Diseases Affecting Middle-Aged and Elderly Individuals With Trisomy 21

Abstract

Background: The life expectancy of individuals with trisomy 21 (Down syndrome, DS) has risen to more than 60 years over the past few decades. As a result, diseases arising in mid and later life have become an issue of major concern in the care of individuals with DS. This article discusses and summarizes, from a multidisciplinary perspective, the diseases commonly affecting this population.

Methods: This narrative review is based on publications identified by a selective literature search, extrapolation of the available evidence, and the authors' personal experience.

Results: Robust epidemiological evidence indicates that many different diseases, which are dealt with by many different medical specialties, are more common in individuals with DS. The genetic background of some of these diseases is now understood down to the molecular level, e.g., primary hypothyroidism or Alzheimer's disease in DS. Recent gains in epidemiological and pathophysiological understanding contrast with a dearth of evidence on treatment for most of these disorders.

Conclusion: In view of the complexity of DS-associated morbidity, it would be desirable for DS-specific multidisciplinary care to be made available to patients with DS.

Figure 1

Overview of common diseases in adults with Down syndrome Persons with Down syndrome are at increased risk for a variety of diseases. While cardiovascular events and solid tumors are less common in adults with DS than in the general population, autoimmune, dermatological, and ear, nose and throat diseases, among others, are much more common, as is genetically determined Alzheimer‘s disease. Because of their importance, childhood hemato-oncological and cardiac diseases are also mentioned in this overview. The following references were used to create the Figure: Refs. 6, 12, 16, 18, 19, 20, 23, 25, 28, 31, 32, 35, 37, e17-e27.

Figure 2

The pathophysiology of Alzheimer‘s disease in Down syndrome The presence of a third copy of the amyloid precursor protein (APP) gene leads to an approximately 50% increase in transcription and translation of the protein. Accordingly, more APP degradation products are produced. As a product of the imprecise limited proteolysis by gamma-secretase, two different cleavage products are formed: amyloid-ß (A)1–40 and Aß1–42. The highly amyloidogenic cleavage product, Aß1–42, present in increased amounts, can no longer be broken down adequately, so that Alzheimer‘s plaques may form in the brain as early as the 2nd decade. The amyloid cascade leads to intraneuronal hyperphosphorylation and fibril formation of the tau protein, which in turn causes cell damage. The role of other genetic factors, such as the increased amount of ß-secretase, which is also encoded on chromosome 21, and the role of epigenetic factors remain poorly understood.