Fibroblasts from ML III patients have numerous cytoplasmic inclusion bodies. The accumulation of material in the lysosomes results from the inability of the lysosomal enzymes to enter the lysosome for normal degradation. A biochemical marker signal is required for proper trafficking of the lysosomal enzymes, from the site of production in the endoplasmic reticulum to the lysosome itself. This marker was identified as a mannose-6-phosphate residue on the lysosomal enzyme that interacts with a specific receptor on the lysosomal membrane, which then triggers entry into the lysosome. The biochemical defect in ML III disease is due to the deficiency of the enzyme UDP-N-acetylglucosamine- N-acetylglucosamine- l-phosphotransferase (abbreviated GlcNAc phosphotransferase) involved in the addition of the mannose-6-phosphate residue. The genetic defect causing this disorder results in mislocalization of the lysosomal enzymes such that they are, in part, secreted from the cell rather than transported into the lysosomes. Many lysosomal enzymes have decreased intracellular activities but increased activities in the serum and urine. The electrophoretic patterns of a number of lysosomal enzymes also are altered in ML III fibroblasts. The disorder mucolipidosis II (ML II, I-cell disease) is clinically and biochemically very similar to ML III, although with more severe characteristics leading to death by 6 years of age. Lysosomal enzyme activities also are very low in fibroblasts and have abnormal electrophoretic patterns different from ML III.
Mutations to the GNPTAB gene cause deficiency of this enzyme. Diagnostic sequencing analysis of the GNPTAB gene coding region is available for Mucolipidosis III A patients and their at-risk relatives on a clinical basis. For patients with mutations not identified by full gene sequencing, a separate deletion/duplication assay is available using a targeted CGH array (LK).
For questions about testing for ML IIIA, call the Emory Genetics Laboratory at (404) 778-8499 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.
1). Leroy JG, Spranger JW. I-cell disease. N Engl J Med. 1970 Sep 10;283(11):598-9.
2). Kudo M, Brem MS, Canfield WM: Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-Hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha/beta-subunits precursor gene. Am. J. Hum. Genet. 78: 451-463, 2006.
3). Olkkonen VM, Ikonen E. Genetic defects of intracellular-membrane transport. New Eng. J. Med. 343: 1095-1104, 2000.
4). Tiede S, Storch S, Lubke T, Henrissat B, Bargal R, Raas-Rothschild A, Braulke T. Mucolipidosis II is caused by mutations in GNPTA encoding the alpha/beta GlcNAc-1-phosphotransferase. Nature Med. 11: 1109-1112, 2005.
- Confirmation of clinical diagnosis of ML IIIA disease
- Prenatal testing for known familial mutation(s).
- Assessment of carrier status in high risk family members known mutation analysis.
Analytical Sensitivity: ~99%.
Submit only 1 of the following specimen types
Preferred specimen type: Whole Blood
Type: Whole Blood
Specimen Requirements:In EDTA (purple top) or ACD (yellow top) tube:
Infants (<2 years): 2-3 ml
Children (>2 years): 3-5 ml
Older Children & Adults: 5-10 ml
Specimen Collection and Shipping: Refrigerate until time of shipment. Ship sample within 5 days of collection at room temperature with overnight delivery.
Specimen Requirements:OrageneTM Saliva Collection kit (available through EGL) used according to manufacturer instructions.
Specimen Collection and Shipping: Store sample at room temperature. Ship sample within 5 days of collection at room temperature with overnight delivery.
- Known mutation analysis (Custom Diagnostics) is available to test family members.
- A deletion/duplication assay for the GNPTAB gene is available separately for individuals where mutations are not identified by sequence analysis.
- 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.