Lysosomal storage disorders — branching viva

Opening branch — the regressing infant with hepatosplenomegaly

A four-month-old who was meeting milestones now regresses over six weeks, with irritability, spastic limbs, and a liver edge 5 cm below the costal margin. The candidate must give a unifying diagnosis of a neuronopathic lysosomal storage disorder, name the sphingolipidosis substrate group, and justify the urgency: the rapid neurodegeneration narrows the window for a disease-modifying transplant, so the confirmatory workup must be completed within days. ^{[1] [3]}

The examiner probes the investigation strategy. The candidate gives the layered approach — urine glycosaminoglycans and oligosaccharides first, then leucocyte enzyme activity, then molecular gene-panel confirmation — and explains why a single low enzyme on a newborn bloodspot is a screen rather than a diagnosis, with pseudodeficiency alleles and late-onset variants producing abnormal screens in children who may never become unwell. ^{[2] [5]}