison Brashear, Beverly M Snively, Kathleen J Sweadner, Jared F. Cook, Laurie J Ozelius
    Abstract:

    OBJECTIVE: To evaluate phenotypic and genotypic presentations of ATP1A3-related disorders. BACKGROUND: ATP1A3 mutations are causative for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). More recently, ATP1A3 mutation has been found to be causative for cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). Genotype-phenotype correlations are discussed. DESIGN/METHODS: All participants underwent DNA screening for ATP1A3 mutations performed by direct sequencing. Participants were evaluated with an extensive battery including a standardized history questionnaire, neurological exam, and cognitive and psychiatric assessments. A subset of participants underwent magnetic resonance imaging (MRI). RESULTS: AHC typically manifests in infants A (encoding p.Asp923Asn) is the only variant reported in both RDP and AHC. The pathogenic variant Glu815Lys may be associated with earlier onset, greater impairment (motor and cognitive), increased likelihood of status epilepticus, and respiratory paralysis. All reported cases of CAPOS have the same heterozygous ATP1A3 missense mutation (c.2452G>A; p.Glu818Lys). CONCLUSIONS: A breadth of observed clinical features indicates central nervous system involvement in ATP1A3-related disorders. The phenotypic and genetic presentation of ATP1A3-related disorders continues to broaden. Study Supported by: NINDS 5R01NS058949-04 Disclosure: Dr. Brashear has received personal compensation for activities with Allergan and Concerta as a consultant. Dr. Brashear has received royalty payments from books. Dr. Brashear has received research support from Ipsen, Merz, Allergan and NINDS. Dr. Cook has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Sweadner has received personal compensation for activities with the University of Toledo and the University of Puerto Rico. Dr. Ozelius has nothing to disclose.,

Laurie J Ozelius - One of the best experts on this subject based on the ideXlab platform.

  • effects of ATP1A3 mutations on brain functional network connectivity 5209
    Neurology, 2020
    Co-Authors: Christopher T Whitlow, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Ihtsham Haq, Jared F. Cook, Mohammad Kawas, Jeongchul Kim, Kiran Kumar Solingapuram Sai, Allison Brashear
    Abstract:

    Objective: The aim of this study was to characterize the effects of ATP1A3 gene mutations of rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) on functional brain network connectivity. We hypothesized that different ATP1A3 gene mutations would be associated with different patterns of brain functional network connectivity compared to controls. Background: ATP1A3 is in the P2 family of ion transport ATPases that establish and maintain electrochemical gradients for Na+ and K+ across the plasma membrane. Little is known about brain functional network connectivity that may underlie ATP1A3 clinical disease phenotypes, including RDP and AHC. Design/Methods: In this IRB-approved study, brain MRI was acquired from all participants, including 10-minutes of resting-state blood oxygen level dependent (BOLD) data. Image pre-processing included file conversion to NIFTI, brain segmentation, head motion correction, and artifact removal from the functional MRI time series data. BOLD data were then co-registered to structural T1-images, and Automated Anatomical Labeling atlas structures used as seeds to map region-to-region connectivity. Group-wise statistical analyses were conducted, with correction for multiple region-to-region comparisons. Results: Compared to controls, RDP was associated with greater connectivity (p Conclusions: ATP1A3 mutations of RDP and AHC are associated with different phenotypes of brain functional network connectivity, suggesting disruption of integrated brain circuitry. Future studies will determine if these differences in ATP1A3-associated functional brain network phenotypes underlie different clinical manifestations of RDP and AHC. Disclosure: Dr. Whitlow has nothing to disclose. Dr. Kawas has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Sai has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Haq has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Boston Scientific. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen and Revance. Dr. Brashear has received research support from Wake Forest.

  • Genotype-structure-phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3.
    Neurology. Genetics, 2019
    Co-Authors: Kathleen J Sweadner, Allison Brashear, Elena Arystarkhova, John T. Penniston, Kathryn J. Swoboda, Laurie J Ozelius
    Abstract:

    Objective We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases ATP1A1 , ATP1A2 , and ATP1A3 . Methods Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology. Results Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of ATP1A3 (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In ATP1A2 (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in ATP1A3 were absent from patient data. The known variants in ATP1A1 fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites. Conclusions Pathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in ATP1A3 that correlates with neurologic outcomes. The absence of “severe” pathogenic variants in ATP1A2 patients predicts that they will manifest either in a different tissue or by death in utero and that new ATP1A1 variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.

