Living on Hope: Researchers Pursue Improved Treatments for Rare, Complex Metabolic Disorders

By Mark Shwartz
Friday, January 1, 2010

For Divya Wadhwani, age 13, the search for the cause of her mysterious and debilitating muscle disorder turned into an eight-year, 8,000-mile odyssey that began when she was a small child in Mumbai, India.

“Divya was perfectly fine until age 4, when her nursery school told us that she was having episodes of slumping,” recalls Mahesh Wadhwani, Divya’s father. “They said that her knees were buckling, and that she was falling down.”

Thirteen-year-old Divya Wadhwani of San Ramon benefits from ongoing treatment at Packard Children’s Hospital for mitochondrial myopathy, a rare neuromuscular condition that claimed the life of her younger sister.

At first, Divya’s doctors suspected an iron deficiency or a rare neurodegenerative disease, but those causes were eventually ruled out, and her condition worsened.

Then, tragedy struck. Divya’s 2-year-old sister, Mallika, developed uncontrollable seizures and died a few months later. Doctors began to suspect that Divya and Mallika shared a mitochondrial disease, an inherited disorder that wreaks havoc on the energy-producing part of the cell called the mitochondrion.

Unfortunately for Divya, there were no laboratories in Mumbai equipped to test for these rare conditions, which affect one in 4,000 children. Then, in 2004, her father got a job reassignment to the United States, and the family moved halfway around the world to San Ramon, Calif.

Within a few months, Divya was at Lucile Packard Children’s Hospital under the care of Greg Enns, MD, one of the country’s leading experts on mitochondrial disease. “I strongly believe that life is an interplay of destiny and fate,” says Mahesh. “You try to put things together, and everything falls into place.”   

Greg Enns, MD, belongs to a team of caregivers who coordinate treatments for children suffering from rare, inherited metabolic disorders.

Enns, director of the Biochemical Genetics Program at Stanford University, ordered a muscle and nerve biopsy, which confirmed that Divya had indeed inherited some type of mitochondrial disorder—but which one?

“Dr. Enns said that it’s like going to a mechanic,” says Mahesh. “We know there’s a problem with the engine, but we don’t know exactly what is causing it, or how you go about fixing it. That’s when the genetic pursuit started, and it took four more years of extensive workup, of trying to eliminate one thing or another, to find an answer.”

Finally, last year, highly specialized tests of Divya’s DNA revealed a defect in a gene called POLG1, which had only recently been identified as a cause of mitochondrial myopathy, a neuromuscular condition with a range of symptoms identical to those of Divya and her late sister, Mallika. The disease is recessive; a blood workup of Divya’s parents confirmed the diagnosis. “Dr. Enns is a gem of a person,” says Mahesh. “Thanks to him, we’re no longer groping in the dark. But there are probably thousands like us who are carriers of this defect, and don’t realize it until the symptoms show up in our children.”

Catching it Early

Mitochondrial diseases belong to a larger group of illnesses known as inherited metabolic disorders. Scientists have identified hundreds of these disorders, each caused by specific genetic mutations that damage key enzymes responsible for converting food into energy or for removing metabolic waste from our cells.

Their complexity makes many of these rare diseases extremely difficult to diagnose and treat. Because their conditions often masquerade as other illnesses, many children with symptoms of a metabolic disorder are brought to the experts at Packard Children’s for a definitive diagnosis.

“Metabolic disorders are challenging to diagnose because they can be caused by so many different mutations affecting so many different genes,” says Enns, the Arline and Pete Harman Endowed Faculty Scholar and an associate professor of pediatrics. There are many different kinds, he adds, each caused by a unique genetic defect. “Some metabolic disorders scream their diagnosis clearly. Others, like Divya’s, are more subtle and more difficult to diagnose conclusively.”

Tina Cowan, PhD, leads the Stanford Clinical Biochemical Genetics Laboratory. In 2009 alone, her lab conducted nearly 6,500 tests for a wide range of metabolic disorders.

Metabolic disorders may be more common than scientists once assumed, says Tina Cowan, PhD, associate professor of pathology and director of the Stanford Clinical Biochemical Genetics Laboratory. In 2009 alone, the Stanford lab conducted nearly 6,500 tests for a wide range of metabolic disorders using blood samples collected from people of all ages—newborns to adults.

“We’re set up to deliver rapid diagnosis and to guide the clinicians in the follow-up care,” Cowan says. “For us, the magic is really the collaboration between the lab and the clinic. Greg Enns and the other doctors tell us what they need, we tell them what we need, and we all work together to make things better for the patient.”

Early diagnosis is the key to treating most metabolic disorders, notes Enns. “We’re excited to be able to diagnose these kids before they have symptoms, because by the time they get sick, their organs can be irreversibly damaged,” he says.

Louanne Hudgins, MD, is the Mosbacher Family Distinguished Packard Fellow and chief of the Division of Medical Genetics.

