Morquio Syndrome (Mucopolysaccharidosis Type IV) Treatment & Management

Updated: Jul 12, 2017
  • Author: Kazuki Sawamoto, PhD, MS; Chief Editor: Maria Descartes, MD  more...
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Treatment

Approach Considerations

Enzyme replacement therapy (ERT; elosulfase alfa [Vimizim]) may improve the activity of daily living (ADL) in patients with Morquio syndrome, although no evidence has shown that ERT can penetrate the avascular cartilage region to improve the bone pathology, which suggest limited benefit for skeletal dysplasia. Long-term investigation is still required.

Hematopoietic stem cell transplantation (HSCT) has improved ADL and mobility after over 10 years of follow-up in several cases; however, careful consideration is required because of a risk.

Surgical interventions must be performed with appropriate timing by a well-trained team in an appropriate facility. Cervical decompression and fusion and tracheal reconstructive surgeries should markedly improve the morbidity and mortality risk.

Overall, the cost/benefit profile and availability of each treatment option should be carefully evaluated.

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Medical Care

Enzyme Replacement Therapy (ERT)

Enzyme replacement therapy (ERT) consists of administration of an enzyme to patients who lack it. ERT for lysosomal storage diseases takes advantage of the fact that the enzyme can be taken up by the cell and targeted to the lysosome via receptor-mediated endocytosis. [104]

Although the concept of ERT was introduced by Christian de Duve in the 1970s, [105] it was not until 2008 that the first preclinical results of ERT for Morquio A syndrome (mucopolysaccharidosis type IVA [MPS IVA]) in an animal model were published. [100] The progress of ERT for Morquio A syndrome was hindered by the difficulty in purifying a stable GALNS enzyme to a large scale and the absence of a spontaneous mouse model for treatment and evaluation. After achieving large-scale purification of phosphorylated GALNS in the laboratory using Chinese hamster ovary cells, pharmacokinetics and pharmacodynamics were evaluated, showing that GALNS enzyme was indeed taken up by cells via the mannose 6 phosphate receptor and distributed systemically in mice after a single injection. [106]

After mouse Galns gene was isolated and its structure elucidated, [97] the three mouse models described above were used in preclinical studies. [83, 98, 99] The first preclinical trial results for Morquio A syndrome mice were published in 2008. The results indicated that Morquio A syndrome mice treated with human recombinant GALNS enzyme weekly for 12 weeks with 250 U/g, 500 U/g, or 1,000 U/g of body weight had normal serum KS levels. [100] In addition, storage material was cleared in liver, bone marrow, and connective tissue in articular cartilage. A limited response was observed in the growth plate and the articular cartilage, since that region is avascular, making enzyme delivery difficult. The limited effectiveness in bone and cartilage suggested that a bone-targeting system could be more effective.

Based on efficacious modifications of other enzymes with acidic tags to target proteins to the bone, the author of this article applied similar technology to target GALNS. [101, 107, 108] An acidic amino acid sequence (aspartic or glutamic acid) has a high affinity for hydroxyapatite; [109] consequently, a similar tag should concentrate GALNS enzyme near bone cells and improve its uptake into such cells.

The recombinant E6-GALNS enzyme had a longer half-life than native enzyme (30 minutes vs 3 minutes), decreasing its plasma clearance. [101] Adult Morquio A syndrome mice treated for 24 weeks with the tagged enzyme or E6-GALNS showed (1) improvement in biodistribution, since bone and bone marrow contained more enzyme than native GALNS and (2) improved clearance of storage materials in bone, ligaments, connective tissues, and heart valves when compared to mice treated with the native enzyme. Mice treated at birth with the tagged enzyme for eight weeks showed better clearance than adult mice treated with the tagged enzyme. [101]

To confirm these observations, the authors treated mice at birth for 15 weeks with the native enzyme and found that the growth plate was more organized with an overall reduction of substrate accumulation in bone compared to that of untreated mice. However, there was less clearance of storage material in fibrous cartilage cells of the articular disc, ligaments, periosteum, and synovium surrounding the femur of Morquio A syndrome mice. In addition, there was a limited response in heart valves. [110] Overall, the preclinical trial with native GALNS on Morquio A syndrome mouse models provided little impact to bone lesions. Native GALNS used in clinical trials had not been tested in Morquio A syndrome mouse models.

