Abstract
BackgroundMucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency. It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments. Data on MPS IVA in Asian populations are scarce.MethodsThis is a multicentre descriptive case series of 21 patients comprising all MPS IVA patients in Malaysia. Mutational analysis was performed by PCR and Sanger sequencing of the GALNS gene in 17 patients.ResultsThe patients (15 females and 6 males) had a mean age (± SD) of 15.5 (± 8.1) years. Mean age at symptom onset was 2.6 (± 2.1) years and at confirmed diagnosis was 6.9 (± 4.5) years. The study cohort included patients from all the main ethnic groups in Malaysia – 57% Malay, 29% Chinese and 14% Indian. Common presenting symptoms included pectus carinatum (57%) and genu valgum (43%). Eight patients (38%) had undergone surgery, most commonly knee surgeries (29%) and cervical spine decompression (24%). Patients had limited endurance with lower mean walking distances with increasing age. GALNS gene analysis identified 18 distinct mutations comprising 13 missense, three nonsense, one small deletion and one splice site mutation. Of these, eight were novel mutations (Tyr133Ser, Glu158Valfs*12, Gly168*, Gly168Val, Trp184*, Leu271Pro, Glu320Lys, Leu508Pro). Mutations in exons 1, 5 and 9 accounted for 51% of the mutant alleles identified.ConclusionsAll the MPS IVA patients in this study had clinical impairments. A better understanding of the natural history and the clinical and genetic spectrum of MPS IVA in this population may assist early diagnosis, improve management and permit timely genetic counselling and prenatal diagnosis.
Highlights
Mucopolysaccharidosis type IVA (MPS IVA, OMIM #253000, Morquio A syndrome) is an autosomal recessive lysosomal storage disease
Mucopolysaccharidosis IVA (MPS IVA) is characterized by a deficiency of the lysosomal enzyme N-acetylgalactosamine6-sulfatase (GALNS), which is required for the degradation of the glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (CS) [1]
The crystal structure of the human GALNS enzyme was obtained from the Protein Data Bank [33] and, using this structure as a template, we modelled the protein structures for novel missense mutations using SWISS-MODEL [34]
Summary
Mucopolysaccharidosis type IVA (MPS IVA, OMIM #253000, Morquio A syndrome) is an autosomal recessive lysosomal storage disease. MPS IVA is characterized by a deficiency of the lysosomal enzyme N-acetylgalactosamine6-sulfatase (GALNS), which is required for the degradation of the glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate (CS) [1] This enzyme deficiency leads to an abnormal accumulation of KS and CS, and their excretion in the urine [1]. Progressive accumulation of KS and CS primarily in cartilage and the extracellular matrix results in systemic skeletal dysplasia, which varies in severity but is present in all patients [2] Clinical features of those with the classical phenotype include short stature, prominent forehead, short neck, pectus carinatum, kyphoscoliosis, genu valgum, hypermobile joints and cervical instability with spinal cord compression [2]. Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive lysosomal storage disease due to N-acetylgalactosamine-6-sulfatase (GALNS) deficiency It results in accumulation of the glycosaminoglycans, keratan sulfate and chondroitin-6-sulfate, leading to skeletal and other systemic impairments.
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