In his keynote lecture from this year’s International Research Congress on FSHD, held virtually on June 25-26, George Padberg, MD, regarded as the father of modern FSHD research, shared observations from his four decades of seeing patients and directing ground-breaking research. Now retired from UMC St. Radboud in the Netherlands, Dr. Padberg was invited to speak about the “Past, Present, and Future of FSHD Research.” Rather than resting on his laurels, Padberg said “I will tell you some of my biases and regrets, and hopefully will inspire others to do better.”
Padberg noted how some people with FSHD are deemed “asymptomatic” because the doctor can spot signs of FSHD but the patient did not complain of any symptoms. Now he wonders if there might be a cognitive component contributing to a kind of symptom denial. “I never asked patients who claimed not to have symptoms—that’s a regret. I should have probed further,” he said. He noted that large numbers of affected individuals are never seen by a doctor. “People deny being affected despite clear signs. There’s an unwillingness to discuss the disease. There’s a denial of diagnosis.” He noted that some evidence suggests the presence in FSHD patients of a condition called anosognosia, defined as “a lack of ability to perceive the realities of one’s own condition.” Others have speculated that FSHD is associated with central nervous system features that increase the incidence of depression and disinhibition (which might lead to a quick temper, outspokenness, impulsive behavior, and creativity).
Pain is another topic Padberg wishes he had investigated more deeply. Up to 90 percent of patients report pain, he noted, but “the 10 percent who don’t are an interesting subgroup.” To date, no one has undertaken quantitive sensory testing to measure individuals’ sensitivity to various pain stimuli (such as temperature, pressure, vibration, and pin prick) nor looked at their brains’ electrical activity or blood flow to search for possible strategies to treat pain in FSHD. “We should have done these studies some time ago,” Padberg said.
Many mysteries remain to be solved
Another striking aspect of FSHD is that muscles weakness seems to vary so much from patient to patient. Nonetheless, “there is a highly characteristic pattern of muscle weakness, otherwise we would never have been able to recognize FSHD as a specific disease,” Padberg said. “Strong deltoid muscle does not occur in any other condition that involves weakness of scapular stabilizers. No other muscle disease with shoulder girdle involvement has this pattern.” Unfortunately, “an explanation is beyond our grasp as we don’t know how muscle are laid down” during the early stages of human gestation.
Another gap in knowledge about the natural history of FSHD has to do with facial muscles, Padberg said. “Self-reported facial weakness is extremely unreliable,” he asserted. Researchers do not know if facial weakness, often seen in childhood, is stable or gets worse over a lifetime. Padberg said researchers need to agree on how to define and measure facial weakness in order to understand its natural history, biomarkers, and relationship with facial muscle pathology. Why is this important? “If we have stem cell therapy” some day, Padberg implied that it might be more feasible to treat the smaller facial muscles than the much larger muscles of the limbs and torso.
Padberg also wondered whether the blood vessels might be involved in FSHD. It’s known that a minority of patients have abnormal vasculature in the eye. Might it be possible that the tiny blood vessels in muscles are also affected? “There is reduced capillary density in muscle,” Padberg noted, as well as “reduced muscle oxygenation that appears to mirror the pattern of fatty infiltration of muscle.” This might be yet another topic worthy of further research, he suggested.
Even as the FSHD field is racing to develop treatments, Dr. Padberg’s talk made a strong case that many mysteries remain to be solved. The answers could lead to better clinical management of symptoms as well as treatment strategies to address broader aspects of this perplexing and complicated condition.
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