Advances in genetic testing and the development of enzyme replacement therapy (ERT) for half a dozen diseases, including Gaucher, Fabry, and Pompe, have led doctors to the vexing question of whether therapy should be initiated when the diagnosis is made or when symptoms first appear.
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A new case study on a young adult diagnosed with Pompe disease in his first year of life suggests that there may well be a long latency period — decades, in fact — from the time the disease is identified to when it begins causing problems for an individual. Pompe disease is caused by mutations (deficiencies) of a gene that makes the enzyme called alpha-glucosidase (GAA).
Pascal Laforêt, MD, of the Institut de Myologie of the Groupe Hospitalier Pitié-Salpêtrière in Paris, and his colleagues, pointed out that the young man, now 21, has developed normally and that there would not have been reason to begin treating him in childhood.
The report, published in the July 13 online edition of Neurology, addresses a looming issue on the horizon for diseases like Pompe that once were fatal but are now buffered by replacing missing or deficient enzymes needed by the body to keep glycogens in check.
“Considering the current constraints of ERT for patients and the very high cost of this treatment — more than $340 000 per year for adults — the observation of such slow, if any, progression of the disease over two decades of life prompts us to recommend a precise assessment of muscle strength, MRI and respiratory function before deciding to treat adults with GAA deficiency,” Dr. Dr. Laforêt and colleagues wrote. “Our present experience with this patient suggests that ERT should probably not be initiated before occurrence of obvious anomalies of vital capacity, muscle strength or muscle deterioration, and MRI abnormalities.”
In the case example, a high fever in childhood led to a blood test that showed increased liver enzymes, and a 1.5 fold hyper-CKemia. A muscle biopsy subsequently revealed a vacuolar myopathy with increased PAS staining. Further testing revealed GAA deficiency. Genetic tests were ordered and two mutations were discovered; one in the GAA gene: c.-32-13T>G, a common mutation found in late-onset Pompe and a novel mutation, c.655G>A (p.Gly219Arg). The boy did not have the GAA gene mutation that is linked to the infantile form of Pompe. He had never complained of muscle weakness.
Clinical trials of ERT in the infantile form of the condition have shown that the replacement therapy — alglucosidase alfa (Myozyme) made by Genzyme — helps in about one-third of children who showed “dramatic improvement of cardiac and motor symptoms,” said Dr. Laforêt.
The infantile form progresses quickly and without ERT infants generally die in the first year of life. There is another form that develops in the second or third year of life and there is an argument in both of these circumstances that younger siblings who test positive for a mutation but do not yet have symptoms should be treated with ERT, said Dr. Laforêt.
There are no strong data on ERT's effectiveness in adults with Pompe, and Dr. Laforêt said that the “clinical improvement of adults is less spectacular and needs long-term follow-up to better evaluate the benefit.”
There are no international guidelines on when to start treatment, he added.
So the question remains: Should a person with the late-onset Pompe be on a twice-monthly infusion of ERT when there are no symptoms and no way to tell when they will develop?
Lessons from this case study suggest that it would not be wise to begin treatment early, at least for late-onset Pompe, said Dr. Laforêt. As was seen in this young man, symptoms could take decades to develop. There are other lysosomal storage diseases where it becomes even trickier. For instance, the symptoms of Fabry disease do not appear until the third or fourth decade of life. Now, some states have recommended newborn screening to pick up a number of lysosomal storage diseases, including Fabry, and this is heating up the debate on when to begin treatment.
“In general, it is unethical to do presymptomatic testing of an adult disorder in childhood,” said Jennifer M. Kwon, MD, associate professor of pediatrics and neurology and associate director of the Clinic for Inherited Metabolic Diseases at Golisano Children's Hospital and the University of Rochester School of Medicine. “When we do screening we look for childhood onset disorders.”
The inherent problem with some of the conditions that are now part of newborn screening programs, including a handful of lysosomal storage diseases, is that there is not a lot known about the diseases and there are no effective treatments. A perfect example is a condition called Krabbe, caused by a defect in the GALC gene. Patients don't make enough galactosylceramidase, a substance that is critical in making myelin. Without myelin, brain cells die and trigger many severe CNS symptoms.
There are two forms, an early form that appears in the first months of life and is fatal by two years old. But there is also a late-onset form that begins in early adolescence, Dr. Kwon explained. New York State implemented screening for Krabbe in 2006. Since then, 200 babies were identified with the genetic mutation but a confirmatory test led to a substantially smaller pool of babies at risk, roughly 25. Further testing showed that four of the babies had the life-threatening infant form. Each of the families was offered the option of the only treatment available: a bone marrow transplant. Of the families, one baby died from transplant complications; the other family refused treatment and their child developed Krabbe; one patient did poorly after the transplant and the fourth has done well as a result of the treatment.
But what about the other 21 infants whose parents have been told that their children are at risk for a fatal disease? “I meet with many of these families and they can't believe that the state is screening their child for a disorder that we know so little about and that we can't even tell them whether their child will ever be affected,” said Dr. Kwon. “Then, we tell them we can watch their child very closely, and they just look at us and say, ‘no thank you.’”
She said that one of the arguments in favor of newborn screening for conditions like Krabbe is that the infants can be followed to better understand the disease process or to have a pool of asymptomatic children to enroll in clinical studies. But Dr. Kwon stressed: “That is not a good reason to have a newborn screening program.”
When treatments emerge for autosomal dominant conditions like Huntington disease, for instance, it will demand clever study designs to know exactly when to deliver medicines and what these substances will do to alter the natural history of the disease, said Raphael Schiffmann, MD, director of the Institute of Metabolic Disease at the Baylor Research Institute in Dallas, TX. “Why identify something that is a risk factor for complications decades later?” Dr. Schiffmann said. “Before we deliver treatments we must have a complete understanding of the disease and the heterogeneity of its natural history.”
Roscoe Brady, MD, scientist emeritus at the NIH, agrees. He began studying lipid metabolism in the 1960s and his laboratory developed and tested the first ERT for Gaucher disease. The first ERT was approved for use in 1991. Today, 5,600 patients with Gaucher disease are on ERT.
Dr. Brady said that many of the patients he treated over the years would have died in childhood without ERT. He added that it is best to begin treatment in patients with mild symptoms. “The earlier the treatment, the better the outcome,” he said.
Patients with Gaucher disease are not treated asymptomatically, he said.
Peter K. Todd, MD, PhD, an assistant professor of neurology at University of Michigan, also agrees. “There is no evidence in late-onset Pompe that waiting to treat makes a difference in the outcome,” Dr. Todd said. “Given the risks and costs involved, researchers have to prove presymptomatic treatment makes a major difference over waiting for symptoms to develop before this should become the standard of care.” He suggested that the field should consider designing placebo-controlled ERT studies in presymptomatic people to assess the long-term outcomes.
As for the young man in the current study, his doctors are holding off on ERT until they determine there is a continued decrease in muscle strength or other signs of muscle deterioration as well as MRI abnormalities.