Severe CNS involvement in a subset of long-term treated children with infantile-onset Pompe disease

Abstract

Introduction: The standard of care for patients with infantile-onset Pompe disease (IOPD) is enzyme replacement therapy (ERT), which does not cross the blood brain barrier. While neuromuscular manifestations of IOPD are well-described, central nervous system (CNS) manifestations of this disorder are far less characterized. Here we describe severe CNS-related neurological manifestations including seizures and encephalopathy in six individuals with IOPD.

Method: We identified six children with IOPD who developed CNS manifestations such as seizures and/or encephalopathy. We studied their brain magnetic resonance imaging scans (MRIs) and graded the severity of white matter hyperintensities (WMHI) using the Fazekas scale scoring system as previously published. Longitudinal cognitive measures were available from 4/6 children.

Results: All six IOPD patients (4 males/2 females) had been treated with ERT for 12-15 years. Seizures and/or encephalopathy were noted at a median age at onset of 11.9 years (range 9-15 years). All were noted to have extensive WMHI in the brain MRIs and very high Fazekas scores which preceded the onset of neurological symptoms. Longitudinal IQ scores from four of these children suggested developmental plateauing.

Discussion: Among a subset of IOPD patients on long-term ERT, CNS manifestations including hyperreflexia, encephalopathy and seizures may become prominent, and there is likely an association between these symptoms and significant WMHI on MRI. Further study is needed to identify risk factors for CNS deterioration among children with IOPD and develop interventions to prevent neurological decline.

Keywords: Case series; Epilepsy; Pompe disease; White matter disease.

Fig. 1.

Brain MRIs from five children with infantile onset Pompe disease with evidence of progressive CNS disease. All six patients had bilateral extensive hyperintense foci in all the lobes of the supratentorial brain as seen on brain MRI and five are shown here. Additionally, Patients 1 and 3 had brainstem involvement, and Patients 3, 4, and 6 had basal ganglia involvement. Patient 1 (CRIM−): Red arrows show CNS involvement in the three axial T2-FLAIR images and a sagittal T1 at the level of (a) centrum semiovale, (b) cerebellum, and (c) posterior limb of internal capsule at age 7 years. (d) New involvement of the brainstem region at age 10 years post-seizures. Patient 2–6 were CRIM+. Patient 2: Orange arrows in an axial T2-FLAIR image at level of lateral ventricles involving the periventricular and subcortical areas at 15 years. Patient 3: Green arrows in the two axial T2-FLAIR images at the level of centrum semiovale (a) at 13.1 years, and at deep gray structures (b – lentiform nucleus and thalamus) at 13.25 years age. Patient 4: Yellow arrows in two axial T2-FLAIR images at the level of (a) centrum semiovale at age 8 years, and (b) involvement of both basal ganglia and internal capsules at age 11 years. Patient 5: Blue arrows in the axial T2-FLAIR images at the level of corona radiata at age 11 years. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2.

Neuropsychological findings over time in children with infantile onset Pompe disease who developed neurological changes (Patient 2–5). Age based standard scores (mean = 100, SD = 15) are plotted for each administration of the Wechsler scale, the Leiter-3, the PPVT, and subtests of the Beery-Buktenica (Beery VMI, Visual Perception, and Motor Coordination) for patients 2–5 at increased ages. The light gray shaded area on each graph represents the average range. The raw scores (total number of items correct) for each subset of the Leitter-3 are also plotted to illustrate each child’s performance over time on this measure.