Immunomodulatory Treatment of a Patient with Cross-Reactive Immunologic Material Negative Infantile Pompe Disease and Hypertrophic Cardiomyopathy

Case Study: Pompe disease is a rare autosomal recessive glycogen storage disease which is caused by mutations in the GAA gene with chromosome 17q25. This results in a deficiency of lysosomal acid α-1, 4 glucosidase (GAA) with glycogen accumulation in lysosomes and in the cytoplasm. Cross-reactive immunologic material (CRIM) negative patients, with a significantly worse prognosis, generally develop high anti-α glucosidase antibodies to an enzyme replacement therapy (ERT).

Case: The patient did not gain weight and suffered from a severe hypertrophic cardiomyopathy at 3 months. The advanced diagnostics showed a reduced α-glucosidase activity of 0.1 µmol/L/h (normal range > 3.3). Molecular genetic analysis found a homozygous mutation in the GAA gene exon 17: c2608 C > T [R870X]. CRIM negative status was confirmed using western blot analysis on skin fibroblasts.

Treatment: Immediately after the diagnosis, we started with the ERT including a regimen of rituximab, methotrexate, and immunoglobulins (Algorithm, Banugaria et al 2013).

Outcome: Within 8 months after initial therapy, the patient had not developed anti-α glucosidase antibodies. CD 19 positive B-cells increased from 0 to 9.3%. Left ventricular mass index, decreased from 520 to 197 g/m² (> 122 severely abnormal). It is assumed that the patient will not need noninvasive ventilation soon. In the meantime, there are no more feeding problems. The development is good. The girl crawls, pulls herself up to standing and sitting almost free. The cognitive and language development are also normal.

Discussion: So far, ERT is the only supportive and effective therapy for Pompe disease. Various authors describe an additional immunomodulatory therapy in patients with CRIM-negative status positive results. These are improved cardio respiratory and muscular parameters and a longer life span. The early start of immunomodulatory therapy in treating our patient has probably resulted in this improved outcome. However, it remains to be seen if the regeneration of the immune system leads to antibody formation or if an immune tolerance is achieved.