AssessmentsMuscular dystrophies and mitochondrial myopathies: Pathology review
USMLE® Step 1 style questions USMLE
A 20-year-old woman is evaluated in the emergency department for a suspected generalized tonic-clonic seizure. The episode occurred an hour ago when she was with her roommate, who states the patient started uncontrollably flexing and extending her upper and lower limbs for 1 minute. She has a history of recurrent seizures for the past 2 years, and she lost partial vision due to occipital lobe infarction last year. Family history is not available because the patient was adopted as a child. Neurological examination shows decreased sensation and weakness of bilateral lower extremities. The patient is admitted for further evaluation. Serum lactate levels are 3.3 mmol/L. Skeletal muscle biopsy shows proliferation of mitochondria that appear bright red compared to the blue myofibers when stained with Gomori trichrome stain. This patient’s condition is best described as which of the following?
Content Reviewers:Antonia Syrnioti, MD
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. 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. 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. 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.
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "Distal muscular dystrophies" Handbook of Clinical Neurology (2011)
- "Muscular Dystrophies" Elsevier Science Limited (2011)
- "Facioscapulohumeral Muscular Dystrophy" CONTINUUM: Lifelong Learning in Neurology (2016)
- "Cognitive Neuroscience: The Biology of the Mind (Fourth Edition)" W. W. Norton (2013)
- "Loose-leaf Version for Genetics: A Conceptual Approach" Macmillan Higher Education (2019)
- "Inheritance of most X-linked traits is not dominant or recessive, just X-linked" American Journal of Medical Genetics (2004)