Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Alternating Hemiplegia of Childhood: gastrointestinal manifestations and correlation with neurological impairments.

BACKGROUND: Alternating Hemiplegia of Childhood (AHC) is caused by mutations of the ATP1A3 gene which is expressed in brain areas that include structures controling autonomic, gastrointestinal, gut motility and GABAergic functions. We aimed to investigate, in a cohort of 44 consecutive AHC patients, two hypotheses: 1) AHC patients frequently manifest gastrointestinal, particularly motility, problems. 2) These problems are often severe and their severity correlates with neurological impairments. RESULTS: 41/44 (93%) exhibited gastrointestinal symptoms requiring medical attention. For these 41 patients, symptoms included constipation (66%), swallowing problems (63%), vomiting (63%), anorexia (46%), diarrhea (44%), nausea (37%), and abdominal pain (22%). Symptoms indicative of dysmotility occurred in 33 (80%). The most common diagnoses were oropharyngeal dysphagia (63%) and gastroesophageal reflux (63%). 16 (39%) required gastrostomy and two fundoplication. Severity of gastrointestinal symptoms correlated with non-paroxysmal neurological disability index, Gross Motor Function Classification System scores, and with the presence/absence of non-gastrointestinal autonomic dysfunction (p = 0.031, 0.043, Spearman correlations and 0.0166 Cramer's V, respectively) but not with the paroxysmal disability index (p = 0.408). CONCLUSIONS: Most AHC patients have gastrointestinal problems. These are usually severe, most commonly are indicative of dysmotility, often require surgical therapies, and their severity correlates with that of non-paroxysmal CNS manifestations. Our findings should help in management-anticipatory guidance of AHC patients. Furthermore, they are consistent with current understandings of the pathophysiology of AHC and of gastrointestinal dysmotility, both of which involve autonomic and GABAergic dysfunction.

D-DEMØ, a distinct phenotype caused by ATP1A3 mutations.

OBJECTIVE: To describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset. METHODS: Review and analysis of clinical and genetic data. RESULTS: Patients shared the above traits and had whole-exome sequencing that showed de novo variants of the ATP1A3 gene, predicted to be disease causing and occurring in regions of the protein critical for pump function. Patient 1 (c.1079C>G, p.Thr360Arg), an 8-year-old girl, presented on day 1 of life with episodic dystonia, complex partial seizures, and facial dysmorphism. MRI of the brain revealed cerebellar hypoplasia. Patient 2 (c.420G>T, p.Gln140His), an 18-year-old man, presented on day 1 of life with hypotonia, tremor, and facial dysmorphism. He later developed dystonia. MRI of the brain revealed cerebellar hypoplasia and, later, further cerebellar volume loss (atrophy). Patient 3 (c.974G>A, Gly325Asp), a 13-year-old girl, presented on day 1 of life with tremor, episodic dystonia, and facial dysmorphism. MRI of the brain showed severe cerebellar hypoplasia. Patient 4 (c.971A>G, p.Glu324Gly), a 14-year-old boy, presented on day 1 of life with tremor, hypotonia, dystonia, nystagmus, facial dysmorphism, and later seizures. MRI of the brain revealed moderate cerebellar hypoplasia. CONCLUSIONS: D-DEMØ represents an ATP1A3-related phenotype, the observation of which should trigger investigation for ATP1A3 mutations. Our findings, and the presence of multiple distinct ATP1A3-related phenotypes, support the possibility that there are differences in the underlying mechanisms.

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.

The epileptology of alternating hemiplegia of childhood.

OBJECTIVE: To report our experience and investigate 5 original hypotheses: (1) multiple types of epileptic seizures occur in alternating hemiplegia of childhood (AHC), and these can be the initial presentation; (2) epileptiform abnormalities often appear well after clinical seizures; (3) nonepileptic reduced awareness spells (RAS) occur frequently; (4) epilepsy is commonly drug resistant but may respond to vagal nerve stimulation (VNS); and (5) status epilepticus (SE) is common and is usually refractory and recurrent. METHODS: We analyzed a cohort of 51 consecutive patients with AHC. RESULTS: Thirty-two of 51 patients had epilepsy: 18 focal seizures, frontal more frequently than temporal, and then posterior. Eleven had primary generalized seizures (tonic-clonic, myoclonic, and/or absence). Epileptic seizures preceded other AHC paroxysmal events in 8 (lag 5.63 ± 6.55 months; p = 0.0365). In 7 of 32, initial EEGs were normal, with the first epileptiform EEG lagging behind by 3.53 ± 4.65 years (p = 0.0484). RAS occurred equally in patients with epilepsy (16 of 32) and patients without epilepsy (10 of 19, p = 1.0). Twenty-eight patients had video-EEG; captured RAS showed no concomitant EEG changes. Nineteen patients (59%) were drug resistant. VNS resulted in >50% reduction in seizures in 5 of 6 (p < 0.04). Twelve patients (38%) had SE (9 of 12 multiple episodes), refractory/superrefractory in all (p < 0.001), and 4 of 12 had regression after SE. CONCLUSIONS: Epilepsy in AHC can be focal or generalized. Epileptic seizures may be the first paroxysmal symptom. EEG may become epileptiform only on follow-up. Epilepsy, although frequently drug resistant, can respond to VNS. RAS are frequent and nonepileptic. SE often recurs and is usually refractory/superrefractory. Our observations are consistent with current data on AHC-ATP1A3 pathophysiology.

