Rationale:
ATP1A3 variants are associated with a spectrum of neurological disorders, including alternating hemiplegia of childhood (AHC) and rapid-onset dystonia-parkinsonism (RDP). Our case report aims to provide evidence of varied phenotypic presentations of the
ATP1A3 variant: c.1838C >T (p.Thr613Met) within a family and highlight the continued gaps in our understanding of
ATP1A3 variants.
Methods: This case report presents two patients, a mother and son, with differing phenotypic presentations of the same ATP1A3 variant.
Results: The mother has a confirmed heterozygous
ATP1A3 variant: c.1838C >T (p.Thr613Met) and exhibits the classic symptoms of rapid-onset dystonia-parkinsonism (RDP) which is traditionally associated with the c.1838C >T (p.Thr613Met) variant. No EEG findings are available for the mother.
The son is a 9-year-old male who was born via emergency caesarian-section due to fetal distress. He has no telangiectasia, pes cavus, visual/hearing disabilities, dystonic events, bulbar symptoms, autonomic dysfunction, or respiratory disturbances. He was diagnosed at 6 years old with absence epilepsy with episodes lasting under 15 seconds. This was well-controlled with Zonisamide and Clobazam. Later, he progressed to also having generalized tonic-clonic seizures that seemed to be triggered by excitement and stimulation and were no longer well-controlled with the previous medication. Lamotrigine was added which led to improvement in his symptoms.
An EEG was taken during seizure activity and demonstrated findings that are suggestive of an underlying generalized epilepsy syndrome with frequent ongoing clinical seizures [Fig. 1]. The presence of intractable seizures that were atypical from the classic absence seizure picture prompted genetic testing. Next-generation sequencing technology identified the same heterozygous
ATP1A3 variant: c.1838C >T (p.Thr613Met) in the son.
Conclusions: Previous case reports examining how
ATP1A3 manifests within families have shown that family members carrying the gene tend to exhibit similar symptoms [1].
Here, we provide evidence of a patient and his mother who both have the same
ATP1A3 variant: c.1838C >T (p.Thr613Met) but with differing phenotypic presentations. This emphasizes the complexity and heterogeneity of
ATP1A3-related disorders, highlighting the need to understand the underlying mechanisms further. We also present a novel association of epilepsy with the phenotypic expressions of the c.1838C >T (p.Thr613Met) variant, which can aid in future diagnosis of childhood epilepsy. Additionally, the positive response of our patient's epilepsy to Lamotrigine offers a potential route for future clinicians in selecting optimal first-line therapeutic interventions for similar patients.
References:
[1] Hully M, Ropars J, Hubert L, et al. Mosaicism in ATP1A3-related disorders: not just a theoretical risk.
Neurogenetics. 2017;18(1):23-28. doi:
10.1007/s10048-016-0498-9Funding: None.