It has been 24 years since the first of Stephanie and Christopher Smith's children got sick, but they didn't know what the culprit was until they became a part of the University of Alabama at Birmingham's Undiagnosed Diseases Program.
It all started with the Smiths' third child, Gage. Soon after, it also became evident that his younger siblings, Aiden and Mandalynn, were sick with the very same unknown illness that he has. Characterized by severe joint inflammation and delayed intellectual development, the condition was relegated to "unknown bone disease" in the children's charts.
The Smiths had been to doctors from Washington, D.C., South Carolina and Florida, but they never got any real answers.
That was until they found themselves in Boaz, Alabama and the children became patients in the Children's of Alabama. There, they met Dr. Robb Lowe, an assistant professor at the Pediatrics Department of the University of Alabama at Birmingham. It was through him that the family became a part of the Undiagnosed Diseases Program, a multidisciplinary effort to unravel the mysteries behind perplexing medical cases that have not been diagnosed.
Through the program and the HudsonAlpha Institute for Biotechnology, Gage, Aiden and Mandalynn underwent whole exome sequencing. Results revealed that the children have two variants in a gene related to mucolipidosis III, an inherited metabolic disorder called lysosomal storage disease.
As cellular structures, lysosomes contain enzymes for breaking down large molecules in cells and recycling the remnants into products that the cell can use. With lysosomal storage disease, the children don't have the ability to store enzymes into the lysosome, preventing them from breaking down molecular material, which instead accumulates in the cells.
The condition is so rare that the Smiths only know of about 650 other cases of lysosomal storage disease. Even Lowe had to self-educate using a study published in 2002.
"The results were mixed in the previous study, but it was a starting place," said Lowe.
The study at least led Lowe to pamidronate, a drug from the bisphosphonate family used for treating bone disease.
In fall 2015, Mandalynn started getting pamidronate infusions every month, and so far, according to her mother, they are seeing the benefits. Now, the 13-year-old is feeling less pain in here joints and legs and her memory and concentration have also improved.
The Smiths are not sure if these positive results will continue, but they find Mandalynn's progress encouraging. For the most part, Stephanie feels relief at finally knowing the name of the disease afflicting three out of her five children, because knowing what it is tells them what to expect and what to prepare for.
The diagnosis is also a triumph for the Undiagnosed Diseases Program because every time a rare disease is identified, new research opportunities open up, and those lead to other discoveries.
"The more we learn about rare genetic conditions, the closer we are to unlocking treatments that will have a meaningful impact on people's lives," said Dr. Bruce Korf, UDP's director and UAB Deepartment of Genetics' chairperson.
