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1.  Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood—a study of 155 patients 
Background
Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype.
Methods
Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient.
Results
In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations.
Conclusions
Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clusters within the ATP1A3 gene. Our description of the clinical profile of patients with the most frequent mutations and the clinical picture of those with less common mutations confirms the results from previous studies, and further expands the spectrum of genotype-phenotype correlations. Our results may be useful to confirm diagnosis and may influence decisions to ensure appropriate early medical intervention in patients with AHC. They provide a stronger basis for the constitution of more homogeneous groups to be included in clinical trials.
Electronic supplementary material
The online version of this article (doi:10.1186/s13023-015-0335-5) contains supplementary material, which is available to authorized users.
doi:10.1186/s13023-015-0335-5
PMCID: PMC4583741  PMID: 26410222
Alternating hemiplegia of childhood; ATP1A3; Genotype-phenotype
2.  De novo mutations in ATP1A3 cause alternating hemiplegia of childhood 
Heinzen, Erin L. | Swoboda, Kathryn J. | Hitomi, Yuki | Gurrieri, Fiorella | Nicole, Sophie | de Vries, Boukje | Tiziano, F. Danilo | Fontaine, Bertrand | Walley, Nicole M. | Heavin, Sinéad | Panagiotakaki, Eleni | Fiori, Stefania | Abiusi, Emanuela | Di Pietro, Lorena | Sweney, Matthew T. | Newcomb, Tara M. | Viollet, Louis | Huff, Chad | Jorde, Lynn B. | Reyna, Sandra P. | Murphy, Kelley J. | Shianna, Kevin V. | Gumbs, Curtis E. | Little, Latasha | Silver, Kenneth | Ptác̆ek, Louis J. | Haan, Joost | Ferrari, Michel D. | Bye, Ann M. | Herkes, Geoffrey K. | Whitelaw, Charlotte M. | Webb, David | Lynch, Bryan J. | Uldall, Peter | King, Mary D. | Scheffer, Ingrid E. | Neri, Giovanni | Arzimanoglou, Alexis | van den Maagdenberg, Arn M.J.M. | Sisodiya, Sanjay M. | Mikati, Mohamad A. | Goldstein, David B. | Nicole, Sophie | Gurrieri, Fiorella | Neri, Giovanni | de Vries, Boukje | Koelewijn, Stephany | Kamphorst, Jessica | Geilenkirchen, Marije | Pelzer, Nadine | Laan, Laura | Haan, Joost | Ferrari, Michel | van den Maagdenberg, Arn | Zucca, Claudio | Bassi, Maria Teresa | Franchini, Filippo | Vavassori, Rosaria | Giannotta, Melania | Gobbi, Giuseppe | Granata, Tiziana | Nardocci, Nardo | De Grandis, Elisa | Veneselli, Edvige | Stagnaro, Michela | Gurrieri, Fiorella | Neri, Giovanni | Vigevano, Federico | Panagiotakaki, Eleni | Oechsler, Claudia | Arzimanoglou, Alexis | Nicole, Sophie | Giannotta, Melania | Gobbi, Giuseppe | Ninan, Miriam | Neville, Brian | Ebinger, Friedrich | Fons, Carmen | Campistol, Jaume | Kemlink, David | Nevsimalova, Sona | Laan, Laura | Peeters-Scholte, Cacha | van den Maagdenberg, Arn | Casaer, Paul | Casari, Giorgio | Sange, Guenter | Spiel, Georg | Boneschi, Filippo Martinelli | Zucca, Claudio | Bassi, Maria Teresa | Schyns, Tsveta | Crawley, Francis | Poncelin, Dominique | Vavassori, Rosaria
Nature genetics  2012;44(9):1030-1034.
Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurologic manifestations. AHC is usually a sporadic disorder with unknown etiology. Using exome sequencing of seven patients with AHC, and their unaffected parents, we identified de novo nonsynonymous mutations in ATP1A3 in all seven AHC patients. Subsequent sequence analysis of ATP1A3 in 98 additional patients revealed that 78% of AHC cases have a likely causal ATP1A3 mutation, including one inherited mutation in a familial case of AHC. Remarkably, six ATP1A3 mutations explain the majority of patients, including one observed in 36 patients. Unlike ATP1A3 mutations that cause rapid-onset-dystonia-parkinsonism, AHC-causing mutations revealed consistent reductions in ATPase activity without effects on protein expression. This work identifies de novo ATP1A3 mutations as the primary cause of AHC, and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in this gene.
doi:10.1038/ng.2358
PMCID: PMC3442240  PMID: 22842232
3.  Identification of a rare 17p13.3 duplication including the BHLHA9 and YWHAE genes in a family with developmental delay and behavioural problems 
BMC Medical Genetics  2012;13:93.
Background
Deletions and duplications of the PAFAH1B1 and YWHAE genes in 17p13.3 are associated with different clinical phenotypes. In particular, deletion of PAFAH1B1 causes isolated lissencephaly while deletions involving both PAFAH1B1 and YWHAE cause Miller-Dieker syndrome. Isolated duplications of PAFAH1B1 have been associated with mild developmental delay and hypotonia, while isolated duplications of YWHAE have been associated with autism. In particular, different dysmorphic features associated with PAFAH1B1 or YWHAE duplication have suggested the need to classify the patient clinical features in two groups according to which gene is involved in the chromosomal duplication.
Methods
We analyze the proband and his family by classical cytogenetic and array-CGH analyses. The putative rearrangement was confirmed by fluorescence in situ hybridization.
Results
We have identified a family segregating a 17p13.3 duplication extending 329.5 kilobases by FISH and array-CGH involving the YWHAE gene, but not PAFAH1B1, affected by a mild dysmorphic phenotype with associated autism and mental retardation. We propose that BHLHA9, YWHAE, and CRK genes contribute to the phenotype of our patient. The small chromosomal duplication was inherited from his mother who was affected by a bipolar and borderline disorder and was alcohol addicted.
Conclusions
We report an additional familial case of small 17p13.3 chromosomal duplication including only BHLHA9, YWHAE, and CRK genes. Our observation and further cases with similar microduplications are expected to be diagnosed, and will help better characterise the clinical spectrum of phenotypes associated with 17p13.3 microduplications.
doi:10.1186/1471-2350-13-93
PMCID: PMC3495055  PMID: 23035971
Familial 17p13.3 duplication syndrome; PAFAH1B1 and YWHAE genes; Array-CGH

Results 1-3 (3)