Science / LGMD2I/R9
Julie, living with Limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9)

What is LGMD2I/R9?

Limb-girdle muscular dystrophy type 2I/R9 is a muscular condition with a significant unmet need.1,2

LGMD2I/R9 Impact

7,000+

7,000+  estimated individuals living with LGMD2I/R9 in the U.S. and Europe3

10+

As many as 10+ years to receive diagnosis due to variability of symptoms1

About LGMD2I/R9

Limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9) is a rare, recessive genetic condition caused by variants in the fukutin-related protein (FKRP) gene.1,4 This gene encodes FKRP, an enzyme involved in a chemical process called glycosylation, during which sugar molecules are attached to proteins. This chain of sugars, known as a glycan chain, allows a critical stabilizer of the muscle cell membrane, alpha-dystroglycan, to function correctly.4

In people with LGMD2I/R9, FKRP does not function at full capacity, leading to instability and injury of muscle cells. Physical symptoms of LGMD2I/R9 typically include loss of muscle mass and muscle wasting, leading to muscle weakness in the legs, arms, and trunk.1,4,5 At later stages, respiratory and cardiac muscles may also grow weak, which can cause respiratory and cardiac complications and eventually, loss of functional independence.1,5 Genetic testing is the only way to confirm a diagnosis of LGMD2I/R9.1

Healthy Muscle Tissue

Laminin A protein in the extracellular matrix, the supportive network that surrounds muscle cells. Laminin acts as an anchor point attaching to the glycan chain to help hold the muscle cell in place.
Glycan Chain A chain of sugars that connects alpha-dystroglycan to laminin. In LGMD2I/R9, this chain is shortened, weakening the connection that stabilizes the muscle cell.
aDG (Alpha-Dystroglycan) A protein that sits in the muscle cell membrane and acts as a critical stabilizer, linking the inside of the muscle cell to the supportive matrix around it.
CTP A molecule that provides the energy ISPD needs to make those building blocks.
ISPD An enzyme that makes the building blocks FKRP uses to extend the glycan chain.
FKRP / Mutant FKRP An enzyme that helps build the glycan chain by attaching sugar molecules. In LGMD2I/R9, mutant FKRP stills works, but not at full capacity, so the chain is left incomplete.
Extracellular Matrix The network of proteins that surrounds and supports muscle cells.
Muscle Cell Membrane The protective outer layer of each muscle cell.
R (Ribitol) The sugar building block that FKRP adds to the glycan chain.
Laminin A protein in the extracellular matrix, the supportive network that surrounds muscle cells. Laminin acts as an anchor point attaching to the glycan chain to help hold the muscle cell in place.
Glycan Chain A chain of sugars that connects alpha-dystroglycan to laminin. In LGMD2I/R9, this chain is shortened, weakening the connection that stabilizes the muscle cell.
aDG (Alpha-Dystroglycan) A protein that sits in the muscle cell membrane and acts as a critical stabilizer, linking the inside of the muscle cell to the supportive matrix around it.
R (Ribitol) The sugar building block that FKRP adds to the glycan chain.
CTP A molecule that provides the energy ISPD needs to make those building blocks.
ISPD An enzyme that makes the building blocks FKRP uses to extend the glycan chain.
FKRP / Mutant FKRP An enzyme that helps build the glycan chain by attaching sugar molecules. In LGMD2I/R9, mutant FKRP stills works, but not at full capacity, so the chain is left incomplete.
Extracellular Matrix The network of proteins that surrounds and supports muscle cells.
Muscle Cell Membrane The protective outer layer of each muscle cell.
Laminin A protein in the extracellular matrix, the supportive network that surrounds muscle cells. Laminin acts as an anchor point attaching to the glycan chain to help hold the muscle cell in place.
Glycan Chain A chain of sugars that connects alpha-dystroglycan to laminin. In LGMD2I/R9, this chain is shortened, weakening the connection that stabilizes the muscle cell.
aDG (Alpha-Dystroglycan) A protein that sits in the muscle cell membrane and acts as a critical stabilizer, linking the inside of the muscle cell to the supportive matrix around it.
R (Ribitol) The sugar building block that FKRP adds to the glycan chain.
CTP A molecule that provides the energy ISPD needs to make those building blocks.
ISPD An enzyme that makes the building blocks FKRP uses to extend the glycan chain.
FKRP / Mutant FKRP An enzyme that helps build the glycan chain by attaching sugar molecules. In LGMD2I/R9, mutant FKRP stills works, but not at full capacity, so the chain is left incomplete.
Extracellular Matrix The network of proteins that surrounds and supports muscle cells.
Muscle Cell Membrane The protective outer layer of each muscle cell.

