Alternating hemiplegia of childhood: evolution over time and mouse model corroboration

Abstract

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by ATP1A3 mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort (n = 42, age 10.24±1.48 years) seen at one US center. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicenter cohort of alternating hemiplegia of childhood patients from France (n = 52). To investigate disease progression in the Mashlool mouse, we performed behavioral testing on a cohort of Mashlool- mice at prepubescent and adult ages (n = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores: p < 0.0001 for the non-paroxysmal disability index, intellectual disability scale, and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score (p = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score (p = 0.035). More patients with EEG background slowing was noted at last follow-up as compared to initial (p = 0.015). Mild worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score (p = 0.001) and first and last non-paroxysmal disability index score scores significantly differed (p = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (1) worse balance beam performance; (2) wider base of support; (3) higher severity of seizures and resultant mortality; and (4) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (1) Non-paroxysmal alternating hemiplegia of childhood manifestations show progression associated with severity of early-life non-paroxysmal disability and age. (2) Progression also occurs in Mashlool mice, confirming that ATP1A3 disease can lead to age-related worsening. (3) Clinical findings provide a basis for counseling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of ATP1A3-related neurodegeneration.

Methodology of a Natural History Study of a Rare Neurodevelopmental Disorder: Alternating Hemiplegia of Childhood as a Prototype Disease

“…The results of this study were useful to refine our OBSERV-AHC study design and procedures and were published in the journal Brain Communications. 3 The experience gained in this study strengthened our final study plan. 9.…”

“…The results of this study were useful to refine our OBSERV-AHC study design and procedures and were published in the journal Brain Communications . 3 The experience gained in this study strengthened our final study plan. Modify the study plan based on the prior experience of the pilot study and further discussions of the study team and statisticians : Based on the above pilot study, we finalized the number of patients, using power analysis, and the statistical methods that will be needed to achieve our goals. Based on this, we confirmed the need for a larger study to represent the population of alternating hemiplegia of childhood because of its heterogeneity and to improve its statistical power.…”

“…In this methodological article, when we state "study," we are referring to our "OBSERV-AHC" natural history study and when we refer to "pilot study," we are referring to our pilot study that has been completed and the results of which have been published. 3…”

Genetically altered animal models forATP1A3-related disorders

“…After injection of KA into the amygdala, Mashl/+ mice show ECG abnormalities in response to seizure activity ( Balestrini et al, 2020 ). Compared with young (5-week-old) Mashl/+ mice, adult (17-week-old) Mashl/+ mice exhibit an inferior beam-walking performance and an increased severity of seizures and mortality induced by cold water (5-10°C) swimming for 4 min ( Uchitel et al, 2021 ), suggestive of disease progression.…”

“…Among 87 patients with AHC, 60% exhibited resting electrocardiogram (ECG) abnormalities ( Balestrini et al, 2020 ). Whether AHC is a progressive disorder remains unclear, but a study of 94 patients with AHC detected mild worsening of motor and intellectual disability with age ( Uchitel et al, 2021 ), while abrupt stepwise deterioration ( Sasaki et al, 2014 ) and progressive brain atrophy ( Saito et al, 1998 ; Sasaki et al, 2017 ) in AHC patients have also been reported. The most common AHC-causing mutations in ATP1A3 are D801N, E815K and G947R ( ), of which E815K has the most severe phenotype ( Sasaki et al, 2014 ; Yang et al, 2014 ).…”