  • The Phenotype of ATP1A3+ Rapid-Onset Dystonia-Parkinsonism (RDP) is Broader than Previously Defined. (P5.039)
    Neurology, 2018
    Co-Authors: Ihtsham Haq, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Jared F. Cook, Cynthia K. Suerken, Charlotte E. Miller, Allison Brashear
    Abstract:

    Objective: To update the phenotype of RDP based on a cohort of ATP1A3 mutation+ individuals. Background: RDP is caused by mutations of the ATP1A3 gene, which encodes the α3 subunit of the Na+/K+ ATPase. The published phenotype of RDP is typified by a rostral to caudal gradient of effect, bulbar dysfunction, and abrupt symptom onset. Our group has reexamined the RDP phenotype in a cohort of 53 mutation-positive subjects ( ATP1A3+ ) with 12 distinct mutations. Design/Methods: We analyzed the cohort with respect to mean Unified Parkinson’s Disease Rating motor subscale (UPDRS3) and Burke-Fahn-Marsden Dystonia Rating Scale (BMFDRS) scores, symmetric parkinsonism, and the presence of bulbar symptoms, a rostrocaudal symptom gradient, frontal lobe dysfunction, and cerebellar dysfunction. Results: Rapidity of onset ( ATP1A3 + individuals, but not universal (61%). Bulbar symptoms were present in 81% of ATP1A3 + subjects. ATP1A3 + individuals were dystonic and parkinsonian (mean±SD BMFDRS 47±33 and UPDRS of 44±23). Frontal lobe function measures (trailmaking, verbal fluency) were lower in the ATP1A3+ group than in a control cohort. Neither the presence of a rostrocaudal gradient nor symmetric parkinsonism were typical of the ATP1A3 + cohort. Only 5.8% of ATP1A3+ subjects displayed a rostrocaudal gradient and were about equally likely to have a symmetric or asymmetric parkinsonism (35% symmetric, 48% asymmetric). A subset (n=12) had formal cerebellar function scale assessments, and 17% of these showed cerebellar dysfunction. Conclusions: ATP1A3 + with RDP subjects typically show rapidity of onset, dystonia, parkinsonism, bulbar symptoms, frontal dysfunction, and possibly cerebellar dysfunction. Neither asymmetric parkinsonism nor the lack of a rostrocaudal gradient can be used to exclude a diagnosis of ATP1A3 + RDP. Our results are affected by the nonhomogenous distribution of mutations, which ranged from 1 instance to 16. Future directions include phenotypic analysis within and between mutation types. Study Supported by: This work was supported by R01NS058949 (PI: Allison Brashear) Disclosure: Dr. Haq has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Suerken has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen, Revance, WorldMeds.

  • ATP1A3 Mutation in Adult Rapid-Onset Ataxia.
    PloS one, 2016
    Co-Authors: Kathleen J Sweadner, Beverly M Snively, Laurie J Ozelius, Jared F. Cook, Christopher T Whitlow, Camilo Toro, Thomas C. Markello, Allison Brashear
    Abstract:

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

  • ATP1A3-Related Disorders: A Broadening of the Phenotypic and Genotypic Presentation (P2.141)
    Neurology, 2015
    Co-Authors: Allison Brashear, Beverly M Snively, Kathleen J Sweadner, Jared F. Cook, Laurie J Ozelius
    Abstract:

    OBJECTIVE: To evaluate phenotypic and genotypic presentations of ATP1A3-related disorders. BACKGROUND: ATP1A3 mutations are causative for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). More recently, ATP1A3 mutation has been found to be causative for cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). Genotype-phenotype correlations are discussed. DESIGN/METHODS: All participants underwent DNA screening for ATP1A3 mutations performed by direct sequencing. Participants were evaluated with an extensive battery including a standardized history questionnaire, neurological exam, and cognitive and psychiatric assessments. A subset of participants underwent magnetic resonance imaging (MRI). RESULTS: AHC typically manifests in infants A (encoding p.Asp923Asn) is the only variant reported in both RDP and AHC. The pathogenic variant Glu815Lys may be associated with earlier onset, greater impairment (motor and cognitive), increased likelihood of status epilepticus, and respiratory paralysis. All reported cases of CAPOS have the same heterozygous ATP1A3 missense mutation (c.2452G>A; p.Glu818Lys). CONCLUSIONS: A breadth of observed clinical features indicates central nervous system involvement in ATP1A3-related disorders. The phenotypic and genetic presentation of ATP1A3-related disorders continues to broaden. Study Supported by: NINDS 5R01NS058949-04 Disclosure: Dr. Brashear has received personal compensation for activities with Allergan and Concerta as a consultant. Dr. Brashear has received royalty payments from books. Dr. Brashear has received research support from Ipsen, Merz, Allergan and NINDS. Dr. Cook has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Sweadner has received personal compensation for activities with the University of Toledo and the University of Puerto Rico. Dr. Ozelius has nothing to disclose.,

Kathleen J Sweadner - One of the best experts on this subject based on the ideXlab platform.

