Posts about neurology from 2 of our recent medical students

drexel_medicine_white_coat_2012

 

Posted by Ilya Grinberg:

Last week I participated in the MDA clinic and there was one patient who really stuck out in my mind. He was a 17 year old male who had Duchenne Muscular Dystrophy. He was completely wheelchair-bound and could barely move any of his extremities. This obviously meant that he was completely reliant on people to take care of him and that he could not participate in the day to day activities that a normal person could. He was also starting to have breathing difficulty and probably would need to start therapy on a ventilator soon too.

DMD is an x-linked recessive disorder that affects boys from an early age. It affects 1 out of 3600 boys so it is not too uncommon. The disease is due to a mutation of the structural protein Dystrophin which is normally found in all muscles. The protein is found on the X chromosome which explains why it is an X-linked disease. Patients are usually born normally but will start gradually developing symptoms during the first few years of life. The first observations are usually progressive muscle weakness in proximal muscles in addition to muscle atrophy. One of the key clinical signs in DMD is calf psuedohypertrophy which occurs due to fibrosis of the necrotic muscle tissue. Another common finding that presents early on is Gower’s sign, where the patient uses his arms to stand up due to weakness in the proximal leg muscles.

Click here to find out more about DMD.

 

Posted by John Soliman:

What is Neurology one may ask? Prior to and during medical school I feel like the exposure to the study of neurology was very limited. Interaction between neurological patients and medical professions was far and few between. I have had little encounters with the realm that lies ahead. Prior to starting the clerkship I was very intimidated due to my lack of knowledge and ignorance. I can say jokingly I barely knew how to spell Neurology. Even the basics of neurology such as anatomy was daunting usually getting hung up on learning one part or area as seen in this video. I have to say I had something in common with Pinky.

After the 4 weeks of neurology I have realized that neurology covers a broad realm of knowledge and information on the central and peripheral nervous system.

During my clerkship I was lucky enough to be exposed to many patients encountering a lot of this medical conditions and problems. I was able to identify and correlate symptoms with disease states and vice versa.

The most memorable experience was the MDA clinic. I was able to meet and was integrated into the care of a lot of the Myotonic dystrophy patients. I was able to see hear their day to day life experience, talk to their care givers and be able to help with their care. After seeing patients like this it really brought “problems” Into perspective. The amazing thing was the broad range of how these medical conditions affect each individual differently.

I had the opportunity to see two brothers who are both affected with Myotonic Dystrophy. One brother can walk, talk and act normal with minimal weakness while the other was wheel chair bound. Talking to them brought home how a muscular dystrophy can affect the lives of affected individuals. Myotonic dystrophy is an autosomal dominant genetic process which means it can affect 50% of the carriers offspring. This may affect a family’s decision on having kids both mentally and psychologically. In this specific case, one of the brothers and his wife decided to adopt children due to the high risk of having a child with myotonic dystrophy. Dealing with something like this is a full time job on its own so it can be draining mentally, physically and financially on families.

Overall the experience has been great as I have gotten to see patients with medical conditions that I may not be able to see again. This clerkship has been knowledgeable and I has encountered a broad real of neurology that I never had experienced in the past.

Click here to find out more about Myotonic Dystrophy.

Click here to find out more about MDA Clinic at Monmouth.

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Exon Skipping for Duchenne Muscular Dsystrophy

There was some exciting data presented at MDA’s 2014 clinical Conference held this week in Chicago regarding gene therapy for Duchenne muscular dystrophy (DMD).

What is exon skipping?

skimming_stones

Many cases of DMD are caused by small deletions in the dystrophin gene which lead to frame shifts and totally disrupt transcription:

If you imagine that the gene is made up of segments (or exons) which ultimately spliced together to make a recipe or message for producing the protein:

exon-skipping-scheme

A deletion of exon 71 would be considered “in frame” because the 70 and 72 could still joint up and allow transcription.  However, a deletion of exons 48 through 50 would be “out of frame” since 47 and 51 do not splice back together to form the message:

exon

The message would become corrupted and the gene product, in this case dystrophin, would be dysfunctional or even totally absent:

frameshift

The drug Eteplirsen will link 47 and 51 back together again, and in so doing restore the reading frame and facilitate transcription of an altered but hopefully functional gene product:

exon skiip

Does it work?

A clinical study started in August 2011

The preliminary results from this study were very encouraging – the boys who received the drug maintained strength and walking ability and there were no treatment related adverse effects.

What’s the next step?

Gene therapy trial for Duchenne Muscular Dystrophy

dmd

Duchenne and Becker muscular dystrophy are both caused by mutations in the same dystrophin gene.

How it this possible?

