Muscular dystrophies and mitochondrial myopathies: Pathology review

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Case study0:00–0:46

At the clinic, 32 year old mary comes with her 6 year old son thomas, after noticing he’s often clumsy, weak, and has trouble climbing the stairs of their house.
Mary is worried because she had a brother who presented the same symptoms as a child, and developed progressive weakness, until he passed away at 23 years old due to respiratory problems.
Upon physical examination, the physician notices that thomas has scoliosis and thick calves. Later that day, 29 year old sarah comes to the clinic with her 10 year old son mike because of progressive muscle weakness and fatigue, as well as vomiting and loss of appetite.
In addition, she mentions that he has experienced seizures. Based on the clinical findings, the physician concludes that both children have some form of inherited muscular disorder, and orders genetic testing to confirm the diagnosis.

Pathology0:46–1:02

Now, let’s go over the two main groups: muscular dystrophies and mitochondrial myopathies.Muscular dystrophies are a group of genetic disorders characterized by muscle degeneration and weakness.

Muscular dystrophies1:02–5:30

Within that group, dystrophinopathies are the most common, and this includes duchenne muscular dystrophy, or dmd for short, and becker muscular dystrophy, or bmd.Both duchenne and becker result from mutations in the dystrophin gene, which is found on the x chromosome.
For your exams, remember that these are x-linked recessive disorders, which means that all carrier males develop the disease, because they only have one x chromosome and thus one dystrophin gene available.
On the other hand, females have two x chromosomes, so even if they have a defective dystrophin gene on one x chromosome, they still have another functional one.
However, only one x chromosome gets expressed and the other is inactivated through a process called x-inactivation or lyonization.
This inactivation is random which means that every cell could have a chance of having the mutated x chromosome be the active copy.
If this is the case for more than half of the muscle cells, they will be a manifesting carrier who will develop symptoms.
People with more cells with the active mutated x chromosome will have more severe symptoms and quicker disease progression.
If less than half of their cells have the active mutated x chromosome, they’ll be an asymptomatic carrier and won’t develop symptoms.
Now, long story short, dystrophin is a protein found on the plasma membrane of muscle fibers to provide mechanical reinforcement and stabilization.
As a result, having defective dystrophin proteins leads to degeneration and instability of muscle fibers, in turn causing muscle weakness.
What determines which disease you get is the type of mutation in the dystrophin gene. Duchenne muscular dystrophy results when the mutation results in no protein being produced at all, for example a nonsense or a frameshift mutation.
On the other hand, becker muscular dystrophy results from mutations like missense mutations that allow a misshapen and partially functional protein to be produced.
So, what's especially high yield is that duchenne ends up being the more severe of the two, with symptoms usually presenting by the age of 5, while becker is basically a milder form of duchenne that presents later on, usually between the ages 10 to 20.
In both disorders, initially, there’s muscle regeneration to compensate for the muscle degeneration and weakness. Over time, the muscle tissue can’t keep up, so it atrophies and gets infiltrated by fat and fibrotic tissue.
This process can occur in any muscle, but it is most noticeable in the muscle of the legs. In a test question, this will classically manifest as calf pseudohypertrophy, where the calves are visibly enlarged, but that's because of fat and fibrotic tissue rather than actual muscle tissue.
As muscle weakness progresses, individuals have a progressive difficulty walking. A very high yield sign is the waddling gait.
This is due to the pelvic girdle muscles becoming weak so the individual will have problems with balance. So to compensate, they will walk by taking short steps while swinging their trunk side to side with each step as a counter balance.
Muscles around the hips and upper legs can also weaken, making it hard for these individuals to stand up. Now, an important term to remember is gowers’ sign, which is when an individual that’s lying on their stomach needs to use their arms to slowly “walk” back up in order to stand.
Individuals can also develop skeletal deformities like scoliosis or hyperlordosis. As muscle weakness progresses, most individuals with duchenne may end up needing a wheelchair by the age of 13, and can become paralyzed from the neck down by the time they’re 21 years old.
On the other hand, for individuals with becker, this progression is usually delayed by about 10 years.Eventually, individuals end up developing serious complications, including respiratory failure because of a weak diaphragm, and dilated cardiomyopathy and arrhythmias, since the dystrophin protein is also expressed in heart muscle.
Unfortunately, these complications often lead to a shortened lifespan. Most individuals with duchenne die in their 20s, and those with becker in their 40s.For diagnosis, people with suspected duchenne or becker muscular dystrophy on physical examination should get appropriate testing.

Diagnosis and treatment of muscular dystrophies5:30–6:28

The first step is getting blood tests for creatine kinase or ck. If ck levels are high, diagnosis can be confirmed through genetic testing that looks for mutations in dystrophin either with a western blot test or dna tests.
Rarely, if genetic testing is inconclusive, a muscle biopsy with staining for dystrophin will be required. Remember that we expect to see an absence of dystrophin in duchenne, and abnormal dystrophin in becker.Unfortunately, there is no cure for muscular dystrophies.
Glucocorticoids can sometimes slow degeneration, but they should be used in moderation, since they are typically also accompanied by side effects like excessive weight gain.
Other treatments like physical therapy and conditioning can improve quality of life, but they don’t reverse the underlying process.

