Rapidly Progressive White Matter Involvement in Early Childhood: The Expanding Phenotype of Infantile Onset Pompe?

Abstract

Glycogen accumulation in the central nervous system of patients with classical infantile onset Pompe disease (IOPD) has been a consistent finding on the few post-mortems performed. While delays in myelination and a possible reduction in processing speed have previously been noted, it has only been recently that the potential for clinically significant progressive white matter disease has been noted. The limited reports thus far published infer that in some IOPD patients, this manifests as intellectual decline in the second decade of life. We present a CRIM negative patient, immunomodulated with rituximab and methotrexate at birth, who despite an initial good clinical response to ERT, at the age of just under 4 years, presented with evolving spasticity in the lower limbs. The investigation of which revealed progressive central nervous system involvement. Given both the earlier onset of the symptoms and consanguineous familial pedigree, extensive biochemical and genetic investigation was undertaken to ensure no alternative pathology was elucidated. In light of these findings, we review the radiology and post-mortems of previous cases and discuss the potential mechanisms that may underlie this presentation.

Classic infantile Pompe patients approaching adulthood: a cohort study on consequences for the brain

“…For example, one patient who learned to walk within the normal age limits showed more abnormalities on the MRI than a patient who became tetraplegic before the age of 1 year. Although white matter changes were seen in the capsula interna, we did not note spasticity as reported by Broomfield et al 20 On the basis of all of these findings we conclude that the white-matter abnormalities on MRI in classic infantile Pompe patients indicate a varied but slowly progressive pattern of white-matter involvement.…”

Diagnosis and Care of Infants and Children with Pompe Disease

“…Low amounts of glycogen are stored in the brain of patients with IOPD [34].Signal alterations predominantly of the central white matter and progressive in some individuals, have been reported by several authors [4,11,12,36,38]. Earlier reports assessing neurocognitive function in smaller groups of patients suggested a normal or only mildly delayed cognitive development [10,39].…”

“…The AIMS (Alberta Infant Motor Scale) is suitable for recording the motor status in the first 18 months of life while the more elaborate PEDI Pompe test (Paediatric Evaluation of Disability Inventory) and/or the simple QMFT (Quick Motor Function Test) can be applied thereafter [4,24].…”

Targeted delivery of acid alpha-glucosidase corrects skeletal muscle phenotypes in Pompe disease mice

“…Additionally, recent evidence suggests a role for glycogen accumulation in tissues other than cardiac and skeletal muscle in the pathology of PD. Abnormalities in the neuromuscular junction have been linked with glycogen deposits in spinal motor neurons in mice 4 , and infantile-onset patients show secondary symptoms indicative of neural involvement 3,29 . Studies normalizing glycogen levels solely in the brain and CNS in PD mice (using AAV gene therapy) have shown correction of some neuromuscular phenotypes even in the absence of improvement in cardiac or skeletal muscle fibers, demonstrating that a full reversion of clinical phenotypes in PD ERT will require multisystem delivery 30,31 .…”

“…Therefore, adding blood-brain barrier crossing functionality to neuronal lysosome targeting in a format such as a bispecific antibody may be able to improve overall efficacy 32,33 . Alternatively, AAV may be delivered via an intrathecal or intracerebroventricular route as well as intravenously to treat both the CNS and skeletal muscle 29,30 .…”