What is Dystrophinopathies?
Dystropinopathies are a collection of muscle disorders that are linked to the X chromosome. The most known amongst these is Duchenne muscular dystrophy (DMD), followed by Becker muscular dystrophy (BMD), and the recently identified DMD-related dilated cardiomyopathy (DCM). DMD is the most severe type and it often shows up in childhood, causing problems with motor development. BMD, on the other hand, tends to develop later in life. These disorders are mostly passed down through the X chromosome, primarily affecting males. However, females can also get a related condition (DCM).
What Causes Dystrophinopathies?
DMD is a gene that’s 2.2 million bases long and consists of 79 segments called exons. It’s located on the X chromosome. Variations that cause health problems often involve deletions or missing parts of the exons, especially in regions 2 to 20 and 44 to 53. These variations make up 60-70% of the problematic DMD gene changes.
Dystrophin, the protein created by the DMD gene, plays an important role in muscle and nerve cells. It’s part of a protein complex that connects the cell’s inner ‘skeleton’ (cytoskeleton) and membrane proteins, which then interact with proteins outside the cell (extracellular matrix proteins).
Risk Factors and Frequency for Dystrophinopathies
The rates of certain medical conditions, specifically DMD (Duchenne Muscular Dystrophy) and BMD (Becker Muscular Dystrophy), vary within the United States. DMD is more common, with a ratio of 1.12 for every person of any age, while BMD occurs less frequently, with a ratio of 0.36. Interestingly, these diseases are found more often in people of Hispanic descent.
Signs and Symptoms of Dystrophinopathies
Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD) and DCM, are all conditions associated with muscular weakness and heart issues. These conditions share many similarities but are also quite distinct. DMD is typically more severe, with most patients needing a wheelchair by the age of 13, while BMD usually doesn’t prompt wheelchair use until after age 16 or later.
DMD typically appears in early childhood and is associated with delayed motor abilities, like standing up from the floor and walking. Parents might notice things like peculiar walking styles and difficulty with tasks involving leg muscles, such as climbing stairs, running, or jumping. Over time, the child’s calf muscles may harden due to the buildup of fat tissue. A noticeable percentage of DMD patients also develop a heart condition known as cardiomyopathy by their teenage years, which affects every individual with DMD by the age of 18. Some kids may have trouble with tasks requiring visual and spatial skills due to executive function impairment. The primary causes of death for those with DMD are usually respiratory or heart failure.
Those with BMD experience muscle weakness typically later in life, sometimes showing up after the age of 30. The main cause of death is usually heart failure due to cardiomyopathy. Unlike DMD, there are no noticeable cognitive impairments for individuals with BMD.
On the other hand, DCM associated with muscular dystrophy tends to progress rapidly and is linked to irregular heartbeat patterns. It doesn’t involve the skeletal muscles, but affected women tend to show a milder form of the disease around the age of 40.
Testing for Dystrophinopathies
When suspecting conditions like Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), and Dilated Cardiomyopathy (DCM), specific tests can be used. The best initial test is the creatine phosphokinase (CK) test. For DMD, we usually see results that are over 10 times the normal limit, and for BMD, results are above 5 times the normal limit. For DCM, CK values could be significantly higher than the normal reference.
Several other tests like aspartate aminotransferase (AST), alanine aminotransferase (ALT), and lactate dehydrogenase (LDH) can also show high values. However, there’s something to keep in mind: these high levels could come from the liver as well. To check if this is the case, you might need to take a gamma-glutamyl transferase test. If the result of this test is normal, it’s likely that a muscle disease like DMD is causing the high enzyme levels.
For an accurate diagnosis, the DMD gene deletion-duplication analysis is the most efficient. This test can reveal the abnormality in about 60 to 70 percent of patients. However, if the result doesn’t confirm the disease, but the symptoms strongly suggest it, sequencing could be recommended. This can help identify the abnormalities in the rest of the cases, which make up about 20 to 30 percent.
Treatment Options for Dystrophinopathies
After diagnosis, it is common to consult with a team of experts including physical therapists, developmental specialists, a cardiologist (when the patient is 6 years old), and genetic counselors.
If a person’s heart isn’t pumping blood well (signified by the left ventricle functioning below 55%), doctors may use medications like ACE inhibitors or beta-blockers to help. If these drugs aren’t tolerated, angiotensin II-receptor blockers could be used as an alternative. For those suffering from heart failure, digoxin and diuretics could be added to their treatment. In severe cases, a heart transplant may be recommended.
Scenarios might come up where a patient develops a spinal condition known as scoliosis. In such cases, they may need to wear a brace or undergo a surgical operation (spinal fusion).
To improve muscle strength, corticosteroids are typically prescribed, especially for children age 2 and up, but not exceeding the age of 15. The treatment can begin with either prednisone or deflazacort when a decline in motor skills is noted. Doctors could use tests to measure lung function and muscle performance in order to ascertain the effectiveness of the treatment, all while checking for side effects such as excessive weight gain, changes in behavior, stomach issues, and weakening of the bones. If severe side effects are noticed, the dosage can be reduced gradually.
To prevent complications and track the patient’s condition, doctors recommend vaccinations against influenza and pneumonia. They also advise monitoring the patient’s weight and nutritional status and encouraging regular exercise to prevent stiffening of the muscles. Testing for substances in the blood is essential as it could indicate bone health among other things. Cardiac evaluations every two years, or more frequently in some cases, are also important, along with tests to measure lung function.
There are some medications and treatments that should be avoided. For instance, the use of botulinum toxin is a no-go. Certain anesthetics shouldn’t be used either, as they have been known to induce severe reactions in a small subset of patients.
What else can Dystrophinopathies be?
Emery-Dreifuss muscular dystrophy is characterized by a combination of stiff joints in early childhood, slowly progressing muscle weakness, and initial muscle wasting in the areas from the upper arm to lower leg (humeroperoneal distribution), which later extends to muscles around the shoulders and hips (scapular and pelvic girdle muscles). Heart complications can appear after the first 20 years of a person’s life. Limb-girdle muscular dystrophy is either inherited from both parents (autosomal recessive) or from one parent (autosomal dominant) and is caused by defects in genes that encode sarcoglycans.
Spinal muscular atrophy presents with lower than normal muscle tone, weakness (but facial muscles remain unaffected), a condition called “tongue fasciculations” where the tongue moves uncontrollably due to nerve cell damage in the front part of the spinal cord, and deep tendon reflexes are absent. This condition can start anytime from birth up to adolescence.
Barth syndrome is a condition that only affects males and is caused by a defect in the TAZ gene. People with this condition experience heart disease, a low count of a type of white blood cells called neutrophils (neutropenia), muscle weakness (skeletal myopathy), and delayed growth before puberty.
