Non-invasive Functional Assessment and Pathogenesis of Morquio A

Официальное название

Non-invasive Functional Assessment and Pathogenesis of Morquio A (NIFAMA)

Обзор

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.

Подробное описание

Mucopolysaccharidosis IVA (MPS IVA, Morquio A Disease) is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme, N-acetylgalactosamine 6-sulfate sulfatase (GALNS). GALNS catalyzes the degradation of the glycosaminoglycans: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). MPS IVA patients develop a characteristic skeletal dysplasia due to the progressive storage of KS and C6S. Patients appear healthy at birth, although some patients present with abnormal skeletal dysplasia even at birth. Patients usually come to medical attention within two years of life because of short trunk dwarfism, odontoid hypoplasia, pectus carinatum, kyphosis, genu valgum, or hypermobile joints. Patients with severe phenotype often do not survive beyond a few decades of life because of cervical instability/stenosis, tracheal obstruction, and cardiopulmonary compromise. Patients require multiple orthopedic surgeries (cervical decompression/fusion, osteotomy, hip reconstruction and replacement, etc.) throughout their lifetime. Enzyme replacement therapy and hematopoietic stem cell therapy are available clinically. Gene therapy and enzyme degradation substrate therapy are under development. In 1998, the investigators began collecting medical information from patients in the Registry Database. The database contains around 400 patients and has established a growth chart that indicates marked poor growth with the imbalance and consequent poor health in MPS IVA. However, since these data are based on responses to a self-completion questionnaire, there are inherent limitations to the data and their interpretation. Current clinical assessments of therapies for MPS IVA patients are a 6-min walk test, a 3-min stair climb test, and forced pulmonary function test. These endurance tests are difficult for small children, patients in wheelchairs, and patients undergoing surgical procedures. Methods used to assess skeletal dysplasia disorders can be expensive, time-consuming, and exhausting for the patients. Better methods for assessment, including in-home evaluations, are needed to evaluate clinical efficacy and to provide optimal clinical treatments for MPS IVA patients. The proposed project will assess multiple domains non-invasively, which includes pulmonary function, bone mineralization, gait pattern, laxity of joints, tracheal function, and hearing function. Proposed non-invasive assessments will provide an effective and innovative way of characterizing the disease and evaluating the benefits of therapies even in small but diverse patient populations despite age and physical handicaps. Over 100 MPS IVA patients have been enrolled in our clinic, making our institution the most popular site in the world and ideally suited to complete this project. The assessment program with non-invasive methods will have a significant impact on science and health by detailing the progression and pathogenesis of major skeletal problems in MPS IVA. The outcome of this project will also define clinical endpoints to measure the efficacy of future clinical products and interventions and may apply to other skeletal dysplasias.

Вмешательства

• Диагностический тест Imaging, gait analysis, growth, joint test, hearing test, questionnaire, etc.
  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; biochemi

Первичные конечные точки

• Change of Total body length [Срок оценки: baseline, 18 months, 36 months, 48 months]
• Change of Body mass index (BMI) [Срок оценки: baseline, 18 months, 36 months, 48 months]
• Change of Height velocity [Срок оценки: baseline, 18 months, 36 months, 48 months]
• Change of QOL questionnaire [Срок оценки: baseline, 18 months, 36 months, 48 months]
• Change of Joint Mobility [Срок оценки: baseline, 18 months, 36 months, 48 months]
• Change of Skeletal survey by x-rays [Срок оценки: baseline, 36 months]
• Change of MRI in cervical spine (distance) [Срок оценки: baseline, 18 months, 36 months, 48 months]
• Change of CT angiography (CTA) (area) [Срок оценки: baseline, 36 months]
• Change of Anesthetic encounters [Срок оценки: baseline, 18 months, 36 months, 48 months]
• Change of Pulmonary Function Tests (CO2 %) [Срок оценки: baseline, 18 months, 36 months, 48 months]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• No

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 1 центр

• Nemours Children's Health, Delaware Valley — Wilmington

Публикации

• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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 IV PMID 14711889

Идентификаторы

NCT: NCT05284006 · 750932-25 · 1R01HD102545-01A1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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