By Dora Leung, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
SYNOPSIS: In this systematic literature review of studies that evaluate motor and locomotion function in patients with adult, late-onset Pompe disease, the clinical spectrum reveals weakness of respiratory, axial, and proximal limb muscles.
SOURCE: Maulet T, Bonnyaud C, Weill C, et al. Motor function characteristics of adults with late-onset Pompe disease. Neurology 2023; 100:e72-e83.
Pompe disease is an autosomal recessive hereditary disorder caused by a deficiency in the lysosomal enzyme acid alpha-glucosidase. The resulting glycogen accumulation in muscle leads to muscle destruction and progressive weakness.
Depending on residual enzyme levels, clinical presentation can be during infancy (severe infantile form), in childhood, or in adulthood with a milder form of the disease. As patients develop progressive motor deficits caused by weakness, walking and climbing abilities deteriorate, with some adult, late-onset Pompe disease (aLOPD) patients requiring assistive devices. The authors’ goal for this literature review was threefold: 1) determine what assessment tools have been used in reports of motor function in aLOPD patients; 2) understand what is known about motor function in these patients; and 3) identify the effects that current therapies have on motor functions.
The literature search of Medline, Embase, and Cochrane identified 58 clinical studies that longitudinally assessed motor function. The most common tool to assess maximal muscle strength (MMS) in patients was manual muscle testing, while about one-third of the studies assessed strength with instruments such as dynamometers, and a few used the quick motor function test (QMFT).
The typical pattern of weakness in aLOPD is symmetric weakness, with the legs more affected than the arms, and proximal limb muscles weaker than distal ones. There were five studies that reported serial MMS exams, and the reported rate of strength decline ranged from 1.3% to 7% per year. The best variables to predict deterioration include lower baseline strength and longer symptom duration. Enzyme level and age of symptom onset did not predict progression.
About 75% of all patients reported across the studies were taking enzyme replacement therapy (ERT). The rate of strength decline in untreated patients has not been well documented, and since most patients now start treatment upon diagnosis when their deficits are relatively mild, the authors concluded that it would be difficult to study the natural history of motor decline in untreated aLOPD patients. The effect of ERT was reported in 16 studies. All studies without control groups reported significant motor improvement in the first three years of treatment. Follow-up studies showed stable muscle power or a decline in strength after three years of ERT, even in patients with initial improvement.
In several controlled studies, there was no significant difference in lower leg strength in the treated vs. untreated group after 1.5 years. One long-term follow-up study of patients receiving ERT reported weaker muscles at 10 years compared with baseline.
Studies that reported the effect of physical therapy or exercise on strength and motor function in a small number of aLOPD patients were of short duration, ranging from 12-26 weeks. Overall, the studies reported improvement in proximal, but not distal, limb strength.
Locomotion or gait assessment focused on walking capacities, such as walking independently and the need for assistive devices. Only a few studies evaluated gait with biomechanical assessment, such as measuring gait parameters and joint kinematics. Gait impairment is common in aLOPD patients, and in a large series, only 18% of 107 patients had normal gait and did not require an assistive device.
Patients with aLOPD performed worse in the six-minute walk distance (6MWD), with slower speed, slower cadence, and shorter stride compared with control groups. Factors associated with worse gait and mobility included older age, longer disease duration, and ventilator use. Across the studies, 30% to 50% of the patients lost ambulation and became wheelchair dependent about 10-15 years after diagnosis.
The effect of ERT on locomotion was reported in 30 of the 58 studies, and most showed significant improvement in 6MWD in the treated group compared with the untreated group. However, long-term follow-up showed a ceiling benefit of the treatment, with a slow decline in 6MWD after three years. In most studies, ERT had no effect on time to walk 10 meters or other functional tests, including the ability to climb stairs, regardless of duration of treatment.
Physical training and exercises showed improvement in 6MWD and the ability to climb stairs, but not in the time required to walk 10 meters. There were few studies of balance in aLOPD patients, and 83% of patients reported impairment.
The authors recommended that future studies of motor function in aLOPD patients should be less reliant on MMS evaluation, which they deemed as less sensitive and less reliable than instrumented assessments, such as isometric dynamometers. They also recommended assessing more functional parameters, such as locomotion and postural control. They also suggested studies using a combination of exercise with ERT to assess their effect on motor function and quality of life.
COMMENTARY
This review showed that patients with aLOPD have progressive symmetric limb weakness, with the legs more affected than the arms, and proximal muscles in shoulder and hip girdles weaker than distal ones.
There are few studies that assess mobility and gait in this population, and most focused on standardized tests such as the 6MWD and Timed Up & Go. Although motor function usually deteriorates along with loss of strength, there is a lack of research into balance and biomechanics of gait. The authors questioned the benefit of ERT on strength and mobility and found that many studies showed significant improvement in both parameters in the short term, but long-term worsening. Because there are no data on the natural history of strength and motor deterioration in these patients, one can argue that these patients could have been worse without treatment.
Based on the few studies with a small number of aLOPD patients using exercise to improve strength, there was benefit even with a short trial duration for proximal muscles, although no change in strength for more distal muscles. The exercise effect also is mixed in mobility and gait, with improved 6MWD and less time required to climb four steps, but no change in time required to walk 10 meters.
Assessment of balance and gait mechanics in the evaluation may provide a better understanding of mobility in neuromuscular patients and may lead to better therapies to prolong walking independence.