Mitochondrial myopathies6:28–9:31

All right, now! Another form of inherited muscular disorders are mitochondrial myopathies, which are a group of inherited neuromuscular disorders that are characterized by dysfunctional mitochondria with the inability to produce enough atp.
The most affected tissues include the brain and muscles, since these are the ones that require the highest levels of atp.
Some of the mitochondrial proteins involved in the electron transport chain are encoded by the mitochondrial dna, while others are encoded by the nuclear dna.
So, what's high yield is that a now, most mitochondrial myopathies are caused by mutations in the mitochondrial dna, which follows maternal inheritance.
This is because, during fertilization, the father’s mitochondria are left behind while the sperm’s nucleus alone enters the egg.
For your exams, it’s important to note that, since mitochondrial dna is maternally inherited, only biological females can pass mutations to their children.
Another high-yield fact is that mitochondrial inheritance shows heteroplasmy, which means that each cell contains hundreds of mitochondria with hundreds of copies of different mitochondrial dna.
As a result, mutations in mitochondrial dna will affect only some mitochondria, leaving the rest unaffected, and the resulting mitochondrial myopathies can have variable clinical presentations and severity, ranging from mild to fatal disease.
Now, the main clinical features of mitochondrial myopathies include fatigue; myalgia; eye-related symptoms like vision loss, ptosis, and ocular dysmotility; and neurological symptoms like seizures, hearing loss, impaired coordination, and cognitive deficits.
For your exams, the most important mitochondrial myopathy to know about MELAS syndrome, which is an acronym for its main symptoms; mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
The onset of MELAS is typically during childhood. Early symptoms can include fatigue and exercise intolerance.
Most individuals with MELAS develop lactic acidosis due to lactic acid buildup in their bodies. Lactic acidosis can lead to fatigue, muscle weakness, abdominal pain, vomiting, and difficulty breathing.
Additionally, before the age of 40, most individuals present with stroke-like episodes involving altered consciousness, hemiparesis or muscle weakness on one side of the body, and hemianopia or vision abnormalities on one side of the visual field.
In addition, individuals may present with severe headaches and seizure, develop visual and hearing loss, and weight loss.
Over time, repeated stroke-like episodes can cause progressive damage to the brain, ultimately leading to blindness, movement problems, and dementia.
Less frequently, individuals with MELAS can develop hearing loss, involuntary muscle spasms, cardiomyopathy, kidney problems, and diabetes mellitus.Now, diagnosis for mitochondrial myopathies begins with a physical and neurological examination, followed by blood tests that may show elevated levels of lactate and creatine kinase in the blood.

Diagnosis and treatment of mitochondrial myopathies9:31–10:25

To confirm diagnosis, genetic testing is done to look for mutations in the genes coding for the electron transport chain proteins, either in the mitochondrial or in the nuclear dna.
Finally, if genetic testing is inconclusive, individuals may require a muscle biopsy. For your exams, keep in mind that this has to show ragged red fibers in gomori trichrome staining, indicating that there’s compensatory proliferation of abnormal mitochondria in the affected muscles.
There's no cure for mitochondrial myopathies, but there are treatment options. Individuals may benefit from regular exercise, as well as vitamins and supplements.All right, as a quick recap… muscular dystrophies include the x-linked recessive disorders duchenne muscular dystrophy, which is caused by mutations that lead to a loss of dystrophin, and becker muscular dystrophy, which is caused by mutations that lead to a misshapen or abnormal dystrophin.

Review10:25–12:18

Individuals present with progressive muscles atrophy, calf pseudohypertrophy, difficulty walking, “waddling” gait, gowers’ sign, and skeletal deformities.
Eventually respiratory muscles and the heart become affected, leading to death. Most individuals with duchenne develop symptoms by the age of 5 while becker tends to develop later, by the age of 10 to 20.
Diagnosis is based on physical examination, blood tests showing high ck levels, genetic testing, and rarely, muscle biopsy.Mitochondrial myopathies are neuromuscular disorders that are most often caused by mutations in mitochondrial dna, which lead to the inability to produce enough atp by mitochondria.
Since mitochondrial inheritance shows heteroplasmy, the resulting mitochondrial myopathies can have variable clinical presentations and severity.
The main clinical features include fatigue, myalgia, eye-related symptoms, and neurological symptoms like seizures, hearing loss, impaired coordination, and cognitive deficits.
An important mitochondrial myopathy is MELAS syndrome, which presents with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.
Diagnosis of mitochondrial myopathies includes physical and neurological examination, followed by blood tests that may show elevated levels of lactate and creatine kinase.
Diagnosis can be confirmed through genetic testing. Finally, some individuals may need muscle biopsy, which will show ragged red muscle fibers.Now back to our cases.

Summary12:18–13:03

The key to diagnose these disorders is to recognize their characteristic clinical findings. Thomas is a 6 year old boy that presents with clumsiness, weakness, and trouble climbing stairs.
The key clues were the calf pseudohypertrophy and the family history of similar symptoms. These point to an inherited muscular dystrophy.
Due to the young age where symptoms manifested, it’s more likely to be duchene and not becker muscular dystrophy. On the other hand, Mike is a 10 year old boy who presents with progressive muscle weakness, fatigue, vomiting, and episodes of seizures.
The systemic symptoms and especially the seizures in combination with progressive muscle weakness point to MELAS. In both cases, genetic testing confirmed the suspected diagnosis.
Muscular dystrophies and mitochondrial myopathies | Osmosis