Cause and effects of MPS IV: an overview

Early and accurate diagnosis is critical to enable disease-specific intervention¹

Mucopolysaccharidosis (MPS) IV, or Morquio syndrome, is a progressive, multisystemic lysosomal storage disorder resulting from a deficiency of the enzymes N-acetylgalactosamine 6-sulfatase 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 lifespan.¹

Perceived disease rarity, heterogeneous presentation and variability in disease progression make diagnosis challenging and early intervention critical.^1,2 Regardless of phenotype, symptoms can progress into end organ damage. Risk factors for increased morbidity include the following^4,5:

• Skeletal dysplasia
• Impaired vision/hearing
• Spinal cord compression
• Short stature and neck
• Respiratory problems
• Cardiac problems
• Gastrointestinal issues
• Endurance and mobility issues
• Surgical frequency
• Increased surgeries

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

Typical presentation

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 opthalmalogical,^1,14,15 ENT,^1,16 hepatic/abdominal¹³ and dental^6,17 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 2to 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

MPS IV: a spectrum of disease progression and presentation

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:

• Severe multisystemic complications^1,19
• Irreversible or end-organ damage¹⁹
• Delay in initiating enzyme replacement therapy (ERT) to address underlying enzyme deficiency²⁰
• Lack of access to disease-specific management, with concomitant increase in risk of surgical mortality^1,6,21,-24

Surgical considerations

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.

Genetics and pathophysiology

Morquio A and MPS IVB are caused by mutations in the GALNS and GLB1 genes, which encode the enzymes N-acetylgalactosamine 6-sulfatase and β-galactosidase, respectively.^1,25 The resulting enzyme deficiencies lead to multiple metabolic pathologies including, most notably, the accumulation of the GAG substrates keratin sulfate and chondroitin-6-sulfate 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

Key management considerations

Ongoing research is transforming patient management:

• There is now greater understanding about the need for multidisciplinary, coordinated care and perioperative care and monitoring.^1,6
• ERT is available for Morquio A, which addresses the underlying metabolic deficit.³⁰

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^1,7:

• Non-steroidal anti-inflammatory drugs for joint pain
• Antibiotics for pulmonary infection
• Oxygen supplementation for pulmonary compromise and obstructive sleep apnoea
• Cervical spine fusion and/or decompression
• Femoral osteotomies for straightening of the legs
• Corrective knee surgery for severe genu valgum deformity

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 Doctors 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 appropriate management should be initiated.^1,26 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.^1,31

Surgical considerations

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 monitoring³²:

• Reduced respiratory capacity
• Impaired cardiovascular function
• Skeletal morphology
• Cervical spinal instability
• Complex airway structure

These factors complicate surgical and anaesthetic care, require pre-planning, and necessitate disease-specific techniques to increase optimal outcomes.³³

Specialised perioperative procedures during anaesthesia, 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

Transitioning to adult care

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.^1,31

These transition plans should be tailored to each patient’s 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 his or her condition.³¹