Clinical Spectrum of ATP1A3

adCORD is an inherited retinal degenerative disorder characterized by progressive deterioration of cone and rod photoreceptors. Affected individuals typically present with progressive loss of vision, reduced visual acuity and problems with color vision from the age of 12. The ATP1A3 mutation D591V has been identified in a single family affected by a form of adCORD.

CAPOS syndrome is characterized by episodes of ataxic encephalopathy and/or weakness during and after a febrile illness. Onset is between ages six months and four years. Some acute symptoms resolve; progression of sensory losses and severity vary.[2]

Familial hemiplegic migraine (FHM) is an autosomal dominant disorder, classified into 3 subtypes, based on the gene involved (CACNA1A in FHM1, ATP1A2 in FHM2 and SCN1A in FHM3). The clinical presentation is highly heterogeneous and some attacks may be severe.

PMG is the most common developmental malformation of the cerebral cortex, characterized by abnormal folding and laminar organization. Recently, de novo and familial mutations in ATP1A3 were found in patients affected by a severe form of PMG characterized by epilepsy and a global developmental delay. PMG mutations include D801N, the most common mutation in AHC (Panagiotakaki et al., 2015), and L924P, which is also observed in early infantile epileptic encephalopathy (EIEE). A 2022 French study expanded the phenotypic spectrum of ATP1A3-related disorders with a new variant associated with hemidystonia and polymicrogyria and thereby, suggests a clinical continuum between the different phenotypes of this condition.[3]

RDP has been characterized by: abrupt onset of dystonia over days to weeks with parkinsonism (primarily bradykinesia and postural instability); common bulbar involvement; and absence or minimal response to an adequate trial of L-dopa therapy, with few exceptions. Often fever, physiologic stress, or alcoholic binges trigger the onset of symptoms. After their initial appearance, symptoms often stabilize with little improvement; occasionally second episodes occur with abrupt worsening of symptoms. Rarely, affected individuals have reported a more gradual onset of symptoms over weeks to months. Anxiety, depression, and seizures have been reported. Age of onset ranges from four to 55 years, although a childhood variation of RDP with onset between ages nine and 14 months has been reported.[4]

RECA is characterized by recurrent neurological decompensation episodes triggered by febrile illness, leading to encephalopathy with acute cerebellar ataxia and occasionally chorea, dystonia, dysarthria, mutism and dysphagia. To date, all RECA cases are associated with substitutions of arginine 756 (R756H, R756C). A very similar ATP1A3-related disorder, febrile-induced paroxysmal weakness and encephalopathy (FIPWE), is also caused by mutations at R756.