Clinical trials in humans consisted of phase I/II (MOR-002), phase II (MOR-008), and phase III (MOR-004). In 2009, the phase I/II started as an open-label, multicenter, dose-escalation study, which enrolled 20 patients aged 5 to 18 years with Morquio A syndrome disease to evaluate safety and tolerability of the drug (GALNS enzyme or elosulfase alfa). Two patients abandoned the trial (one subject had an adverse event, and the other subject withdrew from the study), which continued with 18 subjects. [111]

The study patients received elosulfase alfa over a 36-week dose-escalation period of 12 weeks each (0.1, 1.0, and 2.0 mg/kg/w), followed by 36-48 weeks of additional treatment at 1 mg/kg per week. [112] All patients showed reduced urinary KS levels, and a dose of 2 mg/kg per week was chosen for subsequent studies. [113]

Phase III consisted of a double-blind, randomized, placebo-controlled, multicenter, multinational, 24-week study to compare two dose regimens (2 mg/kg per week vs 2 mg/kg every other week), and 175 patients completed the study. Subjects were divided into three groups, receiving 2 mg/kg per week, 2 mg/kg every other week, or placebo. A modest improvement was found in the 6-minute walk test (6MWT), and a significant reduction in urinary KS was reported among subjects who received a weekly dose of elosulfase alfa. There was no improvement in subjects who received the enzyme every other week. Both elosulfase alfa regimens did not improve endurance in the 3-minute stair climb test (3MSCT). [113]

Owing to the heterogeneous presentation of the disease, it was challenging to evaluate efficacy in a heterogeneous group of patients. Composite analyses of tertiary data points (eg, forced volume vital capacity [FVC], maximum voluntary ventilation [MVV], standing height, growth rate) demonstrated that the group receiving 2 mg/kg per week had benefitted from treatment when changes from baseline 6MWT, 3MSCT, and MVV were combined. [114, 115]

Based on long-term data from an extension study, patients who continued to receive 2 mg/kg per week for another 48 weeks (a total of 72 weeks of treatment) did not show further improvement on 6MWT beyond what was demonstrated during the first 24-week placebo-controlled trial. [116] There was no comparable placebo group in this extension trial. [117] Notably, patients who received placebo during the initial 24-week controlled trial and were subsequently randomized to receive 2 mg/kg per week in the extension study did not show any improvement in 6MWT compared to baseline. [118, 119]

Although data on treatment efficacy are somewhat limited, elosulfase alfa was approved in February 2014 by the US Food and Drug Administration (FDA) and the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP). [120]

The authors have evaluated the effect of ERT on the activity of daily living (ADL) and surgical intervention in patients with Morquio A syndrome. [121] ADL scores among patients younger than 10 years who received ERT (an average of 2.5 years of follow-up) were similar to those of age-matched controls but declined in older patients. Surgical frequency did not decrease after ERT treatment and was not decreased compared to untreated patients. [116, 121] These pathological findings are consistent with the fact that frequency of need for orthopedic surgical interventions has not been reduced by ERT (average duration of ERT, 2.5 ± 1 years). [116, 25, 122] Early ERT treatment at age 21 months did not improve the bone outcome in a patient with severe Morquio A syndrome after 30 months of treatment. [123]

In the United Kingdom, a ”managed access” program was formulated in December 2015 [124] in which a drug is made available for a limited period (eg, 5 years), often at a discounted price, to allow further evidence to be gathered on its effectiveness while ensuring that patients receive access to the drug. Through this study, how well the medicine works in practice can be monitored before future funding decisions are made.

In the Netherlands, costs were initially reimbursed, but reimbursement was stopped when the authorities decided that the data provided were limited to a suboptimal short-term outcome in a heterogeneous population, showing a small effect that was not clinically relevant, [122, 125] as several other EU countries (Sweden, Belgium, Spain) made the same decision. This is agreeable with the statement of Australia’s PBAC, which recently rejected reimbursement for elosulfase alfa. [126]

The statements by these authorities emphasize the importance of cost/benefit in assessing ERT. The cost of ERT is one of the major disadvantages of the treatment. In the United States, the enzyme costs around $1,068 per vial, meaning that, for the typical 22.5-kg patient who needs nine vials per weekly infusion, the annual cost of ERT would be nearly $380,000.