Polysomnography Findings and Sleep Disorders in Children With Alternating Hemiplegia of Childhood.

STUDY OBJECTIVES: Patients with alternating hemiplegia of childhood (AHC) experience bouts of hemiplegia and other paroxysmal spells that resolve during sleep. Patients often have multiple comorbidities that could negatively affect sleep, yet sleep quality and sleep pathology in AHC are not well characterized. This study aimed to report sleep data from both polysomnography (PSG) and clinical evaluations in children with AHC. METHODS: We analyzed nocturnal PSG and clinical sleep evaluation results of a cohort of 22 consecutive pediatric patients with AHC who were seen in our AHC multidisciplinary clinic and who underwent evaluations according to our comprehensive AHC clinical pathway. This pathway includes, regardless of presenting symptoms, baseline PSG and evaluation by a board-certified pediatric sleep specialist. RESULTS: Out of 22 patients, 20 had at least one type of sleep problem. Six had obstructive sleep apnea as documented on polysomnogram, of whom two had no prior report of sleep-disordered breathing symptoms. Patients had abnormal mean overall apnea-hypopnea index of 5.8 (range 0-38.7) events/h and an abnormal mean arousal index of 15.0 (range 4.8-46.6) events/h. Based on sleep history, 16 patients had difficulty falling asleep, staying asleep, or both; 9 had behavioral insomnia of childhood; and 2 had delayed sleep-wake phase syndrome. CONCLUSIONS: Sleep dysfunction is common among children with AHC. Physicians should routinely screen for sleep pathology, with a low threshold to obtain a nocturnal PSG.

Cognitive, adaptive, and behavioral profiles and management of alternating hemiplegia of childhood.

AIM: To determine the neuropsychological abnormalities that occur in alternating hemiplegia of childhood (AHC) and report on our experience in managing them. METHOD: Patients underwent evaluations according to our standardized AHC pathway. Data were entered into our prospective AHC database and then analyzed. RESULTS: Of the cohort of 25 consecutive patients (ages 15mo-42y), eight had initial chief complaints about cognition, 14 language, five attention, and 11 behavior. As compared to population norms means, neuropsychological and behavioral assessment tools (including Child Behavior Checklist, Vineland Adaptive Behavior Scales, Peabody Picture Vocabulary, and Wechsler Intelligence Quotient tests) showed significant impairments in multiple domains: cognition, expressive and receptive language, executive function/attention, and behavior (p<0.05 in all comparisons). Evaluations generated management recommendations in all patients. Twenty had neuropsychiatric diagnoses: 10 attention-deficit/hyperactivity disorder (ADHD), seven disruptive behavior, and three anxiety disorder. Eight out of nine patients with ADHD who were prescribed medications responded to pharmacotherapy. INTERPRETATION: Patients with AHC have developmental difficulties related to impairments in multiple neuropsychological domains. This supports the hypothesis that the underlying AHC pathophysiology involves diffuse neuronal dysfunction. Testing generated recommendations to help manage these difficulties. Patients with AHC also have a range of neuropsychiatric diagnoses, the most common being ADHD which responds to pharmacotherapy. WHAT THIS PAPER ADDS: Patients with alternating hemiplegia of childhood (AHC) have developmental difficulties with underlying neuropsychological impairments. The findings in this study are consistent with an underlying AHC pathophysiology which involves diffuse neuronal, probably largely GABAergic, dysfunction. Patients with AHC have a range of neuropsychiatric diagnoses, the most common being attention-deficit/hyperactivity disorder.

Motor function domains in alternating hemiplegia of childhood.

AIM: To characterize motor function profiles in alternating hemiplegia of childhood, and to investigate interrelationships between these domains and with age. METHOD: We studied a cohort of 23 patients (9 males, 14 females; mean age 9y 4mo, range 4mo-43y) who underwent standardized tests to assess gross motor, upper extremity motor control, motor speech, and dysphagia functions. RESULTS: Gross Motor Function Classification System (GMFCS), Gross Motor Function Measure-88 (GMFM-88), Manual Ability Classification System (MACS), and Revised Melbourne Assessment (MA2) scales manifested predominantly mild impairments; motor speech, moderate to severe; Modified Dysphagia Outcome and Severity Scale (M-DOSS), mild-to moderate deficits. GMFCS correlated with GMFM-88 scores (Pearson's correlation, p=0.002), MACS (p=0.038), and MA2 fluency (p=0.005) and accuracy (p=0.038) scores. GMFCS did not correlate with motor speech (p=0.399), MA2 dexterity (p=0.247), range of motion (p=0.063), or M-DOSS (p=0.856). Motor speech was more severely impaired than the GMFCS (p<0.013). There was no correlation between any of the assessment tools and age (p=0.210-0.798). INTERPRETATION: Our data establish a detailed profile of motor function in alternating hemiplegia of childhood, argue against the presence of worse motor function in older patients, identify tools helpful in evaluating this population, and identify oropharyngeal function as the more severely affected domain, suggesting that brain areas controlling this function are more affected than others.