Clinical Information

Beta-galactosidase is a lysosomal enzyme responsible for catalyzing the hydrolysis of gangliosides. Isolated deficiency of this enzyme can be expressed clinically as 2 different diseases, GM1 gangliosidosis (GM1) and Morquio syndrome B (MPS IVB: mucopolysaccharidosis IVB), or in some patients as a disease that combines the skeletal features of MPS IVB and neurologic features of GM1. Galactosialidosis is also associated with a deficiency of beta-galactosidase but in conjunction with neuraminidase secondary to a defect in protective protein cathepsin A (CTSA). Enzymatic testing is not reliable for carrier detection of these conditions.

GM1 gangliosidosis is autosomal recessive and absent or reduced beta-galactosidase enzyme activity leads to the accumulation of GM1 gangliosides, oligosaccharides, and keratan sulfate. The disorder can be classified into 3 subtypes that vary with respect 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 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.

In MPS IVB, reduced or absent beta-galactosidase activity leads to the accumulation of glycosaminoglycans (GAG), specifically keratan sulfate, in cells, tissues, and organs interfering with their normal function. 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, and cardiac disease but no neurological involvement.

Galactosialidosis (GS) is an autosomal recessive lysosomal storage disease caused by variants in CTSA resulting in a combined deficiency of the enzymes beta-galactosidase and neuraminidase. The disorder can be classified into 3 subtypes that vary with respect to age of onset and clinical presentation. Typical clinical presentation includes coarse facial features, cherry-red spots, and skeletal dysplasia. The early infantile form is associated with fetal hydrops, visceromegaly, skeletal dysplasia, and early death. The late infantile form typically presents with short stature, dysostosis multiplex, coarse facial features, hepatosplenomegaly, and/or heart valve problems. The majority of individuals with the juvenile/adult form of GS are of Japanese ancestry and develop symptoms after 4 years of age, which include neurologic degeneration, ataxia, and angiokeratomas.

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, MPS IVB, or GS 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. Follow-up testing may include LSDS / Lysosomal Storage Disorders Screen, Random, Urine, which analyzes mucopolysaccharides, oligosaccharides, ceramide trihexosides, and sulfatides to help differentiate between the 3 conditions and guide physicians in choosing the best confirmatory molecular testing option, which may include LSDGP / Lysosomal Storage Disease Gene Panel, Varies.