What are GLB1-related Disorders?
GM1-gangliosidosis and mucopolysaccharidosis type IVB (MPSIVB) are two distinct, autosomal recessive lysosomal storage disorders caused by mutations the GLB1 gene. GM1-gangliosidosis results from GLB1 mutations which specifically cause a build up of GM1 gangliosides. This buildup leads to destruction of certain cells in many organs, particularly those in the brain. There is a wide range of severity for this disorder, however most individuals tend to be severely affected. MPSIVB is caused by GLB1 mutations which affect the breakdown of keratan sulfate, a molecule which is found primarily in cartilage and bone. The resulting buildup of keratan sulfate in these tissues causes abnormal bone growth and development.
GM1-gangliosidosis can be broken down into three subtypes.
Type I (Infantile form): Type I is the most common form of GM1-gangliosidosis. Affected infants will have developmental delay followed by regression of milestones typically before six months of age. Another characteristic finding is a cherry-red spot on the macula of the eye. Skeletal dysplasia (short stature, curvature of the spine), hepatosplenomegaly (enlarged liver and spleen), and corneal clouding are also common findings. By one year of age, most infants will be blind and deaf. Some individuals may also have heart disease (cardiomyopathy), seizures and coarse facial features. Progression in Type I-gangliosidosis is rapid and most individuals with this type will pass away before the age of three.
Late-infantile form: The age of onset of this form is between the one and three years of age. Individuals with the late-infantile form exhibit motor and cognitive delay. Similar to the infantile form, there is progressive brain atrophy, and the potential for cardiac disease and skeletal abnormalities. Individuals with this form will also have corneal clouding. Life expectancy is approximately 5 to 10 years.
Juvenile form: The age of onset of this form is between three and ten years of age. Progression of symptoms is slower than the late infantile form. These individuals do not typically have cherry-red spots, enlarged organs or coarse facial features. Life expectancy may be into early adulthood.
Type III (Adult form): This is the mildest subtype and early symptoms include dystonia (abnormal movement featuring sustained muscle contractions) and speech difficulty in the second or third decade of life. Other symptoms may include heart disease, mild brain atrophy, and skeletal abnormalities. Life span is variable and may be shortened.
Mucopolysaccharidosis type IVB is an autosomal recessive condition that causes short stature and skeletal dysplasia. In its severe form, the age of onset is between one to three years. Early signs include kyphoscoliosis (a type of abnormal spine curvature), pectus carinatum (a chest deformity in which the ribs and sternum protrude outwards) and "knocked-knees." Some individuals have an attenuated form with onset in late childhood or adolescence. Other features of MPS IVB include corneal clouding and cardiac disease. Intellectual ability is typically normal.
How common are GLB1-related Disorders?
GM1-gangliosidosis is rare occurring in approximately 1 in 100,000 to 300,000 individuals. The disease is more common in Brazil (1 in 17,000) and in those with Roma ancestry (1 in 10,000). The adult form of the disorder has been observed more frequently in the Japanese population. MPS IVB affects 1 in 250,000 to 1 in 1,000,000 individuals.
How are GLB1-related Disorders treated?
There is no cure for GLB1 related disorders and management focuses on improving quality of life for affected individuals. Physical, occupational, and speech therapies are often recommended. Individuals with GM1 gangliosidosis often need specialized strollers or wheelchairs. It is important to ensure that there is adequate hydration and caloric intake, which may necessitate a feeding tube. Other treatment focuses on managing seizure activity and heart disease. For MPS IVB, there is no treatment and management focuses on physical and occupational therapies. Individuals should also be monitored by pulmonologists, audiologists, ophthalmologists, and cardiologists.
What is the prognosis for people with GLB1-related Disorders?
For GM1-gangliosidosis, the prognosis is poor. The infantile form of this disorder is the most common, however there is a range of severity and some may be mildly affected. For MPSIVB, the prognosis is variable depending on the severity of symptoms. Some may live into adulthood, however life expectancy is shortened.