Long-term outcome and unmet needs in infantile-onset Pompe disease

Abstract

Infantile-onset Pompe disease (IOPD) is characterized by virtually complete absence of acid alpha-glucosidase (GAA)-activity, resulting in rapidly progressive hypertrophic cardiomyopathy (HCM), profound skeletal muscle weakness, and death usually within the first 12 months of life. Enzyme replacement therapy (ERT) with recombinant GAA in humans started in 1999, and pivotal studies demonstrated that the treatment ameliorated HCM, improved motor function in some patients, and prolonged overall and ventilator-free survival. These outcomes led to the approval of ERT in 2006. Implementation of ERT has uncovered multisystemic character of IOPD, not known in the pre-ERT era. Although ERT has substantially improved the prognosis of IOPD, mortality is still considerable, and decline of motor function with time is frequent in long-term survivors. This review details the new complex IOPD phenotype, outlines problems related to ERT, and highlights unmet needs.

Keywords: Infantile-onset Pompe disease (IOPD); enzyme replacement therapy (ERT); long-term outcome; musculoskeletal dysfunction; neurocognitive impairment.

Figure 1

Spinal fusion due to scoliosis and marked hyperlordosis in a 16-year-old girl with IOPD. IOPD, infantile-onset Pompe disease.

Figure 2

Muscle biopsy findings (right lateral vastus muscle) in a CRIM-positive patient with IOPD achieving free walking at age 19 months and still doing so at age 8 years. Biopsies were taken at age 6 months before start of ERT (left panel) and at age 5 years (right panel). H&E staining shows a progressive vacuolar myopathy, while Desmin staining depicts absent desmin in many fibers, reflecting increasing myofibrillar damage. Resin-PAS semithin (R-PAS) sections show distinct glycogen accumulation (stained red) at age 6 months and persistence of such fibers in conjunction with fibers full of empty vacuoles mirroring abnormal autophagy at age 5 years. Notice that fibers being in different stages of disease pathology are located side by side. Electron microscopy (TEM) depicts a fiber with normal myofibrils (lower part of the image) and a completely destroyed one (upper part of the image) at age 6 months, and a fiber with normal myofibrills, but marked lysosomal (Lys) and extralysosomal (arrow) glycogen deposits. CRIM, cross-reactive immunological material; IOPD, infantile-onset Pompe disease; ERT, enzyme replacement therapy. Length of the scale bar in is 20 µm in all light microscopic images.

Figure 3

Photograph of a 15 months old girl with IOPD showing marked facial hypotonia and macroglossia, and demonstrating severe reflux into to the upper third of the oesophagus [from reference (33), used with permission]. IOPD, infantile-onset Pompe disease.

Figure 4

Severe tooth decay in a 4-year-old boy with IOPD. IOPD, infantile-onset Pompe disease.

Figure 5

Brain magnetic resonance imaging in a 5-year-old girl with IOPD demonstrating signal hyperintensities of the central white matter in T2 and TIRM images. IOPD, infantile-onset Pompe disease.