Non-invasive Functional Assessment and Pathogenesis of Morquio A

NCT05284006 | Recruiting

• 2 other identifiers: 750932-251R01HD102545-01A1
• Study Type: observational
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

Morquio A disease is a devastating systemic skeletal disease in which detailed progression and pathogenesis remain unknown. The proposed project aims to establish a non-invasive objective assessment that can be applicable to all ages of patients to better understand the progress of their disease and the most serious clinical problems (cervical instability and stenosis, tracheal obstruction, hyperlaxity of joints, hip dysplasia, and small lung capacity). The outcome of this project will lead to a more precise understanding of the skeletal/pulmonary compromise and defining clinical endpoints in this disease for future clinical trials of current or developing therapies.

Conditions

Mucopolysaccharidosis IV Type A; Morquio A Syndrome; MPS IVA

Keywords

skeletal dysplasia; GALNS; keratan sulfate; tracheal narrowing; short stature

Outcome Measures

Primary Outcomes (17)

• Change of Total body length

  cm: The patient lies on a flat surface with knees flattened to extend the legs fully. Standing height will also be measured

  baseline, 18 months, 36 months, 48 months

• Change of Body mass index (BMI)

  BMI: BMI is a measure of body fat based on height and weight. BMI is a person's weight in kilograms divided by the square of height in meters.

  baseline, 18 months, 36 months, 48 months

• Change of Height velocity

  cm/year: calculating height velocity is a simple matter of measuring a height at two points in time and then dividing the change by the amount of time (year).

  baseline, 18 months, 36 months, 48 months

• Change of QOL questionnaire

  Score: The questionnaire comprises three domains: "Movement," "Movement with cognition," and "Cognition." Each domain has 20 scores. Total score is 60. Higher scores means a better ADL.

  baseline, 18 months, 36 months, 48 months

• Change of Joint Mobility

  Angle Degree: Evaluate the degree of hyperlaxity in the metacarpophalangeal (MCP) joint of the index finger. Each test will be repeated three times to get the average forces from each patient. The device measures the angle and torque at the 2nd metacarpophalangeal joint as it is passively extended. It expresses as rad/Nm.

  baseline, 18 months, 36 months, 48 months

• Change of Skeletal survey by x-rays

  Distance (mm); PA hands bilaterally, Metacarpal 2nd,3rd, 4th, and 5th, bone age assessment. Assessment is performed with a radiograph of the non-dominant hand with a single DP view that includes the distal radius and ulna and all the fingers. Appearances of the carpal bones, metacarpal, phalanges, radius and ulna are compared to standardized versions in one of two main atlases: * Greulich \& Pyle atlas presents a single standardized image for a range of ages of each gender * Tanner-Whitehouse atlas involves the scoring of each carpal bone, the radius and ulna leading to a total score, from which age can be estimated mm; AP lower extremities from pelvis to floor on a single image mm; Length of tibia and fibula mm; For children \< 7 yrs; measure between the epiphyseal plates, measure lengths of femur and tibia.

  baseline, 36 months

• Change of MRI in cervical spine (distance)

  Distance (mm); The following measurements will be used to define cervical instability and stenosis; 1) powers ratio exceeding 1.0 for occipito-C1 instability; 2) less than 13 mm of space available for the cord (SAC) at C1-2 for canal stenosis; 3) ADI measuring more than 5 mm for C1-2 instability; 4) greater than 2 mm offset of C2 interiorly on C3 measured at the spino-laminar (Swishuk's) line for C2-3 instability; 5) sagittal translation in flexion and extension more than 3.5 mm for sub-axial instability.

  baseline, 18 months, 36 months, 48 months

• Change of CT angiography (CTA) (area)

  Area (mm3); Tracheal cross-sectional area will be measured (mm3) at the cervical, thoracic inlet and intrathoracic levels and compared against normative age-matched controls The cross-sectional shape of the trachea will be described using previously described nomenclature. Tortuosity and deviation of the trachea will be described. Course and tortuosity of the innominate artery and relationship to tracheal narrowing will be described. Anteroposterior diameter of the thoracic inlet will be measured. CTA measurements of trachea will be correlated with tracheal diameter measurements obtained from MRI of the cervical spine in order to determine if MR of the cervical spine provides an adequate level of detail to serve as the primary screening tool for tracheal obstruction, thereby reserving CTA for severe cases requiring detailed tracheal information before anesthesia and those requiring tracheal reconstruction.

  baseline, 36 months

• Change of Anesthetic encounters

  Score (1-5); Those patients who undergo during the study period, will have their airway management assessed for difficulty and scored on a 5 point scale . Difficult upper and lower airway scoring (1) normal (2) Difficult upper airway only but relieved easily (3) Difficult upper airway and difficult tracheal intubation (5) Failed upper airway management or tracheal intubation

  baseline, 18 months, 36 months, 48 months

• Change of Pulmonary Function Tests (CO2 %)

  Co2%: Air flow, volume data, flow-volume loops, and oximetry signals using PNT will be recorded using pediatric PFT systems (CO2SMO, Respironics, Wallingford, CT) and software packages (Analysis Plus, Novametrix Medical Systems, Wallingford, CT).