  • effects of ATP1A3 mutations on brain functional network connectivity 5209
    Neurology, 2020
    Co-Authors: Christopher T Whitlow, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Ihtsham Haq, Jared F. Cook, Mohammad Kawas, Jeongchul Kim, Kiran Kumar Solingapuram Sai, Allison Brashear
    Abstract:

    Objective: The aim of this study was to characterize the effects of ATP1A3 gene mutations of rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) on functional brain network connectivity. We hypothesized that different ATP1A3 gene mutations would be associated with different patterns of brain functional network connectivity compared to controls. Background: ATP1A3 is in the P2 family of ion transport ATPases that establish and maintain electrochemical gradients for Na+ and K+ across the plasma membrane. Little is known about brain functional network connectivity that may underlie ATP1A3 clinical disease phenotypes, including RDP and AHC. Design/Methods: In this IRB-approved study, brain MRI was acquired from all participants, including 10-minutes of resting-state blood oxygen level dependent (BOLD) data. Image pre-processing included file conversion to NIFTI, brain segmentation, head motion correction, and artifact removal from the functional MRI time series data. BOLD data were then co-registered to structural T1-images, and Automated Anatomical Labeling atlas structures used as seeds to map region-to-region connectivity. Group-wise statistical analyses were conducted, with correction for multiple region-to-region comparisons. Results: Compared to controls, RDP was associated with greater connectivity (p Conclusions: ATP1A3 mutations of RDP and AHC are associated with different phenotypes of brain functional network connectivity, suggesting disruption of integrated brain circuitry. Future studies will determine if these differences in ATP1A3-associated functional brain network phenotypes underlie different clinical manifestations of RDP and AHC. Disclosure: Dr. Whitlow has nothing to disclose. Dr. Kawas has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Sai has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Haq has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Boston Scientific. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen and Revance. Dr. Brashear has received research support from Wake Forest.

  • Genotype-structure-phenotype relationships diverge in paralogs ATP1A1, ATP1A2, and ATP1A3.
    Neurology. Genetics, 2019
    Co-Authors: Kathleen J Sweadner, Allison Brashear, Elena Arystarkhova, John T. Penniston, Kathryn J. Swoboda, Laurie J Ozelius
    Abstract:

    Objective We tested the assumption that closely related genes should have similar pathogenic variants by analyzing >200 pathogenic variants in a gene family with high neurologic impact and high sequence identity, the Na,K-ATPases ATP1A1 , ATP1A2 , and ATP1A3 . Methods Data sets of disease-associated variants were compared. Their equivalent positions in protein crystal structures were used for insights into pathogenicity and correlated with the phenotype and conservation of homology. Results Relatively few mutations affected the corresponding amino acids in 2 genes. In the membrane domain of ATP1A3 (primarily expressed in neurons), variants producing milder neurologic phenotypes had different structural positions than variants producing severe phenotypes. In ATP1A2 (primarily expressed in astrocytes), membrane domain variants characteristic of severe phenotypes in ATP1A3 were absent from patient data. The known variants in ATP1A1 fell into 2 distinct groups. Sequence conservation was an imperfect indicator: it varied among structural domains, and some variants with demonstrated pathogenicity were in low conservation sites. Conclusions Pathogenic variants varied between genes despite high sequence identity, and there is a genotype-structure-phenotype relationship in ATP1A3 that correlates with neurologic outcomes. The absence of “severe” pathogenic variants in ATP1A2 patients predicts that they will manifest either in a different tissue or by death in utero and that new ATP1A1 variants will produce additional phenotypes. It is important that some variants in poorly conserved amino acids are nonetheless pathogenic and could be incorrectly predicted to be benign.