Careful long-term observations will be required to determine whether limited enzyme delivery to bone and cartilage will be sufficient to improve outcomes in these patients. The response to ERT is likely to depend on the age of the patient when treatment is initiated and the severity of the clinical condition. Patients who respond to ERT are likely to have more storage materials through the airway (mucosa membrane).

ERT may have a clinical effect in terms reducing the proinflammatory factors that are induced when excessive KS levels result in an abnormal structure of the extracellular matrix, leading to relieved arthritis and joint pain, thereby enabling increased physical activity, as described in other types of MPS. [127]

ERT with native enzyme could also improve hearing, reduce recurrent infection, and reduce airway narrowing (if the stor­age materials are released from the airway). Thus, while ERT may benefit some patients with Morquio A syndrome by arresting some aspects of disease progression, the fundamental problems associated with advanced skeletal deformity and joint laxity are unlikely to be solved by current ERT.

The limitations of ERT for Morquio A syndrome open new challenges and opportunities to researchers to improve it and deliver a better product to patients.

Hematopoietic Stem Cell Transplantation (HSCT)

Overview

Hematopoietic stem cell transplantation (HSCT) is a treatment method in which multipotent hematopoietic (blood-forming) stem cells are used to reestablish hematopoietic function that has been present at low levels or has been lost entirely owing to severe illness. These cells (preferably from autologous or allogenic donors) are usually gathered from umbilical cord blood, bone marrow, or peripheral blood and are intravenously injected into a patient whose immune system or bone marrow is not adequate to function as it should.

The immune response of HSCT comprises early and late effects. The potential early adverse effects consist of acute graft versus host disease (GVHD), bacteremia/sepsis, hemorrhagic cystitis, veno-occlusive disease, and mucositis. The potential late effects include chronic GVHD, congestive heart failure, endocrine effects, ocular effects, late-onset infections, and an increased risk of malignancy. [128] HSCT once carried a high mortality risk due to immunological reactions; however, owing to the greatly improved supportive care, donor type, HLA typing, conditioning regimens, and prevention and treatment of serious infections, the mortality and morbidity rates have significantly decreased. [129, 130]

It is preferable that the donation used in HSCT is autologous owing to the low risk of malignancy and low associated morbidity and mortality rates. However, if autologous is not feasible, allogenic transplantation is another option. [130] The HLA typing should be matched as close as possible to avoid GVHD and other immune complications. [129]

Hematopoietic Stem Cell Transplantation for Mucopolysaccharidosis

HSCT for MPS I was used for the first time in 1980. [131] Subsequently, HSCT was used for MPS II in 1981, [132] for MPS VI in 1982, [133] and for MPS VII in 1998. [134] Currently, HSCT has been proven effective for MPS I, II, VI, and VII. [135, 136, 137]

HSCT improves ADL, respiratory function, and biochemical findings and prevents bone deformities if performed early enough (before age 2 years) and before neurologic symptoms appear (if relevant). If instituted after age 2 years, the deformities cannot be reversed, but growth does improve. [24, 25]

HSCT performed in patients with these MPSs demonstrate an improvement in hearing and heart function and a reversal in visceral organ involvement; however, HSCT does not reduce corneal clouding. There is a high risk of mortality if patients are already expressing advanced symptoms of MPS or progressive stage before HSCT is initiated. These patients usually cannot endure the rigorous regimen that HSCT requires; therefore, it is better to perform HSCT in patients who are young and/or otherwise healthy.

Early diagnosis is valuable in the treatment of MPS. HSCT candidates are generally young, otherwise healthy, and strong enough to endure rigorous treatment and in whom ERT is not expected to provide improvement. [25]

Hematopoietic Stem Cell Transplantation for Morquio A Syndrome

HSCT for Morquio A syndrome is an ever-evolving treatment option. Although the number of patients with Morquio A syndrome who have undergone HSCT is limited, beneficial effects have been documented.

In a study by Chinen et al in 2014, the goal was to observe the long-term efficacy of allogenic HSCT. [138] HSCT was performed in a Japanese patient when he was aged 15 years, 8 months. Loud snoring and orthopnea were resolved following HSCT, and the patients ADL score improved following treatment. The patient’s age did not allow for HSCT to reverse existing bone deformity since it was too late for the treatment to be effective. However, over 10 years post-HSCT, the patient could walk over 400 m in parallel despite bilateral leg surgery performed one year later post-HSCT and was kept stable. No further surgical intervention was required. Since 70% of patients with Morquio A syndrome become wheelchair-dependent as they reach their teenaged years and most need multiple surgical interventions, this patient had the benefit of receiving HSCT for a long period of time.

