Late-onset Pompe patients should be watched for symptoms: Study
Young, presymptomatic patients can benefit from early intervention
Young patients with late-onset Pompe disease (LOPD) who do not yet show disease symptoms should be regularly monitored for timely identification of symptoms so that treatment can be started early, a study suggested.
Current diagnostic procedures enable early diagnosis of LOPD even in pre-symptomatic stages, said the researchers, who suggested clinical evaluation once a year and assessment of muscle damage by MRI every other year. “Timely identification of emerging clinical manifestations in presymptomatic LOPD patients, as a result of careful follow-up, is essential to start prompt treatment to modify the disease natural course,” they wrote.
The study, ”Management of presymptomatic juvenile patients with Late-Onset Pompe Disease (LOPD),” was published in Neuromuscular Disorders.
Pompe disease is characterized by the abnormal accumulation of glycogen, a complex sugar molecule, in muscle cells. The disease is caused by mutations in the GAA gene that result in a deficiency of acid alpha-glucosidase (GAA), an enzyme needed to break down glycogen. In LOPD, symptoms appear after the first year of life, and typically include progressive muscle weakness and breathing problems.
Pompe symptoms and progression can vary among patients, and muscle weakness is frequently preceded by a history of exercise intolerance, fatigue, and muscle pain. These signs, along with elevated creatine kinase levels (a blood marker of muscle damage), are part of a preclinical phase of LOPD.
Treating symptoms
Standard Pompe treatment includes enzyme replacement therapy (ERT), which involves the administration of a functional version of GAA, to patients with symptomatic disease. “However, the management of presymptomatic patients, so far, is not particularly detailed, leaving the treatment choice to the competence of muscle disease experts,” the researchers wrote.
The researchers detailed disease management in 13 patients, including two pairs of siblings, diagnosed with LOPD at the presymptomatic stage and followed at hospitals in Germany and Italy. Their mean age at diagnosis was 6.8, though their ages ranged from 1 to 18. Mean clinical follow-up lasted nine years, with a maximum of 18 years.
Ten of these patients were referred to a neurologist due to unexplained and persistent creatine kinase elevation. Two were siblings of diagnosed patients, and one was diagnosed incidentally through a dried blood spot test during routine evaluation for minor surgery.
Their most significant sign before the onset of muscle weakness was elevated creatine kinase, with levels ranging from 374 to 2,935 units/L, above reference levels. One patient also had fatigue and intolerance to prolonged physical exercise, while two had mild alterations in heart structure and function.
Electromyography analysis of muscle electrical activity detected alterations in paravertebral muscles — those that surround the spine — of one patient and in all muscles of another patient.
GAA activity, determined in 11 patients through muscle biopsies or dried blood spots, was low, ranging from 0.8% to 25%. Muscle biopsies showed signs of glycogen accumulation in four cases.
Diagnosis was confirmed by genetic analysis, which detected a c.32-13T>G mutation in of the GAA gene copies of 12 patients. One participant had two different mutations, one in each gene copy, previously associated with more severe disease.
Five patients developed muscle symptoms that occurred from six months to 12 years after diagnosis. Muscle weakness affected the pelvic girdle, which connects the trunk and legs, leading to a “mild waddling gait,” the researchers wrote. Two patients also developed problems in the muscles that hold the shoulder blades in place, and three had weakness in core and lower girdle muscles, causing mild increased curvature of the lower spine.
MRI revealed muscle reduction in four of these patients.
The five patients began treatment with ERT, four with Myozyme (alglucosidase alfa, sold in the U.S. as Lumizyme) and one with Nexviadyme (avalglucosidase alfa, Nexviazyme in the U.S.), which stabilized their motor function and prevented the progression of muscle damage over a mean of eight years. Respiratory function slightly improved or stabilized in three patients, while in two it initially stabilized and then declined several years later.
“Presymptomatic patient management represents an informative opportunity for identifying prognostic factors and monitoring the disease progression under ERT,” the researchers wrote. “Our experience suggests that programs aimed to increase awareness about LOPD among clinicians have been effective for earlier recognition of unspecific symptoms.”
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