Children with classic infantile Pompe disease treated for years with Myozyme (alglucosidase alfa, marketed as Lumizyme in the U.S) exhibit muscle weakness in their lower legs, feet, and hands in addition to the proximal muscle weakness that typifies late-onset Pompe, a Dutch study reported.
Weakness in distal muscles — those farther from the body’s center, or muscles of the lower arms and legs, hands and feet — emerged prior to and was more severe than proximal (body center) muscle weakness, characterizing a new pattern of symptoms specific to Myozyme-treated patients with classic infantile Pompe.
The study, “Distal muscle weakness is a common and early feature in long-term enzyme-treated classic infantile Pompe patients,” was published in the Orphanet Journal of Rare Diseases.
Patients with classic infantile Pompe disease begin showing progressive, generalized muscle weakness and cardiomyopathy (heart muscle disease) before their first birthday. By contrast, symptoms of late-onset Pompe manifest in late childhood or adulthood, and are marked by progressive weakness of proximal muscles.
Typically, classic infantile patients are treated with Myozyme, Sanofi Genzyme‘s enzyme replacement therapy intended to replace the missing or defective alpha-glucosidase enzyme in those with Pompe disease.
Myozyme’s use has considerably improved outcomes for children with classic infantile Pompe, allowing them to meet early childhood milestones such as walking. But studies have also reported residual muscle weakness in those using Myozyme over time.
Investigators at Erasmus MC University Medical Center, in the Netherlands, sought to determine the long-term effects of Myozyme on distal muscle function, and to characterize muscle weakness experienced by classic infantile Pompe patients.
The study, partly funded by Sanofi Genzyme, included 16 children who learned to stand and walk independently by a median age of 1. All had cardiomyopathy, and began treatment with Myozyme at the median age of 3.2 months. Data were collected between 1999 and 2016 when the median patient age was 5.6 years. One 4-year-0ld died from respiratory failure before the study’s end.
Video recordings showed that, at the study’s start, distal muscle weakness was severe enough in 10 children (63%) to prevent them from developing a normal walking gait. The other six showed no early signs of distal muscle weakness, but four lost that ability between between the ages of 3 and 5.
“Only 2 patients — still relatively young (2.9 and 4.3 years) — had a normal heelstrike-gait at the end of follow-up,” the researchers rote.
By the study’s end, four of the 10 patients with initial muscle weakness showed signs of both proximal and distal muscle weakness, and five were no longer able to walk.
All these children acquired normal fine motor skills (hands) and the ability to raise their arms over their heads. By the end of follow-up, a majority (69%) showed no signs of muscle weakness in the upper arms or hands. The other five, 31%, had developed “profound” weakness in finger extensor muscles, mostly of the third and fourth digits, and later weakness in the upper arms.
Notably, upper extremity weakness was observed only in children with severe lower extremity weakness at the study’s start.
“Although many patients now learn to walk under [Myozyme]-treatment, the majority develops distal muscle weakness, most prominent of the feet but also of the hand musculature,” the scientists wrote.
Weakness in the muscles required to flex the ankle and raise the foot toward the shin caused a majority (56%) of these children to use supportive aids, such as splints, at night.
“Distal muscle weakness may lead to loss of joint mobility resulting in development of contractures. Therefore, awareness and early recognition of distal weakness is important for timely application of supportive measures such as splints and foot orthoses,” the researchers wrote.
They also investigated how differing doses of Myozyme might affect muscle function. They found that 20% of patients treated at a low dose (20 mg/kg every two weeks) developed a normal gait without signs of distal and proximal muscle weakness, as did 45% of those given the higher, 40 mg/kg weekly dose.
Among the study limitations were the lack of formal gait analysis, and an inability to assess exact time of onset of distal muscle weakness, the team said.
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