GLB1-related disorders

What are GLB1-related Disorders?

GLB1-related disorders are inherited, lysosomal storage disorders. There are two specific forms of GLB1-related disorders, GM1-gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). Both disorders are caused by harmful genetic changes (mutations) in the GLB1 gene.

The body uses enzymes to break down fats (lipids) and sugars (carbohydrates). This process happens within the lysosome, the digestive system of the cell. When a particular enzyme is missing or not working correctly, the substance the enzyme is supposed to break down accumulates and can be harmful to the body.

Individuals with GLB1-related disorders lack an important enzyme called β-galactosidase, which is necessary for the proper function of lysosomes. This enzyme is responsible for breaking down a variety of proteins, including GM1 gangliosides and keratan sulfate.

GM1-Gangliosidosis

GM1-gangliosidosis is a neurodegenerative condition caused by the buildup of GM1 gangliosides. This buildup is toxic and leads to the destruction of cells in many organs, particularly those in the brain. The severity of the condition varies but most individuals tend to be severely affected. 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 loss of milestones, typically before six months of age. Another characteristic finding is a cherry-red spot on the macula (portion of eye at the center of the retina) of the eye. Other findings of this form include: shortened bones, curvature of the spine (skeletal dysplasia), enlarged liver and spleen (hepatosplenomegaly), and corneal clouding. Most infants will be blind and deaf by the time they turn one. Some infants may also have heart disease (cardiomyopathy), seizures, and enlarged facial features. GM1-gangliosidosis type I progresses quickly, and most infants with this type will pass away before the age of three.

Type II - Late-Infantile and Juvenile Forms

Late-infantile form: The age of onset of this form is between one and three years of age. Children with the late-infantile form typically have motor and cognitive delay. As in the infantile form, there is progressive brain deterioration and the potential for both cardiac disease and skeletal abnormalities. Corneal clouding may also be present. Life expectancy is approximately 5 to 10 years.

Juvenile form: The age of onset of this form is between 3 and 10 years of age. Progression of symptoms is slower than the late-infantile form. These individuals do not typically have cherry-red spots in the eye, 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 abnormal and involuntary muscle movement (dystonia) and speech difficulty in the second or third decade of life. Other symptoms may include heart disease, mild brain deterioration, and skeletal abnormalities. Life expectancy is variable and may be shortened.

Mucopolysaccharidosis Type IVB

Mucopolysaccharidosis type IVB (MPS IVB) is a skeletal condition that is caused by buildup of keratan sulfate, a molecule found primarily in cartilage and bone. The excess keratan sulfate causes abnormal bone growth and development. Individuals with MPS IVB typically experience shortened bone length, abnormal spine curvature (kyphoscoliosis), deformities of the chest and rib bones (pectus carinatum), and "knocked knees." In its severe form, the age of onset is between one and three years. Some individuals have an attenuated form, with onset in late childhood or adolescence. Other features of MPS IVB include corneal clouding, abnormal or missing teeth, and cardiac disease. Intellect is generally not affected.

How common are GLB1-related Disorders?

GLB2-related disorders of all types occur in approximately 1 in 100,000 to 300,000 individuals. The disease may be more common in Brazil and in those with Roma ancestry.

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 require 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 an individual with a GLB1-related Disorder?

For GM1-gangliosidosis, the prognosis is poor. The infantile form of this disorder is the most common, but there is a range of severity, and some may be mildly affected. For MPS IVB, the prognosis is variable, depending on the severity of symptoms. Some may live into adulthood, but life expectancy is shortened.