Abstract
Alternating hemiplegia of childhood is a rare neurological disease characterized by paroxysmal movement disorders and chronic neurological disturbances, with onset before 18 months of age. Mutations in the ATP1A3 gene have been identified in up to 80% of patients. Thirty-nine patients [20 females, 19 males, mean age 25.32 years (7.52–49.34)] have been recruited through the Italian Biobank and Clinical Registry for Alternating Hemiplegia of Childhood. Demographic data, genotype, paroxysmal movement disorders, chronic neurological features, and response to flunarizine have been analyzed. ATP1A3 gene mutations have been detected in 92.3% of patients. Patients have been divided into three groups—p.Asp801Asn mutation patients (26%), p.Glu815Lys cases (23%), and patients with other ATP1A3 mutations—and statistically compared. The Italian cohort has a higher percentage of ATP1A3 gene mutation than reported in literature (92.3%). Our data confirm a more severe phenotype in patients with p.Glu815Lys mutation, with an earlier age of onset of plegic (p = 0.02 in the correlation with other mutations) and tonic attacks. P.Glu815Lys patients most frequently present altered muscle tone, inability to walk (p = 0.01 comparing p.Glu815Lys and p.Asp801Asn mutations), epilepsy, and a more severe grade of dystonia (p < 0.05 comparing p.Glu815Lys and p.Asp801Asn mutations). They have moderate/severe intellectual disability and severe language impairment (p < 0.05). Interestingly, flunarizine seems to be more efficacious in patients with p.Glu815Lys mutation than p.Asp801Asn. In conclusion, our research suggests a genotype–phenotype correlation and provides information on this disorder's features, clinical course, and treatment.
Highlights
Alternating Hemiplegia of Childhood (AHC) (OMIM #614820) is a rare and peculiar neurologic disorder, first described in 1971 [1]
Mutations in the ATP1A3 gene are associated with other neurological diseases such as rapid-onset dystonia-parkinsonism (DYT12, OMIM 128235) [9], cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndrome (OMIM # 601338) [17], the early infantile epilepsy with encephalopathy (EIEE) [18], and the recurrent encephalopathy with cerebellar ataxia (RECA) phenotype [19]
Our study reports genotype–phenotype correlation and provides information on paroxysmal and non-paroxysmal features, clinical course, and treatment of a cohort of 39 Italian AHC patients
Summary
Alternating Hemiplegia of Childhood (AHC) (OMIM #614820) is a rare and peculiar neurologic disorder, first described in 1971 [1]. In 2012, In 2012, two independent research groups - a group of German researchers [9] and an international consortium [10]—identified de novo heterozygous mutations in the ATP1A3 gene performing next-generation sequencing to examine the genome of AHC patients [11]. This finding was replicated by an independent Japanese study that found ATP1A3 mutations in patients with AHC [12]. Pathogenic variants in the ATP1A3 gene are recognized as causing AHC in nearly 80% of patients [13]. It has been widely demonstrated that flunarizine induces a significant improvement in dystonic and plegic episodes [26]
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