In 2016, Yabe et al reported 4 cases involving HSCT in Japanese patients, including the case described above. [139] The patient age at HSCT initiation ranged from 4-15 years (average, 10.5 years). Serious GVHD was not reported as a result of successful administration of allogenic HSCT.

Compared with patients who did not undergo HSCT, the four study patients who underwent HSCT had a higher ADL score, and only one patient underwent a surgical procedure (osteotomy in both legs performed one year post-HSCT), with the follow-up being over 10 years (range: 11 to 28 years, mean: 19 years). The ADL scores among patients who underwent HSCT or ERT were similar to those of age-matched controls younger than 10 years. Among older patients who had undergone ERT, the ADL score decreased with age. This was in contrast to patients who had undergone HSCT, suggesting that HSCT provides a better outcome in terms of ADL, biochemical findings, and respiratory function, although careful long-term observation is required. All four patients who underwent HSCT were able to remain ambulatory, with three being able to walk more than 400 meters. The regular GALNS function of the lymphocytes was found to be at a similar level of the donors 10 years post-HSCT.

A study of 82 patients with Morquio A syndrome found that lower ADL scores resulted from reduced movement and movement with cognition, despite having a high ADL score on the cognitive function portion. [121] ADL scores were shown to decrease, especially in categories that involved movement. The study confirmed that, the earlier HSCT is performed, the more beneficial the outcome in terms of ADL scores later in life. [121, 139] The best ADL score among a patient older than 20 years with a severe Morquio A syndrome phenotype was recorded in a patient who underwent HSCT at age 4 years.

A Chinese study of 4 children with Morquio A syndrome who underwent HSCT [140] found that the average age at the time of transplantation was 2.9 years (range, 1-7 years). The average follow-up time for these patients was 24 months, with the median being 14 months (ranging, 2-119 months). The evaluation given after HSCT showed tremendous improvement in the patients’ joint hypermobility and ligamentous laxity. The reported hepatosplenomegaly, recurrent otitis media, and upper airway obstruction had signs of being in remission, and there was little improvement in thoracic deformity and height. One of the four patients underwent surgery for genu valgus one year after HSCT. The same patient also had spinal cord compression syndrome that remained stable after HSCT. A long-term follow-up of the patients who underwent HSCT showed that an integration of both surgical intervention and HSCT was advantageous in maintaining mobility, respiratory function, and gait.

HSCT is a one-time permanent treatment, is less expensive than ERT ($100,000-$250,000 per HSCT versus $380,000 per year for ERT [24] ), and provides constant enzyme expression. The secretion of the active enzyme reaches various storage tissues and improves skeletal deformities, restrictive and obstructive airway, and abnormal growth development if performed early. [25] The reversal of visceral organ involvement and improved heart function and hearing have also been reported among patients who underwent HSCT. The criteria for HSCT to treat patients with Morquio A syndrome are similar to that used for patients with other MPSs (eg, donor type, age, clinical condition).

Gene Therapy

Gene therapy is based on the administration of autologous cells that contain cDNA, which codes for the normal enzyme so that the protein can be produced and secreted for cell uptake. [94] The main challenges of gene therapy relate to the use of a strong promoter and a stable vector.

In 2004, Toietta et al performed the first ex vivo gene therapy experiment by using the retroviral vector LGSN containing the full-length human GALNS cDNA. GALNS activity in Morquio A syndrome transduced cells were several folds higher than nontransduced cells. The uptake was shown to be mannose-6-phosphate–dependent, and GALNS enzyme activity was shown to reach normal levels for up to six days. [141]

To explore the effect of different promoters in vitro, the elongation factor 1α (EF1) and the cytomegalovirus immediate early enhancer/promoter (CMV) were analyzed in HEK 293 cells. Results showed that cells transfected with EF1apIRES- GALNS continued to have normal GALNS enzyme activity levels for 8 days. [142]

