Objective: To describe a new phenotype related to a novel mutation in ATP1A3 in two women from the same family

Background: Mutations in ATP1A3 have been associated with rapid-onset dystonia-parkinsonism, alternating hemiplegia of childhood, relapsing encephalopathy with cerebellar ataxia (RECA) or cerebellar ataxia, pes cavus, optic atrophy and sensorineural deafness (CAPOS). However, patients can also present paroxysmal dystonia, seizures, cognitive impairment, microcephaly, chorea or hypotonia. A unique presentation of spastic paraparesis and cognitive impairment has been recently reported in nine patients. We aim to report the combination of spastic paraparesis and some ATP1A3 classical manifestations in one family with a novel mutation

Method: Description of two cases

Results: We present two women (mother and daughter) with an undescribed phenotype associated with a mutation in the ATP1A3 gene. The clinical presentation stands out for the presence of slowly progressive spastic paraparesis. They also presented mild cognitive impairment, epileptic seizures, paroxysmal movement disorders of dystonic semiology triggered by menstruation and emotions, and pes cavus. Laboratory studies and cranial and spinal magnetic resonance imaging showed no abnormalities in either of the two patients. The younger patient underwent a Whole-Exome Sequencing (WES), which revealed the presence of the variant ATP1A3 p.Leu802Pro (c.2405T>C). This variant was classified as likely pathogenic in heterozygosity according to the ACMG guidelines. The detected variant is located in a mutational hot-spot of the gene where 17 other missense/in-frame variants have been reported (12 pathogenic, 5 of uncertain significance). Also, in silico prediction tools support a possible deleterious effect on the gene product. Following this discovery, the older patient was proposed for ATP1A3 gene analysis, which she accepted and is pending. Although the phenotype of the two patients does not meet the diagnostic criteria for any of the typical phenotypes associated with ATP1A3 mutations, they have some described common elements that make it likely that the detected mutation is responsible for the symptomatology

Conclusion: The combination of permanent and paroxysmal neurological deficits should prompt out ATP1A3 testing. Spastic paraparesis can be a predominant clinical feature in ATP1A3-related disorders

References: Vezyroglou A, Akilapa R, Barwick K, Koene S, Brownstein CA, Holder-Espinasse M, et al. The phenotypic continuum of ATP1A3-related disorders. Neurology 2022;99(14):e1511–26.

Calame DG, Moreno Vadillo C, Berger S, Lotze T, Shinawi M, Poupak J, et al. Cation leak through the ATP1A3 pump causes spasticity and intellectual disability. Brain 2023;146(8):3162–71.

Salles PA, Mata IF, Brünger T, Lal D, Fernandez HH. ATP1A3-related disorders: An ever-expanding clinical spectrum. Front Neurol 2021;12:637890.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spastic-paraparesis-and-paroxysmal-dystonia-associated-with-a-novel-mutation-in-atp1a3-in-a-spanish-family/