Natural history of Morquio A patient with tracheal obstruction from birth to death

Caitlin Doherty,Lauren W Averill,Mary Theroux,William G Mackenzie,Christian Pizarro,Robert W Mason,Shunji Tomatsu

doi:10.1016/j.ymgmr.2017.11.005

Abstract

Morquio A syndrome (mucopolysaccharidosis IVA, MPS IVA) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase, resulting in systemic accumulation of the partially degraded glycosaminoglycans (GAGs), keratan sulfate and chondroitin-6-sulfate. The accumulation of these GAGs leads to distinguishing features as skeletal dysplasia with disproportionate dwarfism, short neck, kyphoscoliosis, pectus carinatum, tracheal obstruction, coxa valga, genu valgum, and joint laxity. In the absence of autopsied cases and systemic analysis of multiple tissues, the pathological mechanism of the characteristic skeletal dysplasia associated with the disease largely remains a question. Here we report an autopsied case of a 23-year-old male with MPS IVA, who developed characteristic skeletal abnormalities by 4months of age and died of severe tracheal obstruction and hypoventilation originating from respiratory muscle weakness from neurological cord deficit due to cord myelopathy at the age of 23. We analyzed postmortem tissues pathohistologically, including the thyroid, lung, lung bronchus, trachea, heart, aorta, liver, spleen, kidney, testes, humerus, knee cartilage, and knee ligament.Examination of the tissues demonstrated systemic storage materials in multiple tissues, as well as severely ballooned and vacuolated chondrocytes in the trachea, humerus, knee cartilage, and lung bronchus.This autopsied case with MPS IVA addresses the importance of tracheal obstruction for morbidity and mortality of the disease, and the pathological findings contribute to a further understanding of the pathogenesis of MPS IVA and the development of novel therapies.

Highlights

Morquio A syndrome is a lysosomal storage disease (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which is required for the catabolism of glycosaminoglycans (GAGs): keratan sulfate (KS) and chondroitin-6-sulfate (C6S) [1,2,3,4,5,6,7]
We have described the pathologic observations of tissues from an autopsied case with severe tracheal obstruction and respiratory muscle weakness arising from neurological cord deficit due to cord myelopathy to further understand the pathogenesis of MPS IVA
We have demonstrated that 1) the patient presented with severe spinal cord compression, and died of tracheal obstruction and successive respiratory failure as a result of the disease, as caused by respiratory muscle weakness from neurological cord deficit due to cord myelopathy, which is commonly attributed to the causes of mortality and morbidity in MPS IVA patients, and 2) the large majority of chondrocytes in the examined locations were enlarged and vacuolated

Summary

Introduction

Morquio A syndrome (mucopolysaccharidosis IVA, MPS IVA) is a lysosomal storage disease (LSD) caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which is required for the catabolism of glycosaminoglycans (GAGs): keratan sulfate (KS) and chondroitin-6-sulfate (C6S) [1,2,3,4,5,6,7]. MPS IVA is characterized by extensive clinical manifestations including skeletal dysplasia with prominent forehead, dental abnormalities, short neck, short trunk dwarfism, cervical spinal cord compression and atlantoaxial instability, tracheal obstruction, kyphoscoliosis, pectus carinatum, pulmonary complications, laxity of joints, coxa valga, genu valgum, and elevated blood and urine KS [1,2,3,8,9]. Individuals with MPS IVA, with the severe form, often do not survive past their twenties, as the most attributed causes of mortality and morbidity are spinal cord compression, instability of the C1-C2 joint, and airway compromise including tracheal obstruction [1,2,3,8,9]

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