Rare and Ultra Rare Diseases

Abstract

In the last years, rare and ultra rare diseases have attracted worldwide more and more attention. However, there is no universal definition of a rare disease: In Japan the term “orphan disease” describes a condition with a prevalence of 2.5 cases per 10,000 population; in the US 7 cases per 10,000 population. In Europe, an orphan disease is defined as a disorder that affects 5 or less per 10,000 populations. However, the question arises: How rare is a disorder in fact? And in the last time it has become evident that “rare” disorders are more common than it had been assumed. There are several reasons that may explain why the incidence of a disease has apparently increased: As more and more of these conditions have become treatable, for example by enzyme replacement therapy or substrate deprivation, the number of publications on these topics has dramatically grown, leading to an augmentation of the awareness in the scientific community and also in the general public [1,2]. In this process, orphan access journals significantly contributed to the dissemination of knowledge and understanding of orphan diseases. The supposed increase of the incidence of rare diseases can also be explained by the fact that newborn screening has been introduced for some of these conditions such as Fabry disease or Pompe disease, whereby more patients have been detected than it had been expected [3,4]. Newborn screening, however, is associated with the problem that nowadays it cannot be predicted, which individuals who have been found by newborn screening, in their later life will need a treatment and which will never develop any clinical signs and symptoms [5]. Not only for a rare disorder, but also for the term “ultra rare orphan disease” a universally accepted definition is lacking: In the UK it describes a condition that has a prevalence of less than one case per 50,000 population [6]. In the United States an “ultra rare orphan disease” is defined as a disorder that affects less than 2000 people [7]. If a disorder has initially described only in one case, as for example mucopolysaccharidosis type IX (hyaluronidase deficiency), it becomes questionable whether this disorder in fact represents a real entity. However, because many years after the first description more cases with the same biochemical defect and with the same or similar clinical presentation have been detected, it was proven that mucopolysaccharidosis type IX indeed represents a disorder with a known genetic defect [8]. In several patients with significantly different clinical signs and symptoms a genetic defect of the enzyme alpha-galactosaminidase has been found; and because of the broad diversity of the clinical manifestation the question arose whether this enzyme defect is the actual cause of these different conditions. And indeed, which role the alpha-galactosaminidase deficiency plays in the pathogenesis of these different clinical presentations could not be clarified until now [9].