Mucopolysaccharidosis (MPS) IV, or Morquio syndrome, is a progressive, multisystemic lysosomal storage disorder resulting from a deficiency of the enzymes N-acetylgalactosamine 6-sulphatase or β-galactosidase that are responsible for the catabolism of glycosaminoglycans (GAGs),2 which are involved in the building of bones, cartilage, skin, tendons, and many other tissues in the body.3 Two distinct forms are recognised: type A (MPS IVA, Morquio A) and type B (MPS IVB). These types differ in the genetic cause of disease, but signs and symptoms among these forms can be similar and present across the spectrum of disease progression.4
MPS IV is progressive, systemic and lifelong, and it can lead to systemic morbidities and a shortened life span.1
Perceived disease rarity, heterogeneous presentation, and variability in disease progression make diagnosis challenging and early intervention critical.1 Regardless of phenotype, symptoms can progress into end organ damage. Risk factors for increased morbidity include:4,5
The majority of patients with Morquio A do not survive past the second decade of life, with frequent causes of death including respiratory failure, complications from surgery, and cardiac failure.1
Patients with MPS IV, which is commonly perceived as a musculoskeletal condition,1 can present with or develop unpredictable and clinically heterogeneous symptomatology extending well beyond the obvious manifestations.6 The table below illustrates the potential signs and symptoms of Morquio A, which may be observed either alone or in combination with others, and should raise your suspicion of Morquio A.
Progressive, systemic manifestations can lead to potentially severe cardiovascular,1,7–9 pulmonary,1,6,7,10,11 neurological,6,12 musculoskeletal,1,6 rheumatological,5,13 ophthalmological,1,14,15 ENT,1,16 hepatic/abdominal,13 and dental6,17 consequences. In contrast with other MPS disorders, however, patients with MPS IV do not present with cognitive impairment.
Of note, over 70% of patients manifest with unusual skeletal features within the first 2 to 3 years of life.6 Recent research has indicated that approximately 25% of patients with Morquio A syndrome present with a non-classical phenotype.5
Patients can present with classical or non-classical patterns of signs and symptoms. Patients with non-classical phenotype are often reported to have significantly delayed time to diagnosis relative to symptom manifestation.1
Variable disease progression in patients with Morquio A18
Regardless of phenotype,1 symptoms can progress into end-stage organ damage.
Underappreciation of non-classical presentation in Morquio A can lead to delayed or missed diagnoses, with significant impacts:
Surgical need and burden is high among patients with Morquio A. According to a natural history study of Morquio A, 70% of the population (mean age 14.5 years) had at least 1 surgical procedure.7
A patient’s surgical history and need should alert you to the possibility of MPS IV.
Morquio A and MPS IVB are caused by mutations in the GALNS and GLB1 genes, which encode the enzymes N-acetylgalactosamine 6-sulphatase and β-galactosidase, respectively.1,25 The resulting enzyme deficiencies lead to multiple metabolic pathologies including, most notably, the accumulation of the GAG substrates keratan sulphate and chondroitin-6-sulphate in lysosomes throughout the body.1,26
As lysosomes accumulate, they occupy an increasingly greater area of the cytoplasm, obscuring other organelles and disrupting function.27 The defective enzyme activity in MPS IV leads to cell, tissue, and organ system dysfunction that results in the progressive multisystemic morbidities that are the hallmark of this disorder.1,6
Ongoing research is transforming patient management:
Published in 2014, the “International Guidelines for the Management and Treatment of Morquio A Syndrome” establish the standard of care for Morquio A. Due to the progressive nature of the disease, these guidelines urge early initiation of treatment with ERT.
In addition to ERT, ongoing lifetime management and procedural care from a multidisciplinary coordinated care team are critical components to optimising patient outcomes.6 Supportive care includes both medications and surgical interventions, including the following:1,6,7
Due to the unpredictable, multisystemic nature of MPS IVA, regular, multidisciplinary, comprehensive evaluation and treatment from a coordinated care team is also essential to identify signs of organ damage and ensure optimal patient outcomes.1,6 Physicians can optimise their management by creating a personalised management plan for each of their patients, starting with a thorough assessment schedule for each body system affected by MPS IVA.1
Once diagnosis is confirmed, baseline assessments should be performed and ERT should be promptly initiated. ERT can significantly improve endurance, as measured by the 6MWT. Significant change in the 6MWT reflects improvement or decline in the functional status of the cardiac, respiratory, and musculoskeletal systems and a change in disease progression.1,26 Beyond ERT, ongoing comprehensive assessments, symptomatic treatment, and surgical interventions,1,7 continuity of care from the paediatric to the adult setting is a critical consideration for patients and families living with MPS.1,30
Patients with MPS IV often require surgical intervention to address the multisystemic complications of the disease.7 This surgical care is complicated by the nature of the disease.
Patients with MPS IV suffer from multiple factors that can dramatically increase surgical risk and the need for monitoring:33
These factors complicate surgical and anesthetic care, require preplanning, and necessitate disease-specific techniques to increase optimal outcomes.33
Specialized perioperative procedures during anesthesia, such as intubation and extubation, and the use of an intraoperative neuromonitoring checklist, are essential to successful surgical interventions.1,33 An integrated surgical team consisting of MPS VI specialists is crucial for positive, durable outcomes.1
As patients with MPS IV reach adulthood, their relationship with their medical team will change. To help manage this transition, individual plans are necessary to minimise treatment interruptions, extend support beyond the scope of paediatric care and parental support, and ensure that adult patients are knowledgeable in managing MPS IV.1,30
These transition plans should be tailored to each patients specific needs, so that those who can take over their own care will have the necessary tools, and those who are more limited will have the appropriate care and services in place to support them. The plans should include an assessment to determine the patients capacity to successfully achieve his or her outlined goals, as well as his or her knowledge and ability to communicate information about their condition.30