Novel Compound Heterozygous Variants in SLC13A3 Associated With ARLIAK: A Case Report and Review of the Literature
TL;DR
The molecular and phenotypic spectrum of SLC13A3‐related ARLIAK is expanded and the importance of combining sequencing with copy number analysis for accurate diagnosis is underscored, suggesting the need for copy number analysis as part of the diagnostic protocol for suspected ARLIAK cases.
Abstract
SLC13A3 pathogenic variants are associated with acute reversible leukoencephalopathy and α‐ketoglutarate accumulation (ARLIAK), a rare neurological disorder characterized by recurrent episodes of encephalopathy and transient white matter abnormalities. Pathogenic variants reported so far include missense, nonsense and small deletion variants, highlighting substantial allelic heterogeneity. We describe a patient presenting with multiple episodes of acute encephalopathy, elevated urinary α‐ketoglutarate and reversible white matter lesions on MRI, consistent with SLC13A3‐related ARLIAK. Genetic analysis identified novel compound heterozygous variants: a missense variant (p.Leu46Pro) in a highly conserved region and a larger deletion encompassing exons 2–3. Our findings indicate that conventional sequencing alone may miss larger deletions, suggesting the need for copy number analysis as part of the diagnostic protocol for suspected ARLIAK cases. The elevated urinary α‐ketoglutarate in our patient supports its potential as a noninvasive biomarker. MRI findings demonstrated typical transient and reversible white matter abnormalities, aligning with previously reported cases. This study expands the molecular and phenotypic spectrum of SLC13A3‐related ARLIAK and underscores the importance of combining sequencing with copy number analysis for accurate diagnosis. The identification of novel variants contributes to a better understanding of the disease mechanism and suggests a broader allelic heterogeneity than previously recognized.