In February, I saw 4-year-old Davi Silva at the Clinic for Special Children in Strasburg. Every six months, Davi and his parents make the 4,800-mile trip from their home near Rio de Janeiro to the clinic, where they are welcomed by doctors, nurses and counselors whom they’ve come to regard as family.
Davi suffers from a rare genetic disorder called glutaric aciduria type 1, labeled GA1, caused by deficiency of an enzyme that normally degrades two essential amino acids, lysine and tryptophan, which are found in all natural proteins. Blockage of this chemical pathway results in the accumulation of a compound called glutaryl-CoA, which acts as a potent neurotoxin to the developing brain.
High glutaryl-CoA levels in the infant brain can trigger sudden, stroke-like and catastrophic injury to a structure called the striatum, which plays a vital role in the control of muscle tone and coordination.
Davi’s movements appeared abnormal within a few months of life. This was the earliest sign of striatal injury and ultimately led to a diagnosis of GA1. Faced with their son’s rare diagnosis, Davi’s parents frantically sought medical help but found local resources and expertise to be severely limited.
When I first met Davi at the clinic, he was 10 months old and had already suffered irreversible brain damage that left him wracked with nearly continuous, forceful and involuntary muscle contractions — a debilitating neurological condition called generalized dystonia.
Davi’s story is both a cautionary tale and a call to action. It reminds us that by investing in pre-symptomatic detection of genetic health risks early in life, we can often spare people a lifetime of pain and disability. It also underscores the great promise of the genomic revolution: the opportunity to detect genetic predispositions to disease within the first hours of life, and thereby deliver the right therapy to the right person at the right time.
These have been guiding precepts at the clinic since it opened in 1989 to serve as a medical home to children from Old Order Amish and Mennonite communities born with rare and often dangerous genetic disorders.
Rare diseases are not unique to Plain populations, but are found within communities throughout the world — places like Brazil. Certain disorders, however, can be highly enriched in Plain populations because of a genetic “founder effect” — a phenomenon observed in any population that is derived from a small core of ancestors and remains reproductively isolated over many generations.
To take the example of GA1, the birth incidence of this condition is estimated to be 1 per 40,000 newborns worldwide, while Lancaster County Amish experience an incidence about 100-fold higher (1 per 400 births).
After brutal religious persecution during the 16th and much of the 17th centuries, Anabaptist groups such as the Amish and Mennonite traveled to the New World seeking religious asylum. Among the small group of ancestral founders who survived the trans-Atlantic migration was the relatively restricted pool of genes that were then passed down through subsequent generations.
Some of these genes contained spelling errors, called pathogenic (or disease-causing) mutations that we find segregating within Anabaptist populations of today.
At the clinic, we invest heavily in efforts to discover these pathogenic changes and, through our unique collaboration with members of the Plain community, develop innovative, affordable and effective treatment strategies.
Clinic for Special Children founders Dr. D. Holmes Morton and his wife, Caroline, championed a special vision. They believed we could selectively harness knowledge from the biological sciences and human genome project to directly improve the lives of children. Over its nearly 30-year history, the clinic has extended this principle into the lives of children from 42 states and 17 countries.
To date, our laboratory has identified and can diagnose more than 260 different pathogenic gene changes disproportionately represented among the Plain people and also found outside of Plain communities. Nearly half of these endanger the developing brain. On-site molecular testing opens a precious window; it allows us to expose a future health threat, craft precise and timely therapy, and pre-empt disease before it strikes.
GA1 offers a compelling example. In the early 2000s, the clinic started collaborating with a small medical food company, Applied Nutrition, to design an effective medical formula for infants and children with the disorder.
At the time of the clinic’s inception in 1989, Dr. Morton had diagnosed GA1 in 17 Amish children and adults, 94 percent of whom were disabled. Many of these individuals were confined to a wheelchair, emaciated, mute and completely helpless. Since 2005, we have now consecutively treated 40 GA1 patients from birth using the special medical formula designed and tested at the clinic.
Today, 39 (that is, 98 percent) of these children are healthy — walking among you — and can expect to live long and productive lives.
Sadly, there was no such miracle for Davi. And yet, working at the clinic has taught me that although cure is not always possible, there is always a way to offer help that can change someone’s life for the better. I will continue to refine Davi’s diet to safeguard him from further brain injury, carefully adjust his medications to alleviate the pain of dystonic muscle spasms, and share information with his doctor in Brazil to ensure the best possible outcome.
Most importantly, I will never forsake the hope for his brighter future.
Kevin A. Strauss, M.D., is medical director of the Clinic for Special Children in Strasburg, and an adjunct associate research professor at Franklin & Marshall College.