Lysosomal storage disorders — formative SAQs

Question 1 (10 marks)

A four-month-old previously well infant who was smiling and rolling over has stopped meeting milestones over six weeks. Examination reveals irritability, increased tone in the limbs, a liver edge 5 cm below the costal margin, and a preserved gag reflex. A fundal examination shows a cherry-red spot against a pale macula. ^{[1] [3]}

(a) Give a unifying diagnosis and name the substrate group it belongs to. (2 marks) ^[1]

(b) Outline the stepwise confirmatory investigation strategy, naming the first-line screening test and the confirmatory test. (4 marks) ^{[1] [2]}

(c) Explain why the treatment modality depends on whether the central nervous system is involved, naming the two principal disease-modifying options and the constraint on each. (4 marks) ^{[2] [5]}

Model answer

The unifying diagnosis is a neuronopathic lysosomal storage disorder, most likely a sphingolipidosis such as Tay–Sachs (hexosaminidase A deficiency) given the cherry-red spot and rapid regression with organomegaly. The cherry-red spot reflects a normal ganglion-cell-free fovea surrounded by swollen, storage-laden ganglion cells. ^{[1] [3]}

The investigation strategy is layered. First-line screening is urine glycosaminoglycan and oligosaccharide analysis, which is non-invasive and points to the mucopolysaccharidoses and oligosaccharidoses. Confirmatory testing measures enzyme activity in leucocytes (or on a dried blood spot) followed by molecular genetic testing of the relevant gene to define the variant, enable family testing, and guide prognosis. A dilated fundus examination, echocardiogram, and skeletal survey stage the organ involvement. ^{[1] [2]}

The treatment modality depends on central-nervous-system involvement because enzyme replacement therapy is a large intravenous molecule that does not cross the blood–brain barrier and therefore cannot halt neuronopathic decline, whereas haemopoietic stem cell transplant supplies functional enzyme through donor-derived microglia and macrophages and can modify neuronopathic disease — but only if given before irreversible neurological injury. For this child, the rapid neurodegeneration makes the transplant window the central concern, and urgent metabolic referral is required. ^{[2] [5]}