Pathogenesis and treatment of spine disease in the mucopolysaccharidoses

Abstract

The mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders characterized by deficient activity of enzymes that degrade glycosaminoglycans (GAGs). Skeletal disease is common in MPS patients, with the severity varying both within and between subtypes. Within the spectrum of skeletal disease, spinal manifestations are particularly prevalent. Developmental and degenerative abnormalities affecting the substructures of the spine can result in compression of the spinal cord and associated neural elements. Resulting neurological complications, including pain and paralysis, significantly reduce patient quality of life and life expectancy. Systemic therapies for MPS, such as hematopoietic stem cell transplantation and enzyme replacement therapy, have shown limited efficacy for improving spinal manifestations in patients and animal models. Therefore, there is a pressing need for new therapeutic approaches that specifically target this debilitating aspect of the disease. In this review, we examine how pathological abnormalities affecting the key substructures of the spine - the discs, vertebrae, odontoid process and dura - contribute to the progression of spinal deformity and symptomatic compression of neural elements. Specifically, we review current understanding of the underlying pathophysiology of spine disease in MPS, how the tissues of the spine respond to current clinical and experimental treatments, and discuss future strategies for improving the efficacy of these treatments.

Keywords: Animal models; Bone; Intervertebral disc; Lysosomal storage disorder; Mucopolysaccharidosis; Spine; Therapy; Vertebra.

Figure 1

Examples of spinal cord compression (circled) and intervertebral disc degeneration (stars) in the cervical spines of 12 month old MPS I dogs. T2 weighted image; S = spinal cord; C2 = C2 vertebral body/axis. Dorsal is towards the top of the images.

Figure 2

Examples of failed secondary ossification in the vertebral epiphyses and abnormal GAG distribution within the annulus fibrosus of 6-week-old and 6-month-old MPS VII dogs as compared to control animals. Control animals are heterozygous for the GUSB mutation and phenotypically normal. Alcian blue (glycosaminoglycans) and picrosirius red (collagens) double-stained, mid-sagittal histological sections. AF: annulus fibrosus; NP: nucleus pulposus; VB: vertebral body; E: epiphysis; GP: growth plate. Scale bar = 1 mm.

Figure 3

Representative histological images showing hypoplasia of the odontoid process in MPS I dogs during postnatal growth. At 3 months-of-age, delayed calcification of the odontoid is evident in MPS I relative to heterozygous control animals. At 6 and 12 months-of-age, in MPS I the odontoid is smaller and narrower with irregular surface morphology. Arrows: Evidence of decreased cartilage on the ventral articulating surface at older ages. Dashed lines: Approximate location of vertebral body attachment. Alcian blue (glycosaminoglycans) and picrosirius red (collagens) double-stained, mid-sagittal sections. Scale bar = 2 mm.