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Quantitative Muscle Ultrasound as a Window into Disease Progression in Infantile-Onset Pompe Disease

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Infantile-onset Pompe disease (IOPD) is caused by pathogenic variants in the GAA gene, resulting in glycogen accumulation in muscle tissues. IOPD presents at birth or within weeks, with symptoms of hypertrophic cardiomyopathy, hypotonia, and respiratory distress, often resulting in death within two years if left untreated. Enzyme replacement therapy (ERT) has extended survival, enabling patients to reach their 2nd decade. Advances such as early ERT initiation, high dosing, and immune tolerance induction have improved outcomes though residual myopathy remains. Monitoring includes multidisciplinary management with routine physical therapy, blood and urine biomarkers, and more recently, muscle imaging. While, muscle magnetic resonance imaging (MRI) has been used to assess the musculoskeletal involvement of IOPD, it is expensive, time consuming, and not feasible at many centers. Alternatively, quantitative muscle ultrasound (QMUS), a more affordable alternative, provides a quantitative muscle assessment. In recognition of the need for robust monitoring of muscle involvement in IOPD, we evaluated the utility of QMUS to track the severity of IOPD-related myopathy.

Methods:
The echo intensity (EI) measurements from QMUS were retrospectively evaluated in eight IOPD patients on long-term ERT. Longitudinal EI data from seven key muscles deltoid, biceps brachii, triceps brachii, forearm flexors, quadriceps, medial gastrocnemius, and tibialis anterior were collected annually. Each patient underwent 2–3 QMUS evaluations during the study period. EI values greater than 50 units were considered abnormal. An EI sum score, calculated as the mean EI across the seven muscles, was compared to the Gross Motor Function Measure (GMFM) collected during physical therapy assessments using a univariable regression model.

Results:
Eight IOPD patients (5M,3F) were included, with six being CRIM-positive and two CRIM-negative. All patients began ERT between 5 days to 3.5 months of age (median: 7 weeks). QMUS assessments were conducted between 2021 and 2024, with the median age at the first evaluation being 9.5 years (range: 7 months to 21.3 years). All patients had at least one muscle group with an abnormal echogenicity index (EI) score. The QMUS findings varied significantly between patients and correlated with clinical examination outcomes. IOPD-3 had the highest EI across all muscle groups, the most severe IOPD-related myopathy, and required a wheelchair. In contrast, IOPD-8 showed a good clinical response to ERT and had most QMUS results within the normal range, with a GMFM score of 94.06 at the last follow-up at age 3. QMUS also revealed differences between upper and lower extremity muscle groups, with a mean EI of 47.8 in the upper extremities, significantly lower than the lower extremities’ mean EI of 64.2 (p = 0.0001).

 

Conclusion:
QMUS is a promising noninvasive tool for monitoring muscle health in IOPD patients on long-term ERT. This study highlights its potential for tracking disease progression, evaluating treatment response, and assessing functional changes in IOPD.

 

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