From just a tiny sample of blood, a lab can test for 35 rare diseases in newborns that, if left undetected, could lead to seizures, developmental delays, permanent brain damage or death.
If results are positive for a metabolic disorder, these labs turn to the experts at CHOC Children’s metabolic laboratory for further analysis and treatment of newborns just days old.
September is Newborn Screening Awareness Month, and Dr. Jose Abdenur, director of CHOC’s metabolic laboratory, stresses the importance of these newborn screenings in order to prevent such grim scenarios from playing out.
Newborn screening is a public health program that screens all babies for many serious but treatable genetic disorders, and CHOC is one of the state’s largest referral centers for the program. All babies born in California are required to get screened soon after birth, but the diseases babies are screened for varies by state. In Orange County alone, some 38,000 babies are born every year.
CHOC is the only location on the West Coast for children who need cutting-edge treatment for certain metabolic diseases that can be detected from newborn screenings. Further, CHOC’s metabolics program is a leading destination for children from around the world afflicted with certain metabolic disorders, which are rare genetic disorders that result from a missing or defective enzyme in the body. These include disorders such as galactosemia, which impairs the body’s ability to process and produce energy from the sugar galactose, and adrenoleukodystrophy, which causes the buildup of very long-chain fatty acids in the brain.
“There are many, many very good success stories at CHOC, but there are still many things we can improve,” Abdenur says, citing too many false positives for some conditions that make families feel anxious and worried. “But we continue to get better at this.”
Newborn screening began in the 1980s. Over the decades, the Department of Health and Human Services has added recommended disorders for states to screen for in their newborn screening (NBS) programs. There now are 35 core conditions on the so-called Recommended Universal NBS Panel, as well as an additional 26 secondary conditions.
In addition to metabolic disorders, newborn screening can detect disorders related to hematology and immunology — such as sickle cell disease — as well as endocrine disorders, pulmonary diseases including cystic fibrosis, and such neurological conditions as spinal muscular atrophy.
Like most physicians, Dr.
Raymond Wang got into medicine because he wanted to help. He wanted to be
able to tell patients and their families that he could fix whatever was wrong
When it comes to the disease Dr. Wang dedicated his career
to studying, however, he can’t offer such assurances. Hopefully that day is
Dr. Wang and his team at CHOC Children’s are participating
in a clinical trial of a drug intended to treat a rare pediatric disease called
MPS IIIA. It’s a type of Mucopolysaccharidosis,
or MPS, a genetic condition that causes physical abnormalities in young
children and causes them to lose their neurological development.
Also called Sanfilippo syndrome, its early symptoms can mirror
those of autism, but unlike autism, the patients don’t improve, instead
gradually deteriorating until memories and even basic abilities are lost. Most Sanfilippo
patients don’t survive to adulthood.
There is currently no cure.
“When we go into medicine, we come in thinking, ‘All right, I’m
going to help my patients. I’m going to make them better,’ ” says Dr. Wang, a clinical geneticist and
biochemical genetics specialist at CHOC Children’s for the past 12 years. “When you
are faced with the prospect that you can’t help, or at least in the sense that
you can’t make these kids better and cure them, that doesn’t sit well with me.”
Phases II and III of the trial are being conducted by
Lysogene, the French company that developed the experimental treatment. CHOC
Children’s is one of four U.S. hospitals taking part; there are three such sites
in Europe: in France, Germany, and the Netherlands. Lysogene is still enrolling
patients and is seeking a total of 20.
Those patients are hard to find. In his decade of
researching MPS and seeing patients, Dr. Wang estimates he’s only diagnosed 10 cases.
Two of those children were siblings, and tragically both died of the disease.
But Dr. Wang has enrolled one patient in the new trial.
Lysogene sought out Dr. Wang for the trial because of his expertise in
researching and diagnosing the various MPS types. If the Lysogene drug is
eventually approved by the FDA, CHOC should become the first facility on the
West Coast to be able to both diagnose the disease and administer the drug,
which is surgically inserted into brain tissue.
