Mucopolysaccharidosis Type IVA

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: GALNS (HGNC:4122)
• Literature Search: 11/25/2019
• Curation Status: Released (1.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
GALNS	mucopolysaccharidosis type 4A (0009659)	253000	Moderate Actionability

Actionability Assertion Rationale

• All experts agreed with the assertion computed according to the rubric

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Functional somatic manifestations (as defined by quantitative measures of pulmonary function and 6-minute walk test) / Enzyme replacement therapy (ERT) with elosulfase alfa	2	3C	2A	2	9CA
Early mortality / Enzyme replacement therapy (ERT) with elosulfase alfa	2	3C	0D	2	7CD

Severity of Outcome

Prevalence of the Genetic Condition

Mucopolysaccharidosis IVA (MPS IVA) is a rare metabolic disorder. Birth prevalence for MPS IVA is estimated from 1:1,179,000-1:71,000 and point prevalence from 1:1,872,000-1:217,000 depending on the population. However, the studies providing these estimates are compromised by poor reporting and flaws in internal validity, and may over- or under-estimate prevalence, depending on methodology.

Clinical Features (Signs / symptoms)

The lysosomal storage disease MPS IVA, also called Morquio syndrome A, is caused by a deficiency of the enzyme encoded by GALNS and results in the buildup of enzyme substrates in tissues and organs. The degree, number, age of onset, rate of progression, and severity of symptoms varies significantly among affected individuals. As such, MPS IVA has historically been divided into two forms distinguished by severity and rate of progression: a severe and rapidly progressive form and an atypical slowly progressive form. Since neither clinical nor biochemical findings provide clear distinctions, the MPS IVA phenotype is now considered a continuum between the two extremes. Most patients present with severe disease, associated with short stature and severe skeletal/joint abnormalities. Patients presenting with slowly progressive disease do not have this appearance but may show severe impairment in other domains (e.g., cardiorespiratory). Additional clinical findings may include coarse facial features, hearing/vision loss, dental abnormalities, airway abnormalities, and hepatomegaly. Compression of the spinal cord is a common complication that results in neurologic impairment and can lead to premature death.

Natural History (Important subgroups & survival / recovery)

Children with MPS IVA have no distinctive clinical findings at birth. In both the severe and slowly progressive forms initial presentations vary. Most patients (~70%) present before age 3 years. All individuals with MPS IVA develop progressive clinical manifestations. Intellectual abilities are normal at outset; however, spinal compression increases the risk of neurologic compromise. Skeletal abnormalities and muscle weakness, if present, worsen over time. Corneal opacification often causes reduced vision in early childhood. Hearing loss is often noted late in the first decade. Spinal involvement, respiratory failure, and cardiac problems are the main causes of morbidity and mortality.

Although the severe form is usually apparent between 1-4 years of age, often first manifesting as skeletal abnormalities, radiographic abnormalities of the lumbar spine can be detected between birth and 6 months. In these patients, growth is typically normal during infancy and growth delay becomes evident by 3 years of age, resulting in very short stature. These individuals have a shortened lifespan with death often occurring between the first and third decade of life.

The slowly progressive form may not become evident until late childhood or adolescence, often first manifesting as hip problems. Radiographic manifestations associated with dysostosis multiplex may be subtle or absent. These patients often present with normal stature and may demonstrate a widely variable growth pattern. Patients with the slowly progressive form may have normal or near-normal life expectancies.

Likelihood of Outcome

Prevalence of Genetic Variants

The population prevalence of GALNS pathogenic variants was not available. It is estimated that 96-97% of MPS IVA can be attributed to pathogenic variants in GALNS.

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

Below is an overview of common clinical manifestations MPS IVA and prevalence of these manifestations compiled from the large prospective longitudinal MorCAP (Morquio A Clinical Assessment Program) study (baseline data), and several small retrospective chart reviews and case series:

- Mortality due to respiratory failure (retrospective data only): 63%

- Respiratory compromise (airway obstruction, respiratory restriction) (baseline data only): 58%

- Cardiac valve involvement (valve disease, valve regurgitation): 14-43%

- Musculoskeletal manifestations (spine, joint, gait, and other abnormalities): 23-97%

- Eye disorders: >50%-79%

- Ear/labyrinth disorders (e.g., hearing loss, otitis media): 77%

- Abdominal abnormalities (e.g. hepatomegaly, splenomegaly, hernias): 15-26%

Tier 3

In addition, cardiac dysfunction accounts for 15% of patients deaths.

Tier 4

Relative Risk (Includes any high-risk racial or ethnic subgroups)

No information on relative risk was identified.

Expressivity

Pathogenic variants in GALNS predicted to severely affect protein function are common in individuals with rapidly progressive growth failure. In contrast, affected individuals with more conservative genetic changes are more likely to have an atypical phenotype, presumably due to partial enzyme activity.

