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

Shunji Tomatsu,¹ William G Mackenzie,¹ Mary C Theroux,¹ Robert W Mason,¹ Mihir M Thacker,¹ Thomas H Shaffer,¹ Adriana M Montaño,² Daniel Rowan,² William Sly,³ Carlos J Alméciga-Díaz,⁴ Luis A Barrera,⁴ Yasutsugu Chinen,⁵ Eriko Yasuda,¹ Kristen Ruhnke,¹ Yasuyuki Suzuki,⁶ Tadao Orii<sup>7

1</sup>Nemours/Alfred I duPont Hospital for Children, Wilmington, DE, USA; ²Department of Pediatrics, ³Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University, St Louis, MO, USA; ⁴Institute for the Study of Inborn Errors of Metabolism, Pontificia Universidad Javeriana, Bogotá DC, Colombia; ⁵Department of Pediatrics, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan; ⁶Medical Education Development Center, 7Department of Pediatrics, Gifu University, Gifu, Japan

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, flaring 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.

Keywords: mucopolysaccharidosis IVA, keratan sulfate, GALNS, enzyme replacement therapy, gene therapy, hematopoietic stem cell transplantation