Intractable fever and cortical neuronal glycogen storage in glycogenosis type 2

Abstract

Glycogenosis type 2 is an autosomal recessive glycogen storage disorder caused by deficiency of lysosomal acid alpha-glucosidase. Different phenotypes are recognized. The authors describe two children affected by the late infantile form; both presented terminal hyperthermia not caused by infections. Autopsy performed in one case showed diffuse glycogen storage in the CNS neurons. In light of current interest in enzyme replacement therapy, this finding casts some doubt on how effective enzyme replacement therapy will be unless it can be targeted directly into the CNS.

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

“…Glycogen accumulation has previously been reported throughout the central nervous system (Araoz et al 1974;Sakurai et al 1974;Asukata et al 1976;Nakamura et al 1979;Teng et al 2004;Thurberg et al 2006). The decedents also had extensive accumulation in anterior horn cells of the spinal cord and in intestinal ganglion cells, as described previously (Thurberg et al 2006;Martini et al 2001;Teng et al 2004). Glycogen accumulation has also been observed in peripheral nerves in LOPD (Fidziańska et al 2011).…”

“…While none of our three patients had pre-mortem MRI of brain, patient two in this case series had mild, diffuse volume loss on CT scan of the head at 8 months of age, and there was blurring of the gray-white differentiation for patient 3 at 5 months of age. Neuronal loss in brain and spinal cord has been described in postmortem examination (Martini et al 2001). A recent publication noted parenchymal volume loss on brain MRI in a child with infantile Pompe disease at 2 years of age (Burrow et al 2010).…”

Lysosomal Enzyme Replacement of the Brain with Intravenous Non-Viral Gene Transfer

“…Treatment strategies for these conditions include either enzyme replacement therapy or gene therapy. However, neither the recombinant lysosomal enzyme (2), or the viral vector for gene therapy (3,4), cross the brain-capillary endothelial wall, which forms the blood-brain barrier (BBB). Therefore, intravenous administration of either recombinant protein or viral gene therapy is not effective treatment for the brain.…”

Neural deficits contribute to respiratory insufficiency in Pompe disease

“…However, a few Pompe case reports have demonstrated CNS glycogen accumulation (9)(10)(11)(12)(13)(14) and absent or diminished deep tendon reflexes (15,16). In particular, spinal motoneurons seem to be susceptible to excessive glycogen accumulation (10,13,15).…”