The current emphasis, in both the scientific literature and mass media, on the promise of gene therapy and therapeutic cloning has blinded researchers and the public alike to the best way forward in treating genetic diseases. We could not, and have not, waited for genes and their mutations to be identified and for futuristic therapies to be devised. Quietly and efficiently, conventional treatments and symptomatic management have had a growing impact on quality of life and life expectancy of patients with a range of genetic conditions. These are today's treatments for genetic disease.
Patients, after all, suffer not from their mutations but from the functional consequences of these mutations. Several genetic diseases were treatable long before the age of molecular genetics. We did not have to wait for cloning of the phenylalanine hydroxylase gene to treat phenylketonuria with a low-protein diet. Since the 1970s, more than 20 million French babies have been tested at birth, and in 7,000 of them, the condition was detected and treated early. They have avoided mental retardation and are now healthy adults with children of their own. It's fair to say that molecular genetics has had virtually no impact on the treatment of this disease.
The same applies to many other inborn errors of metabolism, in which dietary avoidance of a toxic substrate such as phytanic acid (in Refsum disease), or a dietary supplement (high-carbohydrate diet in glycogen storage diseases, or medium chain triglycerides in fatty acid oxidation disorders) has transformed children's life spans and quality of life.
Dietary management of metabolic diseases is continuously improving, as illustrated by protein glycosylation deficiency. In this case, understanding the mechanism of the disease - impaired isomerization of fructose into mannose - was synonymous with a cure: a life-saving dietary mannose supplement. The same applies to other conditions (see table). Not a year goes by without the elucidation of the mechanism of a metabolic disease resulting in a new therapeutic approach. For these and other rare metabolic conditions, the challenge at the present time is diagnosis, not treatment.
Transplantation is another success story. Pioneers from the previous generation treated hereditary kidney diseases (Alport syndrome, nephronophthisis, and polycystic kidney disease) with kidney transplantation, congenital biliary atresia with liver transplantation, heart malformations with heart transplantation, and immune deficiencies with bone marrow transplantation. There were daring innovations by the orthopedic surgeons and intensive care physicians who first operated on the spines of myopathic children. The pioneers of visceral surgery treated Hirschsprung disease, diaphragmatic hernias, and gastroesophageal malformations.
Electrostimulation of the globus pallidum is a more recent development. It has been used in torsion dystonia due to mutation of the gene DYT1, in Huntington chorea, and in other dystonias. The neurosurgeons responsible, not especially familiar with molecular genetics, I suspect, have done more for these children than the whole community of geneticists combined.
The pharmaceutical industry has contributed safe and effective pharmacologic proteins and enzymes: insulin, growth hormone for the treatment of hereditary dwarfism, factor VIII for hemophilia, and enzyme therapy for lysosomal storage diseases (Gaucher, Hurler, Fabry, and Pompe diseases). Other pharmaceutical interventions have been craftier (see table).
This list should convince the reader that, for now, understanding the mechanism of a genetic disease can yield approaches to circumvent the problem more effectively than can replacement of the mutant gene. Gene therapy and cell therapy will, one day, have their place in the range of treatment options. But let's not put all our eggs in one basket.
Arnold Munnich directs the Genetics Department at the Necker Hospital for Sick Children in Paris and is a professor of genetics at the University of Paris.