Pompe disease, a rare genetic disorder, often manifests with complications extending beyond muscle weakness.A extensive review of published studies reveals that involvement in the brain and spinal cord’s white matter is common, particularly in infantile-onset Pompe disease (IOPD). This underscores the need for vigilant monitoring and tailored care strategies.

Beyond Muscle Weakness: CNS Impact

While Pompe disease is primarily known for its impact on muscle function, its effects on the central nervous system (CNS) are significant. Affected areas include:

• White matter of the brain and spinal cord
• Gray matter
• Blood vessels in the brain

These impacts can lead to a range of neurological symptoms, including hearing impairment, seizures, strokes, hemorrhages, and cognitive delays.

The Study: A Deep Dive into CNS involvement

Italian researchers conducted a systematic review, published in Neuromuscular Disorders, to better understand the extent of CNS involvement in Pompe disease. Their analysis encompassed 81 studies published between 1965 and 2024, involving a total of 627 patients. The patient cohort included:

• 271 IOPD patients (48% of studies)
• 265 late-onset Pompe disease (LOPD) patients (36% of studies)
• 91 patients in studies focusing on both IOPD and LOPD

Patient ages ranged from 1 month to 68 years, providing a broad perspective on the disease’s impact across different life stages. The researchers emphasized that a clearer understanding of such involvement would be beneficial for proper monitoring and potential use of novel outcome measures in clinical trials.

Understanding Pompe Disease: A Genetic Perspective

Pompe disease arises from genetic mutations that disrupt the production or function of GAA, an enzyme essential for breaking down glycogen. This deficiency leads to glycogen accumulation within cells, especially muscle cells, resulting in muscle weakness and poor muscle tone. The disease’s impact extends to the CNS, causing cognitive problems and other neurological issues.

Key Findings: Symptoms and neuroimaging

The review highlighted several key findings regarding CNS involvement:

• Symptoms: 24 studies reported CNS-related symptoms.IOPD patients often experienced cognitive developmental delay and hearing impairment (10% to 62.5% prevalence). LOPD patients presented with seizures, strokes, hemorrhages, and hearing loss.
• Neuroimaging: Of the 41 studies using CT or MRI scans, 25 reported white matter lesions. These lesions where more prevalent in IOPD (40% to 100%) than in LOPD (5% to 22%). Gray matter lesions were documented in all IOPD studies, while some LOPD studies noted mild brain atrophy.
• Blood Vessel Abnormalities: these were more common in LOPD patients (11% to 60% prevalence), with one study reporting 9% prevalence in IOPD patients.
• Cognitive Function: IQ scores ranged from normal to extremely low in IOPD and from normal to low average in LOPD. Executive function,visuomotor skills,and academic levels varied from normal to impaired. Motor and speech delays, along with learning difficulties, were also noted.

Pathological Insights: Glycogen Accumulation

Analysis of CNS tissue from 21 studies revealed glycogen accumulation in nerve cells, causing them to appear ballooned and degenerating. Other affected cells included astrocytes and oligodendrocytes. Affected areas spanned the cerebrum, spinal cord, brainstem, and, to a lesser extent, the cerebellum.

Detailed glycogen deposits were observed in the walls of blood vessels in the brains of LOPD patients. One postmortem study described glycogen buildup in the eyes and optic nerves of an IOPD fetus.

Neurofilament Light Chain (NfL) Levels

Two studies examined NfL levels in IOPD patients. One showed NfL levels increased over time, but there was no correlation between NfL levels and brain MRI abnormalities. The second study found correlations between NfL levels, brain MRI findings, and IQ scores, suggesting NfL as a potential biomarker for nerve damage in Pompe disease.

call to action: Standardized CNS Assessment

The researchers advocate for standardized CNS assessment in all new Pompe disease diagnoses. They suggest that as done for motor, cardiac, and respiratory function, [the CNS] should be assessed at baseline and in regular follow-up in all new [Pompe disease] diagnoses both in infantile and adult subjects. This assessment should include a core set of imaging … and cognitive function evaluation with standardized tests selected for age range of patients.