All 4 of Rebecca Trendy’s sons—Dakota, 24; Charles, 21; Brendan, 18; and Alec, 16—have lysosomal acid lipase deficiency (LAL-D), an inherited liver disease that renders the body unable to digest fats.

The condition is so rare that most doctors have never heard of LAL-D, let alone treated a patient with the disease.

“It took 9 years of testing for my boys to be diagnosed with LAL-D,” said Trendy, of Port Huron, Michigan. “Thankfully their progression was less severe than in some cases—even though one of my boys, Brendan, would have been heading for a liver transplant within 3 years of their diagnosis, without treatment.”

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Ella Smith, 10, of Amherst, Massachusetts, also has LAL-D. She was diagnosed 3 years ago at Boston Children’s Hospital. Her mother, Anne Christa Smith, said her disease was discovered by accident.

Ella Smith, 10, of Amherst, Massachusetts, has LAL-D. Credit: Anne Christa Smith

Looking back, Smith said that, due to LAL-D’s rarity, some tests and signs were definitely missed.

“Ella always had a distended abdomen but was otherwise very thin. I had considered bringing this up to a doctor when she was younger, but I thought that I would be viewed as an overly nervous mother, and talked myself out of it. Ella also had blepharitis, which I went to many doctor visits for, but was missed,” Smith said.

“So many tests were done, but no one tested her cholesterol, which was sky-high. While most children will not have abnormalities, some will, and it seems unfair for the children with rare diseases.  I wonder if Ella had been treated earlier, would her liver be in better condition?”  

Henry Lin, MD, MBA, is an associate professor of pediatrics at Oregon Health & Science University in Portland. In fact, he’s the only board-certified hepatologist in Oregon, a state of 4.2 million inhabitants.

“The reality is that there’s not a lot of research going on in this area right now,” said Dr. Lin, a pediatric gastroenterologist who has advanced training in transplant hepatology. “This is a very rare disease. The clinical prognosis ramifications are there, but a lot of times, if you have a very mild phenotype with elevated lipids, then whether or not you have LAL-D, I’m still basically treating your high cholesterol.”

Henry Lin, MD, MBA, is an associate professor of pediatrics at Oregon Health & Science University (OHSU) in Portland. Credit: OHSU

Dr. Lin, who grew up in Indiana, did his training at Children’s Hospital of Philadelphia (CHOP) in Pennsylvania as well as Northwestern University in Chicago, Illinois, where he specialized in pediatric transplant hepatology. After returning to CHOP, he was involved in numerous clinical studies of Alagille syndrome and other pediatric liver diseases.

“While I haven’t continued in the lab from a professional standpoint, a lot of these lessons have stayed with me in terms of being mindful about how to identify factors that can affect clinical outcomes in children with liver diseases,” he told Rare Disease Advisor in a recent phone interview.

The challenge, Dr. Lin said, is that a child shows up with a symptom and doctors must decide what are all the potential causes of that symptom, and at what point should the child be screened for LAL-D—a disease that affects perhaps 20 out of every million people.

“There’s a spectrum of severity. In very severe cases of LAL-D, it will be fatal in the first 6 months if you do not identify it,” he explained. “If you’re sick early on when you’re an infant, I need to figure out if you have LAL-D, and should I treat you. More typically, you have a mild form that can go undiagnosed for a long time.”

Even if it’s undiagnosed, LAL-D does not necessarily lead to progressive liver disease, he said.

“There are lots of genetic tests now, and it’s nice to know if you have a mutation, but what are the downstream ramifications?” he asked. “And if you didn’t know, does that mean you end up getting a liver transplant that could have been avoided?”

A main challenge is finding those patients who would benefit from sebelipase alfa (Kanuma®), an enzyme replacement therapy developed by Alexion Pharmaceuticals. It’s been on the market since 2015, when it was approved by the US Food and Drug Administration (FDA).

“What’s exciting about LAL‑D in particular is that, theoretically, if you replace deficient enzymes, that can actually help improve a lot of the underlying liver symptoms and potentially could also prevent the need for transplant,” he said. “Treating with enzyme replacement helps to improve liver enzyme levels and decrease overall total cholesterol and triglyceride levels. These are all contributors to progression of a disease.”

Nicole Ward
Nicole Ward, 41, of Birmingham, Alabama, has LAL-D. Credit: Brad Ward

Nicole Ward, 41, a resident of Birmingham, Alabama, was born in 1980 with a distended abdomen. She was promptly diagnosed with Hirschsprung’s disease. But following 2 years of testing, a colostomy, and a colostomy reversal, doctors at Children’s Hospital in Birmingham finally concluded she had cholesteryl ester storage disease, a type of LAL-D.

“It was a time filled with mystery, because there were so few people in the world who had even ever heard of LAL-D,” said Ward. “I have watched friends struggle with various forms of this rare disorder with different levels of severity. But even today, with the degree of genetic testing we have available, LAL-D patients still struggle as before.”

She added: “It’s different than many disorders, in that every patient is affected so individually and there is currently no way to know predict for us what turn things will take. Due to the rarity of the condition, there is also such a small sample group of patients from which to learn that all present different symptoms.”

Four brothers with LAL-D
The four Trendy brothers of Port Huron, Michigan, all have LAL-D. They are, from left to right: Charles, 21; Dakota, 24; Alec, 16; and Brendan, 18. Credit: Rebecca Trendy

Trendy said she’d like to prevent other families from having to go through what she did.

“Early diagnosis is extremely critical with all LAL-D patients. Since the disease is easily detected with just a simple blood draw, newborn screening would be the most ideal,” Trendy said. “But since we’re not there, the 2 key factors to look for are high liver enzymes and high cholesterol levels. Whenever those 2 results come back abnormal, LAL-D testing should be the very next test.”

Trendy added: “I know many times the rare diseases are not the cause, as they are rare for a reason. However, too many physicians look to simple answers and misdiagnose the rare ones.”