How is innovative neurology research energising myasthenia?

Myasthenia gravis (MG) is one of the best characterised neurological disorders. The hallmark of MG is fatigable weakness. This manifests as intermittent ptosis (droopy eyelids), diplopia (double vision), and limb weakness. There are two main types-ocular MG affects just the eyes and eyelids, and generalised MG affects the body, including the bulbar functions of  breathing and swallowing.

By Doctor Jana - http://docjana.com/#/nmj, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=46835961
By Doctor Jana – http://docjana.com/#/nmj, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=46835961

 

The problem in MG is straightforward lack of communication; the nerves and muscles aren’t talking to each other. The two meet up at the neuromuscular junction (NMJ) where the nerves send packages of acetylcholine to bind with acetylcholine receptors (AChR) on the surface of the muscles. The muscles usually acknowledge this by contracting and producing action, but in MG this response is blocked by antibodies to the acetylcholine receptor (AChR antibodies). Like all culprits, it has wily accomplices such as anti-muscle specific kinase (anti-MUSK) antibody.

By No machine-readable author provided. S. Jähnichen assumed (based on copyright claims). - No machine-readable source provided. Own work assumed (based on copyright claims)., Public Domain, https://commons.wikimedia.org/w/index.php?curid=423915
By No machine-readable author provided. S. Jähnichen assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims)., Public Domain, https://commons.wikimedia.org/w/index.php?curid=423915

 

AChR antibodies are produced by a gland in the chest called the thymus. Disturbingly, this rather shabby-looking tissue may become enlarged (thymic hyperplasia), or cancerous (thymoma). The neurologist is therefore quick to request a CT chest scan as soon as MG is confirmed. Alas, the thymus is often normal or even shrivelled, to the delight of the patient who escapes the cardiothoracic surgeon. The neurologist is however ambivalent because surgery often gives a one-off cure, and saves the neurologist from a life-long commitment to monitor toxic treatments. The life of a Neurologist!

With so much known about MG, one would think there is very little on the horizon to put a smile on the faces of people with MG. But this old dog still has a few new tricks, and here are 4 energising reports I came across.

1. Predicting generalisation of ocular MG

By BruceBlaus. When using this image in external sources it can be cited as:Blausen.com staff. "Blausen gallery 2014". Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762. - Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=29452230
By BruceBlaus. When using this image in external sources it can be cited as:Blausen.com staff. “Blausen gallery 2014“. Wikiversity Journal of Medicine. DOI:10.15347/wjm/2014.010. ISSN 20018762. – Own work, CC BY 3.0, https://commons.wikimedia.org/w/index.php?curid=29452230

 

Neurologists are aware that ocular MG could transform to generalised MG, they just don’t know who is at risk. Generalised MG is obviously a worse condition and requires more heavy-duty treatments. After much speculation, a report in JAMA Neurology has found the predictor of MG generalisation. Titled Clinical Utility of Acetylcholine Receptor Antibody Testing in Ocular Myasthenia Gravis, the authors confirmed, for the first time ever, that the risk of generalisation is linked to higher AChR antibody levels. I know, you were expecting some new, cutting-edge test or technology: sorry for the dampener, but sometimes it’s the little things that count. 

2. Linking MG to muscular dystrophy

By Cbenner12 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19555962
By Cbenner12Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=19555962

 

Congenital myasthenia is a slightly different kettle of fish from conventional MG. For one, the diversity of genetic mutations that cause congenital myasthenia is mind-boggling; there are >20 genetic forms of MG such as DOK 7, RAPSYN, LAMB 2, and AGRIN. And these all differ in their presentation and response to treatment. An addition to this long list of congenital myasthenic syndromes should therefore normally not be exciting news. But there is something different in the recent report in the journal Brain about GMPPB (you really don’t want to know what this stands for). The paper, titled Mutations in GMPPB cause congenital myasthenic syndrome, opens up a can of worms because GMPPB also plays a role in causing muscular dystrophy. The authors see this as a bridge between myasthenia and muscular dystrophy. All rather complicated stuff, not quite sure what the implications are, but that’s the reason neurologists exist!

3. Leflunomide for drug-resistant MG

By MarinaVladivostok - Own work, CC0, https://commons.wikimedia.org/w/index.php?curid=27488894
By MarinaVladivostokOwn work, CC0, https://commons.wikimedia.org/w/index.php?curid=27488894

 

Immunosuppression is the ultimate treatment for MG because it reduces the production of the MG-causing antibodies. And the neurologist has a list, an arm length, of immunosuppressive agents to try. This variety of options is helpful because earlier choices may be ineffective, intolerable, or impractical. Azathioprine, methotrexate, mycophenolate …these roll out easily from the neurologist’s pen. Leflunomide would however sound very strange in neurological circles; it is more familiar to rheumatologists who use it to treat rheumatoid arthritis. Neurologists, ever peeping into the rheumatology recipe book, thought why not try Leflunomide in MG. They reported their findings in Journal of Neurology as Leflunomide treatment in corticosteroid-dependent myasthenia gravis: an open-label pilot study. And the recipe worked; 9 of 15 people with severe, steroid-dependent, MG improved on Leflunomide. Great news for when the going gets tough.

