Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA

Abstract

Mucopolysaccharidosis type IVA (MPS IVA) was described in 1929 by Luis Morquio from Uruguay and James Brailsford from England, and was later found as an autosomal recessive lysosomal storage disease. MPS IVA is caused by mutations in the gene encoding the enzyme, N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Reduced GALNS activity results in impaired catabolism of two glycosaminoglycans (GAGs), chondroitin-6-sulfate (C6S) and keratan sulfate (KS). Clinical presentations of MPS IVA reflect a spectrum of progression from a severe ”classical” phenotype to a mild “attenuated” phenotype. More than 180 different mutations have been identified in the GALNS gene, which likely explains the phenotypic heterogeneity of the disorder. Accumulation of C6S and KS manifests predominantly as short stature and skeletal dysplasia (dysostosis multiplex), including atlantoaxial instability and cervical cord compression. However, abnormalities in the visual, auditory, cardiovascular, and respiratory systems can also affect individuals with MPS IVA. Diagnosis is typically based on clinical examination, skeletal radiographs, urinary GAG, and enzymatic activity of GALNS in blood cells or fibroblasts. Deficiency of GALNS activity is a common assessment for the laboratory diagnosis of MPS IVA; however, with recently increased availability, gene sequencing for MPS IVA is often used to confirm enzyme results. As multiple clinical presentations are observed, diagnosis of MPS IVA may require multi-system considerations. This review provides a history of defining MPS IVA and how the understanding of the disease manifestations has changed over time. A summary of the accumulated knowledge is presented, including information from the International Morquio Registry. The classical phenotype is contrasted with attenuated cases, which are now being recognized and diagnosed more frequently. Laboratory based diagnoses of MPS IVA are also discussed.

Diagnosis of Morquio-A patients in Mexico: How far are we from prompt diagnosis?

“…This condition has progressive multisystem dysfunction and impaired functional capacity. Skeletal abnormalities may be first line clinical findings to aid in diagnosis (1,5,6).…”

“…Since Morquio-A patients have not primary neurological involvement (1,2,4,5), an early detection, as well as early treatment could prevent the severe functional impairment seen on these patients, improving outcomes and extending their autonomy (2,(7)(8)(9). Generally, before definitive diagnosis, patients are delayed or misdiagnosed due the lack of knowledge about the disease (10,11).…”

“…Knowing average time of features may help raise clinical suspicion of the disorder at early time (5,15,16).…”

Di-sulfated Keratan Sulfate as a Novel Biomarker for Mucopolysaccharidosis II, IVA, and IVB

“…Patients with a classic (severe) form of MPS IVA have a unique systemic skeletal dysplasia including short-trunk dwarfism, kyphoscoliosis, coxa valga, odontoid hypoplasia, abnormal gait, joint mobility problems, restriction of chest wall movement, and a life span of 20-30 years if an appropriate orthopedic intervention is unavailable. Patients with an attenuated form have a milder skeletal involvement, and most have normal life span (Dũng et al 2013;Yasuda et al 2013;Tomatsu et al 2011Tomatsu et al , 2012aTomatsu et al , 2013aNorthover et al 1996;Montaño et al 2007Montaño et al , 2008Suzuki et al 2001;Hendriksz et al 2013;M€ ollmann et al 2013;Harmatz et al 2013). Patients with MPS IVB show a milder phenotype of skeletal dysplasia than patients with the severe form of MPS IVA.…”

Chondroitin 6-sulfate as a novel biomarker for mucopolysaccharidosis IVA and VII

“…Clinically, a classic (severe) form of MPS IVA is characterized by systemic skeletal dysplasia such as short trunk dwarfism, kyphoscoliosis, coxa valga, odontoid hypoplasia, abnormal gait, joint mobility problems, restriction of chest wall movement, and a life span of 20-30 years. Patients with an attenuated form can have a nearly normal life span, with mild involvement of the skeleton (Dũng et al 2013;Yasuda et al 2013;Tomatsu et al 2011Tomatsu et al , 2012aTomatsu et al , 2013aNorthover et al 1996;Montaño et al 2007Montaño et al , 2008Suzuki et al 2001;Hendriksz et al 2013;M€ ollmann et al 2013;Harmatz et al 2013). In general, patients with MPS IVB have a milder phenotype of skeletal dysplasia.…”