  • The Phenotype of ATP1A3+ Rapid-Onset Dystonia-Parkinsonism (RDP) is Broader than Previously Defined. (P5.039)
    Neurology, 2018
    Co-Authors: Ihtsham Haq, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Jared F. Cook, Cynthia K. Suerken, Charlotte E. Miller, Allison Brashear
    Abstract:

    Objective: To update the phenotype of RDP based on a cohort of ATP1A3 mutation+ individuals. Background: RDP is caused by mutations of the ATP1A3 gene, which encodes the α3 subunit of the Na+/K+ ATPase. The published phenotype of RDP is typified by a rostral to caudal gradient of effect, bulbar dysfunction, and abrupt symptom onset. Our group has reexamined the RDP phenotype in a cohort of 53 mutation-positive subjects ( ATP1A3+ ) with 12 distinct mutations. Design/Methods: We analyzed the cohort with respect to mean Unified Parkinson’s Disease Rating motor subscale (UPDRS3) and Burke-Fahn-Marsden Dystonia Rating Scale (BMFDRS) scores, symmetric parkinsonism, and the presence of bulbar symptoms, a rostrocaudal symptom gradient, frontal lobe dysfunction, and cerebellar dysfunction. Results: Rapidity of onset ( ATP1A3 + individuals, but not universal (61%). Bulbar symptoms were present in 81% of ATP1A3 + subjects. ATP1A3 + individuals were dystonic and parkinsonian (mean±SD BMFDRS 47±33 and UPDRS of 44±23). Frontal lobe function measures (trailmaking, verbal fluency) were lower in the ATP1A3+ group than in a control cohort. Neither the presence of a rostrocaudal gradient nor symmetric parkinsonism were typical of the ATP1A3 + cohort. Only 5.8% of ATP1A3+ subjects displayed a rostrocaudal gradient and were about equally likely to have a symmetric or asymmetric parkinsonism (35% symmetric, 48% asymmetric). A subset (n=12) had formal cerebellar function scale assessments, and 17% of these showed cerebellar dysfunction. Conclusions: ATP1A3 + with RDP subjects typically show rapidity of onset, dystonia, parkinsonism, bulbar symptoms, frontal dysfunction, and possibly cerebellar dysfunction. Neither asymmetric parkinsonism nor the lack of a rostrocaudal gradient can be used to exclude a diagnosis of ATP1A3 + RDP. Our results are affected by the nonhomogenous distribution of mutations, which ranged from 1 instance to 16. Future directions include phenotypic analysis within and between mutation types. Study Supported by: This work was supported by R01NS058949 (PI: Allison Brashear) Disclosure: Dr. Haq has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Suerken has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen, Revance, WorldMeds.

  • ATP1A3 Mutation in Adult Rapid-Onset Ataxia.
    PloS one, 2016
    Co-Authors: Kathleen J Sweadner, Beverly M Snively, Laurie J Ozelius, Jared F. Cook, Christopher T Whitlow, Camilo Toro, Thomas C. Markello, Allison Brashear
    Abstract:

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

  • ATP1A3-Related Disorders: A Broadening of the Phenotypic and Genotypic Presentation (P2.141)
    Neurology, 2015
    Co-Authors: Allison Brashear, Beverly M Snively, Kathleen J Sweadner, Jared F. Cook, Laurie J Ozelius
    Abstract:

    OBJECTIVE: To evaluate phenotypic and genotypic presentations of ATP1A3-related disorders. BACKGROUND: ATP1A3 mutations are causative for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). More recently, ATP1A3 mutation has been found to be causative for cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). Genotype-phenotype correlations are discussed. DESIGN/METHODS: All participants underwent DNA screening for ATP1A3 mutations performed by direct sequencing. Participants were evaluated with an extensive battery including a standardized history questionnaire, neurological exam, and cognitive and psychiatric assessments. A subset of participants underwent magnetic resonance imaging (MRI). RESULTS: AHC typically manifests in infants A (encoding p.Asp923Asn) is the only variant reported in both RDP and AHC. The pathogenic variant Glu815Lys may be associated with earlier onset, greater impairment (motor and cognitive), increased likelihood of status epilepticus, and respiratory paralysis. All reported cases of CAPOS have the same heterozygous ATP1A3 missense mutation (c.2452G>A; p.Glu818Lys). CONCLUSIONS: A breadth of observed clinical features indicates central nervous system involvement in ATP1A3-related disorders. The phenotypic and genetic presentation of ATP1A3-related disorders continues to broaden. Study Supported by: NINDS 5R01NS058949-04 Disclosure: Dr. Brashear has received personal compensation for activities with Allergan and Concerta as a consultant. Dr. Brashear has received royalty payments from books. Dr. Brashear has received research support from Ipsen, Merz, Allergan and NINDS. Dr. Cook has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Sweadner has received personal compensation for activities with the University of Toledo and the University of Puerto Rico. Dr. Ozelius has nothing to disclose.,

Jared F. Cook - One of the best experts on this subject based on the ideXlab platform.

