Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Beta-galactosidase is a lysosomal enzyme responsible for catalyzing the hydrolysis of beta-galactosides. A deficiency of this enzyme is implicated in the following conditions: GM1 gangliosidosis, Morquio syndrome B, and galactosialidosis. Enzymatic testing is not reliable for carrier testing of these conditions.
GM1 gangliosidosis is an autosomal recessive lysosomal storage disorder caused by reduced or absent beta-galactosidase activity. Absent or reduced activity leads to the accumulation of GM1 gangliosides, oligosaccharides, and keratan sulfate. The disorder can be classified into 3 subtypes that vary with regard to age of onset and clinical presentation. Type 1, or infantile onset, typically presents between birth and 6 months with a very rapid progression of hypotonia, dysostosis multiplex, hepatosplenomegaly, central nervous system degeneration, and death usually by 1 to 2 years. Type 2 is generally classified as late infantile or juvenile with onset between 7 months and 3 years and presenting with developmental delays or regression and a slower clinical course. Type 3 is an adult or chronic variant with onset between 3 and 30 years and is typically characterized by slowly progressive dementia with Parkinsonian features and dystonia. The incidence has been estimated to be 1 in 100,000 to 200,000 live births.
Morquio B (MPS IVB) is an autosomal recessive mucopolysaccharidosis caused by reduced or absent beta-galactosidase activity resulting in the accumulation of keratan sulfate in the lysosomes. The mucopolysaccharidoses are a group of disorders caused by the deficiency of any of the enzymes involved in the stepwise degradation of dermatan sulfate, heparan sulfate, keratan sulfate, or chondroitin sulfate (glycosaminoglycans: GAG). Accumulation of GAG in lysosomes interferes with normal functioning of cells, tissues, and organs. 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.
Galactosialidosis is an autosomal recessive lysosomal storage disease (LSD) associated with a combined deficiency of beta-galactosidase and neuraminidase secondary to a defect in the cathepsin A protein. Clinical features are those typically associated with LSDs including coarse facial features, cherry-red spots, and skeletal dysplasia. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation. The early infantile form is associated with fetal hydrops, visceromegaly, skeletal and ophthalmologic disorders, and early death. The late infantile form typically presents with short stature, dysostosis multiplex, coarse facial features, hepatosplenomegaly, and heart valve problems. The juvenile/adult form is characterized by progressive neurologic degeneration, ataxia, cognitive disability, and angiokeratomas. Most of the juvenile/adult form cases have been found in individuals with Japanese ancestry.
Patients with mucolipidosis II/III (I-cell disease) may also demonstrate deficiency of beta-galactosidase in leukocytes, in addition to deficiency of other hydrolases. I-cell disease is an autosomal recessive lysosomal storage disorder resulting in impaired transport and phosphorylation of newly synthesized lysosomal proteins to the lysosome due to deficiency of N-acetylglucosamine 1-phosphotransferase (GlcNAc). Characteristic clinical features include short stature, skeletal and cardiac abnormalities, and developmental delay. Measurement of beta-galactosidase activity is not the preferred diagnostic test for I-cell disease but may be included in the testing strategy.
A diagnostic workup in an individual with GM1 gangliosidosis, Morquio B, or galactosialidosis typically demonstrates decreased beta-galactosidase enzyme activity in leukocytes and/or fibroblasts, however, individuals with galactosialidosis would also have decreased neuraminidase activity in leukocytes and/or fibroblasts. Enzymatic testing is not reliable to detect carriers. Molecular sequence analysis of GLB1 allows for detection of the disease-causing mutations in affected patients with GM1 gangliosidosis or Morquio B, and sequencing of CTSA allows for detection of disease-causing mutations in patients with galactosialidosis.
Diagnosis of GM1 gangliosidosis, Morquio syndrome B, and galactosialidosis
Beta-galactosidase is deficient in GM1 gangliosidosis and Morquio syndrome B. Clinical findings must be used to differentiate between those 2 diseases. The deficiency of beta-galactosidase combined with neuraminidase deficiency (see NEURF / Neuraminidase, Fibroblasts) is characteristic of galactosialidosis.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test is not suitable for carrier detection.
Because beta-galactosidase is decreased in 3 clinically distinct disorders, a careful review of the clinical findings is necessary to differentiate between GM1 gangliosidosis and Morquio syndrome B. Patients with galactosialidosis will also exhibit decreased neuraminidase values in addition to decreased beta-galactosidase.
Interfering factors include lack of viable cells, bacterial contamination, failure to transport tissue in an appropriate media, excessive transport time, and exposure of the specimen to temperature extremes (freezing or >30 degrees C).
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.
> or =7.11 nmol/min/mg protein
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Suzuki Y, Nanba E, Matsuda J, et al: BetaSuzuki Y, Nanba E, Matsuda J, Higaki K, Oshima A Suzuki, Yoshiyuki, et al.-galactosidase deficiency (beta-galactosidosis): GM1 gangliosidosis and Morquio B disease. In The Online Metabolic and Molecular Bases of Inherited Disease. 2014. Edited by D Valle, AL Beaudet, B Vogelstein, et al. New York, McGraw-Hill, Accessed January 27, 2017. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62645114
2. d'Azzo A, Andria G, Bonten E, Annunziata I: Galactosialidosis. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein B, et al: New York, McGraw-Hill, 2014. Accessed May 04, 2015. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62645512
3. Brunetti-Pierri N, Scaglia F: GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab 2008 Aug;94(4):391-396
4. Caciotti A, Garman SC, Rivera-Colon Y, et al: GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta 2011 Jul;1812(7):782-790