Movement disorders in ADAR1 disease: Insights from a comprehensive cohort.

ADAR1 variants are associated to rare and heterogenous neurological conditions, including Aicardi-Goutières syndrome type 6, bilateral striatal necrosis, and dyschromatosis symmetrica hereditaria. Movement disorders (MDs) commonly occur in ADAR1-related diseases although a complete overview on the phenomenology has not been provided yet. Here, a cohort of 57 patients with ADAR1-related diseases, including 3 unpublished patients and 54 previously reported cases, was reviewed. Data on demographics, clinical features of MDs, genetics and biomarkers were collected and descriptive statistics, group analysis for genotype and logistic regression were run. Manifestations of MD characterized the onset of ADAR1-related disease in 60% of patients. Specifically, dystonia occurred in 39% of cases, even as severe status dystonicus, while prevalence of other MDs was lower. Patients often presented brain lesions (>90%) and progressive disease course (43%), fatal in some cases. Clinical presentation and outcome differed among patients with distinct genotype. This review shows that phenomenology of MDs in ADAR1-related diseases is wide and heterogeneous, although a severe motor syndrome (often characterized by dystonia) secondary to brain lesions represents the most common manifestation. Waiting for future development of disease-modifying treatments, an appropriate symptomatic intervention is crucial for ADAR1 patients. Accordingly, a deeper knowledge of phenomenology is fundamental.

Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations.

ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.

ATP1A3-related epileptic encephalopathy responding to ketogenic diet.

BACKGROUND: Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na+-K+ ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported. CASE REPORT: Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development. CONCLUSIONS: Our case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary.