Glycogen-storage and carbohydrate metabolism disorders — formative SAQs

SAQ 1 (10 marks)

A six-month-old boy presents with a distended abdomen noticed by his parents, recurrent early-morning lethargy and one generalised seizure. He feeds every three to four hours and becomes clammy and irritable if a feed is delayed. Examination reveals marked hepatomegaly (liver edge 8 cm below the costal margin), a doll-like facies and growth faltering. A blood sample drawn during a symptomatic, fasted episode shows glucose 1.8 mmol/L, lactate 7.2 mmol/L, urate 0.52 mmol/L, triglycerides 9.1 mmol/L, and a pH 7.28 with a high anion gap; ketones are low. [1] [2]

a) Give the most likely diagnosis and explain how the biochemical tetrad (hypoglycaemia, lactic acidosis, hyperuricaemia, hypertriglyceridaemia with low ketones) arises from the underlying enzyme block. (3 marks) [1]

b) Outline the definitive confirmatory testing, distinguishing molecular genetic testing from a liver enzyme biopsy and stating which you would favour first and why. (2 marks) [1]

c) Detail the long-term dietary and metabolic management, including the role of uncooked cornstarch, continuous overnight glucose, fructose and galactose restriction, and the written sick-day plan. (3 marks) [1] [2]

d) Describe the long-term complications that must be actively surveyed for in this child. (2 marks) [1]

SAQ 2 (10 marks)

A three-month-old girl is referred for progressive hypotonia, poor feeding and respiratory difficulty. She has macroglossia and a loud heart murmur. Her creatine kinase is 4200 U/L, the ECG shows huge QRS voltages across the precordium, and an echocardiogram confirms marked concentric left ventricular hypertrophy. Acid α-glucosidase (GAA) activity on a dried blood spot is profoundly reduced. [5] [6]

a) Name the diagnosis, explain why blood glucose regulation is normal in this disorder despite a glycogen-handling enzyme defect, and contrast its mechanism with the hepatic glycogen storage diseases. (3 marks) [5]

b) Outline the acute and definitive management, including the role and timing of enzyme replacement therapy, and the newer cipaglucosidase alfa plus miglustat regimen. (3 marks) [5] [6]

c) Explain how classic galactosaemia differs from this presentation, describing its toxic-metabolite mechanism and its neonatal clinical syndrome (jaundice, liver dysfunction, cataracts, E. coli sepsis). (2 marks) [12]

d) Discuss the prognostic implications of early versus delayed enzyme replacement in infantile Pompe disease, and the importance of newborn screening. (2 marks) [5]

Marking guide

SAQ 1. The diagnosis is glycogen storage disease type Ia (von Gierke disease, glucose-6-phosphatase deficiency). Glucose-6-phosphatase performs the final step of glycogenolysis and gluconeogenesis — dephosphorylating glucose-6-phosphate to free glucose for hepatic release. When it is deficient, free glucose cannot leave the liver, so the blood glucose falls (fasting hypoglycaemia); the trapped glucose-6-phosphate is shunted down glycolysis to lactate (lactic acidosis); the back-up feeds glycerol and triglyceride synthesis (hypertriglyceridaemia) and purine metabolism (hyperuricaemia); and because glycolysis is fluxing, ketogenesis is suppressed, producing the characteristic non-ketotic picture. Confirm with molecular genetic testing of G6PC (favoured first — non-invasive, enables cascade and prenatal testing), reserving liver enzyme assay for cases where sequencing is uninformative; GSD Ib (SLC37A4, glucose-6-phosphate translocase) is excluded by checking the neutrophil count and considering SLC37A4 sequencing because it adds neutropenia and inflammatory bowel disease. Long-term management is built on preventing fasting: frequent daytime feeds supplemented with uncooked cornstarch (a slowly released complex carbohydrate that extends the fasting interval), continuous overnight glucose via nasogastric or gastrostomy feed to prevent early-morning hypoglycaemia, and restriction of fructose and galactose (which feed the trapped pool) with possible medium-chain triglyceride supplementation. Every family holds a written sick-day plan: at the first sign of illness, fasting or reduced intake, stop fasting, give glucose or cornstarch, and present early. The long-term complications to surveil are hepatic adenoma (with hepatocellular carcinoma risk — annual/biennial liver imaging), renal disease (glomerular hyperfiltration → proteinuria → renal failure — monitor renal function and albuminuria), osteoporosis (bone densitometry), growth failure, anaemia and hyperuricaemic gout. [1] [2]

SAQ 2. The diagnosis is infantile-onset Pompe disease (GSD II, acid α-glucosidase deficiency). Blood glucose is normal because acid α-glucosidase is a lysosomal hydrolase that degrades the small fraction of glycogen entering the lysosome by autophagy — it does not participate in cytosolic glycogenolysis or gluconeogenesis, so hepatic glucose output is intact. Instead, the deficiency causes lysosomal glycogen accumulation in cardiac, skeletal and respiratory muscle, which distends and ruptures the lysosome and triggers autophagic buildup and muscle fibre destruction — producing hypertrophic cardiomyopathy, hypotonia and respiratory weakness rather than hypoglycaemia. This contrasts with the hepatic GSDs, where the cytosolic enzyme block starves the blood of glucose. Management is enzyme replacement therapy with recombinant acid α-glucosidase (alglucosidase alfa), started early before irreversible muscle damage, alongside supportive cardiac and respiratory care (including ventilation for diaphragmatic weakness); the newer cipaglucosidase alfa plus miglustat regimen, established by the PROPEL trial, offers improved efficacy. Classic galactosaemia (galactose-1-phosphate uridylyltransferase deficiency) is a toxic-metabolite disorder: galactose-1-phosphate accumulates and poisons the liver, kidney, lens and ovary, presenting in the neonate on milk feeds with jaundice, liver dysfunction, cataracts, failure to thrive and a predisposition to E. coli sepsis — and it is managed by removing galactose, in contrast to Pompe's enzyme replacement. Prognosis is transformed by early enzyme replacement: untreated infantile Pompe is fatal in infancy, but treatment started early (including in presymptomatic newborn-screened infants) achieves long-term survival with meaningful motor and cardiac function — which is why newborn screening for Pompe (GAA on the bloodspot) is now the standard in many jurisdictions and should be advocated for. [5] [6] [12]