It won’t be apparent until a checkup about six months after
the procedure whether the drug is working.
“We are hoping to prevent regression at the least, or allow
for developmental progression,” Dr. Wang said.
There have been seven different
types of MPS identified: I, II, III, IV, VI, VII and IX, not counting the
subtypes within them. The subtype MPS IIIA, Sanfilippo, strikes about one in
every 100,000 children.
MPS is an inherited disease.
All the types are collectively known as “lysosomal storage diseases.” Lysosomes
are compartments in cells that break down molecules and remove waste products.
different enzymes in the lysosomes break down complex sugars called
glycosaminoglycans, also known as mucopolysaccharides. In MPS,
glycosaminoglycans are not broken down because of a deficiency in one of those
lysosomal enzymes. As a result, the glycosaminoglycans accumulate in the cells
and cause tissue damage.
symptoms can include thickening of the lips and skin, enlarged liver and
spleen, hernias, recurring ear infections, joint pain and stiffness, and
shortness of stature. With Sanfilippo, which attacks brain cells, cognitive impairment
could include delayed speech. Since by itself speech delay isn’t uncommon in
children, Sanfilippo’s initial symptoms only add to the confusion for families.
In the first two to three years of a patient’s life, “there might not be any symptoms,” said Dr. Wang, director of CHOC’s Foundation of Caring Lysosomal Storage Disorder Program . “Nobody ever thinks ‘my kid has Sanfilippo,’ and few doctors think about it. But it starts to be around 3, 4, 5, when hyperactivity starts, and there are questions of autism, and usually what happens is a physician recognizes that kids with Sanfilippo look a little different.”
treatment that has shown success for some kinds of MPS is enzyme-replacement
therapy: delivering synthetic working enzyme using an intravenous solution. It can
reduce the effect of symptoms and improve quality of life. But the treatment
only works if the disease is not located in the brain; unfortunately, the
life-threatening symptoms of Sanflippo are caused by effects of the disease in
the nervous system.
the brains of children with Sanfilippo syndrome, a waste product called heparan
sulfate builds up, causing nerve damage and, over time, the death of nerve
cells. The Lysogene drug includes a package called a
“vector.” It contains genetic instructions that enable treated nerve cells to
make the missing enzyme, called sulfo-hydrolase, which clears out the waste
“Short-term, you can measure things like, is the body
producing sulfo-hydrolase enzyme; is there a reduction in heparan sulfate?” Dr.
Wang says. “But the more important thing is, is this actually helping these children?
What parents really care about is, is it helping their child’s neurologic
function. Is my child not regressing? Is my child maybe even gaining
developmental milestones back?”
Dr. Wang acknowledges that, as a younger doctor, he was fascinated by the diagnostic side, the “sleuthing” part of identifying patients with, and researching, MPS. But over time, after accompanying many MPS patients and their families along difficult and tragic journeys, he knows his motivations now have a higher purpose, beyond intellectual stimulation.
reflects that his involvement in clinical trials for children with
neurodegenerative conditions such as the Lysogene study is “a way for me
personally to channel my feelings of helplessness when we diagnose someone with
a supposedly incurable condition.”
“I know how painful it is for these families,” Dr.
Wang says. “If I can give them the possibility of hope, then that’s what makes
waking up each morning and heading to work worthwhile.”
Learn more about referring
to CHOC’s metabolic disorders specialists.
An $8 million gift from the Foundation
of Caring will help CHOC Children’s advance research for a rare lysosomal
storage disease, ultimately leading to an improved understanding and more
The gift will support CHOC researchers
working to develop next-generation therapies for Pompe disease, a lysosomal
storage disease wherein glycogen builds up in the body’s cells and causes
life-threatening heart failure and muscle weakness in affected babies. In honor
of the gift, the program will be named the Foundation of Caring Lysosomal Storage
Disorder Program at CHOC Children’s.
