Clinical Information

Mucopolysaccharidosis IVA, (MPS IVA; Morquio A syndrome) is caused by reduced or absent N-acetylgalactosamine-6-sulfate sulfatase (GALNS) enzyme activity. The glycosaminoglycans, keratan and chondroitin sulfate, accumulate in multiple tissues but mainly bone, cartilage, heart valves, and cornea. Clinical features and severity of symptoms of MPS IVA are widely variable affecting multiple body systems, in particular the skeletal system. Other clinical features may include short stature, dental anomalies, corneal clouding, respiratory insufficiency, and cardiac disease. Intelligence is usually normal.

Mucopolysaccharidosis type IVB (MPS IVB or Morquio syndrome B) is caused by reduced or absent beta-galactosidase activity leading to the accumulation of glycosaminoglycans, particularly keratan sulfate. MPS IVB typically manifests as a systemic skeletal disorder with variable severity ranging from early severe disease to a later onset attenuated form. Virtually all patients have dysostosis multiplex and short stature along with other symptoms that may include coarse facies, hepatosplenomegaly, hoarse voice, stiff joints, cardiac disease, but no neurological involvement.

GM1 gangliosidosis is also caused by reduced or absent beta-galactosidase activity, however the clinical features include neurological involvement in addition to the skeletal and other systemic findings associated with MPS IVB. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation.

Galactosialidosis is associated with a combined deficiency of beta-galactosidase and neuraminidase secondary to a defect in the cathepsin A protein. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation. Typical clinical presentation is coarse facial features, cherry-red spots, and skeletal dysplasia. The early infantile form is associated with fetal hydrops, skeletal dysplasia, and early death, while the late infantile form is characterized by short stature, dysostosis multiplex, coarse facial features, corneal clouding, hepatosplenomegaly, and heart valve problems.

A diagnostic workup for MPS typically also includes glycosaminoglycan (GAG) determination in urine (MPSQU / Mucopolysaccharides Quantitative, Random, Urine) or blood (MPSBS / Mucopolysaccharidosis, Blood Spot, or MPSER / Mucopolysaccharidosis Quantitative, Serum) and molecular genetic analysis of the relevant gene. For MPS IVA, molecular analysis of the GALNS gene (CGPH / Custom Gene Panel, Hereditary, Next-Generation Sequencing, Varies; specify Gene List ID: EMCP-JUFPRX) and for MPS IVB and GM1 gangliosidosis, molecular analysis of the GLB1 gene (CGPH; specify Gene List ID: EMCP-D5F3YS) allows for detection of disease-causing variants in affected patients and subsequent carrier detection in relatives.

A diagnostic workup for galactosialidosis traditionally includes determination of beta-galactosidase enzyme activity in leukocytes or fibroblasts and neuraminidase activity in fibroblasts followed by molecular analysis of CTSA (CGPH; specify Gene List ID: IEMCP-D1J7U5). Analysis of urine mucopolysaccharides, oligosaccharides, ceramide trihexoside, and sulfatides (LSDS / Lysosomal Storage Disorders Screen, Random, Urine) can help differentiate between galactosialidosis, MPS IVA, and MPS IVB/GM1 to guide physicians in choosing the best confirmatory molecular testing option. See Lysosomal Storage Disorders Diagnostic Algorithm, Part 1.