In 2010, adenoassociated viral vector (AAV) and CMV, EF1, and α1-antitrypsin (AAT) promoters in vitro were evaluated. [143] The eukaryotic AAT promoter resulted in equal or higher enzyme activity levels compared with the CMV promoter, and co-transduction with SUMF1, the enzyme required to activate GALNS, led to a substantial elevation of the enzyme activity (50%-70%) of normal control levels in deficient cells. [143]

The Morquio A syndrome mouse models were used to evaluate gene therapy in vivo. Using AAV2 viral vector and the CMV promoter, the authors of this article have evaluated in vitro and in vivo the affinity of an AAV2 vector to bone matrix, hydroxyapatite (HA) (unpublished). By inserting an aspartic acid octapeptide (D8) immediately after the N-terminal region of the VP2 capsid protein, the authors showed that this bone-targeting vector had significantly higher HA affinity and vector genome copies in bone compared with the unmodified vector. Using the same mouse model, the authors found that D8/CBA-GALNS increased activity levels in bone three months postinjection, reaching therapeutic levels of an enzyme (unpublished). Variations in gene therapy could maximize the efficiency of the transduction to deficient cells, as well as to hard-to-reach tissues.

Summary

ERT and HSCT are clinically available for patients with Morquio A syndrome. Gene therapy remains under investigation.

ERT has been shown to improve the endurance of patients in clinical trials when administered weekly via intravenous infusion (2 mg/kg of body weight) but only moderately improves 6-minute walk test (6MWT) results, since the extension clinical trial did not show a significant improvement over the placebo control group. ERT has a limited effect on bone lesions in these patients. [113]

Because of its limited clinical benefit and high cost, ERT remains unapproved or unreimbursed as a form of treatment in several countries. [24] Precise long-term observations are needed to ascertain whether limited enzyme delivery to the cartilage and bone will result in adequate benefit.

HSCT should provide more clinical benefit than ERT, although careful assessment is required before HSCT is performed.

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Surgical Care

To correct cervical cord compression, decompression/fusion surgery is needed to stabilize the upper cervical spine. [144, 145, 146] This is recommended for patients with atlantoaxial instability who express signs of myelopathy, significant instability of greater than 8 mm, or cord signal change on a T2-weighted MRI. This surgery is challenging owing to the hypoplastic spine and anesthesia troubles due to the difficult airway. A halo vest support may be needed following surgery, and the acquisition of a postoperative critical care bed and neuromonitoring for possible spinal cord injury for all surgeries longer than 45 minutes are recommended. [24, 144, 145, 146] Prophylactic treatment of atlantoaxial instability is not recommended, and a clinical and imaging evaluation is necessary to determine whether surgical stabilization of the occipital-cervical junction is required. [24, 147]

Gibbus deformity (thoracolumbar kyphosis) is corrected with surgical stabilization if the patient shows signs of continued progression (curves up to 70° below the level of the conus) or myelopathy. [24] For advanced curves, anterior and posterior fusion or three-column correction is recommended, [24] followed by 3 months of postoperative bracing. [24]

In patients with hip dysplasia and osteonecrosis, surgical intervention should correct the global acetabular deficiency and prevent progressive subluxation and attenuating arthrosis. [24] Surgical intervention for hip dysplasia is controversial because of corresponding femoral head necrosis but is needed if the subluxation is painful. [24] Surgical reconstruction of the hip that devotes particular attention to both the femoral and acetabular sided pathology provides the best radiographic outcomes. Other recommended surgeries include San Diego (Dega) innominate osteotomy, shelf arthroplasty for the pelvic side of the hip with a femoral varus osteotomy, augmentation with an acetabular shelf (in patients that are prone to subluxation), and total hip arthroplasty (in young adult patients who have pain and cannot be treated with reconstruction). [24, 148]

Lower-extremity valgus such as genu valgum makes walking painful, leading to corrective knee surgery. Two-hole growth modulation plates are recommended, especially for small children, with growth guidance techniques. [24, 149, 150] Osteotomy of the proximal tibia or distal femur is recommended instead among patients with limited growth. [24] In patients with arthritis in addition to genu valgum, total knee arthroplasty or significant lateral release and allograft augmentation may be needed. [151, 152] Ankle valgus is treated with screw hemiepiphysiodesis through the medial malleolus to correct the valgus deformity found in the lower extremities and to augment overall extremity alignment. [24] Flat foot, or pes valgus, is treated with custom orthotics and rarely with surgery if the pain does not respond to the orthotics. [24]

