Large-conductance calcium-activated potassium channel haploinsufficiency leads to sensory deficits in the visual system: a case report

Abstract

Background: Mutations in the genes encoding the large-conductance calcium-activated potassium channel, especially KCNMA1 encoding its α-subunit, have been linked to several neurological features, including intellectual disability or autism. Associated with neurodevelopmental phenotypes, sensory function disturbances are considered to be important clinical features contributing to a variety of behavioral impairments. Large-conductance calcium-activated potassium channels are important in regulating neurotransmission in sensory circuits, including visual pathways. Deficits in visual function can contribute substantially to poor quality of life, while therapeutic approaches aimed at addressing such visual deficits represent opportunities to improve neurocognitive and neurobehavioral outcomes.

Case presentation: We describe the case of a 25-year-old Caucasian male with autism spectrum disorder and severe intellectual disability presenting large-conductance calcium-activated potassium channel haploinsufficiency due to a de novo balanced translocation (46, XY, t [9; 10] [q23;q22]) disrupting the KCNMA1 gene. The visual processing pathway of the subject was evaluated using both electroretinography and visual contrast sensitivity, indicating that both retinal bipolar cell function and contrast discrimination performance were reduced by approximately 60% compared with normative control values. These findings imply a direct link between KCNMA1 gene disruption and visual dysfunction in humans. In addition, the subject reported photophobia but did not exhibit strabismus, nystagmus, or other visual findings on physical examination.

Conclusions: This case study of a subject with large-conductance calcium-activated potassium channel haploinsufficiency and photophobia revealed a visual pathway deficit at least at the retinal level, with diminished retinal light capture likely due to bipolar cell dysfunction and an associated loss of contrast sensitivity. The data suggest that large-conductance calcium-activated potassium channels play an important role in the normal functioning of the visual pathway in humans, and that their disruption may play a role in visual and other sensory system symptomatology in large-conductance calcium-activated potassium channelopathies or conditions where disruption of large-conductance calcium-activated potassium channel function is a relevant feature of the pathophysiology, such as fragile X syndrome. This work suggests that the combined use of physiological (electroretinography) and functional (contrast sensitivity) approaches may have utility as a biomarker strategy for identifying and characterizing visual processing deficits in individuals with large-conductance calcium-activated potassium channelopathy. Trial registration ID-RCB number 2019-A01015-52, registered 17/05/2019.

Keywords: BKCa; Case report; Contrast sensitivity; Electroretinography; KCNMA1.

Fig. 1

Summary data from ERG single flash and flicker stimulation. A Example RETeval report, showing measurements for the ISCEV standard LA single flash and flicker protocol. B ERG waveform trace summarizing the comparison of ERG recordings from both the KCNMA1^−/+ subject (red) and a published healthy control (black) cohort [12] in response to stimulation with the ISCEV standard LA single flash protocol. Summary of LA-ERG (C) a-wave and D b-wave amplitude recordings measured in response to stimulation with single flash light protocol. E Representative raw waveform trace of LA-ERGs produced by flicker light stimulation protocol from the KCNMA1^−/+ subject (red) and data from a published healthy control cohort of similar age [12] (black) in response to a 28.3 Hz train of repeated flashes of light (flickers protocol). F Comparison of LA-ERG waveform parameters recorded from the KCNMA1^−/+ subject and the published healthy control cohorts in response to 28.3 Hz flicker stimulation [12]. G Summary data table for LA-ERG single flash and flicker protocol

Fig. 2

Data summary from LEA SYMBOLS low-contrast sensitivity test. A When calculating the total number of successes to discriminate symbols (25 maximum) for each of the three viewing distances (1, 3, and 5 m), significant reductions in scores from the KCNMA1^−/+ subject were observed at 3 m and 5 m. B Summary data table for LEA SYMBOLS low-contrast sensitivity test. C Although no difference was observed at 1 m of distance, D the KCNMA1^−/+ subject exhibited significantly lower contrast sensitivity compared with published data for healthy volunteers [12] at nominal contrast values of < 5% for 3 m of distance and E no response at all at 5 m of distance