Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood—a study of 155 patients

Panagiotakaki, Eleni; De Grandis, Elisa; Stagnaro, Michela; Heinzen, Erin L.; Fons, Carmen; Sisodiya, Sanjay; de Vries, Boukje; Goubau, Christophe; Weckhuysen, Sarah; Kemlink, David; Scheffer, Ingrid; Lesca, Gaëtan; Rabilloud, Muriel; Klich, Amna; Ramirez-Camacho, Alia; Ulate-Campos, Adriana; Campistol, Jaume; Giannotta, Melania; Moutard, Marie-Laure; Doummar, Diane; Hubsch-Bonneaud, Cecile; Jaffer, Fatima; Cross, Helen; Gurrieri, Fiorella; Tiziano, Danilo; Nevsimalova, Sona; Nicole, Sophie; Neville, Brian; van den Maagdenberg, Arn M. J. M.; Mikati, Mohamad; Goldstein, David B.; Vavassori, Rosaria; Arzimanoglou, Alexis

doi:10.1186/s13023-015-0335-5

Orphanet Journal of Rare Diseases

Table 1 Genotype—phenotype correlations

From: Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood—a study of 155 patients

Genotype	Phenotype of patients encountered in this study
Genotype	Number of patients	Age at onset: first event/first hemiplegic attack	Age at last observation/Gender	Intellectual disability	Walking problems	Ataxia	Dystonia	Hemiplegia/Double hemiplegia attacks	Tonic attacks	Epilepsy	Other patients’ references
Cluster 1
p.Ser137Phe	1	Unknown	20y / F	++	Unknown	+	+	++++	++++	++	[21, 31]
p.Ser137Tyr	2	4 m / 4 m	9y / F	++	-	+	+	++++	Unknown	Remission	[21, 34, 35]
p.Ser137Tyr	2		2y / M	+	+		-	++++	-	-	[21, 34, 35]
Cluster 2
p.Ala264_Ala289delinsValLeuGly	1	2 m / 2 m	34y / M	-	++ (Regression- lost walking)	-	+++	+	+	-
p.Ile274Asn	1	Neonatal / 33 m	10y / M	+	-	-	+	+++++	+	-	[21, 22, 31]
p.Glu324Gln	1	1 m / 5 m	16y / M	+++	++ (Regression)	-	+++	++++	++++	-	[31]
p.Leu326Arg	1	8 m / 15 m	4y / F	+	-	-	-	Remission	Remission	-	[31]
c.993 + 1_993 + 2del ^$	1	12 m / 12 m	6y / M	-	-	-	+	+++	+	Remission
p.Cys333Phe	1	1 m / 15 m	4y / M	+	+ (Regression)	-	+	++++	+++	Remission	[21, 31]
p.Gly358Ser	1	Neonatal / 6 years	11y / M	+++	+	+		+++++	++++	++++
Cytoplasmic domain between Cluster 2 and 3
p.Cys596Arg	1	1 m / 24 m	21y / M	+++	-	+	+	+++	+++	+	[31]
p.Leu715Pro ^$	1	Neonatal / 3 m	2y / M	++	++	+	+	+++++	+	+++++
Cluster 3
p.Gly755Ser	3	4 m / 5 m	24y / M	-	-	Unknown	++	+++++	+++++	Remission	[21, 31, 33–35]
		6 m / 8 m	8y / M	+	-	++	Unknown	++++	++++	++
		6 m / 6 m	8y / M	Unknown	-	+	-	++++	-	-
p.Ser772Arg	2	9 m / 9 m	20y / M	++	+	+	++	+	+	+	[22, 31, 35]
p.Ser772Arg	2	5 m / 10 m	7y / M	++	-	-	++	++++	++++	-	[22, 31, 35]
p.Asn773Ser	2 mono-zygotic twins	Neonatal / 22 m	10y / F	+	-	-	-	++	+	Remission	[21]
p.Asn773Ser	2 mono-zygotic twins	Neonatal / 22 m	10y / F	+	-	-	-	+++	++++	Remission	[21]
p.Asp801Asn	57	2 m / 7 m (medians)	Median 15.7y	++	-	+++	++	++++	++++	+	[8, 21–23, 31, 33–35]
p.Asp801Val ^$	1	21 m / 21 m	23y / M	-	-	++	+	Remission	++++	-
p.Thr804Ile	2	2 m / 9 m	13y / F	+	-	-	+	++	++	-	[31, 33]
p.Thr804Ile	2	5 m / 5 m	10y / F	++	-	+	-	++	++	-	[31, 33]
p.Met806Arg	1	13 m / 13 m	6y / M	+	-	-	+	+++	+++	Remission	[21]
p.Ile810Asn ^£	1	7 m / 8 m	20y / M	++	-	+	-	+++	+++	Remission	[35]
p.Ser811Pro	2	1 m / 1 m	24y / F	++	+	++	++	+++++	+++++	++	[21, 31]
p.Ser811Pro	2	1 m / 1 m	20y / F	++	++	+	++	++++	-	+	[21, 31]
p.Glu815Lys	22	1 m / 6 m (medians)	Median 7.8y	+++	++	++	+++	++++	++++	+++	[8, 21–23, 31, 33–35]
Cluster 4
p.Leu839Pro	1	Neonatal	3 m / F	NA	NA	NA	++	+	++++	-	[31, 35]
c.2542 + 1G > A	1	1 m / 10 m	26y / F	++	+	-	+	+	-	+++	[21, 22, 31, 33]
p.Leu888Pro ^$	1	1 m / 7 m	19y / M	+++	-	-	++	++	++	+++
p.Val919del	2	Unknown	3y / F	+++	++		+	+++	+++	+	[21, 31]
p.Val919del	2	Neonatal / 5 m	17y / M	++	-	-	++	++++	++++	-	[21, 31]
p.Asp923Asn	2	4 m / 29 m	7y / F	-	-	+	-	+++	-	-	[34, 35, 40]
p.Asp923Asn	2	11 m / 24 m	4y / F	+	-	-	+	++	-	-	[34, 35, 40]
p.Cys927Phe	1	18 m / 18 m	15y / F	++	-	+	-	Remission	+++++	-	[34]
p.Cys927Trp	1	4 m / 4 m	37y / M	+	-	+	+	+	Remission	Remission
Cluster 5
p.Gly947Arg	15	3 m / 6 m (medians)	Median 15y	+	-	+	+	+++	+++	+	[8, 21, 31, 33–35]
p.Glu951Lys	1	4 m / 10 m	20y / M	++	+	+++	+	Remission	++	-
p.Ala955Asp	1	Neonatal	4y / M	+++	++	-	+	+++++	++++	++	[21]
p.Asp992Tyr	1	4 m / 8 m	32y / M	+	Unknown	Unknown	+++	+++	++	+	[21, 34]

Novel mutations found in this study are given in bold characters. Of them, de novo mutations (both parents available and tested negative) are marked by the symbol $; Y: years, M: male, F: female, m: months; £: p.Ile810Asn (c.2429 T > A) corresponds to the Myshkin mice mutation; Remission, means no present at the last observation; First event: first paroxysmal event of the disease, either hemiplegic or other (i.e. abnormal ocular movements, double hemiplegia, tonic/dystonic attacks); Unknown: missed information; NA: not applicable because of young age at last observation. Reference sequences for corresponding ATP1A3 transcript and protein were [NM_152296.3] and [Uniprot P13637], respectively

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ISSN: 1750-1172

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