At Packard, expectant mothers can be tested even before their child is born. Louanne Hudgins, MD, the Mosbacher Family Distinguished Packard Fellow and chief of the Division of Medical Genetics at Stanford, and Enns, working jointly, recently diagnosed and treated a boy in the womb for ornithine transcarbamylase (OTC) deficiency, the most severe form of urea cycle defect, a disorder that occurs when the liver is missing a crucial enzyme that helps eliminate nitrogen waste. Without that enzyme, ammonia can build up in the bloodstream and cause severe brain damage if not treated quickly.

“We gave the mother a bolus of medication that lowered the ammonia while she was in labor, and when the boy was delivered, his ammonia levels were under control,” says Enns. “When I was training, OTC deficiency was a death sentence or meant permanent neurological damage, at best. End of story. To see this boy stable and awaiting a liver transplant is definitely a step in the right direction. It’s a wonderful era for biochemical genetics.”

Newborn Screening

Early diagnosis took a giant leap forward in 2005 when the State of California expanded its newborn genetic screening program to include some 40 metabolic disorders. The screening process is simple: A few drops of blood are taken from the newborn’s heel and shipped to a lab for analysis. Newborn screening already has changed the prognoses for several metabolic disorders, including a disease called medium chain acyl-CoA dehydrogenase (MCAD) deficiency, in which a particular enzyme doesn’t break down medium chain fats normally. “MCAD deficiency is the poster child for the expanded newborn screening program,” says Enns. “MCAD children typically look fine, but if their body becomes stressed, say by a viral infection or flu, these kids can suffer fatal complications.”

In the past, roughly two-thirds of children with MCAD deficiency died or ended up neurologically impaired. “But since newborn screening began, we’ve had tremendous success identifying and treating these children before they fall ill,” says Enns. “Now it’s unusual for a child with MCAD deficiency even to suffer neurological problems.”

Enns was instrumental in convincing the California legislature to expand newborn screening to include metabolic disorders. Today, Packard is a designated Area Service Center, screening 100,000 newborns annually. When an infant tests positive, members of Enns’ team, including genetics counselor Rachel Cox, MS, get the call. “Most positive newborns in Northern California are referred to us,” she says. “We speak with the pediatrician and family about what a positive newborn screen means, how to care for a child with a suspected disorder, and what steps we need to take to confirm or disprove the diagnosis.”

Cox and her colleagues also coordinate clinical trials of new drugs to treat metabolic disorders and train graduate students enrolled in genetic counseling at Stanford—one of only three master’s degree programs in California.

“Packard is an amazing place to be,” says Cox. “We’re in the center of such exciting progress, not only on the medical campus but also in biotechnology and pharmaceutical research. We focus on preventive care and catching babies as soon as they’re born so we can improve their long-term prospects, and our ability to do that starts with basic science.”

Biochemical Smoke

Divya’s ongoing treatment includes a cocktail of five dietary supplements—special antioxidants designed to eliminate dangerous free radicals in her system that are the byproduct of her faulty metabolism. “If your car doesn’t work right, you make a lot of smoke in the tailpipe,” explains Enns. “If your mitochondria don’t work right, you make what I call biochemical smoke—large quantities of charged oxygen atoms, called free radicals, which the body can’t eliminate.” In 2009, Enns, Cowan, and their Stanford colleagues conducted a landmark study confirming that people with a variety of mitochondrial diseases have significantly lower levels of glutathione, the body’s main antioxidant defense. It was the first study to hold out the possibility that a natural biomarker, in this case glutathione, could eventually be useful in diagnosing these disorders, which are too complex for routine newborn screening.

To determine if patients like Divya are responding to therapy, Enns hopes to develop another test that measures excess free radicals in the blood, a state known as oxidative stress, that is also involved in Parkinson disease, diabetes, Alzheimer’s disease, and cancer. “So these rare genetic diseases will give insight into more common disorders, and affect future treatment for many illnesses,” he says.

Enns and his colleagues also are conducting clinical trials of potential enzyme replacement therapies for lysosomal storage diseases—metabolic disorders that occur because the body is unable to produce an enzyme that allows the cell’s recycling plant, called the lysosome, to function properly. Without the enzyme, the lysosome gets clogged with discarded bits of cellular material that normally would be recycled. Over time, this can damage the brain, heart, and skeletal muscles.

“The problem is that enzyme replacement therapy is very expensive,” says Hudgins. “It can cost up to $400,000 a year. And an enzyme infusion can’t cross the blood-brain barrier, so while these kids’ hearts may function more appropriately, they’re not necessarily decreasing their cognitive impairment. Families might ask, is it really worth it?”

One Day at a Time

Divya Wadhwani appears to be responding well to therapy, and continues to build her strength by swimming once a week and exercising daily.

Today, Divya appears to be responding well to therapy. For example, her glutathione levels have gone up, an indication that the antioxidant cocktails may be having an effect. She continues to build her strength by swimming once a week and exercising daily. And Enns is considering enrolling her in a clinical trial of a promising new drug being developed by a local pharmaceutical company. But it’s unclear whether any of these treatments will work in the long run.

“Any kind of breakthrough would be a miracle, so we have to live on hope,” says Mahesh. “From our experience, we know that Packard Children’s is moving in the right direction to unravel these mysteries,” he adds. “Families like ours who are directly impacted by this live life one day at a time. Who knows, one fine day we may have a cure.”