Mucopolysaccharidosis Type IVB: GLB1 Gene Sequencing

Mucopolysaccharidosis type IV B (Morquio syndrome, MPS IV B) is a member of a group of inherited metabolic disorders collectively termed mucopolysaccharidoses (MPSs). The MPSs are caused by a deficiency of lysosomal enzymes required for the degradation of mucopolysaccharides or glycosaminoglycans (GAGs). Morquio syndrome type IVB is caused by deficiency of the enzyme beta galactosidase. Deficiency of this enzyme leads to accumulation of the GAG, keratan sulfate, in the lysosomes.

Symptoms of Morquio syndrome include the excretion of specific urinary glycosaminoglycans and skeletal abnormalities. Most individuals affected by Morquio syndrome do not have coarse facial features or mental retardation. Skeletal manifestations of Morquio syndrome include: odontoid hypoplasia, a striking short trunk dwarfism, and genu valgus. Compared to other patients with MPS, those with Morquio syndrome tend to have greater spine involvement with scoliosis, kyphosis, and severe gibbus, as well as platyspondyly, rib flaring, pectus carinatum, and ligamentous laxity. Odontoid hypoplasia is the most critical skeletal feature to recognize in any patient with Morquio syndrome. In earlier clinical descriptions, MPS Type IVA was considered to have more severe manifestations than type IVB. However, with the ability to differentiate between types A and B by enzyme analysis, it is understood that significant variability in clinical expression exists within both groups. No clear clinical differentiation between Morquio syndrome type IVA and IVB exists.

Mutations to the GLB1 gene cause deficiency of beta-galactosidase. Diagnostic sequencing analysis of the GLB1 gene coding region is available for MPS IV B patients and their at-risk relatives on a clinical basis.

For questions about testing for MPS IV B, call EGL Genetics at 470-378-2200 or 855-831-7447. For further clinical information about lysosomal storage diseases, including management and treatment, call the Emory Lysosomal Storage Disease Center at (404) 778-8565 or (800) 200-1524. For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array.

References:
1). Paschke E, Milos I, Kreimer-Erlacher H, Hoefler G, Beck M, Hoeltzenbein M, Kleijer W, Levade T, Michelakakis H, Radeva B. Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B. Hum Genet. 2001 Aug;109(2):159-66.
2). Santamaria R, Chabas A, Coll MJ, Miranda CS, Vilageliu L, Grinberg D. Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies. Hum Mutat. 2006 Oct;27(10):1060.

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• Confirmation of a clinical diagnosis of MPS IV B Disease
• Prenatal testing for known familial mutation(s).
• Assessment of carrier status in high risk family members - known mutation analysis.

Full Sequencing: PCR amplification of 16 exons contained in the GLB1 gene coding region will performed on patient genomic DNA. Direct sequencing of amplification products is performed in both the forward and reverse directions using automated fluorescence dideoxy sequencing methods. Patient gene sequences are compared to a normal reference sequence. Sequence variations are then classified as mutations, benign variants unrelated to disease or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members.

This assay does not interrogate the promoter region, deep intronic regions or other regulatory elements. Large deletions are not detected by this analysis. Results of molecular analysis must interpreted in the context of the patient\'s clinical and/or biochemical phenotype.

• Mucopolysaccharide screen (urine GAG) (GA)
• Lysosomal enzyme screening panel (LS)
• Known mutation analysis (Custom Diagnostics) is available to test family members.
• A deletion/duplication assay is available separately for individuals where mutations are not identified by sequence analysis. Refer to the test requisition or contact the laboratory for more information.
• Prenatal testing is available for known familial mutations only. Please call the Laboratory Genetic Counselor for specific requirements for prenatal testing before collecting a fetal sample.

Requisition Forms

• Comprehensive Molecular Test Requisition Form
• Lysosomal Storage Disorders Test Requisition Form

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