Alternating Hemiplegia of Childhood: Genotype–Phenotype Correlations in a Cohort of 39 Italian Patients

Cordani, Ramona; Stagnaro, Michela; Pisciotta, Livia; Tiziano, Francesco Danilo; Calevo, Maria Grazia; Nobili, Lino; Grandis, Elisa De

doi:10.3389/fneur.2021.658451

Cited by 13 publications

(8 citation statements)

References 30 publications

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“…With whole exome sequencing (WES), we were able to end the diagnostic odyssey for this family. Some studies have shown that symptoms of AHC can be improved with the use of Flunarizine (Cordani et al, 2021 ; Kusunoki et al, 2020 ). Flunarizine is a selective calcium channel entry blocker with calmodulin binding properties and histamine H1 blocking activity (Upadhyay & Ali, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population

Ford,

Littlejohn,

German

et al. 2023

Molec Gen & Gen Med

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BackgroundGenomic medicine is revolutionizing the diagnosis of rare diseases, but the implementation has not benefited underrepresented populations to the same degree. Here, we report the case of a 7‐year‐old boy with hypotonia, global developmental delay, strabismus, seizures, and previously suspected mitochondrial myopathy. This proband comes from an underrepresented minority and was denied exome sequencing by his public insurance.MethodsAfter informed consent was obtained, buccal cells from the proband were collected and whole exome sequencing was performed. Illumina Dragen and Emedgene software was used to analyze the data at Baylor Genetics. The variants were further intepreted according to ACMG guidelines and the patient's phenotype.ResultsThrough whole‐exome sequencing (WES) under the Community Texome project, he was found to have a heterozygous de novo pathogenic variant in the ATP1A3 gene located on chromosome 19q13.ConclusionIn retrospect, his symptomatology matches the known medical conditions associated with the ATP1A3 gene namely Alternating Hemiplegia of Childhood 2 (AHC), a rare autosomal dominant disorder with an incidence of 1 in one million. His single nucleotide variant, (c.2401G>A, p.D801N), is predicted to be damaging. The specific amino acid change p.D801N has been previously reported in ClinVar along with the allelic variant p.D801Y and both are considered pathogenic. The identification of this variant altered medical management for this patient as he was started on a calcium antagonist and has reported no further hemiplegic episodes. This case illustrates the value of implementing genomic medicine for precision therapy in underserved populations.

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Section: Discussionmentioning

confidence: 99%

Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population

Ford,

Littlejohn,

German

et al. 2023

Molec Gen & Gen Med

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“…Any of these dysfunctions may have an important long-term effect on children with AHC. The episodes of hemiplegic episodes tend to decrease as the child gets older, [1,2] and in a recent study by Cordani et al, [51] epileptic seizures were found in 24/39 (62%) of AHC patients, which may have a deleterious role in the course of the disorder. particularly if seizures are drug-resistant.…”

Section: Alternating Hemiplegia Of Childhoodmentioning

confidence: 99%

“…Despite the growing number of pathogenic variants described, the most extensive cohort studies conducted in various populations have shown that 3 variants account for approximately 60% of all cases. [51] The p.Asp801Asn variant is detected in 30%–43%, p.Glu815Lys is responsible for 16%–35%, and p.Gly947Arg is responsible for 8%–15% of cases. [6,52,53] Other gene mutations (CACNA1A, SLC1A3, and SLC2A1) have occasionally been related to AHC showing similar clinical presentations.…”

Section: Alternating Hemiplegia Of Childhoodmentioning

confidence: 99%

“…Mutations in ATP1A3 are more frequent causes of AHC, presenting in about 78% of the cases [10] and 92% in a recent Italian study. [51] Aside AHC and ATP1A3 mutations have been linked to other clinical entities, such as ATP1A3 -related disorders. These disorders represent a clinical continuum that includes various distinct entities: AHC, rapid-onset dystonia-parkinsonism (RPD), [18] and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndromes.…”