Tier 3

Genotypic and phenotypic heterogeneity has been observed, and patients may show severe manifestations in one domain, but not in another (e.g., severe respiratory disease, but normal height).

Tier 3

Intervention Effectiveness

Patient Management

Upon diagnosis of MPS IVA, a multidisciplinary team should be established with a coordinating physician with experience in lysosomal storage disorders and a multisystem evaluation conducted to set a baseline to guide ongoing assessments and initiation of treatment. Initial evaluations should include physical exam, comprehensive medical history, cardiac and ear-nose-throat (ENT) evaluations, assessments of respiratory function (e.g., endurance testing, polysomnography), hip/spine imaging, and brain MRI.

Tier 2

To address the underlying enzyme deficiency, long-term enzyme replacement therapy (ERT) with elosulfase alfa at a dose of 2 mg/kg/week through intravenous infusion should be initiated in all patients as soon as possible after diagnosis. This recommendation is based on a 24-week phase III randomized clinical trial with 120-week open-label cross-over extension including patients with a broad range of phenotypes. At week 24 all outcomes evaluated between patients who underwent weekly infusions of 2 mg/kg (n = 58) versus placebo (n = 59) showed statistically insignificant trends toward improvement, including the primary endpoint of 6-minute walk test (6-MWT) distance as well as secondary and tertiary endpoint measures of endurance and respiratory function and growth. In the 120-week open label extension study, the modified per protocol (MPP) analysis patients adherent to weekly ERT (n = 124) experienced improved endurance from baseline at 120-weeks with a 6-MWT distance of 39.9 meters (m) (standard error: 10.1 m), though in the open-label extension there was no placebo or other dosage group for comparison. In contrast to the typical natural history of the disease, no significant trend toward decline was observed after 5 years of treatment (n=17 patients). In a separate trial of 25 patients on weekly ERT infusions, improved subjective pain scores and reductions in the number of pain locations and pain descriptor words at 52 weeks were reported.

Tier 1

No data on survival in MPS IVA patients on ERT has been published; however, guidelines cite extrapolation from MPS VI patients where relative risk of death was 3.03x higher in standard of care patients than those on galsulfase ERT.

Tier 2

An additional 120-week follow-up study of the phase III trial reported sustained improvements from baseline in respiratory function in patients after long-term weekly ERT use, including mean increases of 9.2 % for forced vital capacity (n=112 patients), 8.8 % for forced expiratory volume in 1 second (n=113 patients), and 6.1 % for maximum voluntary ventilation (n=105 patients).

Tier 5

Beyond ERT, manifestations are managed symptomatically according to existing care regimens. Such management may include spinal and other orthopedic surgeries, cardiac valve replacement, and surgical/non-surgical interventions for airway obstruction.

Tier 1

Additionally, further orthopedic, airway/ENT and respiratory, cardiac, and ophthalmologic interventions are recommended based on clinical manifestations. Surgical procedures should be performed by (or under the guidance of) specialist surgeons with experience in MPSs, in medical centers with intensive care units with coordination of the entire care team after anesthetic risk has been evaluated. Management of pain via conventional pharmco- and physiotherapy approaches should be a fundamental part of the care to improve quality of life and maintain mobility.

Tier 2

Most MPS IVA patients will require surgery under anesthesia; since MPS IVA patients are high anesthetic risk, all procedures requiring general anesthesia or sedation should be provided by an experienced anesthetic team that can perform emergency tracheotomy. It is critical to maintain a neutral neck position during surgeries, intubation, and extubation to avoid paralysis. These recommendations are based on case studies and case series suggesting routinely difficult intubation/extubation due to airway obstruction, which has in cases resulted in tracheal obstruction, paralysis, or death. Further, patients should undergo neurophysiological monitoring during high-risk procedures.

Tier 1

Surveillance

Routine multi-system monitoring and assessments by the multidisciplinary care team, including comprehensive physical exam and history collection of sleep-disordered breathing, are recommended to track the course of disease and to guide timely intervention to avoid irreversible damage and to maintain long-term quality of life. For instance, if respiratory symptoms are not diagnosed and treated early, respiratory failure may ensue and lead to early death.

Tier 2

Annual assessments should include endurance testing using the 6-MWT unless the patient has limited ambulation, urinary keratan sulphate levels, and age-adjusted audiometric assessments for both conductive and sensory-neural hearing loss.

Tier 1

Circumstances to Avoid

Based on limited case reports, intrathecal and epidural anesthetic techniques are high-risk and should be avoided when possible. Hypotension should be avoided during all surgical procedures to maintain spinal cord perfusion and protect spinal cord function. Based on one case report, the Ross procedure, where the aortic valve is replaced by the patient’s own pulmonary valve, is contraindicated in patients with systemic valvular disease and should not be employed in patients with MPS IVA.

Tier 1

Efforts should be made to minimize radiation exposure and X-ray images only requested when clinically useful.

