Gm1-gangliosidosis
GM1 gangliosidosis is a rare inherited lysosomal storage disorder characterized by the accumulation of the sphingolipid GM1 and other carbohydrate molecules in cells, particularly those in the brain and internal organs. This condition arises from mutations in the GLB1 gene that encodes lysosomal acid β-galactosidase, leading to various degrees of enzyme deficiency. The disease has several forms, including infantile, juvenile, and adult types, with symptoms ranging from facial abnormalities and muscle weakness in infants to progressive ataxia and cardiomyopathy in adults.
Diagnosis typically involves measuring β-galactosidase activity in blood or skin samples, and affected individuals often excrete elevated levels of galactose-containing oligosaccharides in their urine. While there is currently no cure, research is ongoing into potential treatments such as enzyme replacement therapy, gene editing, and stem cell therapy. The prognosis varies significantly by age of onset, with infantile cases typically resulting in a very low survival rate past the first year of life. Genetic counseling is recommended for families affected by GM1 gangliosidosis, as siblings have a 25% risk of inheriting the condition.
Gm1-gangliosidosis
ALSO KNOWN AS: GM1 gangliosidosis; generalized gangliosidosis; β-galactosidase deficiency
DEFINITION GM1 gangliosidosis or GM1 gangliosidosis is an inherited lysosomal storage disorder in which the sphingolipid GM1 and other carbohydrate-bearing molecules accumulate in cells of the brain and internal organs. GM1 gangliosidosis is caused by mutation of the gene encoding for lysosomal acid β-galactosidase.
Risk Factors
GM1 gangliosidosis is a rare inherited disease in which all affected individuals have received mutated forms of the β-galactosidase gene from both parents. Frontiers in Genetics in 2021 that the incidence of infantile GM1 gangliosidosis is 1 in 100,000–200,000 newborns; the adult form of GM1 gangliosidosis has been reported predominantly in patients of Japanese ancestry. There are no environmental risk factors.
Etiology and Genetics
The gene encoding for lysosomal acid β-galactosidase, GLB1, is found on chromosome 3 (3p22.3). GM1 gangliosidosis is caused by a rare recessive allele, and individuals who inherit two copies of mutated, dysfunctional GLB1 accumulate β-galactosidase substrates in lysosomes. The cell membrane sphingolipid GM1 accumulates in nervous tissue, and keratan sulfate and other carbohydrates accumulate in cells of several internal organs. Accumulation of these substrates leads to the devastating symptoms exhibited by patients with GM1 gangliosidosis. The details of how accumulation of β-galactosidase substrates leads to disease are not clear, but neuronal apoptosis, endoplasmic reticulum stress response, myelin deficiency, and inflammatory responses have been proposed to play a role in the pathology of GM1 gangliosidosis.
Many mutations in GLB1 have been found to cause GM1 gangliosidosis, and the severity of disease corresponds to the degree to which these mutations affect β-galactosidase activity. Mutations that result in infantile GM1 gangliosidosis are most severe, with β-galactosidase activity levels at only 0.07–0.3 percent of the levels found in normal tissues. Juvenile GM1 gangliosidosis is associated with mutations that reduce β-galactosidase levels to 0.3–4.8 percent, and patients with adult GM1 gangliosidosis have up to 9 percent residual activity.
A subset of mutations in GLB1 causes Morquio syndrome IV (mucopolysaccharidosis IV; MPS IV) Type B, a skeletal disease with no neurologic degeneration.
Symptoms
Symptoms of infantile GM1 gangliosidosis are generally present from birth. They include coarsened facial features, facial edema, muscle weakness, and failure to thrive. Cherry-red macular spots are present in the eyes of about 50 percent of patients. Other symptoms emerge over the first few months of life, including seizures, ataxia, blindness, deafness, difficulty swallowing, enlargement of the spleen and liver, and a variety of skeletal irregularities.
Patients with the juvenile form also accumulate GM1 in the brain, although onset is later than in patients with the infantile form. Ataxia is a common early symptom and is followed by rapid mental and motor deterioration.
The adult form of GM1 gangliosidosis is highly variable, but progressive ataxia, dystonia, cardiomyopathy, skeletal irregularities, and abnormalities in gait and speech are common.
Screening and Diagnosis
Patients with GM1 gangliosidosis excrete large amounts of galactose-containing oligosaccharides that can be detected in the urine. Diagnosis is confirmed with a test measuring β-galactosidase activity in skin or blood samples. Activity is nearly absent in patients with the infantile form and reduced in patients with juvenile or adult GM1 gangliosidosis. A variety of other tests may also be used, including skeletal radiography, neuroimaging with CT scan or MRI, ultrasound, echocardiography, electrocardiography, and electroencephalography.
Treatment and Therapy
There is no cure for GM1 gangliosidosis. Most treatments are aimed at relieving symptoms. Current research into new treatments centers on gene replacement therapy. As of 2024, the most promising new treatments were enzyme replacement therapy (ERT), substrate reduction therapy (SRT), stem cell therapy, and gene editing. However, their effectiveness was limited because of the restrictiveness of the blood-brain barrier (BBB). Researchers believed that gene editing could be curative because it would fix the causative gene.
Prevention and Outcomes
There is no means to prevent GM1 gangliosidosis. One-fourth of the siblings of GM1 patients will also have the disease, and should be made available for parents of an affected child. Genetic testing of cells obtained by or can detect the presence of the disease in the fetus. Outcome depends on the age of onset and the degree of β-galactosidase activity. Only about 5 percent of affected newborns with infantile GM1 gangliosidosis survive the first year of life. Patients with juvenile GM1 gangliosidosis typically develop symptoms around one year of age and usually die between ages three and seven. Onset of adult GM1 gangliosidosis can occur between the ages of three and thirty. Death usually occurs after the age of twenty.
Bibliography
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