Expanding the Spectrum of Autosomal Dominant ATP6V1A-Related Disease: Case Report and Literature Review

Abstract

Background: Developmental and epileptic encephalopathies (DEE) are a group of disorders often linked to de novo mutations, including those in the ATP6V1A gene. These mutations, particularly dominant gain-of-function (GOF) variants, have been associated with a spectrum of phenotypes, ranging from severe DEE and infantile spasms to milder conditions like autism spectrum disorder and language delays.

Methods: We aim to expand ATP6V1A-related disease spectrum by describing a six-year-old boy who presented with a febrile seizure, mild intellectual disability (ID), language delay, acquired microcephaly, and dysmorphic features.

Results: Genetic analysis revealed a novel de novo heterozygous pathogenic variant (c.82G>A, p.Val28Met) in the ATP6V1A gene. He did not develop epilepsy, and neuroimaging remained normal over five years of follow-up. Although ATP6V1A mutations have traditionally been linked to severe neurodevelopmental disorders, often with early-onset epilepsy, they may exhibit milder, non-progressive phenotypes, challenging previous assumptions about the severity of ATP6V1A-related conditions.

Conclusions: This case expands the known clinical spectrum, illustrating that not all patients with ATP6V1A mutations exhibit severe neurological impairment or epilepsy and underscoring the importance of including this gene in differential diagnoses for developmental delays, especially when febrile seizures or dysmorphic features are present. Broader genotype-phenotype correlations are essential for improving predictive accuracy and guiding clinical management, especially as more cases with mild presentations are identified.

Keywords: ATP6V1A mutation; intellectual disability; speech delay.

Figure 1

Clinical phenotype of the patient showing microcephaly, long face (), mild malar hypoplasia (), mild hypotelorism (), and lifted ears (*) (a), with particular focus on teeth characterized by enamel dysplasia () (b).

Figure 2

Standard 19-electrode EEG (20 s/pag—20 µV/mm). (a) first sleep EEG at the age of 5 years. Normal background sleep activity during N2 NREM phase, adequate representation of the physiological spindles, with some superimposed delta waves on the fronto-temporal regions. (b) The last follow-up wake EEG at the age of 11 years. Normal background activity with occipital alfa rhythm at 8 Hz. No sign of slow or epileptiform abnormality.

Figure 3

Magnetic Resonance Imaging (MRI) of the reported patient (a) sagittal Fluid Attenuated Inversion Recovery (FLAIR) sequence; (b) axial T1-weighted inversion recovery (IR) sequence. MRI showed no typical alterations of ATP6V1A patients (e.g., hypomyelination and encephalic hypoplasia/atrophy).