De novo exonic duplication of ATP1A2 in Italian patient with hemiplegic migraine: a case report

Abstract

Background: Sporadic Hemiplegic Migraine is a rare form of migraine headache. Mutations in three different genes, two ion-channel genes and one encoding an ATP exchanger, CACNA1A, ATP1A2 and SCN1A are all responsible for the FHM phenotype, thus indicating a genetic heterogeneity for this disorder. Here, we described a de novo exonic duplication of ATP1A2 in an Italian patient with Hemiplegic Migraine.

Case presentation: We describe the case of a young woman (33 year old) who suffered from the age of 8 years of episodic weakness of the limbs, associated to other subjective and objective features. From aged 25, she developed neurological symptoms, like dizziness, blurred vision and an MRI scan revealed aspecific peritrigonal white matter hyperintensities. Aged 32 she suffered of right hemisomatic sudden-onset paresthesias, hypoesthesia and hyposthenia and the patient was genetically investigated for sporadic hemiplegic migraine.

Conclusions: Here we report, for the first time, an exonic duplication in the ATP1A2 associated with hemiplegic migraine. The variation identified involves exon 21 of the ATP1A2 and is expected to alter the function of the alpha(2) subunit of the Na(+)/K(+) pump; the de novo nature of the duplication further supports its pathogenic role. To date, no other CNVs have been described in the ATP1A2 but only point mutations are reported. The novel mutation may result impaired M9 transmembrane domain, in a loss-of-function of the alpha(2) Na(+)/K(+)-ATPase with glutamate accumulation, alteration of synaptic function and neurotransmission.

Keywords: ATP1A2; De novo; Duplication; Hemiplegic migraine.

Fig. 1

MRI scan images revealing aspecific peritrigonal white matter hyperintensities. The control MRI was performed after 6 months and 1 year and confirmed the small focal peritrigonal white matter hyperintensities in T2/FLAIR. Hypertension, heart valvular disease and other vasculophaties were excluded. Transcranial doppler US no detected the micro-embolic signals. Another MRI was performed after 2 years and the picture is unvaried

Fig. 2

Pedigree of the Italian family. Filled symbols represent affected individuals and open symbols non-affected individuals

Fig. 3

a ATP1A2 duplication in SHM patient obtained by MLPA assay. For each probe, the ratio < 0.75 stands for deletion; and the ratio > 1.3 stands for duplication. b ATP1A2 quantification by Real Time PCR in patient and in unaffected relatives