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Long term survival in patients with classic infantile Pompe disease reveals a spectrum with progressive brain
J J A van den Dorpel1, M J Mackenbach1, M H G Dremmen2
1Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Center for Lysosomal and Metabolic Diseases, The Netherlands.
Insights
Most patients with classic infantile Pompe disease develop progressive brain abnormalities and cognitive decline. Early intervention targeting the central nervous system is crucial for improving outcomes in these patients.
Area of Science:
- Neurology
- Pediatrics
- Genetics
Background:
- Classic infantile Pompe disease is a rare genetic disorder affecting multiple organ systems.
- Enzyme replacement therapy (ERT) is the standard treatment, but its efficacy in addressing central nervous system (CNS) manifestations is limited.
- Understanding the natural history of brain abnormalities and cognitive decline in these patients is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the pattern and progression of brain abnormalities in patients with classic infantile Pompe disease.
- To assess the impact of these abnormalities on cognitive functioning over time.
- To identify potential therapeutic targets for CNS involvement.
Main Methods:
- A longitudinal cohort study including 19 patients with classic infantile Pompe disease treated with ERT.
- Brain MR imaging (T1, T2, FLAIR) was used to classify and track abnormalities using a 12-point rating scale.
- Cognitive development was assessed using Wechsler IQ tests, and associations were analyzed using linear regression models.
Main Results:
- Ninety-five percent of patients developed progressive brain abnormalities, starting in the periventricular white matter and extending to other brain regions.
- Cognitive functioning, including full scale IQ, performance IQ, and processing speed, significantly declined with increasing age.
- Each point increase on the MRI rating scale correlated with a significant decline in all IQ index scores.
Conclusions:
- Long-term survivors with classic infantile Pompe disease frequently experience worsening brain MRI abnormalities and cognitive decline.
- These findings underscore the urgent need for novel therapies capable of crossing the blood-brain barrier to effectively treat the CNS phenotype.
- Targeting CNS manifestations is essential for improving the overall prognosis and quality of life for patients with this condition.
Abstract:
The aim of this longitudinal cohort study, is to provide more insight into the pattern of brain abnormalities, and possible consequences for cognitive functioning, in patients with classic infantile Pompe disease. We included 19 classic infantile Pompe patients (median age last assessment 8.9 years, range 1.5-22.5 years; 5/19 CRIM negative), treated with ERT. Using MR imaging of the brain (T1, T2, and FLAIR acquisitions), we classified progression of brain abnormalities on a 12-point rating scale at multiple time points throughout follow-up. Additionally we noted specific white matter patterns and examined atrophy. Cognitive development was studied using Wechsler IQ assessments obtained by certified neuropsychologists. The association between age and cognitive functioning, and MRI ratings and cognitive functioning was assessed by linear regression models. All but one patient developed brain abnormalities. The abnormalities progressed in a similar pattern throughout the brain, with early involvement of periventricular white matter, later followed by subcortical white matter, gray matter structures, and juxtacortical U-fibers. We found a significant decline (p < 0.01), with increasing age for full scale IQ, performance IQ and processing speed, but not for verbal IQ (p = 0.17). Each point increment in the 12-point MRI rating scale was associated with a significant decline (3.1-6.0 points) in all the IQ index scores (p < 0.05). The majority of long-term surviving patients in our cohort develop incremental brain MRI abnormalities and decline in cognitive functioning. This highlights the need for new therapies that can cross the blood-brain barrier in order to treat this CNS phenotype.
