Pinpointing a proper diagnosis

“My eyesight was one of the biggest issues for me throughout my life,” said Pam. “It still is.”

Pam, who was born in 1957 before the advent of newborn screening, lives with classical homocystinuria (HCU). Classical HCU is caused by a deficiency of the cystathionine beta-synthase (CBS) enzyme that is necessary for metabolizing protein. Food with protein contains methionine, an essential amino acid we need to live. A byproduct of metabolizing methionine is an amino acid called homocysteine. Because of the deficient CBS enzyme, people with classical HCU cannot break down homocysteine and methionine and clear it from the body. This results in toxic levels of homocysteine and puts people at risk for heart attack, stroke, bone malformation, lens dislocation – even among young children. The condition can also cause cognitive developmental delays and intellectual disability.

The early years

Pam’s parents noticed she was having trouble with her vision around the age of 2. An ophthalmologist saw that her lenses were already nearly completely dislocated then; she was prescribed “coke-bottle glasses”. Then at the age of 12, she switched to contacts and was astounded at how much she hadn’t been seeing until then. “For the first time in my life, I could see the leaves on trees, and I could read things that weren’t too far away. It was a life changer for me.”

While in elementary school, Pam tended to need a little extra help, always sitting in the front row and staying with a tutor after class. “But I did fine,” Pam says. “My parents’ philosophy was always ‘Do the best you can, and as long as you’re doing the best you can, you know that’s all we ask of you.’”

Pam’s family thought she had Marfan syndrome. Marfan syndrome is a genetic condition that affects the body’s connective tissue and can cause issues in many parts of the body including the heart, bones, joints, and eyes. Dislocated lenses are common in Marfan syndrome, and people with the disorder tend to be very tall like Pam is. In ninth grade, Pam began having problems with scoliosis, yet another common Marfan syndrome symptom.

What didn’t quite add up is that Pam wasn’t experiencing any heart issues, which is common in Marfan syndrome. But the diagnosis still seemed the best fit with what the family knew and what Pam was facing. “My parents were always really good about searching out the best people they could find to help me with the different issues that I was experiencing.”

After high school, Pam attended the University of Nevada, Reno. She joined a sorority, succeeded in college, and graduated with a teaching degree in special education. In her third year of work, she describes the day that she went to school with “a little curtain going across my left eye.” By the end of the day, she had no eyesight in that eye. The school nurse was too nervous to tell Pam what she thought was wrong.

Still just in her 20s, she underwent surgery to repair her detached retina followed by numerous (technologically early) laser surgeries to help restore her vision.

Pam early years

Symptoms and complications pile on

After college, Pam married and moved to Carson City, Nevada. One day, while coordinating with other staff and teachers at work, a colleague noticed she was not communicating clearly, expressed serious concern and went to find the school nurse. Dizzy, but otherwise hopeful everything was fine, Pam finished out the day, only to discover she’d had a stroke. She was only 46 years old.

Then came the blood clots in the lungs. At this time, Pam was seeing experts in the Stanford Marfan syndrome clinic. Looking for answers as to her pulmonary embolisms and strokes, Pam discovered a link on the Marfan Foundation’s website for related disorders.

“I saw homocystinuria for the first time. The symptoms – blood clots, strokes, eye problems, back problems – and all of a sudden, I thought, I bet this is what I have had all my life.”

Following a call to her doctors at Stanford about her suspicions, they performed blood tests. Pam’s homocysteine level was 412, many, many times a normal value. “We believe you might have nailed what you have,” Pam recalls her doctor saying. She also had a genetic test performed, confirming classical HCU.

After more than 50 years, Pam had an accurate diagnosis. Then came a new way of living to help manage this rare metabolic condition.

Living with a new diagnosis and finding medical experts

All foods with protein have methionine which breaks down into homocysteine. However, without the CBS enzyme to metabolize them, these two amino acids can reach toxic levels in people with classical HCU and cause the problems experienced by Pam. The genetic disorder is managed through a highly restrictive low-protein diet combined with betaine, B6, and a formula to replace necessary amino acids that are missing due to the restrictive diet. That made for a drastic change in Pam’s life. She loves to cook and – even in childhood – enjoyed gourmet meals prepared by her mother.

Pam acknowledges that the diet is hard for her as an adult and can sometimes be isolating. “Getting together with my brother and sisters can be hard sometimes. None of us grew up knowing I had this rare disease, so it’s difficult to understand the restrictions I’m faced with now.” While acknowledging how difficult it has been for her, she can’t fathom how much more difficult it must be for children.

Pam has also struggled to find doctors who are familiar with homocystinuria and has shuttled between clinics in Reno, Los Angeles, at Stanford, and now at the Children’s Hospital of Orange County.

At 66, Pam says she is the oldest person with the condition she or her doctors know of in the U.S.  “Sometimes it’s a little scary because doctors that follow patients with homocystinuria are frequently pediatric geneticists who are following kids with phenylketonuria (PKU). I am in my late 60s and have a pediatric specialist.”

Today, Pam enjoys swimming and cooking and spending time with her children and their families. Her vision has deteriorated further since the time of this interview and that has made for more life adjustments. She feels sometimes like a cat with nine lives who has used up 6 or 7 of them, and at the same time, like there is an angel who is looking out for her. Given everything she has gone through, Pam continues to live by the words of her parents, do the best you can.

Pam in Kitchen

Looking ahead to new approaches in newborn screening

As Pam has experienced, the consequences of a half-century delay in diagnosis of classical HCU can be devastating. While HCU was officially added to the U.S. Recommended Uniform Screening Panel for newborns in 2009, and some states began testing long before, experts have estimated upwards of half of babies who are more severely affected by classical HCU (those who don’t respond to B6 treatment) are missed due to the insensitivity of the biomarker most states are testing. Newborn screening wasn’t an option for Pam. Working closely with the patient advocacy organization HCU Network America (HCUNA), Travere is supporting modernization in biochemical newborn screening protocols for classical HCU. This incredibly important public health service should be modernized to help all rare families reach an accurate diagnosis more quickly.