Well, the genetic code which is translated to from proteins “talks” in words made of three letters (base pairs).

dmd dna

A gene mutation that deletes only one or two base pairs, or worse still signals the end of the word (known a “premature stop codon”) will result it a very abnormal dysfunctional gene product, leading to complete deficiency of functioning dystrophin, and the more severe Duchenne Muscular Dystrophy.

dmd muscle bx

Normal muscle bx (a) vs Duchenne muscular dystrophy (b) with complete absence of dystrophin (d)

However a gene mutation (deletion) that removes base pairs in a multiples of three is called an in-frame mutation, and causes a (sometimes only minor) qualitative change in the dystrophin protein, leading to the milder Becker’s muscular dystrophy.

Ataluren (also known as PTC124) is a small molecule designed to overcome premature stop codons.

alturen

Put simply, the idea is that it might convert some Duchenne boys in to a milder form (more like Becker’s) of muscular dystrophy by allowing them to produce some more normal dystrophin.

The drug can only help boys affected with premature stop codons confirmed by DNA testing.

The drug is currently undergoing Phase III trialsClick here for more information.

Duchenne Muscular Dystrophy

Posted by Elliot Dubowitch from Drexel University College of Medicine Class of 2014

Duchenne muscular dystrophy (DMD) is one of the four main groups  of muscular dystrophy, a muscle disorder that affects and weakens the musculoskeletal system.

Muscular dystrophies are genetically inherited and progressive.

DMD is inherited in an x-linked manner.  This means that the mother, who is unaffected, is a carrier for the disease and has a 50% chance of passing it on to her male children.

The disease is caused by a deficiency in the Dystrophin protein, a complex that anchors the muscle to surrounding tissue.

dystrophin

This disease has a wide spectrum of symptom severity, depending on the type of genetic mutation, with Duchenne being very severe, and Becker’s muscular dystrophy being much more mild.

The symptoms in DMD are not usually present at birth.  As the child ages, however, they symptoms will gradually become worse and worse.  Most children are unable to walk by thirteen years of age and die in their twenties due to respiratory failure.

One of the earliest signs of DMD is called to as the “Gower Maneuver.”  Although not pathognomonic for DMD, this maneuver is a sign for proximal muscle weakness and is often correlated with DMD.  Below is a clip of a child performing to Gower’s maneuver to stand.  The patient must “walk” up his body using his hands from a sitting position due to weakness in his hip and thigh muscles.  Below is a video clip demonstrating this.

Another early sign is calf pseudohypertrophy.  Although the muscle looks bigger, it is not necessarily stronger, as the functional muscle is replaced by nonfunctional fibrous tissue.

Unfortunately, there is currently no cure for DMD.  However, there is symptomatic treatment available, such as respiratory support, cardiovascular monitoring and treatment and (if needed) surgery for scoliosis.

Steroids are the only current medication that has been shown to keep the boys walking longer.  A study was conducted in which one group of boys were given steroids daily, whereas the other group of boys were given steroids 10 days on and 10 days off.  The boys receiving daily steroids walked on average until the age of 14.5 year, while the boys receiving steroids intermittently walked to only 12 years of age.  The boys receiving continuous steroids also had more side effects including weight gain, mood swings, increase risk of infection, and other side effects of steroid usage.  If one is to consider steroid use, it is imperative to remember that it must be used at the time the child is still ambulating.  The boy will not regain lost function, however he may retain his current function longer.  In the future we hope that new drugs like VBP-15 will hopefully provide the benefits of corticosteroids without some of the side effects.

Genetic research is currently being done to hopefully find a cure for this disease.

VBP-15 for Duchenne Muscular Dystrophy

Prednisone has been used since the 1970s for delaying the otherwise obligatory progressive motor deterioration seen in  Duchenne Muscular Dystrophy (DMD.

A good deal of data has been acquired over the years.  In fact there are even ongoing studies looking at different dosing regimens.

The drug is typically started between ages 4-6 at a dose of 0.75 mg/Kg.  However, steroid cause may side effects to Duchenne boys, including weight gain and behavioral problems.

How does it work?  We’re not sure, but we think the medication stabilizes muscle membranes and inhibiting cytotoxic T-cells.

Side effects are mediated by binding sites in the cell nucleus which lead to initiation of metabolic pathways :
NM2

The new drug VBP-15 is molecularity very similar to Prednisone, but lacks the 11 beta hydroxy arm, which reduces the metabolic side effects, without affecting the beneficial membrane stabilizing effects:

nm3

VBP-15 has been shown to improve muscle strength and function in an animal model of DMD without the metabolic side effects of Prednisone:

nm4

Clinical trials in humans are expected to begin in 2013-14.

Watch this space for more information.

BYM338 (Bimagrumab) for Inclusion Body Myositis – New cure or next dud?