  • effects of ATP1A3 mutations on brain functional network connectivity 5209
    Neurology, 2020
    Co-Authors: Christopher T Whitlow, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Ihtsham Haq, Jared F. Cook, Mohammad Kawas, Jeongchul Kim, Kiran Kumar Solingapuram Sai, Allison Brashear
    Abstract:

    Objective: The aim of this study was to characterize the effects of ATP1A3 gene mutations of rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) on functional brain network connectivity. We hypothesized that different ATP1A3 gene mutations would be associated with different patterns of brain functional network connectivity compared to controls. Background: ATP1A3 is in the P2 family of ion transport ATPases that establish and maintain electrochemical gradients for Na+ and K+ across the plasma membrane. Little is known about brain functional network connectivity that may underlie ATP1A3 clinical disease phenotypes, including RDP and AHC. Design/Methods: In this IRB-approved study, brain MRI was acquired from all participants, including 10-minutes of resting-state blood oxygen level dependent (BOLD) data. Image pre-processing included file conversion to NIFTI, brain segmentation, head motion correction, and artifact removal from the functional MRI time series data. BOLD data were then co-registered to structural T1-images, and Automated Anatomical Labeling atlas structures used as seeds to map region-to-region connectivity. Group-wise statistical analyses were conducted, with correction for multiple region-to-region comparisons. Results: Compared to controls, RDP was associated with greater connectivity (p Conclusions: ATP1A3 mutations of RDP and AHC are associated with different phenotypes of brain functional network connectivity, suggesting disruption of integrated brain circuitry. Future studies will determine if these differences in ATP1A3-associated functional brain network phenotypes underlie different clinical manifestations of RDP and AHC. Disclosure: Dr. Whitlow has nothing to disclose. Dr. Kawas has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Sai has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Haq has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Boston Scientific. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen and Revance. Dr. Brashear has received research support from Wake Forest.

  • Factors in the disease severity of ATP1A3 mutations: Impairment, misfolding, and allele competition.
    Neurobiology of disease, 2019
    Co-Authors: Elena Arystarkhova, Ihtsham Haq, Timothy Luebbert, Fanny Mochel, Rachel Saunders-pullman, Susan Bressman, Polina Feschenko, Cynthia Salazar, Jared F. Cook, Scott Demarest
    Abstract:

    Dominant mutations of ATP1A3, a neuronal Na,K-ATPase α subunit isoform, cause neurological disorders with an exceptionally wide range of severity. Several new mutations and their phenotypes are reported here (p.Asp366His, p.Asp742Tyr, p.Asp743His, p.Leu924Pro, and a VUS, p.Arg463Cys). Mutations associated with mild or severe phenotypes [rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), or early infantile epileptic encephalopathy (EIEE)] were expressed in HEK-293 cells. Paradoxically, the severity of human symptoms did not correlate with whether there was enough residual activity to support cell survival. We hypothesized that distinct cellular consequences may result not only from pump inactivation but also from protein misfolding. Biosynthesis was investigated in four tetracycline-inducible isogenic cell lines representing different human phenotypes. Two cell biological complications were found. First, there was impaired trafficking of αβ complex to Golgi apparatus and plasma membrane, as well as changes in cell morphology, for two mutations that produced microcephaly or regions of brain atrophy in patients. Second, there was competition between exogenous mutant ATP1A3 (α3) and endogenous ATP1A1 (α1) so that their sum was constant. This predicts that in patients, the ratio of normal to mutant ATP1A3 proteins will vary when misfolding occurs. At the two extremes, the results suggest that a heterozygous mutation that only impairs Na,K-ATPase activity will produce relatively mild disease, while one that activates the unfolded protein response could produce severe disease and may result in death of neurons independently of ion pump inactivation.