Section: Ahc and Atp1a3-related Disordersmentioning

confidence: 99%

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Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review

et al. 2022

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Alternating Hemiplegia of Childhood (AHC) is a rare disorder with onset in the first 18 months of life characterized by stereotyped paroxysmal manifestations of tonic and dystonic attacks, nystagmus with other oculomotor abnormalities, respiratory and autonomic dysfunctions. AHC is often associated with epileptic seizures and developmental delay. Hemiplegic paroxysm is the most remarkable symptom, although AHC includes a large series of clinical manifestations that interfere with the disease course. No cure is available and the treatment involves many specialists and therapies. Flunarizine is the most commonly used drug for reducing the frequency and intensity of paroxysmal events. Mutations in ATP1A2, particularly in ATP1A3, are the main genes responsible for AHC. Some disorders caused by ATP1A3 variants have been defined as ATP1A3-related disorders, including rapid-onset dystonia-parkinsonism, cerebellar ataxia, pes cavus, optic atrophy, sensorineural hearing loss, early infant epileptic encephalopathy, child rapid-onset ataxia, and relapsing encephalopathy with cerebellar ataxia. Recently, the term ATP1A3 syndrome has been identified as a fever-induced paroxysmal weakness and encephalopathy, slowly progressive cerebellar ataxia, childhood–onset schizophrenia/autistic spectrum disorder, paroxysmal dyskinesia, cerebral palsy/spastic paraparesis, dystonia, dysmorphism, encephalopathy, MRI abnormalities without hemiplegia, and congenital hydrocephalus. Herewith, we discussed about historical annotations of AHC, symptoms, signs and associated morbidities, diagnosis and differential diagnosis, treatment, prognosis, and genetics. We also reported on the ATP1A3-related disorders and ATP1A3 syndrome, as 2 recently established and expanded genetic clinical entities.

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“…Affected children also develop dysautonomic symptoms that may require emergency cardiopulmonary resuscitation. Although flunarizine is effective in decreasing the frequency and magnitude of hemiplegic attacks ( Cordani et al, 2021 ), the medication does not necessarily prevent sudden unexpected death in epilepsy or cardiac arrhythmia ( Jaffer et al, 2015 ). Thus, the long-term outcomes of AHC need to be improved.…”

Section: Introductionmentioning

confidence: 99%

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress

Fujii,

Kanemasa,

Okuzono

et al. 2024

Disease Models &Amp; Mechanisms

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Pathogenic variants in ATP1A3, the α3 subunit of the Na+/K+-ATPase-encoding gene, cause alternating hemiplegia of childhood (AHC) and related disorders. Impairments in Na+/K+-ATPase activity are associated with the clinical phenotype. However, it remains unclear whether additional mechanisms are involved in the exaggerating symptoms under stressed conditions in patients with AHC. We herein report that the intracellular loop (ICL) of ATP1A3 interacted with RNA-binding proteins, such as EIF4G, PABPC1 and FMRP. Both the siRNA-mediated depletion of Atp1a3 and ectopic expression of the p.R756C-variant ATP1A3-ICL in Neuro2a cells resulted in excessive phosphorylation of ribosomal protein S6 and increased susceptibility to heat stress. In agreement with these findings, iPSCs from a patient with the p.R756C variant were more vulnerable to heat stress than control iPSCs. Neurons established from the patient's iPSCs showed lower calcium influxes in responses to stimulation with ATP than controls. These data indicated that inefficient protein synthesis contributes to the progressive and deteriorating phenotypes of patients with the p.R756C variant among a variety of ATP1A3-related disorders.

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Alternating Hemiplegia of Childhood: Genotype–Phenotype Correlations in a Cohort of 39 Italian Patients

Cited by 13 publications

References 30 publications

Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population

Precision therapy for a medically actionable ATP1A3 variant from a genomic medicine program in an underserved population

Alternating hemiplegia of childhood: a distinct clinical entity and ATP1A3-related disorders: A narrative review

ATP1A3 regulates protein synthesis for mitochondrial stability under heat stress

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