Becker muscular dystrophy inheritance

Becker muscular dystrophy (BMD) is a genetic neuromuscular disease characterized by progressive muscle weakness and atrophy that predominantly affects boys.

BMD shares many of the same symptoms as Duchenne muscular dystrophy (DMD), although BMD tends to be milder and progress more slowly. Because they both result from mutations in the DMD gene, BMD inheritance follows the same pattern as DMD.

How is Becker muscular dystrophy inherited?

Genes are organized into chromosomes. There are 23 pairs of chromosomes, one inherited from the mother and one inherited from the father. However, the pair of “sex chromosomes” is different:

• Females inherit two X chromosomes, one from each parent.
• Males inherit a single X chromosome from their mother and a Y chromosome from their father.

BMD is an X-linked disease, meaning the disease-causing gene is located on the X chromosome. This means the condition mostly affects males, as they have just one copy of the X chromosome.

Specifically, both DMD and BMD develop due to mutations (or changes that affect function) in the DMD gene, which is responsible for making a protein called dystrophin. In BMD, the faults in this gene mean that dystrophin does not work as it should.

Females have two X chromosomes, so a healthy DMD gene on one often can compensate for a faulty copy on the other.

What are the chances of passing BMD to children?

BMD is inherited through the X chromosome. A child’s risk depends on which parent carries the mutated DMD gene and whether the child inherits an X or Y chromosome. Males who inherit the mutation develop BMD, while females who inherit it may or may not develop symptoms.

When the mother carries the family DMD variant

The condition is far less likely to manifest in females because they usually have a second X chromosome with a working copy of the DMD gene. However, females with one faulty gene can still develop symptoms.

A daughter of a woman who carries a mutated DMD gene has a 50% chance of inheriting it and becoming a BMD carrier. If she does, each of her children has a 50% chance of inheriting the mutation, even if she has no symptoms.

When the father has BMD

A father with BMD cannot pass on a mutated DMD gene to his sons, as they inherit their father’s Y chromosome.

If he has daughters, they would inherit his X chromosome and the faulty DMD gene with it. This means that they would become carriers and may or may not develop symptoms. If they have sons in the future, they can pass the DMD variant on to them.

The table below shows the BMD inheritance pattern and subsequent risk of developing BMD.

Can Becker occur without a BMD family history?

Each child of a carrier mother has a 50% chance of inheriting the mutated DMD gene. Sons who inherit it develop BMD; daughters become carriers and may have symptoms.

About half of people with BMD have no known family history. The mutation may be new (de novo), or it may have passed through female carriers whose symptoms were absent or mild. Earlier affected relatives may also have lived before BMD could be diagnosed.

Germline mosaicism

BMD can also develop without a family history due to germline mosaicism. This means that the DMD gene variation is present in some of a woman’s eggs, but not in most other cells of her body, so it may not be detected by standard genetic tests that usually use blood or saliva.

Blood tests cannot detect mutations present only in egg cells. If a woman tests negative as a carrier but has a child with BMD, clinicians may suspect germline mosaicism.

A recent study found signs of germline mosaicism in about 8.1% of families of children with a de novo DMD variant. The study also found that women with a negative genetic test but a son with a DMD-linked disease (known as a dystrophinopathy) had an average of a 5.8% risk of giving birth to another son with the condition.

Why can Becker affect relatives differently?

Two relatives can have different experiences with BMD, depending on whether they are a carrier or have inherited and developed the disease. However, other factors can affect the symptoms that occur and the severity of the disease.

Muscle fiber distribution

A single muscle fiber has thousands of nuclei that control how the muscle expands and contracts. In female BMD carriers, some nuclei within a muscle fiber may produce working dystrophin while others do not because of X-chromosome inactivation. If the dystrophin-producing nuclei are spread fairly evenly, they can help protect more of the muscle fiber.

However, if the working nuclei are unevenly distributed, some areas of the muscle fiber may have too little dystrophin and therefore lack protection and become damaged.

Dystrophin and muscle repair

When a muscle gets damaged, special repair cells called satellite cells step in to repair the tissue. If the repair cells do not carry the mutated dystrophin-producing gene, the muscle is able to recover properly.

But if the repair cells carry the faulty DMD gene, or if the body starts to run out of dystrophin-producing satellite cells over time, the muscle cannot fix itself and turns into scar tissue. This can cause the permanent weakness associated with BMD symptoms.

Difference in heart muscle cells

The heart muscle works differently from skeletal muscles and does not have the same repair system, making it uniquely vulnerable to dystrophin-related problems.

Because of this, some carriers might have very little leg or arm weakness but still experience a type of heart muscle weakness called dilated cardiomyopathy.

Severe X-chromosome anomalies

Rarely, a female carrier may not have a second X chromosome, or it may be damaged. This means that no backup chromosome can step in to provide healthy dystrophin-producing function

In this rare genetic situation, a female may develop severe symptoms, similar to a male.

What does the DMD variant mean for female carriers?

Despite not experiencing the full effect of the gene mutation, females can still show some symptoms of insufficient dystrophin production. A female carrier of a mutated DMD gene who is experiencing symptoms of BMD is referred to as a manifesting carrier.

Possible heart and muscle symptoms

Around 1 in 10 women who are BMD carriers have heart problems, which could include:

• cardiomyopathy
• issues with electrical conduction through the heart chambers
• irregular heart rhythms

Heart problems may cause no symptoms at first, making regular checkups important. As time goes on, they can cause shortness of breath during moderate exercise and become life-threatening without care. Some carriers with symptoms also develop muscle weakness; rarely, they need a wheelchair.

Recommended health monitoring

A genetic test can determine whether a female relative of someone with BMD is a carrier. If her carrier status is confirmed, she should regularly undergo close cardiac monitoring and strength evaluations to help manage symptoms if they arise.

Carriers who do not show symptoms should have cardiac assessments every three to five years, while those with symptoms should undergo cardiac testing more frequently

Which relatives should consider genetic testing?

The most reliable method for identifying carriers in the family is genetic testing. While de novo cases can arise, this can help you guide family planning and act as a foundation for important healthcare discussions right down the family tree.

Any woman with a family history of dystrophinopathy could benefit from genetic testing. Those with the following should consider it:

• brothers or sons with a dystrophinopathy diagnosis
• mothers and sisters who are confirmed carriers
• maternal uncles and cousins who live with dystrophinopathy
• maternal cousins or aunts who carry a mutated DMD gene

Females who experience specific symptoms are also candidates for BMD carrier testing, including:

• unexplained muscle symptoms
• unexplained heart/cardiac symptoms
• unexplained elevated creatine kinase levels

Once a diagnosis of dystrophinopathy is confirmed in a family, a genetic counselor can help family members determine whether they would benefit from genetic testing.

How can genetic counseling help families?

Genetic counselors can support you and your family during the turning point that is a BMD diagnosis. You may worry about:

• your child’s health
• whether you can pass on the changed gene
• whether more children might be on the horizon for you
• the risk of manifesting
• whether it may affect other family members
• how you are possibly going to start having these conversations with people

Sharing genetic results with family can be difficult, especially when a mutation traces back several generations. The grandmother’s or great-grandmother’s living sisters and their descendants may also be eligible for testing.

Genetic counselors can help you work through this challenging stage. They can:

• put together a detailed family tree and medical history
• work out who else needs testing
• organize the tests
• help you understand the results
• work out your reproductive options with BMD ahead of future pregnancies
• provide emotional support during what can be a charged and frightening period

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