Aditi Tiwari1, Seva Khambadkone1, Michael Regner2, Anna Dennis3, Amy Yang3, Kimberly Kripps3, Xinran Xiang1
1Pediatric Neurology, 2Fetal Neuroradiology, 3Molecular and Medical Genetics, Oregon Health & Science University
Objective:
To highlight an atypical MRI pattern and haplotype effects in an 18-month-old patient with late infantile-onset Krabbe Disease (LIKD).
Background:
Krabbe disease occurs due to deficiency of the enzyme galactocerebrosidase (GALC), leading to toxic accumulation of psychosine and progressive demyelination. Phenotypic spectrum, including age of onset and severity, is determined by GALC genotype, residual GALC activity, and psychosine levels. LIKD presents between 6 and 36 months and typically predominantly involves the periventricular white matter (PVWM) and deep gray nuclei.
Design/Methods:
Case report and literature review. ChatGPT 5.0 was used during literature review.
Results:
Case Report: This child, previously typically developing, presented with 2 months of severe motor developmental regression and lower limb stiffness. Examination showed intact mentation with bulbar weakness, axial hypotonia, and spastic hypertonicity and extensor posturing of the legs. MRI demonstrated symmetric T2-FLAIR hyperintensities of the corona radiata and posterior PVWM extending along the corticospinal tracts (CST) without involvement of the deep grey nuclei or infratentorial white matter. Ultrarapid whole genome sequencing yielded 5 heterozygous variants in GALC, two likely pathogenic (c.850 G>A, p.G284S and c.939_941del, p.Y314del), one of uncertain significance (c.1760 T>C, p.I587T), and two possibly benign modifiers/pseudodeficiency variants. Together with clinical presentation and elevated psychosine levels, this was diagnostic for LIKD.
Conclusions:
CST-predominant demyelination without significant involvement of additional sites, an imaging phenotype associated with juvenile/adult-onset Krabbe, has only been reported in rare cases of LIKD and likely explains the patient’s motor predominance and relative cognitive-sparing presentation. The combination of the heterozygous G284S and I587T variants is associated with quickly progressive LIKD, illustrating haplotype effects. We suspect one or more of the other variants are acting as modifiers, potentially contributing to this unique imaging and clinical phenotype. Our case highlights the importance of recognizing the full spectrum of neuroimaging findings for timely diagnosis of genetic and metabolic disorders.
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