Homocystinuria due to cystathionine beta-synthase deficiency

Andreas Schulze MD PhD (Dr. Schulze of the University of Toronto has no relevant financial relationships to disclose.)
Tyler Reimschisel MD, editor. (Dr. Reimschisel of Vanderbilt University has received contracted research grants from Shire and Vtesse.)
Originally released September 17, 2004; last updated August 8, 2016; expires August 8, 2019

This article includes discussion of homocystinuria due to cystathionine beta-synthase deficiency, classical homocystinuria, CBS deficiency, cystathionine beta-synthase deficiency, homocystinuria, and homocystinuria due to cystathionine beta-synthase deficiency. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism affecting large and small arteries and veins are the most common clinical features in homocystinuria. Homocystinuria is an inherited metabolic disease that is caused by deficiency of the enzyme cystathionine beta-synthase. Despite manifestation of symptoms in childhood some affected individuals were discovered in the second to fourth decade only when presenting with severe thromboembolic complication. In this article, the author reviews this disease and explains why homocystinuria, particularly the pyridoxine-responsive and most readily treatable form of the disease, is still underrecognized.

Key points

 

• Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism affecting large and small arteries and veins are the most common clinical features of homocystinuria.

 

• Homocystinuria is a rare inborn error of metabolism caused by mutations in the cystathionine beta-synthase gene.

 

• Total homocysteine in plasma, often higher than 200 µmol/L (normal <15 µmol/L), and increase of plasma methionine allows diagnosis of cystathionine beta-synthase deficiency.

 

• Early and lifelong consequent treatment with diet and vitamins leads to significantly better outcome in affected patients.

Historical note and terminology

Homocystinuria caused by cystathionine beta-synthase deficiency is an inborn error of the transsulfuration pathway. The disorder is biochemically characterized by accumulation of homocysteine, methionine, and a variety of other metabolites of homocysteine in the body and, ultimately, excretion in the urine. The disease was discovered in 1962 by Carson, Neill, and colleagues when individuals with intellectual disability were screened for abnormal urinary amino acids (Carson and Neill 1962; Field et al 1962). Two years later, the enzymatic defect was identified by Mudd and colleagues (Mudd et al 1964). Since then, considerable experience has defined the clinical phenotype, the abnormal biochemistry, and the natural history of the disease (Mudd et al 1985). Dislocation of the optic lens, osteoporosis, thinning and lengthening of the long bones, intellectual disability, and thromboembolism affecting large and small arteries and veins are the most common clinical features (Mudd et al 1985).

In 1967, Barber and Spaeth reported that 3 cystathionine beta-synthase-deficient patients responded to high doses of pyridoxine (vitamin B6), with decrease of plasma methionine levels to normal and virtual elimination of homocystine from plasma and urine (Barber and Spaeth 1967). This observation has since been extended to many additional patients by many authors. It became obvious that there are 2 distinct populations of homocystinuric patients, one of which responds to treatment with pyridoxine and one that does not (Gaull et al 1969; Mudd et al 1970; Mudd et al 1985; Hu et al 1993). The autosomal recessive inheritance of cystathionine beta-synthase deficiency was reported by Finkelstein and colleagues in 1964 (Finkelstein et al 1964). The gene has been cloned and mapped to chromosome 21 in the subtelomeric area q22.3 (Munke et al 1988). The human cystathionine beta-synthase cDNA sequence was published in 1993 (Kraus et al 1993). Crystallization and preliminary crystallographic analysis of a protein construct that contains the full-length cystathionine beta-synthase from Homo sapiens has recently been achieved (Oyenarte et al 2012), and the structure of the human enzyme has recently been published (Ereno-Orbea et al 2013).

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