Cognitive Decline, Neurologic Involvement, and Neonatal Crisis in ABCC9-Related Intellectual Disability and Myopathy...

The ABCC9 gene encodes the widely expressed SUR2 subunit of ATP-sensitive potassium (K_ATP) channels. Autosomal recessive loss-of-function variants in ABCC9 cause ABCC9-related Intellectual disability and Myopathy Syndrome (AIMS). Here, we sought to compile multiple case reports from previously unidentified individuals with the primary objective of further establishing the clinical consequences of ABCC9 variants.

We combine multiple case reports with genetic diagnoses and functional tests of recombinant K_ATP channels.

We report 5 cases of AIMS, including a neonate, and a woman who presented as a sexagenarian with signs of dementia. All variants are predicted to lead to nonsense mediated decay of ABCC9 transcripts and/or drastic truncation of SUR2. Functional tests of recombinant channels confirm that disease-associated SUR2 truncations cause a complete loss-of-function. These new cases further demonstrate the prominence of white matter abnormalities resembling periventricular leukomalacia or small vessel disease as a key hallmark of the disorder, alongside developmental delay, intellectual impairment, seizures, and fatigability. These latest findings also highlight neonatal presentation of disease, deterioration following surgical procedures, and the potential for motor and cognitive decline, which should be monitored in older individuals.

These findings provide new insights into the spectrum of pathology and natural history of AIMS. This new cohort underscores that AIMS is characterized by the combination of periventricular leukomalacia, developmental delay and intellectual disability, and muscle weakness and fatigability - and is driven by biallelic loss-of-function variants in ABCC9.