“This incredibly generous gift from the Foundation of Caring will help accelerate our work to unlock the challenges of Pompe disease and other lysosomal storage disorders, advancing our vision to develop permanent cures for patients with these conditions,” said Dr. Raymond Wang, a CHOC metabolic disorders specialist and director of the Foundation of Caring Lysosomal Storage Disorder Program. “We’re so tremendously grateful to have the Foundation of Caring’s support in CHOC’s goal to protect the magic of childhood.”
Dr. Wang’s work around Pompe disease
drew the attention of the Foundation of Caring several years ago, when he began
treating the great-granddaughter of the Foundation’s founder after she was
diagnosed with the condition.
With previous support from the Foundation
of Caring, Dr. Wang and his team have already made significant strides in its study
of Pompe disease, having built a growing research team that’s used CRISPR/Cas9
technology to edit the genome to create animal models of Pompe disease. The
Foundation of Caring’s gift will allow Dr. Wang and his team to expand upon
this work and use CRISPR to cure Pompe disease and lysosomal storage disorders.
“We are so pleased to support the
important work of Dr. Wang and his team at CHOC to help find better treatment
or, even better, a cure for Pompe disease for patients affected by the condition
worldwide,” said the Foundation of Caring Board of Directors.
Bringing new hope to patients and their families, CHOC Children’s is now among a few hospitals in the country to offer treatment for a rare genetic brain condition that has previously been considered a death sentence for children.
CHOC has been fast tracked to commercially provide Brineura, the first and only treatment for CLN2 disease, also known as late infantile Batten disease. The condition typically begins with language delays and seizures before age 3, and rapidly progresses to dementia, blindness, loss of the ability to walk and talk, and death in childhood.
Bringing Brineura to CHOC is the product of three years of work by metabolic specialist Dr. Raymond Wang.
“This is huge,” Dr. Wang says. “You’re taking a progressive and fatal disease and stopping it. Having seen how heartbreaking it is for families to see the child they know get slowly robbed from them, the fact that we can offer these families hope, is tremendous. Something like this is the very reason I went into medicine and specialized in metabolic disorders: to provide hope to families affected by rare disorders such as late infantile Batten disease.”
Dr. Wang works closely with CHOC neurosurgeon Dr. Joffre Olaya to administer the medicine. Each patient has an Ommaya reservoir implanted under their scalp, which allows the medicine to be infused directly into their brains.
In a sterile procedure every two weeks, Dr. Olaya and a team of highly trained nurses insert a needle into the reservoir to administer the medication. The infusion lasts four hours, and after four hours of observation, the patients can go home.
While not a cure, the drug can slow the progression of the disease. Over a three-year period, patients treated during clinical trials showed no progression of the disease, which was radically different from the disorder’s natural course. The medication improves quality of life and buys patients critical time as researchers continue to search for a cure.
Having the treatment available close to home is a game changer for the Bowman family. A participant in the clinical trial, Ely Bowman, 4, would travel every 10 days with his parents from Orange County to Columbus, Ohio, for treatment.
But now, the Bowmans need only to drive a few miles to CHOC for this critical treatment.
“For Ely to be home and have consistency and we can still have some fun is wonderful,” his mother, Bekah, says. “We can see him thriving.”
The work of a CHOC Children’s metabolic disorders specialist and is highlighted in a recent Science magazine article.
The article hinges on Dr. Raymond Wang’s work to help a patient with a rare condition called Niemann-Pic Type C, a condition that causes cholesterol to accumulate in the brain, lungs, liver and spleen, leading to deterioration and early death.
Not only is the young girl doing well after Dr. Wang began an experimental treatment, but her family’s foundation also provided funding that allowed Dr. Wang to continue research that could help children with a rare metabolic diseases called mucopolysaccharidoses, or MPS.
To that end, the piece examines the tug of war felt by some physicians when balancing patient care and research. Despite a physician’s strong interest and commitment, research eludes many due to a lack of time and funding.