Tier 2

Treatment of tachycardia with beta blockers should be avoided, as elevated heartrate in patients may be needed to compensate for small stroke volume.

Tier 2

Nature of Intervention

Nature of Intervention

ERT with elosulfase alfa is well-tolerated. Most adverse events in clinical trials were mild-to-moderate infusion associated reactions (IARs), including headache, nausea, vomiting, pyrexia, chills, and abdominal pain. Serious IARs were observed, including anaphylaxis, hypersensitivity, and vomiting; as such the first dose of ERT should be administered by a clinician with experience in metabolic disorders and take place within an infusion center/hospital with facilities for effective management of allergic/anaphylactic reactions. Non-sedating antihistamine premedication is required to mitigate potential for serious IARs and close observation for signs of hypersensitivity during and after infusion is necessary. Cessation of ERT should be considered on an individual basis where the burden of infusion outweighs the benefits of treatment.

Context: Pediatric

Physical manifestations and very limited lung capacity in this patient population make it challenging for patients to perform some functional monitoring tests reliably according to standardized guidelines. Some MPS IVA patients with limited ambulation are unable to perform the 6-MWT, and therefore endurance must be assessed via alternative methods, such as the timed 25-foot walk test which has been adapted for MPS IVA patients in order to allow patients to cover the 25 feet distance by crawling or rolling if walking is not possible. Respiratory function tests by spirometry should only be used to assess changes in lung volume and obstruction in children over 5 years of age.

Context: Pediatric

Chance to Escape Clinical Detection

Larger numbers of pathogenic variants contributing to heterogeneous clinical presentation, and observations of atypical phenotypes make diagnosis challenging. Vertebral changes may resemble those of other skeletal disorders/dysplasias, increasing the chance of delayed or incorrect diagnosis.

Context: Pediatric

Tier 3

In some instances atypical MPS IVA can manifest only with hip pain at the onset of disease, which can lead to an initial misdiagnosis of Legg-Calve-Perthes disease.

Context: Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			GALNS			253000	0009659

References List

Akyol MU, Alden TD, Amartino H, Ashworth J, Belani K, Berger KI, Borgo A, Braunlin E, Eto Y, Gold JI, Jester A, Jones SA, Karsli C, Mackenzie W, Marinho DR, McFadyen A, McGill J, Mitchell JJ, Muenzer J, Okuyama T, Orchard PJ, Stevens B, Thomas S, Walker R, Wynn R, Giugliani R, Harmatz P, Hendriksz C, Scarpa M. (2019) Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance. Orphanet journal of rare diseases. 14(1750-1172):137.

Hendriksz CJ, Berger KI, Giugliani R, Harmatz P, Kampmann C, Mackenzie WG, Raiman J, Villarreal MS, Savarirayan R. (2015) International guidelines for the management and treatment of Morquio A syndrome. American journal of medical genetics. Part A. 167A(1552-4833):11-25.

Hendriksz CJ, Berger KI, Parini R, AlSayed MD, Raiman J, Giugliani R, Mitchell JJ, Burton BK, Guelbert N, Stewart F, Hughes DA, Matousek R, Jurecki E, Decker C, Harmatz PR. (2016) Impact of long-term elosulfase alfa treatment on respiratory function in patients with Morquio A syndrome. Journal of inherited metabolic disease. 39(1573-2665):839-847.

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MUCOPOLYSACCHARIDOSIS, TYPE IVA; MPS4A. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 253000, (2020) World Wide Web URL: http://omim.org/

National Institute for Health and Care Excellence (NICE). Elosulfase alfa for treating mucopolysaccharidosis type IVa. Highly specialised technologies guidance [HST2]. (2014) Accessed: 2015-12-06. URL: https://www.nice.org.uk/guidance/hst2

Politei JM, Gordillo-González G, Guelbert NB, de Souza CFM, Lourenço CM, Solano ML, Junqueira MM, Magalhães TSPC, Martins AM. (2018) Recommendations for Evaluation and Management of Pain in Patients With Mucopolysaccharidosis in Latin America. Journal of pain and symptom management. 56(1873-6513):146-152.

Regier DS, Oetgen M, Tanpaiboon P. (1993) Mucopolysaccharidosis Type IVA. GeneReviews^®.

Solanki GA, Martin KW, Theroux MC, Lampe C, White KK, Shediac R, Lampe CG, Beck M, Mackenzie WG, Hendriksz CJ, Harmatz PR. (2013) Spinal involvement in mucopolysaccharidosis IVA (Morquio-Brailsford or Morquio A syndrome): presentation, diagnosis and management. Journal of inherited metabolic disease. 36(1573-2665):339-55.

White KK, Jester A, Bache CE, Harmatz PR, Shediac R, Thacker MM, Mackenzie WG. (2014) Orthopedic management of the extremities in patients with Morquio A syndrome. Journal of children's orthopaedics. 8(1863-2521):295-304.