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]

Second branch — the cherry-red spot

The same fundus examination reveals a cherry-red spot against a pale macula. The candidate names Tay–Sachs (hexosaminidase A deficiency) and Sandhoff, explains that the cherry-red spot reflects a normal ganglion-cell-free fovea surrounded by swollen storage-laden ganglion cells, and lists the other disorders that produce it (Niemann–Pick A/B, some Gaucher and metachromatic leukodystrophy cases). The teaching point is that the finding confirms a neuronopathic sphingolipidosis and that enzyme replacement cannot reach the brain, so management is supportive with transplant considered only for the few amenable disorders given early. [1] [3]

Third branch — the cardiomyopathy infant

The case shifts to a three-month-old with poor feeding, a gallop, marked concentric left-ventricular wall thickening, a short PR interval, profound hypotonia, weak reflexes, and a markedly raised creatine kinase. The candidate diagnoses classic infantile Pompe (acid alpha-glucosidase deficiency), discriminates it from sarcomeric cardiomyopathy on the neuromuscular findings and creatine kinase, and describes the time-critical management: enzyme replacement with alglucosidase alfa started as soon as the diagnosis is confirmed, which can reverse the cardiomyopathy and transform survival. [4]

Closing synthesis

The examiner asks for the single unifying principle. The candidate states that every lysosomal storage disorder reduces to four questions — which enzyme, which substrate, is the brain involved, and what is the window for the therapy that reaches it — and that the neuronopathic versus non-neuronopathic split governs the choice between enzyme replacement therapy (for the viscera) and haemopoietic stem cell transplant (for the brain, given early). [2] [5]