DUCHENNE MUSCULAR DYSTROPHY

Duchenne Muscular Dystrophy is a rare, but tragic, X-linked recessive genetic condition. It’s due to a single broken protein. The protein in question just happens to be the largest protein in the entire human body: dystrophin. Dystrophin is a part of skeletal muscle apparatus that anchors the sarcomere. In Duchenne’s, the broken dystrophin protein is still present but it isn’t very good at anchoring. It’s just a big broken protein. When patients contract any muscle, they drag the faulty dystrophins across the skeletal architecture over and over, inducing inflammation and muscle atrophy over time. I guess the dystrophin isn’t totally worthless, because patients don’t really experience many symptoms until about age 5. 

How do I identify it?

There will be delayed motor milestones. They have to use their arms to prop themselves up when standing (Gower’s sign). They have exaggerated lumbar lordosis (weakness of back muscles). Their calves atrophy, and fat accumulates there, which makes their calves look big (calf pseudohypertrophy). Their gait becomes waddling. They eventually can’t take stairs or walk. This condition can be detected using blood work -- their CK levels will be very high at birth (and presumably their entire lives, but idk). Electromyography (EKG’s of the muscles) assist in the diagnosis. Muscle biopsies are the gold standard. 

What are the complications?

Eventually, often in their late teens or early twenties, patients succumb to heart disease (dilated cardiomyopathy and arrhythmias) or respiratory infections (aspiration pneumonia). 

Becker’s Muscular Dystrophy is essentially the same problem as Duchenne’s Muscular Dystrophy, only less severe. The Duchenne mutation is a frameshift (and frameshifts are bad). But in Becker’s, the mutation is not a frameshift. But it’s a similar pathophysiology. The symptoms onset a little later (adolescence) and they progress a little slower. The prognosis is better, although cardiac disease and mental retardation may occur. 

MYOTONIC DYSTROPHY

Myotonic Dystrophy is another genetic condition, but unlike the first two, its pattern of inheritance is autosomal dominant. Another difference is that it onsets in adulthood, usually in the 20’s or 30’s. 

Which gene is mutated? 

The answer is MDPK (myotonic dystrophy protein kinase). Scientists haven’t pinned down exactly what this protein does, but they do know it’s involved in the skeletal muscles. The mutation here is a trinucleotide repeat. This may sound familiar if you know much about Huntington’s disease. There are stretches in our DNA where 3 or 4 nucleotides will repeat over and over again, but they should only repeat a set number of times. In Myotonic Dystrophy, the repeating segment is CTG. It shouldn’t repeat more than 37 times. Someone with 30 repeats would be asymptomatic. Someone with 38 repeats would have mild-ish symptoms. 100 repeats cause severe symptoms. In a phenomenon that geneticists call “anticipation,” the number of repeats in children is usually longer than in parents. So children will have more severe symptoms and earlier onsets than their parents. 

What are the symptoms?

Breaking down the word “myotonic” can give you a clue about this disease. “Myo” means muscle, and “tonic” means tone.  The defining symptom is spastic weakness. They have high muscle tone! 

There are some other weird symptoms common to this condition, and a helpful way to remember them is with the CTG mnemonic: Cataracts, Toupee (baldness) and Gonadal atrophy. These patients are also at risk for arrhythmias and intellectual disability. 

CTG

MITOCHONDRIAL MYOPATHY

This one is a mutation in mitochondrial DNA, and without healthy mitochondria, oxidative phosphorylation won’t work. Remember that if the mom has a mitochondrial disease, all of her kids will inherit it. This condition is rare, like all mitochondrial diseases. When diseased muscle cells are examined under a microscope, the cells show “ragged red fibers” under a microscope, which are actually trucked up mitochondria getting pushed to the cell’s periphery. This one’s pretty rare, consider it low yield. 

But I’m dying to know what the symptoms are!

In addition to flaccid weakness, patients get a nasty constellation of symptoms sometimes referred to with the acronym MELAS. They will be very, very sick. After all, mitochondria are involved in many, many processes!

Mitochondrial Encephalopathy (confused)

Lactic Acidosis

Seizures / Strokes

McARDLE’S DISEASE

Myophosphorylase Deficiency

Glycogen Storage Disease Type V

McArdle’s Disease is a disease where your muscles can’t use glycogen (specifically, it’s a deficiency in the glycogen phosphorylase enzyme). When you begin to exercise, your muscles quickly run out of ATP, start to starve and cramp like crazy. If the muscles are constantly under stress like this, the body is likely to think they’re unnecessary, and is liable to digest them (seen on histology as chewed-out pink pockets, or subsarcolemmal vacuoles, on the image below). So it breaks down some of that muscle. As a consequence, ammonia levels will rise in the blood. If they exercise so much that their skeletal muscle cells die, myoglobin can spill out of those dying cells and enter the bloodstream. Myoglobin darkens the urine and damages the kidneys (which is similar to what happens in rhabdomyolysis).

What’s the cause?

Autosomal recessive. 

What’s the timeline of symptoms?

It begins in adolescence. With strenuous exercise they develop severe cramps. 

