Autopsy indicates brainstem and spinal neuropathology in late‐onset Pompe Disease

Abstract

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the gene encoding acid alpha-glucosidase (GAA), the enzyme responsible for lysosomal breakdown of glycogen. The rate of PD progression corresponds to the amount of residual GAA enzyme activity. Infantile-onset Pompe disease is caused a by a complete lack of GAA activity, with patients typically progressing to cardiorespiratory failure within the first year of life. Late-onset PD patients retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents a histological analysis of the brainstem and spinal cord from a male PD patient who was diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, displayed progressive respiratory insufficiency with requirement for nocturnal ventilation at age 40, required 24-hour non-invasive ventilation by age 43, and passed away from respiratory failure at age 54. Autopsy was performed approximately 8 hours after death with informed consent. The brain and spinal cord were preserved in a 20% formalin solution and embedded in paraffin for subsequent histological assessment. Tissue sections were cut at 4 µm and stained with periodic acid-Schiff (PAS) to assess glycogen content, cresyl violet to assess neuronal morphology, and Iba-1 to characterize microglia as a marker of neuroinflammation. Positive PAS confirmed glycogen accumulation in neurons throughout the medulla and spinal cord. However, striking differences in neuronal morphology were present across the neuraxis. Hypoglossal motoneurons in the medulla (n=46, soma size: 421 ± 159 µm2) and putative motoneurons in the ventral cervical horn (n=50, soma size: 487 ± 189 µm2) had an atrophied, elongated appearance. In contrast, lumbar (n=63, soma size: 1363 ± 677 µm2) and sacral motoneurons (n=31, soma size: 1411 ± 633 µm2) had the classic ballooned morphology seen in early-onset PD. The Iba-1 staining showed an accumulation of microglia in the white matter of the cervical cord. In contrast, Iba-1 staining was localized to the gray matter in the lumbo-sacral spinal cord. These histological data confirm glycogen accumulation and pathology in brainstem and spinal neurons in late-onset PD. Further, the markedly atrophied appearance of hypoglossal and mid-cervical motoneurons is consistent with neurodegeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle.