Review Question - QID 106624

This patient presents with findings suggestive of homocystinuria, which include progressive developmental delay, marfanoid habitus, and family history of very early thromboembolic events. Homocystinuria may be caused by a deficiency of cystathionine synthase.

Homocystinuria is a congenital metabolic disorder which presents with Marfanoid habitus (tall stature with long, thin extremities), congenital lens dislocations (notably downward, as opposed to upward in Marfan's disease), and mental retardation. Homocysteine is elevated in the urine. The disease results from the inability to break down homocysteine, typically as a result of cystathionine synthase deficiency. Notably, vitamin B6 is a cofactor for cystationine synthase, and deficiency of vitamin B6 can mimic the disorder. Other potential causes for homocystinuria include decreased affinity of cystathionine synthase for pyridoxal phosphate and homocysteine methyltransferase deficiency.

Waisbren discusses the presentation in homocystinuria. In addition to the skeletal and ocular abnormalities discussed above, patients can have significant hematologic problems, notably including severe blood clots. Additionally, beyond the presence of mental retardation, significant psychiatric disorders can be present, including mood disorders and behavior disorders.

Skovby et al. discuss epidemiology and screening. One screening method involves testing for elevated levels of methionine in the blood. Because loss of cystathionine synthase blocks the pathway of metabolism of homocysteine to cysteine, excess homocysteine is shunted down another metabolic pathway which results in methionine. This method of screening likely underestimates the prevalence, as some vitamin B6 responsive patients will be missed by this method.

Illustration A depicts the pathways involved in homocysteine metabolism.

Incorrect answers:
Answer 1: Cystinuria is caused by a defect in renal amino acid transporters, and typically shows hexagonal crystals in the urine.
Answer 3: Phenylketonuria is caused by decreased phenylalanine hydroxylase, and presents with musty smell, fair skin, and mental retardation.
Answer 4: Alkaptonuria is caused by deficiency of homogentisic acid oxidase, and presents with dark connective tissue and brown sclera.
Answer 5: Maple syrup urine disease is caused by inability to degrade branched chain amino acids and presents with urine that smells like maple syrup.