Collagen XII Related Disorders
Collagen XII related disorders (COL12-RD) are characterized by genetic mutations in the COL12a1 gene. This gene encodes the alpha chain type XII collagen family (COL12), and is a member of the FACIT (fibril-associated collagen with interrupted triple helices) family that interacts with other extracellular matrix proteins.
Clinical Features of COL12-RD*
Hypermobile distal joints
Proximal joint contractures
Scoliosis and/or Kyphosis
High arched palate
Motor milestones delayed or never acheived
*Many COL12-RD affected individuals do not manifest all of these symptoms, making diagnostics confirmation complex.
Genetic testing is the only way to confirm a COL12-RD. However, given the rarity and broad spectrum of this condition, genetic testing is often inconclusive, returning results that include variant(s) of unknown significance (VOUS/VUS).
Inconclusive testing results require further testing and examination by a neuromuscular specialist familiar with COL12 to confirm or eliminate this diagnosis. Additional testing may include muscle imaging, skin biopsy, blood tests and physical examination to assist with confirmation.
Physiology of COL12a1
COL12a1 interacts with other extracellular matrix proteins to form the environment that surrounds muscle cells. It performs critical functions by supporting muscle cell stability and regeneration while allowing the muscle cell to adhere to the matrix. Genetic mutations in COL12a1 may lead to COL12-RD, but not all genetic mutations cause disease. Inheritance of mutations may be either autosomal dominant, autosomal recessive or de novo (spontaneous). COL12-RD is a spectrum disorder that may manifest with mild or severe symptoms. The ability to walk will vary, ranging from gaining and retaining ambulation, to delayed ambulation to achieving or losing ambulation later in life, requiring mobility assistance. Creatine kinase levels in the blood may be normal to slightly elevated.
COL12a1 is a large gene with few confirmed disease causing mutations making diagnosis of COL12-RD very complex. There is also symptom overlap with Ehlers-Danlos Syndrome (EDS), further complicating accurate diagnosis. Research is ongoing to identify more variants causing these disorders.
If you or your child have muscle weakness and have received genetic testing results indicating a possible diagnosis of a COL12-related neuromuscular disorder, please get in touch with Cure CMD staff. We will provide you with information about registering in the CMDIR and potentially connecting you with neuromuscular experts who are leading the effort to confirm or eliminate COL12 as a diagnosis.