  • The Phenotype of ATP1A3+ Rapid-Onset Dystonia-Parkinsonism (RDP) is Broader than Previously Defined. (P5.039)
    Neurology, 2018
    Co-Authors: Ihtsham Haq, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Jared F. Cook, Cynthia K. Suerken, Charlotte E. Miller, Allison Brashear
    Abstract:

    Objective: To update the phenotype of RDP based on a cohort of ATP1A3 mutation+ individuals. Background: RDP is caused by mutations of the ATP1A3 gene, which encodes the α3 subunit of the Na+/K+ ATPase. The published phenotype of RDP is typified by a rostral to caudal gradient of effect, bulbar dysfunction, and abrupt symptom onset. Our group has reexamined the RDP phenotype in a cohort of 53 mutation-positive subjects ( ATP1A3+ ) with 12 distinct mutations. Design/Methods: We analyzed the cohort with respect to mean Unified Parkinson’s Disease Rating motor subscale (UPDRS3) and Burke-Fahn-Marsden Dystonia Rating Scale (BMFDRS) scores, symmetric parkinsonism, and the presence of bulbar symptoms, a rostrocaudal symptom gradient, frontal lobe dysfunction, and cerebellar dysfunction. Results: Rapidity of onset ( ATP1A3 + individuals, but not universal (61%). Bulbar symptoms were present in 81% of ATP1A3 + subjects. ATP1A3 + individuals were dystonic and parkinsonian (mean±SD BMFDRS 47±33 and UPDRS of 44±23). Frontal lobe function measures (trailmaking, verbal fluency) were lower in the ATP1A3+ group than in a control cohort. Neither the presence of a rostrocaudal gradient nor symmetric parkinsonism were typical of the ATP1A3 + cohort. Only 5.8% of ATP1A3+ subjects displayed a rostrocaudal gradient and were about equally likely to have a symmetric or asymmetric parkinsonism (35% symmetric, 48% asymmetric). A subset (n=12) had formal cerebellar function scale assessments, and 17% of these showed cerebellar dysfunction. Conclusions: ATP1A3 + with RDP subjects typically show rapidity of onset, dystonia, parkinsonism, bulbar symptoms, frontal dysfunction, and possibly cerebellar dysfunction. Neither asymmetric parkinsonism nor the lack of a rostrocaudal gradient can be used to exclude a diagnosis of ATP1A3 + RDP. Our results are affected by the nonhomogenous distribution of mutations, which ranged from 1 instance to 16. Future directions include phenotypic analysis within and between mutation types. Study Supported by: This work was supported by R01NS058949 (PI: Allison Brashear) Disclosure: Dr. Haq has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Suerken has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen, Revance, WorldMeds.

  • ATP1A3 Mutation in Adult Rapid-Onset Ataxia.
    PloS one, 2016
    Co-Authors: Kathleen J Sweadner, Beverly M Snively, Laurie J Ozelius, Jared F. Cook, Christopher T Whitlow, Camilo Toro, Thomas C. Markello, Allison Brashear
    Abstract:

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

  • ATP1A3-Related Disorders: A Broadening of the Phenotypic and Genotypic Presentation (P2.141)
    Neurology, 2015
    Co-Authors: Allison Brashear, Beverly M Snively, Kathleen J Sweadner, Jared F. Cook, Laurie J Ozelius
    Abstract:

    OBJECTIVE: To evaluate phenotypic and genotypic presentations of ATP1A3-related disorders. BACKGROUND: ATP1A3 mutations are causative for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). More recently, ATP1A3 mutation has been found to be causative for cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). Genotype-phenotype correlations are discussed. DESIGN/METHODS: All participants underwent DNA screening for ATP1A3 mutations performed by direct sequencing. Participants were evaluated with an extensive battery including a standardized history questionnaire, neurological exam, and cognitive and psychiatric assessments. A subset of participants underwent magnetic resonance imaging (MRI). RESULTS: AHC typically manifests in infants A (encoding p.Asp923Asn) is the only variant reported in both RDP and AHC. The pathogenic variant Glu815Lys may be associated with earlier onset, greater impairment (motor and cognitive), increased likelihood of status epilepticus, and respiratory paralysis. All reported cases of CAPOS have the same heterozygous ATP1A3 missense mutation (c.2452G>A; p.Glu818Lys). CONCLUSIONS: A breadth of observed clinical features indicates central nervous system involvement in ATP1A3-related disorders. The phenotypic and genetic presentation of ATP1A3-related disorders continues to broaden. Study Supported by: NINDS 5R01NS058949-04 Disclosure: Dr. Brashear has received personal compensation for activities with Allergan and Concerta as a consultant. Dr. Brashear has received royalty payments from books. Dr. Brashear has received research support from Ipsen, Merz, Allergan and NINDS. Dr. Cook has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Sweadner has received personal compensation for activities with the University of Toledo and the University of Puerto Rico. Dr. Ozelius has nothing to disclose.,

Beverly M Snively - One of the best experts on this subject based on the ideXlab platform.

