Congenital Muscular Dystrophies

Congenital muscular dystrophies (CMD) are a group of genetic diseases characterized by muscle wasting that is evident at birth or shortly thereafter, with symptoms appearing before a child is able to walk. Around six to nine of every million babies born around the world are affected by CMD.

At present, more than 30 different types of CMD are recognized, each with characteristic clinical manifestations and caused by particular genetic changes. For about 40% of CMD cases, the underlying genetic cause is unknown.

Types of CMD

CMD can be broadly classified into several groups, based on the particular type of molecular changes that result from different disease-causing mutations. Some forms of CMD are named after the scientists who first formally described them — one example is “Ulrich CMD” — while others are described by how they manifest. So, for example, one type is called “CMD with cerebellar involvement.”

Almost all types of CMD are inherited in an autosomal recessive manner, which means that a child must inherit disease-causing mutations from both biological parents in order to develop the condition. The only exceptions are LMNA-related CMD and some forms of collagen 6-related CMD, which are inherited in an autosomal dominant pattern, in which one mutated gene is enough to cause disease.

CMD associated with structural proteins

Many of the most common types of CMD are caused by defects in genes related to the basal membrane or extracellular matrix, which are protein networks outside of cells that help to give tissue its structure and keep all the cells in the right position.

Laminin-alpha 2 related dystrophies (LAMA2-RD) — also called merosin-deficient CMD or MDC1A — are caused by mutations that impair the production of an extracellular matrix protein called laminin-211 (also sometimes called merosin). Most people with LAMA2-RD attain trunk control, but few are ever able to stand or walk unassisted. Breathing problems are a major complication in LAMA2-RD, and about a third of patients develop seizures during childhood.

Collagen 6-related CMD (Col6-RD), as the name suggests, is caused by mutations that impair the production of a structural protein called collagen VI. These disorders can range from a severe form termed Ulrich CMD, to a milder muscle disease called Bethlem myopathy. Most people with Col6-RD develop the ability to walk independently as young children, but as the disease progresses, they lose that ability; most are unable to walk by about age 10. Patients commonly have joint contractures — loss of mobility due to shortening of tissues and muscles — particularly in the joints closer to the trunk, and many develop an abnormal curvature of the spine known as scoliosis.

LMNA-related CMD is caused by defects in the protein LMNA, which helps to provide the structure of the nuclear envelope — the membrane barrier that surrounds a cell’s nucleus, where DNA is stored. Severe muscle weakness in the neck characterizes LMNA-related CMD and leads to “head drop,” with rapid worsening of motor function. Heart problems are common for people with this CMD type, and contribute to reduced life expectancy.

Dystroglycanopathies

A protein called dystrophin plays a critical role in maintaining connections between the inside of cells, where muscle contraction occurs, and the extracellular matrix that holds tissue in place. To work properly, the dystrophin protein needs to be modified by adding a number of specialized sugar-containing motifs. CMDs that are caused by problems in the production or modification of the dystrophin protein are called dystroglycanopathies or DGPs.

The severity of symptoms varies widely across different types of dystroglycanopathies, and also can vary substantially even in people with disease-causing mutations in the same gene. Most people with dystroglycanopathies experience progressively worsening muscle weakness that mainly affects proximal muscles (those closest to the torso). Vision problems and abnormal brain structures also are common.

Specific DGPs include Walker-Warburg syndrome, muscle-eye-brain disease, CMD with cerebellar involvement, CMD with muscle hypertrophy (enlargement), and CMD with severe intellectual disability. Fukuyama CMD is a dystroglycanopathy that is particularly common in Japan.

CMD associated with SEPN1

The protein SEPN1 is located on a muscle cell structure called the sarcoplasmic reticulum — the muscle’s version of the endoplasmic reticulum that produces proteins the rest of the cell needs to function. The SEPN1 protein plays a pivotal role in regulating levels of calcium inside of muscle cells, which helps to regulate muscle contraction. Several types of CMD are associated with deficits in this protein, including CMD with desmin inclusions, CMD with spinal rigidity, and multi-minicore disease.

Patients with these types of CMD usually start experiencing symptoms, such as delayed motor development and muscle weakness in the neck, before their 2nd birthday. Symptoms generally are stable or ease during the first few decades of life, and then start to slowly get worse around age 30. Most people with SEPN1-associated types of CMD are able to walk independently.

Notably, many people with these types of CMD have weakness in the diaphragm, a muscle needed to suck air into the lungs when you breathe. Consequently, most patients will require mechanical ventilation, particularly at night, to help them get enough oxygen.

Other forms of CMD

A number of other types of CMD have been described, and there are likely more that have not yet been formally characterized. Other conditions also can manifest with symptoms similar to CMD, which can make diagnoses complicated.

Megaconial CMD, caused by mutations in a gene called CHKB, is characterized by developmental delays, intellectual disability, abnormal behaviors (e.g., autistic traits), and ichthyosis, or unusually dry, scaly skin.

The genes MSTO1 and MICU1 both are involved in the functioning of mitochondria, the so-called “powerhouse of the cell.” Mutations in these genes can result in CMD characterized by muscle weakness, fatigue, and intellectual disability, among other symptoms.

Marinesco-Sjogren syndrome (MSS) is a genetic childhood disease characterized by severe intellectual disability, early-onset cataracts (clouding of the eye lens), and muscle disease. A disease with manifestations overlapping CMD and MSS, caused by abnormalities in a protein called INPP5K, has been described, and is characterized by an abnormally small head, short stature, intellectual disability, and muscle weakness that first affects muscles near the torso.

Another form of CMD is caused by mutations in a gene called GGPS1. It is characterized by low muscle tone that usually is present from birth, as well as hearing loss and abnormal ovarian function in females.

 

Last updated: Jan. 27, 2022, by Marisa Wexler MS

 


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