Back in 1991, when Daniel was an infant, not nearly as much was known about congenital hyperinsulinism as there is now. Combine its rarity — 1 child in 50,000 births — with the spectrum of symptoms, with cases ranging from relatively mild to severe hypoglycemia, and it’s easy to see why it took several months for Daniel to get the help he needed.

Daniel was having seizures, and local doctors didn’t know why. During one early episode, Daniel turned blue, so his mother, Tina, called for an ambulance. Once at the hospital, the Emergency Room doctor checked Daniel’s blood sugar and told her, “His blood sugar is so low, I don’t know how he is still alive. He should be dead or in a coma.”

Rare disorder causes hypoglycemia

That was the family’s introduction to hyperinsulinism (HI), a rare genetic disorder that causes overactive cells in the pancreas to excrete too much insulin, leading to extremely low blood sugar levels (hypoglycemia). Hypoglycemia can bring on seizures.

About congenital hyperinsulinism

Daniel was transferred to the closest pediatric hospital to the family’s home in Zanesville, Ohio. When medical management failed to increase his blood sugar levels to the normal range, Daniel underwent an 85% pancreatomy. After the surgery — with the help of diazoxide — his sugar levels stabilized.

Unfortunately, the frequent and lengthy seizures in his first few months of life, paired with the GLUD-1 genetic mutation not identified until 29 years later, led to global developmental delays and behavioral issues.  

When Daniel was around 5, the grand mal seizures (also known as a generalized tonic-clonic seizures) returned. Theorizing that they were the result of the stress on his neurological system from his earlier seizures, doctors put him on Depakote®, an antiseizure medicine. The severity and number of seizures were reduced, but Daniel still experienced them. It made for a challenging life. His behavior issues caused problems, even in special education settings, that resulted in him being removed from class.

“He would tell me, ‘Mommy, I don’t know why I’m acting this way.’ It was heartbreaking,” Tina says.

Next up: Too much ammonia

Beginning when he was 10 years old, it came to Tina’s attention that Daniel had elevated levels of ammonia in his blood — normal levels are less than 30 micromole per liter (µmol/L) and his ranged from 79 to 281 µmol/L — but the reason was unclear.

“Throughout the years, I took him to doctor after doctor after doctor,” Tina says. “They were honest with me. They said, ‘This is beyond my expertise.’”

In 2020, after Mari Mori, MD, MS, a clinical geneticist at Nationwide Children’s Hospital in Columbus, ordered genetic screening, he was found to have a mutation in the GLUD-1 gene, which causes hyperinsulinism/hyperammonemia (HI/HA) syndrome, the second most common form of congenital hyperinsulinism.

“I knew that something had been going on under the surface all those years, and we finally had the answer,” Tina says.

Since Depakote has a side effect of elevating ammonia and his levels were already high, he was switched to Epidiolex®, a Food and Drug Administration-approved prescription cannabidiol (CBD), which has halted Daniel’s tonic-clonic seizures; however he still has very mild myoclonic seizures, a type characterized by sudden, unintended muscle jerking. His occur at night and are generally frequent.

Help with seizures and HI/HA at CHOP

Dr. Mori told the family about a special program at CHOP that brings together physicians from several different specialties to care for individuals with GLUD-1 mutations. The Epilepsy Neurogenetics Initiative (ENGIN) addresses difficult-to-treat or unexplained epilepsies by integrating genetic results into treatments. It also has special expertise in creating individualized care plans for patients whose underlying endocrinology problems — such as HI/HA — are driving their seizures.

From the ENGIN team, Daniel was seen by epileptologist Mark Fitzgerald, MD, PhD, endocrinologist Elizabeth Rosenfeld, MD, and clinical dietitian Lauren Cherry, MS, RD, LDN, who supports the Congenital Hyperinsulinism Center.

Dr. Fitzgerald gave Tina some suggestions of additional epilepsy medications that may help to limit Daniel’s myoclonic seizures.

Daniel had stopped needing diazoxide to keep his blood sugar levels safe since 2013, but his blood sugars were now in the high range, which is common for individuals who’ve had a near-total pancreatectomy. Dr. Rosenfeld prescribed a medication to help bring them back to a healthy level. She also explained how diet plays an integral role in managing HI/HA because eating protein causes blood sugars to drop rapidly.

Cherry helped Tina understand how to change Daniel’s diet to level out his blood sugars and avoid the dips triggered by eating protein by itself. “She recommended keeping carbohydrates and proteins in balance and focusing on low glycemic foods,” Tina says.

In addition to the collaboration among experts, what sets the ENGIN program apart is its research into the connection between the GLUD-1 gene and seizures that may very well go beyond the HI/HA diagnosis. Because CHOP sees more HI/HA patients than any other center in the world, there is the opportunity to follow these individuals over time and track the full spectrum of their neurological manifestations and determine which medications have the highest probability at mitigating the seizures. ENGIN’s longer-term goal is to develop precision therapies that address GLUD-1 epilepsies.

Improving quality of life

Back home in Ohio, Daniel, now 31, stays active. He likes to play basketball, ride his bike, go swimming, watch Jeopardy and Bubble Guppies, and listen to music. “He does pretty well, considering what he’s been through,” says Tina.

Sometimes, she thinks back 30 years ago and wonders “what if.”

“I think about the importance of checking blood sugars in the first few weeks or months of life, and how if our pediatrician had done that at the beginning, it would have changed Daniel’s entire future. There were a lot of near misses that could have prevented the adverse episodes. But I can’t go back and change anything. I can only look to the future.