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.

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

Figure 1

Clinical features of an MPS IVA patient. Notes: The three-year-old patient in the figure had bone deformities (short stature, pectus carinatum, kyphoscoliosis, genu valgum, prominent forehead, and abnormal gait) (height 90 cm, 50th percentile of male Morquio A growth chart; bodyweight 14 kg). For patients with the attenuated form of the disease, the symptoms are not so prominent or clinically conspicuous in childhood and progress more slowly. Usually the first noticeable symptoms in a severe form of MPS IVA patients are bone deformity, abnormal gait (tendency to fall down), and hyperlaxity (knock-knee, floppy wrists, cervical instability). Later, most patients develop hearing loss, feasibility of infection, easy fatigue, and cervical myelopathy. Copyright © 2005, The Carol Ann Foundation and The International Morquio Organization. Images reproduced with permission from Slide 74. Educational CD for Morquio. Tucson, AZ: The Carol Ann Foundation and The International Morquio Organization; 2005. Abbreviation: MPS IVA, mucopolysaccharidosis type IVA.

Figure 2

Hypothesis of pathogenesis of cervical instability and cervical spinal cord compression. Notes: Spinal cord compression is the most critical key feature to recognize in MPS IVA patients. Odontoid hypoplasia, ligamentous laxity, and extradural GAG deposition, can result in atlantoaxial subluxation with cord compression, leading to cervical myelopathy. A history of exercise intolerance in patients with MPS IVA often predicts the presence of occult cervical myelopathy, which can also cause bowel and bladder dysfunction and weakness or paralysis. Mortality and morbidity rates are primarily related to the atlantoaxial instability and subsequent cervical myelopathy. Severely affected patients, primarily related to cervical instability, often do not survive beyond the second or third decade of life. A minor fall or extension of the neck can result in cord transection and subsequent quadriparesis or sudden death. Copyright © 2005, The Carol Ann Foundation and The International Morquio Organization. Reproduced with permission from Slide 53. Educational CD for Morquio. Tucson, AZ: The Carol Ann Foundation and The International Morquio Organization; 2005. Abbreviations: GAG, glycosaminoglycan; KS, keratan sulfate; MPS IVA, mucopolysaccharidosis type IVA.

Figure 3

MRI image of cervical spine in an MPS IVA patient aged 3 years. Notes: The arrow shows the spinal cord compression. A baseline study of the upper cervical anatomy is recommended no later than 2 years or at diagnosis using flexion/extension X-ray films. If pain associated with weakness or tremors (clonus) in the arms or legs occur, the patient should have studies of the neck to evaluate for the slippage (subluxation) of the neck vertebrae and compression of the spinal cord. X-rays and MRI will be taken with neck flexed and extended and will be monitored annually to check the situation. Abbreviations: MPS IVA, mucopolysaccharidosis type IVA; MRI, magnetic resonance imaging.

Figure 4

Post-cervical fusion operation. (A) C1–C2 stability has been achieved with internal fixation and bone grafting. (B) Postoperative immobilization in children for whom stability cannot be achieved is managed with a halo vest.

Figure 5

Anesthesia care of MPS IVA patient. (A) Head and neck stabilization (fixation) during surgery to achieve the most stable cervical spine alignment. The position of the head in relationship to the neck is very important here. Head should be positioned in slight extension in order to facilitate optimal patency and unobstructed breathing. (B) Chest X-ray showing tortuous trachea and bronchi in a patient with MPS IVA (left) Fiberoptic bronchoscope showing the distorted appearance of the carina and left bronchus in the same patient (right). Notes: The tortuous and redundant trachea with buckling of main trachea easily possible with change in head and neck position. Arrow 1 shows the stretched and abnormally shaped lumen of the left bronchus. Arrow 2 shows the redundancy and buckling of the main trachea. Abbreviation: MPS IVA, mucopolysaccharidosis type IVA.

Figure 6

X-ray photographs of a lateral view of thoracolumbar vertebra before BMT and 2.5 years after BMT. Note: Platyspondylia and anterior beaking of thoracolumbar vertebra increased slightly in size and the margin of vertebra became clear. Abbreviation: BMT, bone marrow transplantation.

Figure 7

Mechanism of bone-targeting system. Notes: Negatively-charged AAA-tagged enzyme will circulate in blood for longer time and (1) will be delivered to bone more efficiently, (2) will bind with calcium sites on HA, (3) will be released from HA by proteolytic process, and (4) will be taken up by the receptor-mediated pathways. Abbreviations: AAA, triple adenine; HA, hydroxyapatite.

Figure 8

Mechanism of multiple AAA-targeting system. Note: viral capsid in the right panel has multiple copies of D8 integrated into capsid proteins, showing the retargeting of gene vector to bone (hydroxyapatite in the mineral region) schematically. Abbreviations: AAA, triple adenine; AAV, adeno-associated virus; D8, eight Asp acidic amino acids.