Current and emerging treatments and surgical interventions for Morquio A syndrome: a review

Abstract

Patients with mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome) have accumulation of the glycosaminoglycans, keratan sulfate, and chondroitin-6-sulfate, in bone and cartilage, causing systemic spondyloepiphyseal dysplasia. Features include lumbar gibbus, pectus carinatum, faring of the rib cage, marked short stature, cervical instability and stenosis, kyphoscoliosis, genu valgum, and laxity of joints. Generally, MPS IVA patients are wheelchair-bound as teenagers and do not survive beyond the second or third decade of life as a result of severe bone dysplasia, causing restrictive lung disease and airway narrowing, increasing potential for pneumonia and apnea; stenosis and instability of the upper cervical region; high risk during anesthesia administration due to narrowed airway as well as thoracoabdominal dysfunction; and surgical complications. Patients often need multiple surgical procedures, including cervical decompression and fusion, hip reconstruction and replacement, and femoral or tibial osteotomy, throughout their lifetime. Current measures to intervene in disease progression are largely palliative, and improved therapies are urgently needed. A clinical trial for enzyme replacement therapy (ERT) and an investigational trial for hematopoietic stem cell transplantation (HSCT) are underway. Whether sufficient enzyme will be delivered effectively to bone, especially cartilage (avascular region) to prevent the devastating skeletal dysplasias remains unclear. This review provides an overview of historical aspects of studies on MPS IVA, including clinical manifestations and pathogenesis of MPS IVA, orthopedic surgical interventions, and anesthetic care. It also describes perspectives on potential ERT, HSCT, and gene therapy.

Enzyme replacement therapy in newborn mucopolysaccharidosis IVA mice: Early treatment rescues bone lesions?

“…Patients have marked short stature, hypermobile joints, and weak muscular strength, leading to frequent falling (2, 10, 11, 12, 14, 15, 16). The data of adult ERT in MPS IVA mice showed that the response to pathological improvement in bone lesions is refractory and that the column structure with vacuolated chondrocytes remains disorganized (1).…”

“…Mucopolysaccharidosis IVA (MPS IVA; Morquio A syndrome) is an inherited autosomal recessive LSD (2). Two MPS IV subtypes result from deficiencies in different lysosomal enzymes that sequentially degrade keratan sulfate (KS): N-acetylgalactosamine-6-sulfate sulfatase (GALNS) for MPS IVA and β-galactosidase for MPS IVB (2). MPS IV occurs in 1 in 200,000 live births in British Columbia (3).…”

“…After a period of seemingly normal development, patients exhibit a range of initial symptoms including short stature, odontoid dysplasia, protrusion of the chest, genu valgum, kyphoscoliosis, hyperlaxity of joints, and abnormal gait before 3 years of age (2, 10, 11, 12, 13, 14, 15). Gibbus deformity has been noticed in some of patients even at birth, and radiographs show signs of the abnormal lumbar vertebrae (16).…”

Gene therapy for Mucopolysaccharidoses

“…The modified vector was released from HA, and its enzyme activity in bone two-weeks p.i. was 8.7-fold higher than in mice treated with unmodified vector [10,70]. Immunohistochemistry analysis of the in vivo transduction experiment showed that the modified AAV2 vector increased expression of the GALNS gene and its enzyme activity in the bone of MPS IVA knock-out mice.…”

Paraplegia after epidural-general anesthesia in a Morquio patient with moderate thoracic spinal stenosis

“…1 The resultant abnormalities of chondrogenesis and subsequent osteogenesis (dysostosis multiplex) 2 are largely responsible for the typical phenotype with conspicuous elements such as short stature, kyphoscoliosis, prominent bell/barrel-shaped chest, frontal bossing, genu valgum (“knock knees”), and joint laxity. 3,4 The latter two abnormalities frequently necessitate orthopedic interventions to achieve limb realignment. 2,4 …”