Beta-Galactosidase, Blood Spot
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 gangliosides. The deficiency of this enzyme can be seen in the following conditions: GM1 gangliosidosis, Morquio syndrome B, and galactosialidosis. Enzymatic testing is not reliable for carrier detection 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, presenting with developmental delays, and a having a slower progression. 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.
Mucopolysaccharidosis type IVB (MPS IVB, Morquio B) is an autosomal recessive lysosomal storage disorder caused by reduced or absent beta-galactosidase activity. 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; GAGs). Accumulation of GAGs (also known as mucopolysaccharides) in lysosomes interferes with normal functioning of cells, tissues, and organs. MPS IVB is caused by a reduced or absent activity of the beta-galactosidase enzyme and gives rise to the physical manifestations of the disease. Clinical features and severity of symptoms of MPS IVB are widely variable ranging from severe disease to an attenuated form, which generally presents at a later onset with a milder clinical presentation. In general, symptoms may include coarse facies, short stature, hepatosplenomegaly, hoarse voice, stiff joints, cardiac disease, but no neurological involvement.
Galactosialidosis is an autosomal recessive lysosomal storage disease 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 regard 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. The late infantile form typically presents with short stature dysostosis multiplex, coarse facial features, corneal clouding, hepatosplenomegaly, and heart valve problems. The juvenile/adult form is typically characterized by progressive neurologic degeneration, ataxia, and angiokeratomas. The incidence of the juvenile/adult form is greater 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 or fibroblasts; however, additional testing and consideration of the patient’s clinical findings are necessary to differentiate between these conditions. Individuals with GM1 gangliosidosis can have characteristic abnormalities on urine oligosaccharides and have elevated keratan sulfate in urine (however to a lesser degree than seen in patients with Morquio B). Individuals with Morquio B can have increased keratan sulfate in urine. Molecular sequence analysis of the GLB1 gene allows for detection of the disease-causing mutations in affected patients with GM1 gangliosidosis or Morquio B. Individuals with galactosialidosis demonstrate abnormalities on urine oligosaccharides as well as decreased neuraminidase activity in fibroblasts. Sequencing of the CTSA gene allows for detection of disease-causing mutations in patients with galactosialidosis.
Diagnosis of beta-galactosidase deficiency (GM1 gangliosidosis, Morquio B disease and galactosialidosis) in blood spot specimens
Properly submitted specimens with results less than 5.0 nmol/h/mL are consistent with beta-galactosidase deficiency (GM1 gangliosidosis, Morquio B disease, or galactosialidosis). Further differentiation between GM1, Morquio B, and galactosialidosis is dependent on the patient's clinical findings and results of additional biochemical testing.
Normal results (> or =5.0 nmol/hour/mL) are not consistent with beta-galactosidase deficiency.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test cannot reliably determine carrier status.
This test does not differentiate between GM1 gangliosidosis, Morquio B, and galactosialidosis.
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 =5.0 nmol/hour/mL
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Suzuki Y, Nanba E, Matsuda J, et al: Beta-Galactosidase Deficiency (Beta-Galactosidosis): GM1 Gangliosidosis and Morquio B Disease. In The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL BeaudetL, B Vogelstein, KW Kinzler et al. New York, McGraw-Hill; 2014. Accessed January 27, 2017. Available at www.ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62645114
2. Chamoles NA, Blanco M, Gaggioli D, Casentini C: Hurler-like phenotype: enzymatic diagnosis in dried blood spots on filter paper. Clin Chem 2001;47:2098-2102
3. Regier DS, Tifft CJ: GLB1-Related Disorders. In GeneReviews. Edited by RA Pagon, MP Adam, HH Ardinger et al. Accessed January 30, 2017. Available at www.ncbi.nlm.nih.gov/books/NBK164500/
4. Fernandes, Saudubray, van den Berghe, Walter. Inborn Metabolic Diseases: Diagnosis and Treatment. Fourth edition. Edited by J Fernandes, J-M Saudubray, G van den Berghe, JH Walter. Springer Science. 2006