GM1 Gangliosidosis

GM1 gangliosidosis is a rare genetic disease that progressively damages the central nervous system (CNS) of children

Baby in parent’s arms

Disease Background

GM1 gangliosidosis is an inherited lysosomal storage disease that leads to progressive damage to both the CNS and the peripheral tissues
- GM1 gangliosidosis is an autosomal recessive disorder, which means that it is passed from parents to children. The parents usually do not have GM1 gangliosidosis themselves, but they each carry one copy of the mutated gene and can pass it to their children
- Specific characteristics of GM1 gangliosidosis may include rapidly progressing neurological decline, resulting in reduced muscle tone, progressive CNS dysfunction, deafness, blindness, rigidity, and skeletal dysplasia

Mechanism Of Disease

GM1 gangliosidosis is caused by loss-of-function (LOF) mutations in the galactosidase beta 1 (GLB1) gene.

The GLB1 gene is responsible for producing an important protein, beta-galactosidase (β-gal), within the cells of the nervous system (neurons) that transmit information
β-gal is an enzyme that the body needs to process (metabolize) a key lipid within the nerve cells, known as GM1 ganglioside
Without enough of the β-gal enzyme, GM1 ganglioside builds up to toxic levels within a part of the cell, called the lysosome, that digests large molecules into smaller parts for reuse elsewhere in the cell
It’s this accumulation of lipids within the lysosome that destroys nerve function

Image of mutated gene

Incidence

Worldwide, GM1 gangliosidosis affects up to approximately 1 per 100,000–200,000 live births

Lysosomal accumulation of GM1 gangliosides in the CNS

Healthy neuron functional β-gal

Healthy neuron functional β-gal

In people with healthy GLB1 genes, there is enough β-gal enzyme available to metabolize the GM1 ganglioside lipids and keep them at normal levels, which allows the neurons to function properly.

GM1 gangliosidosis neuron dysfunctional β-gal

GM1 gangliosidosis neuron dysfunctional β-gal

In people with GM1 gangliosidosis, a mutation in the GLB1 gene causes a decrease in β-gal activity, leading to a toxic buildup of the GM1 ganglioside lipids. This buildup results in cell death, degeneration of the neurons, and onset of symptoms.

Types

GM1 gangliosidosis appears as a spectrum of disease, with severity generally determined by how much of the β-gal enzyme is available within the cell
- Earlier onset and greater severity of disease are generally associated with lower levels of β-gal activity

GM1 gangliosidosis has four clinical types, classified by the age that symptoms first appeared
- Type 1 (Early Onset Infantile): The most common (>60%) and most severe form of the disease. Age of onset is before 6 months with life expectancy into early childhood
- Type 2a (Late Onset Infantile): Age of onset is ≥6 months to 2 years with life expectancy into mid-to-late childhood
- Type 2b (Juvenile): Age of onset is ≥2 to 5 years with variable life expectancy into late childhood to early adulthood
- Type 3 (Adult): Age of onset is ≥5 years with highly variable life expectancy, possibly into third or fourth decade

Father holding a baby

Mother comforting a baby

Management

There are no approved disease-modifying treatments available for GM1 gangliosidosis
- Currently managed with symptomatic and supportive care only
- Early diagnosis is critical due to the rapid neurodegeneration caused by GM1 gangliosidosis
Passage Bio is investigating a novel gene therapy, PBGM01, in the treatment of GM1 gangliosidosis

Learn more about PBGM01.

Children with Early Onset Infantile (Type 1) and Late Onset Infantile (Type 2a) GM1 gangliosidosis may be eligible for enrollment in clinical trials of investigative therapies, so early diagnosis is critical. Caregivers should reach out to their healthcare professional to learn more.