The broad phenotype of homocystinuria

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Homocystinuria, an autosomal recessive disorder of sulfur-containing amino acid metabolism, has a broad range of presentations and severity, and is now included in some newborn screening programs. Most of these screening programs use elevations in blood methionine as the marker.

Recent advances in the molecular biology of homocystinuria have demonstrated that it is actually a family of disorders, with a variety of mutations in the cystothionine beta-synthetase gene. As population genetic studies have looked specifically for mutations in this gene, it has become clear that homocystinuria has a very broad range of clinical phenotypes, which may correlate with the specific mutations.

In this issue of The Journal, Janosik et al report an elegant, very complex study of one of the mutations associated with homocystinuria: c.1105C>T. Some aspects of this study will be of greatest interest to metabolic specialists, but there are also messages here for all clinicians. As we are learning with cystic fibrosis, genetic disorders we once considered fairly uniform in presentation and natural history may actually be quite variable based upon the specific mutation involved. This is clearly the case with homocystinuria; indeed, because elevated methionine in the newborn period is not present in all forms of the disease, it may not always be detected on newborn screening. As we begin to dissect out the way in which specific mutations may (or may not) produce disease, we may also obtain clues to aid in therapy. For now, when clinicians consider homocystinuria in an older child with vascular disease, thrombophilia, or similar complaints, the fact that the child “passed” newborn screening is not sufficient to exclude the diagnosis.