GM2 activator deficiency
GM2 activator deficiency is a rare, progressive inherited disorder that causes brain injury due to the accumulation of fatty substances in the central nervous system.
Overview
GM2 activator deficiency, also known as GM2 gangliosidosis, AB variant, is a rare inherited disorder that causes progressive brain injury. Most individuals have the acute infantile form, with symptoms appearing between 4 and 12 months of age.
Symptoms
Infants with the acute form typically experience a slowing of development and muscle weakness. They may lose previously acquired skills such as sitting or crawling. Other symptoms include:
- Exaggerated startle reaction to loud noises
- Seizures
- Vision loss
- Intellectual disabilities
- Cherry-red spot (an eye abnormality identified during examination)
Affected infants eventually become unable to respond to their environment and typically do not survive past early childhood. Milder, late-onset forms of the disease also exist, though they are less clearly defined due to the extreme rarity of the condition.
Causes
The disorder is caused by variants in the GM2A gene, which provides instructions for the ganglioside GM2 activator protein. This protein is essential for the function of the enzyme beta-hexosaminidase A within lysosomes—cellular compartments that digest and recycle molecules.
The activator protein binds to a fatty substance called GM2 ganglioside and presents it to beta-hexosaminidase A for breakdown. When the activator is deficient, GM2 ganglioside accumulates in the body, particularly in the central nervous system, leading to the neurological damage characteristic of this lysosomal storage disorder.
Inheritance
GM2 activator deficiency is inherited in an autosomal recessive pattern. This means both copies of the GM2A gene in each cell must have a variant to cause the disorder. Parents of an affected individual each carry one copy of the altered gene but typically do not exhibit symptoms.