Other CMDs

Some affected individuals with CMD do not have genetic confirmation of disease. This means that either genetic testing was done and no mutation identified or genetic testing has not been completed or revisited. Clinical presentation and muscle or skin biopsy may point towards a known CMD subtype.

There are still new genes to be discovered that can lead to a CMD. For instance, in 30-50% of Walker Warburg, cases a genetic mutation is not found in any of the currently known genes that lead to a Dystroglycanopathy. Children and adults who present with classic clinical features of Collagen VI-CMD may not carry a mutation in any of the Collagen VI genes.

Merosin positive CMD is not a diagnosis, but rather a classification that indicates the presence of merosin on muscle or skin biopsy ruling out LAMA2-CMD. Consultation with an expert in congenital muscle disorders is the first step in identifying a diagnosis. Next generation sequencing, now widely available, can be used to test multiple genes at the same time, whether this is the first round of testing or the revisiting of the search for a diagnosis as an older child or adult. As new genes leading to a CMD are discovered and added to genetic testing panels, a genetic diagnosis may be possible, even if none was previously found.

COL12

Characteristics of COL12-RD *

Muscle weakness
Respiratory weakness
Hypermobile distal joints
Proximal joint contractures
Scoliosis and/or Kyphosis
Facial Weakness
High arched palate
Motor milestones delayed/never achieved

* Many COL12-RD affected individuals do not manifest all of these symptoms, making diagnostics confirmation complex.

Diagnosing COL12-RD

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.

Collagen 12

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.

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 received genetic testing results indicating a possible diagnosis of a COL12-RD, please register with us in the CMDIR. We may be able to connect you with neuromuscular experts who are working to confirm or eliminate COL12 as a diagnosis.

RYR1

In partnership with

Characteristics of RYR1-CMD

Hypotonia
Muscle weakness
Respiratory weakness
Joint contractures
Scoliosis
Facial weakness
Feeding and swallowing issues

Diagnosing RYR1

A genetic test would provide a more definitive answer and would be less invasive than a muscle biopsy.

For more information about this group of disorders, please visit ryr1.org

RYR1

Ryanodine receptor 1 gene produces the ryanodine receptor 1 gene protein (RYR1) is part of the ryanodine receptors family. A genetic mutation of this disease can lead to RYR1 Related Myopathy (RYR1-CMD). Afflicted individuals with a RYR1 mutation will have clinical features of both congenital myopathy and congenital muscular dystrophy. Afflicted individuals can be susceptible to another disease called malignant hyperthermia which can prove to be fatal if not diagnosed properly and early.

Physiology of RYR1

The RYR1 gene provides instructions for making a protein called ryanodine receptor 1. This protein is part of a family of ryanodine receptors, which form channels that transport positively charged calcium atoms (ions) within cells. Channels made with the ryanodine receptor 1 protein play a critical role in muscles used for movement (skeletal muscles).

For the body to move normally, skeletal muscles must tense (contract) and relax in a coordinated way. Muscle contractions are triggered by the flow of positively charged ions, including calcium, into muscle cells. When muscles are at rest, calcium ions are stored in a cellular structure called the sarcoplasmic reticulum inside each muscle cell. In response to certain signals, the RYR1 channel releases calcium ions from the sarcoplasmic reticulum into the surrounding cell fluid (cytoplasm). The resulting increase in calcium ion concentration stimulates muscle fibers to contract, allowing the body to move. The process by which certain

chemical signals trigger muscle contraction is called excitation-contraction (E-C) coupling.

Afflicted individuals will have early onset of symptoms which could include muscle weakness and delayed motor skills. Failure to thrive could be a result of poor feeding and swallowing issues. Afflicted patients can develop severe scoliosis early in life. Respiratory issues can develop resulting in nocturnal ventilation.

It is important to be diagnosed properly since afflicted individuals can develop malignant hyperthermia. Malignant hyperthermia occurs in response to some anesthetic gases, which are used to block the sensation of pain, and with a particular type of muscle relaxant. If given these drugs, people at risk for malignant hyperthermia may experience muscle rigidity, breakdown of muscle fibers (rhabdomyolysis), a high fever, increased acid levels in the blood and other tissues (acidosis), and a rapid heart rate. The complications of malignant hyperthermia can be life-threatening unless they are treated promptly.

RYR1-CMD is a slow or non-progressive disease. It can be either autosomal recessive or autosomal dominant.

TTN

In partnership with

Characteristics of Titinopathy

Muscle weakness
Respiratory weakness
Droopy eyelids (ptosis)
High arched palate
Scoliosis
Cardiac Involvement

Diagnosing Titinopathy

A genetic test would provide a more definitive answer and would be less invasive than a muscle biopsy.

For more information about this group of disorders, please visit titinmyopathy.com

Titinopathies

The titin gene (TTN) manufactures a very large muscle protein called titin found in the cardiac and skeletal muscles. A mutation of this gene can lead to following conditions: Centronuclear Myopathy, and Limb-Girdle Muscular Dystrophy type 2J (LGMD2J).

Physiology of Titin

Titin is a large protein that is essential for the muscle to work, both skeletal and cardiac. Within muscle cells, titin is an essential component of structures called sarcomeres. Sarcomeres are the basic units of muscle contraction; they are made of proteins that generate the mechanical force needed for muscles to contract. Titin has several functions within sarcomeres. One of the protein's main jobs is to provide structure, flexibility, and stability to these cell structures. Once the muscle has contracted titin helps the muscle go

back to its resting position. Genetic mutations of titin lead muscles not contracting and relaxing normally thus leading to muscle weakness/fatigue.

Centronuclear Myopathy is a group of myopathies that involve muscle weakness and wasting in the skeletal muscles. The mutation of the TTN genetic mutation is one of the causes of Centronuclear Myopathy. Onset can begin at birth to early adulthood and symptoms can vary among family members. Muscle weakness can delay motor skills and pain can make walking or exercising difficult. Atrophy and severe weakness may lead to some affected individuals needing wheelchair assistance. The genetic mutation involving TTN

is autosomal recessive.

Limb-Girdle Muscular Dystrophy type 2J (LGMD2J) is a form of limb-girdle muscular dystrophy. The mutation of the TTN gene deletes certain amino acids and replaces them with other amino acids at the

end of the titin protein. LGMD2J causes weakness and wasting of the skeletal muscles particularly the shoulders, hips and limbs. Onset begins in childhood and severe disability can occur within 20 years. Loss of ambulation can occur between third and sixth decade. The TTN genetic mutation involving LGMD2J is autosomal recessive.

Other Diseases Associated with the Titin gene:

A mutation of the titin gene can also lead to the following diseases: Familial Hypertrophic Cardiomyopathy, Dilated Cardiomyopathy 1G, Early on-set Myopathy with Fatal Cardiomyopathy, Proximal Myopathy with Early Respiratory Muscle Involvement and Tardive Tibial Muscular Dystrophy.