GM1 gangliosidosis: Description, Causes and Risk Factors:
GM1 gangliosidosis is an inherited disorder that progressively destroys nerve cells (neurons) in the brain and spinal cord. Some researchers classify this condition into three major types based on the age at which signs and symptoms first appear. Although the three types differ in severity, their features can overlap significantly. Because of this overlap, other researchers believe that GM1 gangliosidosis represents a continuous disease spectrum instead of three distinct types.
Mutations in the GLB1 gene cause GM1 gangliosidosis. The GLB1 gene provides instructions for making an enzyme called beta-galactosidase (?-galactosidase), which plays a critical role in the brain. This enzyme is located in lysosomes, which are compartments within cells that break down and recycle different types of molecules. Within lysosomes, ?-galactosidase helps break down certain molecules, including a substance called GM1 ganglioside. GM1 ganglioside is important for normal functioning of nerve cells in the brain.
Mutations in the GLB1 gene reduce or eliminate the activity of ?-galactosidase. Without enough functional ?-galactosidase, GM1 ganglioside cannot be broken down. As a result, this substance accumulates to toxic levels in many tissues and organs, particularly in the brain. Progressive damage caused by the buildup of this ganglioside leads to the destruction of nerve cells in the brain, causing many of the signs and symptoms of GM1 gangliosidosis.
Conditions such as GM1 gangliosidosis that cause molecules to build up inside the lysosomes are called lysosomal storage disorders. In general, the severity of GM1 gangliosidosis is related to the level of ?-galactosidase activity. Individuals with higher enzyme activity levels usually have milder signs and symptoms than those with lower activity levels because they have less accumulation of GM1 ganglioside within the body.
Coarse facial features.
- Generalized skeletal dysplasia.
- Macular cherry-red spots.
- Developmental delay.
- Slowly progressing dementia with Parkinsonian features.
- Intellectual impairment progresses with time.
- Speech and gait disturbance.
Diagnosis of this gangliosidosis can be confirmed by measurement of acid ? -galactosidase activity in peripheral blood leukocytes. Patients with the infantile form have almost no enzyme activity, whereas patients with the adult form may have residual activity of 5-10% of reference values. Overlap is often present between homozygote without GM1 gangliosidosis and heterozygote carriers; therefore, screening for heterozygote carriers using enzyme analysis is not reliable.
CT and MRI: Neuroimaging using CT scan or MRI generally reveals diffuse atrophy and white matter demyelination with or without basal ganglia changes. Bilateral T2-weighted hyperintensities in the putamen are a frequently reported MRI finding in adult-onset disease. Mild cerebral atrophy may also be observed in the adult form. MR spectroscopy has demonstrated increased striatal myoinositol.
Electroencephalography: This test may reveal generalized dysrhythmia and epileptogenic foci.
Ultrasound: An ultrasound of the abdomen may reveal organomegaly.
Electrocardiography: Signs of cardiomyopathy may be observed.
Echocardiography: Signs of cardiomyopathy or valvulopathy may be observed.
Molecular testing is useful to confirm the diagnosis and to identify the disease causing mutation within a family to allow for carrier testing and prenatal diagnosis.
At present only symptomatic treatments are available for GM1 gangliosidosis. Bone marrow transplantation was successful in an individual with infantile/juvenile GM1 gangliosidosis; however, no long-term benefit was reported. Pre-symptomatic cord-blood hematopoietic stem-cell transplantation has been advocated by some as a possible treatment because of success in other lysosomal storage disorders.
Substrate reduction therapy mediated by N-butyldeoxynojirimycin (ZavescaSM
) has been used with encouraging results for the treatment of patients with mild-to-moderate type 1 Gaucher disease, Niemann-Pick disease type C and chronic GM2 gangliosidosis type Sandhoff. Interesting results have also been reported in a mouse model of GM1 gangliosidosis.
Active research in the areas of enzyme replacement and gene therapy for GM1 gangliosidosis is ongoing but has not advanced to human trials.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.