3, 4 Diaminopyridine for anti-MUSK MG

Thankfully not all MG treatment involves immunosuppression. One approach is to prevent the break down of the enzyme (esterase) that breaks down acetylcholine-got it? In this way there will be more acetylcholine available to counter the effect of AChR antibodies. Medications that work in this way are called acetylcoline esterase inhibitors (ACEI). It’s OK to  re-read all this before proceeding!

Pyridostigmine is the quintessential ACEI. But this is not effective in the more severe anti-MUSK MG where typical MG treatments don’t work so well. Neurologists have tried all sorts, including Rituximab, to varying success. What to do when all fails? A paper in the journal Neurology offers some hope that anti-MUSK MG may respond to 3,4 Diaminopyridine. This will be heart-warming news to all neurologists, if they ignore the fact that it is a single case report! But hey, from little acorns grow giant oak trees.

Want to dig deeper into MG? Try this update on myasthenia gravis.

Will a pill really hold the cure for CMT?

Charcot Marie Tooth disease (CMT) is the most important inherited peripheral neuropathy. As with most genetic diseases, there is no cure for CMT. The best neurologists can offer at the moment is supportive treatment for complications of CMT such as foot drop and foot deformities.

By Benefros at English Wikipedia - Own work, originally from en.wikipedia; description page is/was here., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2111831
By Benefros at English Wikipedia – Own work, originally from en.wikipedia; description page is/was here., CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=2111831

 

Neurologists are however very keen to go beyond platitudes and ankle supports for their patients with CMT. The holy grail of course is gene therapy, but this is still a far-off dream. As neurologists labour towards this utopia, they are also looking down to earth at drug treatments.

Prompted by reports that Vitamin C, yes Vitamin C,  effectively prevented neuropathy in mice, neurologists carried out a major trial in people with CMT. This was reported in Lancet Neurology titled Ascorbic acid in Charcot–Marie–Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial. Alas, Vitamin C was way off the mark in CMT.

Macrophages and red blood cells. The Journal of Cell Biology on Flikr. https://www.flickr.com/photos/thejcb/4115424607
Macrophages and red blood cells. The Journal of Cell Biology on Flikr. https://www.flickr.com/photos/thejcb/4115424607

Not deterred, the indefatigable neurologists have turned their sights on another agent. Perhaps because Vitamin C is too common, they went for something more exotic this time- inhibition of colony stimulating factor 1 (CSF1). The reason for picking on CSF1 is the observation that CMT is characterised by a low level inflammatory process, and CSF1 promotes inflammation by stimulating the production of the inflammatory cells called macrophages. The plan therefore is to wipe out macrophages by cutting their supply line, CSF 1. And the military-style strategy went according to plan.

Five baby mice eating icecream. Radagast on Flikr. https://www.flickr.com/photos/radagast/1417560
Five baby mice eating icecream. Radagast on Flikr. https://www.flickr.com/photos/radagast/1417560

The study, reported in the journal Brain, is titled Targeting the colony stimulating factor 1 receptor alleviates two forms of Charcot-Marie-Tooth disease in mice. The researchers fed an inhibitor of CSF 1 to mice models of CMT. Following the successful outcome, they proudly announced that “an orally administered inhibitor of CSF1R may offer a highly efficacious and safe treatment option for at least two distinct forms of the presently non-treatable Charcot-Marie-Tooth type 1 neuropathies“. Two for the price of one! Next stop, human trials-the waterloo of many a researcher!

DNA rendering. ynse on Flikr. https://www.flickr.com/photos/ynse/542370154
DNA rendering. ynse on Flikr. https://www.flickr.com/photos/ynse/542370154

 

Do you want to explore the genetic neuropathies a bit more? You couldn’t do better than this excellent review in Practical Neurology by Alexander Rossor, Matthew Evans, and Mary Reilly titled A practical approach to the genetic neuropathies. Click away!

What’s happening at the cutting edge of MSA?

Multiple system atrophy (MSA) is a mimic of Parkinson’s disease (PD). Neurologists suspect MSA in people with apparent PD who, in addition, have other defining features. In many people with MSA their prominent symptoms are cerebellar dysfunction (MSA-C), and these have unsteadiness and incoordination of movements. In other people with MSA the predominant symptoms are of Parkinsonism, and this type is called MSA-P.

By Images are generated by Life Science Databases(LSDB). - from Anatomography[1] website maintained by Life Science Databases(LSDB).You can get this image through URL below. 次のアドレスからこのファイルで使用している画像を取得できますURL., CC BY-SA 2.1 jp, https://commons.wikimedia.org/w/index.php?curid=7769113
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Making a diagnosis of MSA is gratifying, but treating it is frustrating. Only about a third of people with MSA respond to the standard PD medication, Levodopa. Furthermore, MSA confers a shortened life expectancy. It is therefore important that neurologists resolve the mystery of MSA, and they are indeed hacking away at its cutting-edge.

