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]

Question 2 (10 marks)

A three-month-old presents with poor feeding, sweating with feeds, and a gallop rhythm. Echocardiography shows marked concentric left-ventricular wall thickening; the electrocardiogram shows a short PR interval. The infant is profoundly hypotonic with weak reflexes, and the creatine kinase is markedly raised. [4]

(a) Give the most likely diagnosis and the deficient enzyme. (2 marks) [4]

(b) Justify your answer with three discriminating features that separate this from sarcomeric hypertrophic cardiomyopathy. (3 marks) [4]

(c) Describe the time-critical management and the expected effect of early treatment on the cardiomyopathy. (5 marks) [2] [4]

Model answer

The most likely diagnosis is classic infantile Pompe disease (glycogen storage disease type II), caused by deficiency of the lysosomal acid alpha-glucosidase (GAA). Glycogen accumulates in lysosomes, producing the cardiomyopathy and the skeletal-muscle weakness. [4]

Three features discriminate Pompe from a sarcomeric cardiomyopathy: the combination of profound hypotonia and weak reflexes, the markedly raised creatine kinase indicating muscle breakdown, and the short PR interval on the electrocardiogram. The cardiomyopathy of Pompe is infiltrative (glycogen storage) rather than sarcomeric, and the neuromuscular findings are the key distinguishing clue. [4]

Management is time-critical because untreated classic infantile Pompe is rapidly fatal within the first year. Enzyme replacement therapy with recombinant alglucosidase alfa, started as soon as the diagnosis is confirmed, can reverse the cardiomyopathy and transform survival. The infant is stabilised for heart failure with careful fluid handling, and an urgent cardiology and metabolic referral is made to begin enzyme replacement without delay. Long-term care is multidisciplinary, with residual myopathy and ongoing infusion burden expected. [2] [4]