The Phenotypic Continuum of ATP1A3-Related Disorders

Abstract

Background and objectives: ATP1A3 is associated with a broad spectrum of predominantly neurologic disorders, which continues to expand beyond the initially defined phenotypes of alternating hemiplegia of childhood, rapid-onset dystonia parkinsonism, and cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome. This phenotypic variability makes it challenging to assess the pathogenicity of an ATP1A3 variant found in an undiagnosed patient. We describe the phenotypic features of individuals carrying a pathogenic/likely pathogenic ATP1A3 variant and perform a literature review of all ATP1A3 variants published thus far in association with human neurologic disease. Our aim is to demonstrate the heterogeneous clinical spectrum of the gene and look for phenotypic overlap between patients that will streamline the diagnostic process.

Methods: Undiagnosed individuals with ATP1A3 variants were identified within the cohort of the Deciphering Developmental Disorders study with additional cases contributed by collaborators internationally. Detailed clinical data were collected with consent through a questionnaire completed by the referring clinicians. PubMed was searched for publications containing the term "ATP1A3" from 2004 to 2021.

Results: Twenty-four individuals with a previously undiagnosed neurologic phenotype were found to carry 21 ATP1A3 variants. Eight variants have been previously published. Patients experienced on average 2-3 different types of paroxysmal events. Permanent neurologic features were common including microcephaly (7; 29%), ataxia (13; 54%), dystonia (10; 42%), and hypotonia (7; 29%). All patients had cognitive impairment. Neuropsychiatric diagnoses were reported in 16 (66.6%) individuals. Phenotypes were extremely varied, and most individuals did not fit clinical criteria for previously published phenotypes. On review of the literature, 1,108 individuals have been reported carrying 168 different ATP1A3 variants. The most common variants are associated with well-defined phenotypes, while more rare variants often result in very rare symptom correlations, such as are seen in our study. Combined Annotation-Dependent Depletion (CADD) scores of pathogenic and likely pathogenic variants were significantly higher and variants clustered within 6 regions of constraint.

Discussion: Our study shows that looking for a combination of paroxysmal events, hyperkinesia, neuropsychiatric symptoms, and cognitive impairment and evaluating the CADD score and variant location can help identify an ATP1A3-related condition, rather than applying diagnostic criteria alone.

Figure 1. Symptom Combinations in Our Subject Cohort

(A) Phenotypes in our cohort are extremely variable, with none of the patients sharing a combination of neurologic signs and symptoms. (B) Looking only at the most common 11 signs and symptoms, only 2 pairs of patients have overlapping features. (C) If we group symptoms into 4 categories: (1) neuropsychiatric symptoms, (2) hyperkinetic movement disorders, (3) paroxysmal episodes, and (4) cognitive impairment almost half our cohort (n = 11) has a phenotype combining all 4 categories and almost all individuals (22/24 individuals) have a phenotype combining 3 of the 4 categories.

Figure 2. ATP1A3 Variants

(A) Distribution of variants across the α3 subunit of the sodium/potassium transporting ATPase. Location of protein domains is shown across the protein: turquoise, 1–10 transmembrane domains; red, actuator domain; orange, phosphorylation site; green, nucleotide binding site. Variants are color-coded per phenotype. (B) Frequency of phenotypes among the 1,000 + reviewed patients reported in the literature from 2004 to 2021. (C) Eight most frequent variants responsible for ATP1A3-related disorders in the 1,000 + reviewed patients reported in the literature from 2004 to 2021. Each variant leads to a specific phenotype. AHC = alternating hemiplegia of childhood; CAPOS = cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss syndrome; COS = childhood onset schizophrenia; D-DEMØ = dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø), and neonatal onset of symptoms; EIEE = early infant epileptic encephalopathy; IP = intermediate phenotype; RDP = rapid-onset dystonia parkinsonism; RECA = relapsing encephalopathy with cerebellar ataxia.

Figure 3. CADD Scores

CADD scores associated with benign/likely benign ATP1A3 variants published in ClinVar (green) are significantly lower than the novel ATP1A3 variants in our patient cohort (orange) (p = 2.94e-39), and ATP1A3 variants published as pathogenic in the literature (purple) (p = 1.05e-84). There is no significant difference between the novel and published pathogenic variants (p = 0.167). CADD = Combined Annotation-Dependent Depletion.

Figure 4. Constraint Analysis

Missense allele counts for all ATP1A3 missense variants were obtained from gnomAD v2.1.1. Missense amino acid substitutions are represented in grey (top section). We constructed a heatmap representing intolerance to missense changes, ranging from dark green through yellow, orange, and red with increasing intolerance (dark green = >20 variants, light green = 11–20 variants, yellow = 8–10 variants, light red 1–3 variants, dark red 0 variants). All pathogenic mutations from the literature (missense in green, small deletions/duplications in pink, and a sole frameshift mutation at residue 89 in red) and our cohort (all missense in yellow) and their distribution across the protein are shown (bottom section). The grey and white vertical shading represents mutation clusters and deserts, respectively. Highly constrained regions encompass transmembrane domains 2–9 (turquois), the phosphorylation site (orange), and the end of the nucleotide binding site (green), while the actuator domain (red) is situated in a mutation desert.