"We now know that the disease is the result of an enzyme deficiency in the liver," says Pezziardi. This enzyme is responsible for keeping the amino acid phenylalanine ("Phe") — abundant in protein-rich foods — at tolerable levels. In PKU sufferers, some of the surplus phenylalanine is metabolized into phenylketone (phenylpyruvate) and then excreted in the urine, but the rest accumulates in the body. Too much phenylalanine, however, hinders protein synthesis in the brain and thus leads to damage.

The classic remedy is a stringent low-protein diet in order to control the intake of phenylalanine. Meat, nuts, dairy products, and many other "normal" foodstuffs are strictly taboo, and even breast milk must be carefully rationed. In addition, children with PKU receive special dietary supplements to provide the vitamins, minerals, and remaining amino acids that are lacking in their diet. Regular blood tests are a must, and great discipline is required right up until the end of adolescence. In the early days, dietary therapy for PKU was halted before puberty — until, that is, it was discovered that brain development during adolescence is much greater than once thought. Today the medical world favors procedures to manage phenylalanine levels throughout a patient's life. 

Such therapy has an immense impact, as is illustrated by the case of the Italian woman Laura Galluppi. Through unfortunate circumstances, her PKU remained undiscovered until the age of 12, when she began receiving proper treatment. At the age of 21 she won three equestrian medals at the 2007 Special Olympics in Shanghai.

For a large number of patients, phenylalanine levels can be controlled by means of an ingenious trick. In order to function, the hepatic enzyme responsible for metabolizing phenylalanine requires a helper — the so-called cofactor BH4 (tetrahydrobiopterin). In the case of many PKU sufferers, the enzyme, although present in a damaged form, works more effectively when levels of BH4 are increased. This is precisely what Pezziardi and his colleagues have been able to achieve. Tetrahydrobiopterin is administered in the form of a special preparation that Merck is now introducing throughout Europe. "For many patients, this research advance brings major relief, since it considerably helps them maintain their Phe levels within a normal range," Pezziardi explains, more than 300 patients in Europe, are now benefiting from this new treatment. And this number is growing, thus cementing the reputation that Merck has acquired in the field of orphan diseases. Yet aside from the obvious benefits that such research brings, does it also make sound business sense for an internationally leading pharmaceutical company to develop a treatment for a disease that in Germany, for example, has an incidence of only one in every 8,500 births and in Turkey, the country with the world's highest rate of PKU, slightly less than one in 2,500 births?

It is Christian Henke's job to address  this question. As one of the experts for pricing and health economics at Merck in Darmstadt, he spends his time analyzing the healthcare market, its regulations, and the resulting risks and opportunities. "Orphan drugs are subject to special provisions; that's the crucial point," he explains. In the EU this includes a market exclusivity lasting several years. A company that is the first to develop a drug for an orphan disease is thereby protected against direct competition for a certain period, thus enabling it to recoup its costs. Set against such advantages are also considerable risks. Unsurprisingly, patients for the required clinical  trials are rare. Therefore, government agencies help with the approval process. "Because the disease is rare, the price of the drug will often turn out to be higher than a mass-produced medicinen," Henke explains. "But there is acceptance of that. After all, it often marks the first time treatment is available for the serious and often costly disease. And providers such as health insurance companies know that the total costs are going to remain limited, because there are, of course, very few patients." Moreover, as Pezziardi explains: "This kind of development generally involves a new area of research, so motivation and curiosity levels are high among the scientists involved — I recognize it in myself — and that has a positive effect.” After all, it may well turn out that research in the field of orphan diseases generates really important ideas in the future — just as Ivar Asbjørn Følling's discovery of PKU was the start of a deeper understanding of genetic metabolic disorders.