Hexosaminidase A (MUGS), Serum
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Tay-Sachs disease (TSD), variant B1 is a rare variant of the gangliosidoses, a group of lysosomal storage disorders characterized by the accumulation of GM2 gangliosides in neurons due to deficient hexosaminidase A (Hex A) enzyme activity. Hex A is a heterodimer, consisting of 1 alpha and 1 beta subunit. The other major hexosaminidase (Hex B) consists of 2 beta subunits and is not capable of hydrolyzing GM2 gangliosides.
TSD variant B1 is a rare variant that has an increased frequency in individuals with Portuguese ancestry. The most common mutation causing the B1 variant is the R178H in the HEXA gene. This mutation results in the synthesis and assembly of an alpha subunit that renders the enzyme unable to hydrolyze its physiological substrate (ie, GM2 ganglioside), yet capable of hydrolyzing some synthetic substrates used to assess Hex A activity, such as 4-methylumbelliferyl N-acetylglucosamine (MUG). Using the MUG substrate, the Hex A activity of individuals with B1 variant mutation(s) appears to be within or near the normal range. Conversely, the B1 variant enzyme is unable to hydrolyze the sulfated MUG derivative MUGS (4-methylumbelliferyl N-acetylglucosamine 6-sulphate). Therefore, distinguishing the B1 variant from normal requires the use of MUGS substrate.
In general, the clinical presentation of the B1 variant typically presents with a later age of onset. Individuals who are compound heterozygotes for the B1 variant with a null allele typically present with a juvenile presentation. An individual who is homozygous for the B1 variant typically presents with a later onset and a milder, chronic clinical presentation.
See Hexosaminidase: Subunit Location of the Synthesis and Substrate of Dimeric Isoenzymes of Hexosaminidase in Multimedia.
Refer to Carrier Testing for Tay-Sachs Disease and Other GM2 Gangliosidosis Variants: Supplementing Traditional Biochemical Testing with Molecular Methods, MML Communique 2004 Jul;29(7) for more information regarding diagnostic strategy (article is available online at MayoMedicalLaboratories.com/media/articles/communique/mc2831-0704.pdf).
A second-order test for diagnosing the B1 variant of Tay-Sachs disease
This test should be ordered when the patient exhibits Tay-Sachs symptoms, but has tested as normal, ambiguous, or carrier by either NAGS / Hexosaminidase A and Total Hexosaminidase, Serum or NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes.
Interpretation is provided with report.
The B1 mutation results in depressed Hex A isoenzyme (as assayed by 4-MUGS), whereas it reacts normally to 4-MUG.
Follow-up testing using leukocytes is recommended for ambiguous results.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
If carrier screening for Tay-Sachs or Sandhoff disease is desired in a pregnant female and testing was not performed prior to pregnancy, please refer to NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex or NAGW / Hexosaminidase A and Total Hexosaminidase, Leukocytes for testing on the patient or partner.
Note: Serum assay results are not valid on pregnant females and will not be run. The recommended test for Tay-Sachs carrier screening (regardless of gender or pregnancy status) is NAGR / Hexosaminidase A and Total, Leukocytes/Molecular Reflex.
Because of the nature of Tay-Sachs screening, it is imperative that abnormal results reach the physician promptly so that the couple can be provided with genetic counseling and that additional specimens can be collected quickly, if necessary. Therefore, Mayo Medical Laboratories requires the name and phone number of the ordering physician to accompany the specimen.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
1.23-2.59 U/L (normal)
1.16-1.22 U/L (indeterminate)
0.58-1.15 U/L (carrier)
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Tutor JC: Biochemical characterization of the GM2 gangliosidosis B1 variant. Braz J Med Biol Res 2004 Jun;37(6):777-783
2. Bayleran J, Hectman P, Saray W: Synthesis of 4-methylumbelliferyl-beta-D-N-acetylglucosamine-6-sulfate and its use in classification of GM2 gangliosidosis genotypes. Clin Chim Acta 1984;143:73-89
3. Inui K, Wenger DA: Usefulness of 4-methylumbeliferyl-6-sulfo-2-acetamido-2-deoxy-beta-D-glucopyranoside for the diagnosis of GM2 gangliosidoses in leukocytes. Clin Genet 1984;26:318-321
4. Ben-Yoseph Y, Reid JE, Shapiro B, Nadler HL: Diagnosis and carrier detection of Tay-Sachs disease: direct determination of Hexosaminidase A using 4-methylumbelliferyl derivative of beta-N-acetyl-glucosamine-6-sulfate and beta-N-acetylgalactosamine-6-sulfate. Am J Hum Genet 1985;37:733-740
5. Fuchs W, Navon R, Kaback MM, Kresse H: Tay-Sachs disease: one-step assay of beta-N-acetylhexosaminidase in serum with a sulphated chromogenic substrate. Clin Chim Acta 1983;133:253-261