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Inherited metabolic disorders flashcards

11 high-yield MRCP Part 1 cards from the Intellect Medicos Basic sciences & statistics course. Try to answer each question before you open it — then study them properly with spaced repetition, which brings each card back just before you would forget it.

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1. What is the mainstay of management of phenylketonuria?

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   Lifelong low-phenylalanine diet with a tyrosine-supplemented protein substitute.

   Why? Phenylalanine hydroxylase deficiency (autosomal recessive) raises phenylalanine and lowers tyrosine; early diet prevents intellectual disability. It is detected on newborn blood-spot screening.

2. What is the first-line treatment of homocystinuria?

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   Pyridoxine (vitamin B6); add a low-methionine diet, betaine, folate and B12 if needed.

   Why? Cystathionine beta-synthase uses B6 as a cofactor, so high-dose B6 boosts residual enzyme activity in responsive patients.

3. In which direction does the lens dislocate in homocystinuria, and how does this differ from Marfan syndrome?

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   Homocystinuria: downwards (inferonasal). Marfan: upwards (superotemporal).

   Why? Both cause a Marfanoid habitus, but homocystinuria is autosomal recessive with learning disability and thrombosis.

4. A 40-year-old has early spinal arthritis, blue-black pigmentation of the ear cartilage and sclera, and urine that darkens on standing. Which drug reduces homogentisic acid production in this condition?

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   Nitisinone.

   Why? Alkaptonuria is homogentisate oxidase deficiency (autosomal recessive); nitisinone blocks an earlier enzyme in tyrosine breakdown. Diagnosis is by raised urinary homogentisic acid.

5. What is the key management of von Gierke disease (glucose-6-phosphatase deficiency)?

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   Avoid fasting: frequent feeds with uncooked cornstarch (including overnight), plus allopurinol for hyperuricaemia.

   Why? Without glucose-6-phosphatase the liver cannot release free glucose, causing severe fasting hypoglycaemia with lactic acidosis, hyperlipidaemia and hyperuricaemia.

6. What is the specific treatment for Pompe disease (acid maltase deficiency)?

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   Enzyme replacement therapy with recombinant acid alpha-glucosidase.

   Why? Pompe is a lysosomal glycogen storage disease; the infantile form causes cardiomegaly, hypotonia and macroglossia (ECG: short PR, large QRS).

7. A 19-year-old has muscle cramps and red-brown urine after exercise. If he rests briefly and carries on, his symptoms ease (a 'second wind'). What is the characteristic result on ischaemic forearm exercise testing?

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   No rise in venous lactate (a flat lactate curve).

   Why? McArdle disease (GSD type V) is muscle glycogen phosphorylase deficiency, so muscle cannot break down glycogen to make lactate; CK is raised.

8. A 20-year-old man has burning pain in his hands and feet, reduced sweating, clusters of dark red papules between the umbilicus and knees, and proteinuria. Which enzyme is deficient?

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   Alpha-galactosidase A (Fabry disease, X-linked recessive).

   Why? Globotriaosylceramide (ceramide trihexoside) builds up in nerves, kidneys, heart and blood vessels: neuropathic pain, angiokeratomas, renal failure, LVH and early stroke.

9. Which enzyme is deficient in Gaucher disease, the commonest lysosomal storage disorder?

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   Glucocerebrosidase.

   Why? Glucocerebroside accumulates in macrophages ('Gaucher cells' with wrinkled tissue-paper cytoplasm), causing hepatosplenomegaly, bone pain, osteoporosis and avascular necrosis of the femoral head.

10. Tay–Sachs and Niemann–Pick disease both cause a cherry-red macula. Which clinical sign distinguishes them?

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    Hepatosplenomegaly: present in Niemann–Pick, absent in Tay–Sachs.

    Why? Tay–Sachs is hexosaminidase A deficiency (GM2 ganglioside builds up in neurons); Niemann–Pick is sphingomyelinase deficiency (foam cells in liver and spleen).

11. A 3-year-old boy has developmental delay, dystonia and bites his lips and fingers. His nappies contain orange crystals. Which enzyme is deficient?

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    HGPRT (hypoxanthine-guanine phosphoribosyltransferase) — Lesch–Nyhan syndrome, X-linked recessive.

    Why? Without purine salvage, purines are broken down to uric acid, causing hyperuricaemia, gout and urate stones.