  • effects of ATP1A3 mutations on brain functional network connectivity 5209
    Neurology, 2020
    Co-Authors: Christopher T Whitlow, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Ihtsham Haq, Jared F. Cook, Mohammad Kawas, Jeongchul Kim, Kiran Kumar Solingapuram Sai, Allison Brashear
    Abstract:

    Objective: The aim of this study was to characterize the effects of ATP1A3 gene mutations of rapid-onset dystonia Parkinsonism (RDP) and alternating hemiplegia of childhood (AHC) on functional brain network connectivity. We hypothesized that different ATP1A3 gene mutations would be associated with different patterns of brain functional network connectivity compared to controls. Background: ATP1A3 is in the P2 family of ion transport ATPases that establish and maintain electrochemical gradients for Na+ and K+ across the plasma membrane. Little is known about brain functional network connectivity that may underlie ATP1A3 clinical disease phenotypes, including RDP and AHC. Design/Methods: In this IRB-approved study, brain MRI was acquired from all participants, including 10-minutes of resting-state blood oxygen level dependent (BOLD) data. Image pre-processing included file conversion to NIFTI, brain segmentation, head motion correction, and artifact removal from the functional MRI time series data. BOLD data were then co-registered to structural T1-images, and Automated Anatomical Labeling atlas structures used as seeds to map region-to-region connectivity. Group-wise statistical analyses were conducted, with correction for multiple region-to-region comparisons. Results: Compared to controls, RDP was associated with greater connectivity (p Conclusions: ATP1A3 mutations of RDP and AHC are associated with different phenotypes of brain functional network connectivity, suggesting disruption of integrated brain circuitry. Future studies will determine if these differences in ATP1A3-associated functional brain network phenotypes underlie different clinical manifestations of RDP and AHC. Disclosure: Dr. Whitlow has nothing to disclose. Dr. Kawas has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Kim has nothing to disclose. Dr. Sai has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Haq has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Boston Scientific. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen and Revance. Dr. Brashear has received research support from Wake Forest.

  • The Phenotype of ATP1A3+ Rapid-Onset Dystonia-Parkinsonism (RDP) is Broader than Previously Defined. (P5.039)
    Neurology, 2018
    Co-Authors: Ihtsham Haq, Beverly M Snively, Kathleen J Sweadner, Laurie J Ozelius, Jared F. Cook, Cynthia K. Suerken, Charlotte E. Miller, Allison Brashear
    Abstract:

    Objective: To update the phenotype of RDP based on a cohort of ATP1A3 mutation+ individuals. Background: RDP is caused by mutations of the ATP1A3 gene, which encodes the α3 subunit of the Na+/K+ ATPase. The published phenotype of RDP is typified by a rostral to caudal gradient of effect, bulbar dysfunction, and abrupt symptom onset. Our group has reexamined the RDP phenotype in a cohort of 53 mutation-positive subjects ( ATP1A3+ ) with 12 distinct mutations. Design/Methods: We analyzed the cohort with respect to mean Unified Parkinson’s Disease Rating motor subscale (UPDRS3) and Burke-Fahn-Marsden Dystonia Rating Scale (BMFDRS) scores, symmetric parkinsonism, and the presence of bulbar symptoms, a rostrocaudal symptom gradient, frontal lobe dysfunction, and cerebellar dysfunction. Results: Rapidity of onset ( ATP1A3 + individuals, but not universal (61%). Bulbar symptoms were present in 81% of ATP1A3 + subjects. ATP1A3 + individuals were dystonic and parkinsonian (mean±SD BMFDRS 47±33 and UPDRS of 44±23). Frontal lobe function measures (trailmaking, verbal fluency) were lower in the ATP1A3+ group than in a control cohort. Neither the presence of a rostrocaudal gradient nor symmetric parkinsonism were typical of the ATP1A3 + cohort. Only 5.8% of ATP1A3+ subjects displayed a rostrocaudal gradient and were about equally likely to have a symmetric or asymmetric parkinsonism (35% symmetric, 48% asymmetric). A subset (n=12) had formal cerebellar function scale assessments, and 17% of these showed cerebellar dysfunction. Conclusions: ATP1A3 + with RDP subjects typically show rapidity of onset, dystonia, parkinsonism, bulbar symptoms, frontal dysfunction, and possibly cerebellar dysfunction. Neither asymmetric parkinsonism nor the lack of a rostrocaudal gradient can be used to exclude a diagnosis of ATP1A3 + RDP. Our results are affected by the nonhomogenous distribution of mutations, which ranged from 1 instance to 16. Future directions include phenotypic analysis within and between mutation types. Study Supported by: This work was supported by R01NS058949 (PI: Allison Brashear) Disclosure: Dr. Haq has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Suerken has nothing to disclose. Dr. Cook has nothing to disclose. Dr. Miller has nothing to disclose. Dr. Sweadner has nothing to disclose. Dr. Ozelius has nothing to disclose. Dr. Brashear has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ipsen, Revance, WorldMeds.