Posted by Jeffrey Schneider, MSIV, Drexel University College of Medicine

There has recently been a flurry of news articles about a new treatment in clinical trials for Inclusion Body Myositis. Novartis has announced that BYM338 (Bimagrumab) has recently received FDA breakthrough status for the treatment of inclusion body myositis. What does this mean and what are the implications? Is this a cure or sensationalist hype? What do we need to know about BYM338 other than a sorely needed name change. Before we get to that let’s talk a little about inclusion body myositis.

What is Inclusion Body Myositis?

Inclusion Body Myositis (IBM) is a progressive disease of muscle weakness. Myositis, derived from Greek as many of our beloved medical terms are, is aptly named as it is a disease characterized by inflammation of the muscle. This disease most commonly presents insidiously with weakness of the fingers and quadriceps (thigh). This leads to difficulty with everyday activities like walking or holding objects. Some may also develop dysphagia (difficulty swallowing). The disease may occur sporadically (sIBM) and rarely as Hereditary IBM. It is not a fatal disease but the progressive muscle weakness means that many will rely on assistance for walking and everyday activity within 5 years.  This condition can often be difficult to diagnosis and can be aided with the help of a muscle biopsy.

Epidimiology

IBM is an age related disease that typically affects those 50 and older. Men are more often affected It is the most common of the inflammatory myopathies but is still a relatively rare condition

Differential Diagnosis

A common laboratory finding of myositis is an elevated in Creatine Kinase (CK).  CK, however, is not specific for just Inclusion Body Myositis and many conditions may also have this abnormal laboratory finding. More commonly cholesterol lowering drugs like Statins and Fibrates may lead to myositis. IBM may be mistaken for the other inflammatory myopathies, polymyositis and dermatomyositis. Polymyositis and dermatomyositis are treated with steroids and other immunosuppressive drugs of which have little effect on IBM which can sometimes be the clue that you might be dealing with IBM.

Pathology

The cause of IBM is not fully understood. What is evident is that there is an element of muscle inflammation and an element of muscle degeneration. A muscle biopsy will show the architecture of muscle at the microscopic level. Some of the key features that help to identify IBM are of course the inclusion body itself which are abnormal clumps of protein and tubules. Another feature are rimmed vacuoles which are empty pockets found within the cells. They are found in other inflammatory myopathies but occur in greater numbers in IBM.

Here is another biopsy slide showing some of the characteristic vacuoles and also the inflammatory cells in the endomysium (the layer that surrounds each individual muscle fiber).

Current Treatment

Unlike dermatomyositis and polymyositis there is currently no effective treatment of IBM.  Studies have shown the failure of steroids and other immunosuppressive agents.  Therefore it is approached symptomatically with physical therapy and exercise.

Where does that leave us now?

Novartis’ recent announcement is quite an interesting one. BYM338 (Bimagrumab) is a monoclonal antibody targeted to a very specific receptor on muscles cells. Monoclonal antibody therapy is a very field based on the human body’s own immune system.  B cells, a type of white blood cell, produce millions of variations on a common antibody to target infection. When the right antibody is found to bind to an infectious particle that B cell will undergo a series of interactions leading to cloning of that cell. This is the monoclonal proliferation that leads to a highly specific response. Researchers  have taken advantage of this concept to create highly targeted drugs.

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In the case of BYM338 (Bimagrumab), it is targeted to Type II Activin receptors on muscle tissue. This receptor normally binds an enzyme called Myostatin which inhibits muscle growth. By blocking this receptor the drug is blocking the effect of Myostatin and in theory allowing muscle growth. It is a novel approach to muscle degeneration seen in IBM.An interesting side note is that there is a breed of cattle with a defect in the gene for myostatin. The Breed is called Belgian Blue, their mutation leads to non-functioning Myostatin. They also look like this…

So is this the cure to IBM that we have been looking for. Currently the data has not been published so it is impossible to say. What we do now is that the FDA has approved BYM338 for “breakthrough” status. What this means is that the FDA is going to expedite the review of BYM338 based on what it has seen so far. This does not mean that it is a new breakthrough therapy that has passed all of its tests but rather that the FDA is intrigued by its prospects. It is also important to know that BYM338 has only gone through Phase II of Clinical trials. Phase I assesses the safety of a drug. Phase II trials are compared against placebo with a relatively small sample size (100-300). Phase 3 trials and FDA review will most likely take several more years before we will find out whether BYM338, or rather endearingly BYM338, lives up to its expectations. Could this drug be expanded to treat muscle wasting in cancer patients or the elderly? That is something developers are probably interested in but we currently don’t have the published data to support it. Could this effectively treat IBM? Maybe. Could this be a dud? Possibly. Will it be expensive? Most definitely.