To improve tracheal obstruction, new tracheal reconstructive surgery has been developed. [35, 40] The procedure comprises reimplantation of the innominate artery and excision of the redundant trachea with end-to-end anastomosis. [35, 40] As of late 2016, surgery has been successful in five patients with severe tracheal obstruction and declining respiratory status, three of whom had been receiving ERT (1-5 years). Postsurgery, each patient has substantially improved respiratory function and ADL scores, although long-term follow-up is still needed. This surgical intervention should be performed in a well-trained facility familiar with Morquio syndrome, if possible.

Tracheostomy, which has been used to improve airway obstruction, is a notoriously challenging procedure to perform in patients with Morquio A syndrome because of inherent respiratory and anatomic problems, such as a tortuous and redundant trachea, an exceptionally short neck, and the inability to hyperextend the neck because of fixed cervical vertebrae. Maintaining the tracheostomy in good shape is also a challenge. These complications, along with the availability of a novel tracheal intervention, may reduce the need for tracheostomy in the future.

In patients with corneal clouding, corneal transplantation may be an option. However, this procedure is not always successful.

To help alleviate deafness, ventilating tubes may be placed to minimize episodes of acute otitis media and chronic middle ear effusions. [153]

Sleep apnea is resolved with tonsillectomy and adenoidectomy or high-pressure nasal continuous positive airway pressure (CPAP) and supplemental oxygen. [24] Bilevel positive airway pressure (BiPAP) may also be used in place of CPAP if the patient opts for the noninvasive management of sleep apnea. However, without proper treatment, patients with severe tracheal obstruction are highly susceptible to dying of sleep apnea and other related complications.

Patients with Morquio syndrome have major anesthesia risks owing to a difficult airway and major tracheal obstruction. Death or severe handicaps during the anesthetic procedure have been reported as a result of an anesthesia complication. [24]

It is critical that any surgical intervention is performed by a well-trained team familiar with Morquio syndrome.

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Consultations

Genetic counseling is needed to discuss the genetic risks in patients with Morquio syndrome or who are at risk of Morquio syndrome. Depending on the counseling outcome, genetic testing may be used as a follow-up.

Consultations with an anesthesiologist, cardiothoracic surgeon, geneticist, ophthalmologist, orthopedist, otolaryngologist, and hematologist are vital to the patient’s well-being.

Consultation with a dietician is required to maintain proportional body weight and height. Obesity diminishes the patient’s activity of daily living (ADL).

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Diet

Patients with Morquio syndrome require a balanced diet to maintain a proportional stature. 

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Activity

A person with Morquio syndrome (mucopolysaccharidosis type IV) can participate in activities as tolerated with a few important restrictions.

Contact sports could damage the cervical spine and should be avoided.

Repetitive motions at work or with sports could strain abnormal joints and should also be avoided.

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Complications

Morquio syndrome is associated with many complications, including skeletal abnormalities, corneal clouding, hearing problems, dental cavities, narrowing airway, cervical myelopathy, atlantoaxial instability, laxity of joints (floppy wrists, knock-knee), and valvular and coronary heart disease. [24] Patients with Morquio syndrome typically do not have carpal tunnel syndrome, although their wrists are typically enlarged and curved.

Although individuals with Morquio syndrome have tachycardia, cardiac and hemodynamic alterations (eg, arterial hypertension) have not been described or documented in younger patients. [26] However, there does seem to be an age-progressive disproportion of the intrathoracic organs of patients with Morquio syndrome, followed by aortic root extension and thickened left ventricles, with reduced stroke volumes, impaired diastolic filling patterns, and increased heart rate.

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Long-Term Monitoring

Many tests should be performed annually or bi-annually to monitor the health of patients with Morquio syndrome, as follows: [153]

  • Urinary and serum KS and C6S assessment
  • Health assessment questionnaire
  • ENT examination
  • Hearing test
  • Skeletal survey of the hips, spine, and knees in pediatric patients
  • MRI of the neck
  • Pulmonary function testing
  • Sleep study
  • Vision tests, including pressure, split lamp, and funduscopy
  • CT for tracheal obstruction
  • Ultrasonography of the heart and electrocardiography (every other year) [24, 26]
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