LGMD2I/R9 Muscle Tissue

Laminin A protein in the extracellular matrix, the supportive network that surrounds muscle cells. Laminin acts as an anchor point attaching to the glycan chain to help hold the muscle cell in place.
Glycan Chain A chain of sugars that connects alpha-dystroglycan to laminin. In LGMD2I/R9, this chain is shortened, weakening the connection that stabilizes the muscle cell.
aDG (Alpha-Dystroglycan) A protein that sits in the muscle cell membrane and acts as a critical stabilizer, linking the inside of the muscle cell to the supportive matrix around it.
R (Ribitol) The sugar building block that FKRP adds to the glycan chain.
CTP A molecule that provides the energy ISPD needs to make those building blocks.
ISPD An enzyme that makes the building blocks FKRP uses to extend the glycan chain.
FKRP / Mutant FKRP An enzyme that helps build the glycan chain by attaching sugar molecules. In LGMD2I/R9, mutant FKRP stills works, but not at full capacity, so the chain is left incomplete.
Extracellular Matrix The network of proteins that surrounds and supports muscle cells.
Muscle Cell Membrane The protective outer layer of each muscle cell.
Laminin A protein in the extracellular matrix, the supportive network that surrounds muscle cells. Laminin acts as an anchor point attaching to the glycan chain to help hold the muscle cell in place.
Glycan Chain A chain of sugars that connects alpha-dystroglycan to laminin. In LGMD2I/R9, this chain is shortened, weakening the connection that stabilizes the muscle cell.
aDG (Alpha-Dystroglycan) A protein that sits in the muscle cell membrane and acts as a critical stabilizer, linking the inside of the muscle cell to the supportive matrix around it.
R (Ribitol) The sugar building block that FKRP adds to the glycan chain.
CTP A molecule that provides the energy ISPD needs to make those building blocks.
ISPD An enzyme that makes the building blocks FKRP uses to extend the glycan chain.
FKRP / Mutant FKRP An enzyme that helps build the glycan chain by attaching sugar molecules. In LGMD2I/R9, mutant FKRP stills works, but not at full capacity, so the chain is left incomplete.
Extracellular Matrix The network of proteins that surrounds and supports muscle cells.
Muscle Cell Membrane The protective outer layer of each muscle cell.
Laminin A protein in the extracellular matrix, the supportive network that surrounds muscle cells. Laminin acts as an anchor point attaching to the glycan chain to help hold the muscle cell in place.
Glycan Chain A chain of sugars that connects alpha-dystroglycan to laminin. In LGMD2I/R9, this chain is shortened, weakening the connection that stabilizes the muscle cell.
aDG (Alpha-Dystroglycan) A protein that sits in the muscle cell membrane and acts as a critical stabilizer, linking the inside of the muscle cell to the supportive matrix around it.
R (Ribitol) The sugar building block that FKRP adds to the glycan chain.
CTP A molecule that provides the energy ISPD needs to make those building blocks.
ISPD An enzyme that makes the building blocks FKRP uses to extend the glycan chain.
FKRP / Mutant FKRP An enzyme that helps build the glycan chain by attaching sugar molecules. In LGMD2I/R9, mutant FKRP stills works, but not at full capacity, so the chain is left incomplete.
Extracellular Matrix The network of proteins that surrounds and supports muscle cells.
Muscle Cell Membrane The protective outer layer of each muscle cell.

Healthy Muscle Tissue

LGMD2I/R9 Muscle Tissue

Terminologies
  1. Laminin: A protein in the extracellular matrix, the supportive network that surrounds muscle cells. Laminin acts as an anchor point attaching to the glycan chain to help hold the muscle cell in place.
  2. Glycan Chain: A chain of sugars that connects alpha-dystroglycan to laminin. In LGMD2I/R9, this chain is shortened, weakening the connection that stabilizes the muscle cell.
  3. aDG (Alpha-Dystroglycan): A protein that sits in the muscle cell membrane and acts as a critical stabilizer, linking the inside of the muscle cell to the supportive matrix around it.
  4. R (Ribitol): The sugar building block that FKRP adds to the glycan chain.
  5. CTP: A molecule that provides the energy ISPD needs to make those building blocks.
  6. ISPD: An enzyme that makes the building blocks FKRP uses to extend the glycan chain.
  7. FKRP / Mutant FKRP: An enzyme that helps build the glycan chain by attaching sugar molecules. In LGMD2I/R9, mutant FKRP stills works, but not at full capacity, so the chain is left incomplete.
  8. Extracellular Matrix: The network of proteins that surrounds and supports muscle cells.
  9. Muscle Cell Membrane: The protective outer layer of each muscle cell.
Sammy, living with Limb-girdle muscular dystrophy type 2I/R9 (LGMD2I/R9)

Community’s Unmet Need

The current standard of care for LGMD2I/R9 relies on supportive management, such as pain management techniques. These options don’t address the root cause of the condition and thus do not affect muscle wasting or functional decline.1,5 Targeted treatments are urgently needed. Moreover, there is often a significant delay between symptom onset and diagnosis of LGMD2I/R9, which may delay medical management.

Genetic Testing

Genetic testing is the only way to confirm a diagnosis of LGMD2I/R9.1 Accurate diagnosis may open new avenues for medical management, including participation in clinical research studies and providing vital information to ensure appropriate care. Speak to your healthcare provider for information on genetic testing for LGMD2I/R9. For additional information on genetic testing resources, visit the Lantern Project, Detect Muscular Dystrophy, LGMD2I/R9 Research Fund, or knowlgmd.com.

On Rare: LGMD2I/R9

On Rare with David Rintell and Mandy Rohrig

References