Syndromes, Clinical Syndromes, Genetic Syndromes, and Associations

CAUTION2The term syndrome gets used a lot by healthcare professionals and by the public in general. Most people have a fairly good idea of what it means, but it may be helpful to look a little closer. Syndrome comes from a Greek word meaning concurrence, things that are commonly found together. So, syndrome is generally used to refer to a group or pattern of symptoms that typically go together.  That much is pretty straight forward. Sometimes, however, syndrome has a narrower, more specific meaning. It can refer to a group or pattern of symptoms that typically go together AND that result from a single primary cause. For example, MECP2 duplication syndrome is a good example of syndrome being used in this way. Individuals who have this syndrome share a collection of similar symptoms that are commonly found together AND that result primarily from at least one extra copy of the MECP2 gene. There are other individuals who share many of the same symptoms, but they don’t have MECP2 Duplication Syndrome if it is not being caused by an extra copy of the MECP2 gene. Furthermore, just having an extra copy of the MECP2 gene does not mean that an individual has MECP2 Duplication Syndrome; one has to have the symptoms. For example, carriers have the same duplication but are protected against having symptoms, so they do have MECP2 duplication but they do not have MECP2 duplication syndrome. Sometimes the terms genetic syndrome or clinical syndrome are used. For example, Rett Syndrome is considered a clinical diagnosis of a clinical syndrome. This means that an individual is considered to have Rett syndrome if a child has the classic symptoms of the syndrome, regardless of whether she or he has the typical genetic cause (a defect in the MECP2 gene) that results in underexpression, a clinical diagnosis of Rett syndrome is made.  It is important to remember that Rett syndrome was first described in 1966 and the role of the MECP2 gene in causing most cases was not discovered  until 1999. So, at least until that time, a precise genetic criterion would have been impossible. Similarly most cases of Angelman syndrome can be traced to a specific genetic cause, but not all cases can be. Not all true syndromes (those whose collection of symptoms can be traced to a genetic cause) are genetic syndromes. For example, Fetal Alcohol Syndrome, Shaken Baby Syndrome, or Post-Polio Syndrome are true syndromes that can be traced to single specific causes, but not genetic causes. Sometimes the term  Association is used to refer to a collection of symptoms or characteristics that commonly are found together when no single fundamental cause can be identified. For example, CHARGE Association, refers to a group of findings that are commonly found together, but the reason for the association has remained unclear, at least until recently, when advances in genetic testing have helped to identify a genetic basis for at least many of the cases. So, why does any of this matter? Many of the possible treatments being explored are aimed at the genetic conditions that underlie these syndromes or at the specific proteins that these genes produce. Others are are aimed at one or more of the symptoms. Those that are aimed at symptoms are likely to benefit those with the same symptoms regardless of the genetic basis for those symptoms. However, those that are aimed at the underlying genetic basis are unlikely to help those with the clinical diagnosis but who do not have the same genetic syndrome and in some cases they could actually make things worse. For example, many of the individuals with MECP2 duplication syndrome were previously diagnosed with Rett syndrome and generally fit the clinical diagnosis. Their underlying genetic problem, however, was exactly the opposite, and treatments designed to increase MeCP2 activity in Rett syndrome would magnify their symptoms while they helped those with genetically based Rett syndrome. As a result, genetic syndrome classification will become more important as genetic and metabolic treatments become more available.

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