CRIM‐negative infantile Pompe disease: 42‐month treatment outcome

Abstract

Pompe disease is a rare lysosomal glycogen storage disorder characterized by deficiency of acid !-glucosidase enzyme (GAA) and caused by mutations in the GAA gene. Infantile-type Pompe disease is a multiorgan disorder presenting with cardiomyopathy, hypotonia, and muscular weakness, which is usually fatal. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) has recently been shown to be effective and subsequently yielded promising results in cross-reactive immunologic material (CRIM)-positive patients. CRIM-negative patients showed a limited response to ERT and died or were ventilator dependant. Over a period of 44 months, we monitored cognitive and motor development, behavior, auditory function, and brain imaging of a CRIM-negative infantile Pompe disease patient on rhGAA and monoclonal anti-immunoglobulin E (anti-IgE) antibody (omalizumab) treatment due to severe allergic reaction. Cardiorespiratory and skeletal muscle response was significant, with almost normal motor development. Cognitive development-in particular, speech and language-deviated increasingly from normal age-appropriate development and was markedly delayed at 44 months, unexplained by moderate sensorineural hearing impairment. Brain magnetic resonance imaging (MRI) at 18, 30, and 44 months of age revealed symmetrical signal alteration of the deep white matter. Titer values of IgG antibodies to rhGAA always remained <1:800. The potential role of omalizumab in immune modulation remains to be

Postmortem Findings and Clinical Correlates in Individuals with Infantile-Onset Pompe Disease

“…Ventricular dilatation was also observed in brain MRI in three of five participants who had serial MRI scanning (Chien et al 2006). Finally, serial MRI in a CRIM-negative patient demonstrated white matter abnormalities despite normal myelination (Rohrbach et al 2010). Glycogen accumulation in central and peripheral nervous system in the GAA knockout mouse model 6 neo (À) /6 neo(À) was extensive, but varied in distribution and intensity.…”

Phase I/II Trial of Adeno-Associated Virus–Mediated Alpha-Glucosidase Gene Therapy to the Diaphragm for Chronic Respiratory Failure in Pompe Disease: Initial Safety and Ventilatory Outcomes

“…One potential reason for the limited efficacy of ERT in ventilator-free survival is that GAA is not transported across the blood-brain barrier (Kikuchi et al, 1998) and therefore likely cannot correct neural glycogen accumulation, especially in motoneurons. As such, progressive accumulation of glycogen in the central nervous system (CNS) may lead to ongoing dysfunction or loss of motoneurons and progressive dysfunction of motor units (Rohrbach et al, 2010).…”

Sustained immune tolerance induction in enzyme replacement therapy–treated CRIM-negative patients with infantile Pompe disease

“…Of the 4 patients who developed titers during the study period, only one patient developed HSAT. Although there are 3 cases previously reported describing CRIM-negative patients who did not develop HSAT without ITI, one patient received omalizumab, an IgG monoclonal antibody that binds to IgE, for a severe allergic reaction to alglucosidase alfa; the other sibling pair had a splice site mutation in heterozygosity (35,36). A role for omalizumab in preventing the development of an IgG response cannot be excluded in this case.…”