  baseline, 18 months, 36 months, 48 months

• Change of Pulmonary Function Tests (Resistance)

  Resistance (R); The method is rapid (20 sec) allowing the evaluation of total respiratory impedance (Zrs) that is based on total respiratory resistance (Rrs) and total respiratory reactance (Xrs). Rrs includes the airway, lung tissue, and chest wall resistance, whereas Xrs represent the balance of two (an elastic and an inertial) components.

  baseline, 18 months, 36 months, 48 months

• Change of Pulmonary Function Tests (percent Rib Cage)

  percent Rib Cage; TAM is a measure of chest wall motion and breathing patterns, as well as tidal volume contribution to the thoracic and abdominal compartments. TAM uses two elastic bands, one placed around the ribcage (RC) at the nipple line, and one placed around the abdomen (ABD) at the umbilicus. Two bands measure TAM (movement \& synchrony) of the patient's RC and ABD.

  baseline, 18 months, 36 months, 48 months

• Change of Z-score of Bone mineral density (BMD)

  Lumbar spine and bilaterally distal femurs BMD will be measured using Hologic 1000 W DEXA. The following variables will be collected from each scan: BMD, bone mineral content (BMC), and bone area. Z-scores will be calculated from published norms for the lateral distal femur and from the Hologic pediatric reference database for the spine. Z-scores will be calculated from published norms for the lateral distal femur and from the Hologic pediatric reference database for the spine.

  baseline, 18 months, 36 months, 48 months

• Change of Hearing function (db SPL)

  Otoacoustic noise levels (db SPL); Thresholds of middle ear muscle reflex will be obtained to assess the middle ear. The range of testing levels ranges 70 and 105 dB SPL, and the thresholds above 100 dB SPL or no response will be considered as abnormal responses.

  baseline, 18 months, 36 months, 48 months

• Change of Gait analysis (Nm/kg)

  Children's movement will be analyzed with a 3D motion analysis system while they walk a 30 m walkway. Joint kinetics will be analyzed using force plates that are embedded in the walkway. The investigators will evaluation joint kinematics (Nm/kg - Newton meters/kg).

  baseline, 18 months, 36 months, 48 months

• Change of Biochemical biomarkers (KS)

  Measure KS in blood (ng/ml). LC/MS/MS will be used to analyze the disaccharides produced from KS. KS will be digested to disaccharides by keratanase II. Blood KS is expressed as ng/ml.

  baseline, 18 months, 36 months, 48 months

• Change of Biochemical biomarkers (C6S)

  Measure C6S in blood (ng/ml). LC/MS/MS will be used to analyze the disaccharides produced from C6S. C6S will be digested to disaccharides by keratanase II. Blood C6S is expressed as ng/ml.

  baseline, 18 months, 36 months, 48 months

Study Arms (1)

Mucopolysaccharidosis IVA

Patients affected by MPS IVA. The diagnosis of MPS will be confirmed by deficient enzyme activity of \< 5% of normal activity level as measured in plasma, leukocytes, or fibroblasts.

Diagnostic Test: Imaging, gait analysis, growth, joint test, hearing test, questionnaire, etc.

Interventions

Imaging, gait analysis, growth, joint test, hearing test, questionnaire, etc. DIAGNOSTIC_TEST

This study includes 15 major assessments: clinical assessment procedures; anthropometric measurements; activity of daily living and quality-of-life questionnaires; gait kinematics and kinetics analysis; pulmonary function tests (PFT); skeletal radiographs and dual-energy x-ray absorptiometry (DXA); MRI in cervical spine, temporal bones, and hip; computed tomography angiography (CTA) for tracheal obstruction; CT for temporal bones; anesthetic encounters; joint mobility; hearing function; biochemical analyses; and pathological analyses.

Mucopolysaccharidosis IVA

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

The studies proposed here will involve a minimum of 60 subjects who have the biochemical defect of GALNS. There is no limitation in the age range. All patients will be included, whether ambulatory or not, with presence or absence of planned surgical operation, and whether received ERT. The study population will consist of male and female patients with the diagnosis of MPS IVA, also known as Morquio A disease. Before any study procedures, all potential subjects and their parents/legal guardians will be informed about the purpose and conduct of the study. They will be prospectively followed every 18 months at Nemours Children's Health, Delaware Valley.

You may qualify if:

• Patients affected by MPS IVA. The diagnosis of MPS IVA is confirmed by deficient enzyme activity of \< 5% of normal activity level as measured in plasma or leukocytes.

Sponsors & Collaborators

• Nemours Children's Clinic: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Nemours Children's Health, Delaware Valley

Wilmington, Delaware, 19803, United States

RECRUITING

Related Publications (10)

• Pizarro C, Davies RR, Theroux M, Spurrier EA, Averill LW, Tomatsu S. Surgical Reconstruction for Severe Tracheal Obstruction in Morquio A Syndrome. Ann Thorac Surg. 2016 Oct;102(4):e329-31. doi: 10.1016/j.athoracsur.2016.02.113.

