Limits...
Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.

Viollet L, Glusman G, Murphy KJ, Newcomb TM, Reyna SP, Sweney M, Nelson B, Andermann F, Andermann E, Acsadi G, Barbano RL, Brown C, Brunkow ME, Chugani HT, Cheyette SR, Collins A, DeBrosse SD, Galas D, Friedman J, Hood L, Huff C, Jorde LB, King MD, LaSalle B, Leventer RJ, Lewelt AJ, Massart MB, Mérida MR, Ptáček LJ, Roach JC, Rust RS, Renault F, Sanger TD, Sotero de Menezes MA, Tennyson R, Uldall P, Zhang Y, Zupanc M, Xin W, Silver K, Swoboda KJ - PLoS ONE (2015)

Bottom Line: We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations.This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes.However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.

ABSTRACT
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

No MeSH data available.


Related in: MedlinePlus

Ages at unsupported sitting acquisition in each group of patients defined by their genotype.Cumulative probability of acquiring unsupported sitting by patients presenting the E815K mutation, compared to patientsmutation (3b). Patients with the E815K mutation are likely to gain unsupported sitting at a later age than patients in each of the other groups (respectively P = 0.0002 and P = 0.0020).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4440742&req=5

pone.0127045.g003: Ages at unsupported sitting acquisition in each group of patients defined by their genotype.Cumulative probability of acquiring unsupported sitting by patients presenting the E815K mutation, compared to patientsmutation (3b). Patients with the E815K mutation are likely to gain unsupported sitting at a later age than patients in each of the other groups (respectively P = 0.0002 and P = 0.0020).

Mentions: All patients with the D801N or E815K mutation had onset of their first paroxysmal symptoms by 18 months of age. The 6 patients presenting an atypical late onset of the disease had a rare ATP1A3 variant or did not have any detectable ATP1A3 mutation. Those patients with a mutation in ATP1A3 had a significantly earlier median age at onset (5 months earlier) than for those without a mutation (P-value = 0.008). When contrasting the most common mutations, the age at onset for patients with the E815K mutation was 2.7 months earlier than those with other types of ATP1A3 mutations (P-value<0.0001), as well as 2.7 months earlier than those with the D801N mutation (P-value<0.0001) (Fig 2). Patients with E815K mutations achieved unsupported sitting later than those with the D801N mutation (P-value = 0.0020) and later than those with other mutations (P-value = 0.0002) (Fig 3). Patients with E815K mutations were also more likely to achieve independent walking later than those with other mutations (P-value = 0.0264) (Fig 4). Finally, patients with E815K mutation were almost 3 times more likely to present with status epilepticus during the course of the disease than the patients with other types of ATP1A3 mutations (P-value = 0.0206. Table 3)


Alternating Hemiplegia of Childhood: Retrospective Genetic Study and Genotype-Phenotype Correlations in 187 Subjects from the US AHCF Registry.

Viollet L, Glusman G, Murphy KJ, Newcomb TM, Reyna SP, Sweney M, Nelson B, Andermann F, Andermann E, Acsadi G, Barbano RL, Brown C, Brunkow ME, Chugani HT, Cheyette SR, Collins A, DeBrosse SD, Galas D, Friedman J, Hood L, Huff C, Jorde LB, King MD, LaSalle B, Leventer RJ, Lewelt AJ, Massart MB, Mérida MR, Ptáček LJ, Roach JC, Rust RS, Renault F, Sanger TD, Sotero de Menezes MA, Tennyson R, Uldall P, Zhang Y, Zupanc M, Xin W, Silver K, Swoboda KJ - PLoS ONE (2015)

Ages at unsupported sitting acquisition in each group of patients defined by their genotype.Cumulative probability of acquiring unsupported sitting by patients presenting the E815K mutation, compared to patientsmutation (3b). Patients with the E815K mutation are likely to gain unsupported sitting at a later age than patients in each of the other groups (respectively P = 0.0002 and P = 0.0020).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4440742&req=5

pone.0127045.g003: Ages at unsupported sitting acquisition in each group of patients defined by their genotype.Cumulative probability of acquiring unsupported sitting by patients presenting the E815K mutation, compared to patientsmutation (3b). Patients with the E815K mutation are likely to gain unsupported sitting at a later age than patients in each of the other groups (respectively P = 0.0002 and P = 0.0020).
Mentions: All patients with the D801N or E815K mutation had onset of their first paroxysmal symptoms by 18 months of age. The 6 patients presenting an atypical late onset of the disease had a rare ATP1A3 variant or did not have any detectable ATP1A3 mutation. Those patients with a mutation in ATP1A3 had a significantly earlier median age at onset (5 months earlier) than for those without a mutation (P-value = 0.008). When contrasting the most common mutations, the age at onset for patients with the E815K mutation was 2.7 months earlier than those with other types of ATP1A3 mutations (P-value<0.0001), as well as 2.7 months earlier than those with the D801N mutation (P-value<0.0001) (Fig 2). Patients with E815K mutations achieved unsupported sitting later than those with the D801N mutation (P-value = 0.0020) and later than those with other mutations (P-value = 0.0002) (Fig 3). Patients with E815K mutations were also more likely to achieve independent walking later than those with other mutations (P-value = 0.0264) (Fig 4). Finally, patients with E815K mutation were almost 3 times more likely to present with status epilepticus during the course of the disease than the patients with other types of ATP1A3 mutations (P-value = 0.0206. Table 3)

Bottom Line: We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations.This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes.However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

View Article: PubMed Central - PubMed

Affiliation: Pediatric Motor Disorders Research Program, Departments of Neurology and Pediatrics, University of Utah, Salt Lake City, Utah, United States of America.

ABSTRACT
Mutations in ATP1A3 cause Alternating Hemiplegia of Childhood (AHC) by disrupting function of the neuronal Na+/K+ ATPase. Published studies to date indicate 2 recurrent mutations, D801N and E815K, and a more severe phenotype in the E815K cohort. We performed mutation analysis and retrospective genotype-phenotype correlations in all eligible patients with AHC enrolled in the US AHC Foundation registry from 1997-2012. Clinical data were abstracted from standardized caregivers' questionnaires and medical records and confirmed by expert clinicians. We identified ATP1A3 mutations by Sanger and whole genome sequencing, and compared phenotypes within and between 4 groups of subjects, those with D801N, E815K, other ATP1A3 or no ATP1A3 mutations. We identified heterozygous ATP1A3 mutations in 154 of 187 (82%) AHC patients. Of 34 unique mutations, 31 (91%) are missense, and 16 (47%) had not been previously reported. Concordant with prior studies, more than 2/3 of all mutations are clusteredin exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K(26%) and 11 had G947R (8%) mutations [corrected].Patients with an E815K mutation demonstrate an earlier age of onset, more severe motor impairment and a higher prevalence of status epilepticus. This study further expands the number and spectrum of ATP1A3 mutations associated with AHC and confirms a more deleterious effect of the E815K mutation on selected neurologic outcomes. However, the complexity of the disorder and the extensive phenotypic variability among subgroups merits caution and emphasizes the need for further studies.

No MeSH data available.


Related in: MedlinePlus