Social impairments in alternating hemiplegia of childhood.

AIM: To evaluate presence and severity of social impairments in alternating hemiplegia of childhood (AHC) and determine factors that are associated with social impairments. METHOD: This was a retrospective analysis of 34 consecutive patients with AHC (19 females, 15 males; mean age: 9y 7mo, SD 8y 2mo, range 2y 7mo-40y), evaluated with the Social Responsiveness Scale, Second Edition (SRS-2). RESULTS: SRS-2 scores, indicating level of social impairment, were higher than population means (75, SD 14 vs 50, SD 10, p<0.001). Of these, 27 out of 34 had high scores: 23 severe (>76), four moderate (66-76). All subscale domains, including social cognition, social communication, social awareness, social motivation, restricted interests, and repetitive behavior, had abnormal scores compared to population means (p<0.001). High SRS-2 scores were associated with the presence of autism spectrum disorder (ASD) and epilepsy (p=0.01, p=0.04), but not with other scales of AHC disease symptomatology. All nine patients who received formal evaluations for ASD, because they had high SRS-2 scores, were diagnosed with ASD. INTERPRETATION: Most patients with AHC have impaired social skills involving multiple domains. ASD is not uncommon. High SRS-2 scores in patients with AHC support referral to ASD evaluation. Our findings are consistent with current understandings of the pathophysiology of AHC and ASD, both thought to involve GABAergic dysfunction. WHAT THIS PAPER ADDS: Most patients with alternating hemiplegia of childhood (AHC) have impaired social skills involving multiple domains. These impairments are significant compared to population means. Most patients with AHC have high Social Responsiveness Scale, Second Edition (SRS-2) scores. Patients with AHC with high SRS-2 scores are likely to have autism spectrum disorder.

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

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 centre. 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 multicentre cohort of alternating hemiplegia of childhood patients from France (n = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural 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 were noted at last follow-up as compared to initial (P = 0.015). Similar 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, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that ATP1A3 disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling 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.

Magnetic resonance imaging volumetric analysis in patients with Alternating hemiplegia of childhood: A pilot study.

Quantitative MRI is increasingly being used as a biomarker in neurological disorders. Cerebellar atrophy occurs in some Alternating Hemiplegia of Childhood (AHC) patients. However, it is not known if cerebellar atrophy can be a potential biomarker in AHC or if quantitative MRI is a reliable method to address this question. Here we determine the reproducibility of an MRI-volumetrics method to investigate brain volumes in AHC and apply it to a population of 14 consecutive AHC patients (ages 4-11 years). We studied method reproducibility in the first 11 patients and then performed correlation of cerebellar volumes, relative to published normal population means, with age in all 14. We used FreeSurfer 6.0.0 to automatically segment MRI images, then performed manual resegmentation correction by two different observers. No significant differences were observed in any of ten brain regions between the two reviewers: p > .591 and interclass Correlation Coefficient (ICC) ≥0.975 in all comparisons. Additionally, there were no significant differences between the means of the two reviewers and the automatic segmentation values: p ≥ .106 and ICC ≥0.994 in all comparisons. We found a negative correlation between cerebellar volume and age (R = -0.631, p = .037), even though only one patient showed any cerebellar atrophy upon formal readings of the MRIs by neuroradiology. Sample size did not allow us to rule out potential confounding variables. Thus, findings from this cross-sectional study should be considered as exploratory. Our study supports the prospective investigation of quantitative MRI-volumetrics of the cerebellum as a potential biomarker in AHC.