RHABDOMYOSARCOMA

Skeletal Muscle Cancer

Rhabdomyosarcomas are malignant cancers of premature skeletal muscle cells. There are several forms, but it classically onsets in the genitourinary tracts of fetuses.

What is ‘rhabdomyo-’ referring to?

Rhabdomyocytes are cells that aren’t frequently found in adults, but they are present in embryos. They are precursors to striated muscle cells. 

How will the patient present?

Most rhabdomyosarcomas are embryonic. After child birth, the delivery team will immediately notice the tell tale sign of rhabdomyosarcomas. There will be a grapelike, necrotic tumor protruding from the genitals. 

Is it common? Please say it’s not common.

Sadly it is. At least, within the realm of childhood malignancies it is. It accounts for 3% of childhood cancers.

Does it only appear in children?

No, it can appear in adults. And it can appear in any other part of the body where there is dense skeletal muscle. But since skeletal muscle doesn’t replicate, it’s super rare.

RHABDOMYOLYSIS refers to the rapid collapse and death of muscle tissue. It results in exquisite muscle pain and weakness. Rhabdo is most commonly seen with extreme exertion that occurs in the setting of dehydration, which includes marathon runners as well as seizures and tetanus. Other causes include arterial ischemia, crush injuries, snake bites and extreme electrolyte abnormalities. Rhabdo is fairly similar to another cell death disorder, tumor lysis syndrome. Muscle cells release potassium and phosphate when they die -- but they also release myoglobin. Myoglobin is highly nephrotoxic. It turns urine the color of tea. The key to diagnosing myoglobinuria is by comparing the urine dipstick results to the formal urinalysis. Dipsticks are rudimentary tools, and they mistake myoglobin for its tetramer cousin hemoglobin. That’s why dipsticks inadvertently call myoglobinuria 3+ hematuria. But on the urinalysis, there will be no RBCs. The treatment for rhabdo is with fluids, fluids and then fluids. 

POLYMYALGIA RHEUMATICA is an autoimmune myopathy that classically causes proximal muscle stiffness (shoulder stiffness). It does not cause weakness. Most cases of PR simultaneously have temporal arteritis (very high yield). Treat with steroids. 

FIBROMYALGIA is a diagnosis of exclusion for chronic pain and fatigue. By definition, the patient should have an unrevealing diagnostic workup. There is no accepted pathophysiologic model, although some researchers tout the oversensitized nerve theory -- where depression and anxiety can lead to a generalized state of chronic inflammation that manifests as generalized pain. Current guidelines recommend that the diagnosis be made with multiple muscular tender points (although the mechanism for this is shaky). Mostly occurs in overweight middle aged women. There are strong ties to depression. The best treatment is exercise, followed by antidepressants. 

DRUG INDUCED HYPERMETABOLIC STATES

There are several medication-induced diseases that are characterized by vital sign abnormalities, confusion and neuromuscular problems.

MALIGNANT HYPERTHERMIA is caused by a broken cellular receptor on skeletal muscles called the ryanodine receptor. This little receptor plays a critical job, connecting the neurological system to the musculoskeletal system. When the body wants to move a muscle, it sends a message through a neuron. That neuron releases acetylcholine once it reaches the muscle. Acetylcholine triggers a wave of electricity powered by sodium ions. That wave courses over the exterior of the muscle, eventually burrowing deep into the muscle’s T-tubules. That burst of energy is used to push a few calcium ions into the muscle cells. Calcium is what makes muscles move, but this small new influx of calcium is not nearly enough to generate movement. But it can trigger the release of even more calcium. You see, all muscle cells contain their own huge bathtubs full of calcium ions, called the sarcoplasmic reticulum. The receptor that controls this payload is the ryanodine receptor. Some people are born with a mutated receptor that can be triggered not only by calcium, but also by certain medications like inhaled anesthetics or succinylcholine. These medications are used to put people to sleep, usually for surgery, intubation or a medical procedure. So in a genetically susceptible individual, the administration of anesthesia will rapidly induce massive widespread muscle contraction. The first sign is often jaw clenching caused by contraction of the masseter muscles. Full body muscle rigidity will ensue, as will extreme imbalances in vital signs (tachycardia, hypertension, fever). Hyperthermia is actually an advanced finding in most cases. If you happen to notice these findings in your anesthetized patient, you can treat them with Dantrolene, a medication that blocks ryanodine receptors. 

SEROTONIN SYNDROME refers to an overdose of serotonergic medications. There are a lot of serotonergic drugs, many of which are used in psychiatry: SSRIs, SNRIs, TCAs, MAO-Is, ondansetron, tramadol, dextromethorphan, linezolid, St. John’s wort and, of course, ecstasy (MDMA). Serotonin syndrome onsets over a period of several hours, creating a hypermetabolic state with ramped up vitals and confusion. Patients will typically have overexcited neurons, which manifests as twitchiness, hyperreflexia, hypertonia, clonus and seizures. Treat with benzos and Cyproheptadine, a serotonin blocker. 

NEUROLEPTIC MALIGNANT SYNDROME is the slow, creeping onset (hence the term “malignant”) of muscular “lead pipe” rigidity and autonomic instability seen with high-potency antipsychotics, like Haloperidol. The treatment is largely supportive, you should start by taking them off of the causative antipsychotic.