  PMID: 27645974 BACKGROUND

• Baratela WA, Bober MB, Thacker MM, Belthur MV, Oto M, Rogers KJ, Mackenzie WG. Cervicothoracic myelopathy in children with Morquio syndrome A: a report of 4 cases. J Pediatr Orthop. 2014 Mar;34(2):223-8. doi: 10.1097/BPO.0000000000000074.

  PMID: 24096444 BACKGROUND

• Dede O, Thacker MM, Rogers KJ, Oto M, Belthur MV, Baratela W, Mackenzie WG. Upper cervical fusion in children with Morquio syndrome: intermediate to long-term results. J Bone Joint Surg Am. 2013 Jul 3;95(13):1228-34. doi: 10.2106/JBJS.J.01135.

  PMID: 23824392 BACKGROUND

• Sitoula P, Mackenzie WG, Shah SA, Thacker M, Ditro C, Holmes L Jr, Campbell JW, Rogers KJ. Occipitocervical fusion in skeletal dysplasia: a new surgical technique. Spine (Phila Pa 1976). 2014 Jul 1;39(15):E912-8. doi: 10.1097/BRS.0000000000000381.

  PMID: 24825152 BACKGROUND

• Doherty C, Stapleton M, Piechnik M, Mason RW, Mackenzie WG, Yamaguchi S, Kobayashi H, Suzuki Y, Tomatsu S. Effect of enzyme replacement therapy on the growth of patients with Morquio A. J Hum Genet. 2019 Jul;64(7):625-635. doi: 10.1038/s10038-019-0604-6. Epub 2019 Apr 24.

  PMID: 31019230 BACKGROUND

• Montano AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A Registry: clinical manifestation and natural course of Morquio A disease. J Inherit Metab Dis. 2007 Apr;30(2):165-74. doi: 10.1007/s10545-007-0529-7. Epub 2007 Mar 8.

  PMID: 17347914 BACKGROUND

• Whyte MP, Fujita KP, Moseley S, Thompson DD, McAlister WH. Validation of a Novel Scoring System for Changes in Skeletal Manifestations of Hypophosphatasia in Newborns, Infants, and Children: The Radiographic Global Impression of Change Scale. J Bone Miner Res. 2018 May;33(5):868-874. doi: 10.1002/jbmr.3377. Epub 2018 Feb 14.

  PMID: 29297597 BACKGROUND

• Tomatsu S, Okamura K, Taketani T, Orii KO, Nishioka T, Gutierrez MA, Velez-Castrillon S, Fachel AA, Grubb JH, Cooper A, Thornley M, Wraith E, Barrera LA, Giugliani R, Schwartz IV, Frenking GS, Beck M, Kircher SG, Paschke E, Yamaguchi S, Ullrich K, Isogai K, Suzuki Y, Orii T, Kondo N, Creer M, Noguchi A. Development and testing of new screening method for keratan sulfate in mucopolysaccharidosis IVA. Pediatr Res. 2004 Apr;55(4):592-7. doi: 10.1203/01.PDR.0000113767.60140.E9. Epub 2004 Jan 7.

  PMID: 14711889 BACKGROUND

• Tomatsu S, Montano AM, Oguma T, Dung VC, Oikawa H, de Carvalho TG, Gutierrez ML, Yamaguchi S, Suzuki Y, Fukushi M, Kida K, Kubota M, Barrera L, Orii T. Validation of keratan sulfate level in mucopolysaccharidosis type IVA by liquid chromatography-tandem mass spectrometry. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S35-42. doi: 10.1007/s10545-009-9013-x. Epub 2010 Jan 27.

  PMID: 20107903 BACKGROUND

• Montano AM, Tomatsu S, Brusius A, Smith M, Orii T. Growth charts for patients affected with Morquio A disease. Am J Med Genet A. 2008 May 15;146A(10):1286-95. doi: 10.1002/ajmg.a.32281.

  PMID: 18412124 RESULT

Biospecimen

Retention: SAMPLES WITH DNA

Blood, surgical specimens, urine

MeSH Terms

Conditions

Mucopolysaccharidosis IV; Dwarfism

Interventions

Diagnostic Imaging; Gait Analysis; Growth; Hearing Tests

Condition Hierarchy (Ancestors)

Mucopolysaccharidoses; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Bone Diseases, Developmental; Bone Diseases; Musculoskeletal Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Diagnostic Techniques and Procedures; Diagnosis; Gait; Physical Examination; Physical Functional Performance; Physical Fitness; Health; Population Characteristics; Growth and Development; Physiological Phenomena; Diagnostic Techniques, Otological

Study Officials

• Shunji Tomatsu, MD PhD

  Nemours Children's Care

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Shunji Tomatsu, MD PhD

CONTACT

3022987336; stomatsu@nemours.org

Greg Stets

CONTACT

302-298-6504; gstets@nemours.org

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal research scientist and Professor

Study Record Dates

• First Submitted: February 9, 2022
• First Posted: March 17, 2022
• Study Start: May 1, 2021
• Primary Completion: April 30, 2026
• Study Completion: April 30, 2026
• Last Updated: May 14, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)