in research, often based on a remote promise of personal gain and at a very real personal expense” (Dietz, 2010, p. 862).

Delineating the general value or multiplier effect of research on specific rare diseases is important because such research may otherwise be undervalued when policy makers consider the absolute numbers of people likely to benefit from a particular public investment in research. Studies of rare diseases often meet other criteria that policy makers consider, for example, that the condition to be studied imposes a serious burden on the health and well-being of affected individuals.

Notwithstanding the label rare disease, most adults probably have known at least one person and possibly several people who have a rare condition. They may have grieved with a family that lost an infant to trisomy 13 or another rare chromosomal disorder. They may know a child or young adult who is living with sickle cell disease or Marfan syndrome. They may be offering support to a relative or friend who has been diagnosed with ovarian cancer or amyotrophic lateral sclerosis in mid- or late life.

Although most of the conditions just cited affect tens of thousands of Americans, each meets the definition of rare disease established in a 1984 amendment to the 1983 Orphan Drug Act (P.L. 97-414): a disease or condition that affects fewer than 200,000 people in the United States (21 USC 360bb). Less common is a large group of rare diseases that affect perhaps a few hundred to a few thousand individuals each but that are generally unknown to most people, including many physicians. In addition, the published literature includes hundreds of extremely rare conditions with reported numbers of affected individuals in the single or double digits, for example, atransferrinemia (a metabolic disorder affecting the transport of iron through the blood) (Beutler et al., 2000) and reticular dysgenesis (a severe immunodeficiency disorder) (Pannicke et al., 2009).

Various estimates place the number of rare conditions at 5,000 to 8,000, and newly identified disorders are reported almost weekly (see Chapter 2). Box 1-1 shows just a few examples of the variety of rare diseases. Most result from genetic mutations, often inherited. Others are caused by infectious or toxic agents. The cause of some is unknown.

In aggregate, rare diseases afflict millions of Americans of all ages and more millions globally. Most are serious and life-altering, and many are life-threatening or fatal. Because the number of people affected with any one specific rare disease is relatively small, a host of challenges complicates the development of effective drugs and medical devices to prevent, diagnose, treat, or cure these conditions. In recent decades, scientists, advocates, policy makers, and others have done much to try to address these challenges. Yet despite these efforts, only a small fraction of rare diseases currently have effective treatments.

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