Clinical and genetic analysis in alternating hemiplegia of childhood: Ten new patients from Southern Europe

Vila‐Pueyo, Marta; Pons, Roser; Raspall-Chaure, Miquel; Marcé‐Grau, Anna; Carreño, Oriel; Sintas, Cèlia; Cormand, Bru; Pineda-Marfà, Mercè; Macaya, Alfons

doi:10.1016/j.jns.2014.06.014

Cited by 18 publications

(13 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since mutations in ATP1A3 were first identified in 2012 in patients with AHC, the prevalence of mutations in sporadic patients meeting classic diagnostic criteria for AHC has ranged from 70% to 100% across a variety of ethnic backgrounds [ 12 – 20 ]. The 2 most common mutations, D801N and E815K, account for more than 60% of all ATP1A3 mutations resulting in an AHC phenotype [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

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 clustered in exons 17 and 18. Of 143 simplex occurrences, 58 had D801N (40%), 38 had E815K (26%) and 11 had G937R (8%) mutations. 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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Our study was based on the hypothesis that paroxysmal episodes are linked to a defective brain energy supply. The following observations are consistent with this hypothesis: i) paroxysmal episodes in AHC share some common triggering factors seen in patent disorders of brain energy metabolism such as glut1 deficiency syndrome [ 2 , 12 , 23 , 24 , 27 ]; ii) attacks can generally be terminated by inducing sleep that might reflect a reduced brain energy demand [ 2 , 12 ]; iii) an anecdotal report mentions the sustained disappearance of paroxysmal episodes on a ketogenic diet, which efficiently compensates for defective brain glucose metabolism [ 14 , 15 , 18 ]; iv) neuroimaging studies of interictal brain glucose metabolism showed focal areas of reduced glucose metabolism in AHC patients [ 16 ] and in an AHC mouse model [ 17 ]; and v) Na + /K + ATPase dysfunction might influence sodium-dependent brain glucose transportation, particularly in situations where brain energy demand is increased [ 28 – 30 ]. Triheptanoin has been shown to improve cerebral bioenergetics in various conditions associated with brain energy defects [ 19 , 20 , 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…Both clinical and radiological data have raised the possibility that a transient brain energy deficit might play a critical role for the paroxysmal manifestations of AHC. Clinical observation found similar triggering factors in AHC and in obvious disorders of brain energy metabolism such as GLUT1 deficiency syndrome [ 12 , 14 , 15 ]. Imaging studies described cerebral glucose hypometabolism on interictal period in human [ 16 ] and in a AHC mouse model (Myshkin mice) [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood

Hainque

Caillet

Leroy³

et al. 2017

Orphanet J Rare Dis

View full text Add to dashboard Cite

BackgroundBased on the hypothesis of a brain energy deficit, we investigated the safety and efficacy of triheptanoin on paroxysmal episodes in patients with alternating hemiplegia of childhood due to ATP1A3 mutations.MethodsWe conducted a randomized, double-blind, placebo-controlled crossover study of triheptanoin, at a target dose corresponding to 30% of daily calorie intake, in ten patients with alternating hemiplegia of childhood due to ATP1A3 mutations. Each treatment period consisted of a 12-week fixed-dose phase, separated by a 4-week washout period. The primary outcome was the total number of paroxysmal events. Secondary outcomes included the number of paroxysmal motor-epileptic events; a composite score taking into account the number, severity and duration of paroxysmal events; interictal neurological manifestations; the clinical global impression-improvement scale (CGI-I); and safety parameters. The paired non-parametric Wilcoxon test was used to analyze treatment effects.ResultsIn an intention-to-treat analysis, triheptanoin failed to reduce the total number of paroxysmal events (p = 0.646), including motor-epileptic events (p = 0.585), or the composite score (p = 0.059). CGI-I score did not differ between triheptanoin and placebo periods. Triheptanoin was well tolerated.ConclusionsTriheptanoin does not prevent paroxysmal events in Alternating hemiplegia of childhood. We show the feasibility of a randomized placebo-controlled trial in this setting.Trial registrationThe study has been registered with clinicaltrials.gov (NCT002408354) the 03/24/2015.

show abstract

“…But the glucose level in these children were not documented. 12 Sasaki et al demonstrated cerebral glucose deficiency in AHC patients by positron emission tomography (PET). Low glucose metabolism was found in the frontal lobes, putamen, and cerebellum of patients with AHC as measured by fluoro-2-deoxy-D-glucose PET.…”

Section: Discussionmentioning

confidence: 99%

Alternating Hemiplegia of Childhood in an Infant with Symptoms Resembling Glucose Transporter 1 Deficiency

et al. 2017

View full text Add to dashboard Cite

Glucose transporter type 1 (glut1) deficiency syndrome presents with developmental delay, microcephaly, and recurrent seizures during infancy, as well as cerebrospinal fluid (CSF) hypoglycorrhachia and mutations in the SLC2A1 gene. We describe a baby with microcephaly, global developmental delay, seizures from 3 months of age, and CSF glucose in the lower limit of normal range, with heterozygous p.Glu815Lys mutation of the ATP1A3 gene and no mutation in the SLC2A1 gene. Mutations in ATP1A3 gene are associated with alternating hemiplegia of childhood (AHC). Interestingly the baby developed episodes of recurrent bouts of alternating hemiplegia from 13 months of age. The case is reported to highlight ATP1A3 mutation as a probable etiology for glut1 deficiency like syndrome and AHC. A brief review of literature emphasizing the overlapping paroxysmal and nonparoxysmal symptoms of the two conditions is also included.

show abstract

Clinical and genetic analysis in alternating hemiplegia of childhood: Ten new patients from Southern Europe

Cited by 18 publications

References 24 publications

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

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

A randomized, controlled, double-blind, crossover trial of triheptanoin in alternating hemiplegia of childhood

Alternating Hemiplegia of Childhood in an Infant with Symptoms Resembling Glucose Transporter 1 Deficiency

Contact Info

Product

Resources

About