  • ATP1A3 Mutation in Adult Rapid-Onset Ataxia.
    PloS one, 2016
    Co-Authors: Kathleen J Sweadner, Beverly M Snively, Laurie J Ozelius, Jared F. Cook, Christopher T Whitlow, Camilo Toro, Thomas C. Markello, Allison Brashear
    Abstract:

    A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

  • ATP1A3-Related Disorders: A Broadening of the Phenotypic and Genotypic Presentation (P2.141)
    Neurology, 2015
    Co-Authors: Allison Brashear, Beverly M Snively, Kathleen J Sweadner, Jared F. Cook, Laurie J Ozelius
    Abstract:

    OBJECTIVE: To evaluate phenotypic and genotypic presentations of ATP1A3-related disorders. BACKGROUND: ATP1A3 mutations are causative for rapid-onset dystonia-parkinsonism (RDP) and alternating hemiplegia of childhood (AHC). More recently, ATP1A3 mutation has been found to be causative for cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS). Genotype-phenotype correlations are discussed. DESIGN/METHODS: All participants underwent DNA screening for ATP1A3 mutations performed by direct sequencing. Participants were evaluated with an extensive battery including a standardized history questionnaire, neurological exam, and cognitive and psychiatric assessments. A subset of participants underwent magnetic resonance imaging (MRI). RESULTS: AHC typically manifests in infants A (encoding p.Asp923Asn) is the only variant reported in both RDP and AHC. The pathogenic variant Glu815Lys may be associated with earlier onset, greater impairment (motor and cognitive), increased likelihood of status epilepticus, and respiratory paralysis. All reported cases of CAPOS have the same heterozygous ATP1A3 missense mutation (c.2452G>A; p.Glu818Lys). CONCLUSIONS: A breadth of observed clinical features indicates central nervous system involvement in ATP1A3-related disorders. The phenotypic and genetic presentation of ATP1A3-related disorders continues to broaden. Study Supported by: NINDS 5R01NS058949-04 Disclosure: Dr. Brashear has received personal compensation for activities with Allergan and Concerta as a consultant. Dr. Brashear has received royalty payments from books. Dr. Brashear has received research support from Ipsen, Merz, Allergan and NINDS. Dr. Cook has nothing to disclose. Dr. Snively has nothing to disclose. Dr. Sweadner has received personal compensation for activities with the University of Toledo and the University of Puerto Rico. Dr. Ozelius has nothing to disclose.,

  • ATP1A3 mutations in infants a new rapid onset dystonia parkinsonism phenotype characterized by motor delay and ataxia
    Developmental Medicine & Child Neurology, 2012
    Co-Authors: Allison Brashear, Jonathan W Mink, Deborah F Hill, Niki Boggs, Vaughn W Mccall, Mark Stacy, Beverly M Snively, Laney S Light, Kathleen J Sweadner, Laurie J Ozelius
    Abstract:

    We report new clinical features of delayed motor development, hypotonia, and ataxia in two young children with mutations (R756H and D923N) in the ATP1A3 gene. In adults, mutations in ATP1A3 cause rapid-onset dystonia-Parkinsonism (RDP, DYT12) with abrupt onset of fixed dystonia. The parents and children were examined and videotaped, and samples were collected for mutation analysis. Case 1 presented with fluctuating spells of hypotonia, dysphagia, mutism, dystonia, and ataxia at 9 months. After three episodes of hypotonia, she developed ataxia, inability to speak or swallow, and eventual seizures. Case 2 presented with hypotonia at 14 months and pre-existing motor delay. At age 4 years, he had episodic slurred speech, followed by ataxia, drooling, and dysarthria. He remains mute. Both children had ATP1A3 gene mutations. To our knowledge, these are the earliest presentations of RDP, both with fluctuating features. Both children were initially misdiagnosed. RDP should be considered in children with discoordinated gait, and speech and swallowing difficulties.