Genetics

The general assumption is that MSA is acquired rather than inherited. This assumption did not dissuade neurologists from looking for MSA genetic risk factors, and their quest has led to the discovery of a candidate MSA gene. This is called coenzyme Q2 4-hydroxybenzoate polyprenyltransferase, or simply the COQ2 gene. This gene was first touted in a 2013 paper in the New England Journal of Medicine titled Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy. Using whole genome sequencing, the authors identified COQ2 gene mutations in both sporadic and familial cases of MSA. Another paper in Neurology in 2016, titled New susceptible variant of COQ2 gene in Japanese patients with sporadic multiple system atrophy, reported that the COQ2 gene mutation is more likely in MSA-C than in other types of MSA.

You may explore the genetics of MSA further in this paper in Neurobiology of Aging titled Genetic players in multiple system atrophy: unfolding the nature of the beast.

Differential diagnoses

When neurologists are considering the diagnosis of MSA, they come up against many disorders jostling to confuse them. There are of course PD and related conditions such as progressive supranuclear palsy (PSP). There is also the endless list of conditions which cause either cerebellar or autonomic dysfunction. The neurologist is usually cautious to exclude these known differential diagnoses of MSA. But what happens when they come across a mimic that isn’t in the textbooks? Such is the situation with this case report published in Movement Disorders of Concomitant Facioscapulohumeral Muscular Dystrophy and Parkinsonism Mimicking Multiple System Atrophy.

This case defies the law of parsimony, Occam’s razor. To paraphrase, this law states that a single diagnosis is the most likely cause for a patient’s clinical features. Clearly in some cases such as this, the neurologist must disregard William of Occam, and make multiple diagnoses.

Investigations
Hot cross bun. Liliana Fuchs on Flikr. https://www.flickr.com/photos/akane86/5208128379
Hot cross bun. Liliana Fuchs on Flikr. https://www.flickr.com/photos/akane86/5208128379

Neurologists often request some tests to confirm their suspicion of MSA. The usual investigation is the painless but claustrophobic magnetic resonance imaging (MRI). In MSA, this shows shrinking or atrophy of the cerebellum. It may also show the hot cross bun sign, a characteristic pattern of shrinking of the chunky middle section of the brainstem, the pons.

Big MRI. liz west on Flikr. https://www.flickr.com/photos/calliope/223220955
Big MRI. liz west on Flikr. https://www.flickr.com/photos/calliope/223220955

Some neurologists are not satisfied with this culinary sign and have explored other radiological indicators of MSA. They studied an MRI technique called diffusion tensor imaging tractography (DTI tractography) and reported their findings in the Journal of Neurology. Their paper titled Characteristic diffusion tensor tractography in multiple system atrophy reports that DTI tractography appears to distinguish MSA-C from other causes of cerebellar dysfunction.

Biomarkers

Biomarkers again, so soon after my previous blog post, What is the state of parkinson’s disease biomarkers. The whole idea behind biomarkers is their potential to make for an easier and earlier diagnosis. They are all the rage in neurodegenerative diseases, and MSA can’t be an exception. The first potential MSA biomarker is α-synuclein, the abnormal protein that is found in the brains of people with PD, MSA and Lewy body disease (LBD), the so-called synucleopathies. Researchers have now discovered that α-synuclein also resides in the skin. They carried out skin biopsies in people with PD and MSA and found skin deposits of α-synuclein in both. Writing in the journal Movement Disorders, they showed that in PD, the deposits were mainly in autonomic nerve fibers, whilst in MSA they were in the larger somatic nerves. Time to brush up those skin biopsy skills!

The second potential biomarker is optical coherence tomography (OCT). This is reported in Movement Disorders in a paper titled Progressive retinal structure abnormalities in multiple system atrophy. The authors used OCT to measure the thickness of the retina of the eye. They demonstrated that the retina is thin in both PD and MSA, but the thinning advances more rapidly in MSA than in PD. If confirmed, this would be a handy, and painless, biomarker.

Potential treatments
Syringe and vaccine. Niaid on Flikr. https://www.flickr.com/photos/niaid/14329622976
Syringe and vaccine. Niaid on Flikr. https://www.flickr.com/photos/niaid/14329622976

The objective of all research is to arrive at effective treatments. There is unfortunately no bright treatment looming in the MSA horizon because the research so far have produced disappointing results. Such failures include Rifampicin, Fluoxetine and Lithium. There is however no scarcity of potential therapeutic candidates. The most exciting is a vaccine against MSA. For this and other research efforts read this excellent review in Advances in Clinical Neurology and Rehabilitation (ACNR) titled Updates on potential therapeutic targets in MSA.

 

 

What is the state of Parkinson’s disease biomarkers?

Neurologists are always cautious when making a diagnosis of Parkinson’s disease (PD). This shouldn’t be the case because PD is not difficult to recognise-at least not most of the time. For one, PD has classical clinical signs- the trio of resting tremor, slow movements (bradykinesia), and stiffness (rigidity). For another, it is asymmetrical, starting and remaining worse on one side of the body.

All these features are however vague in the early stages of PD. To make matters worse, there are many other diseases that mimic PD. These include multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Lewy body disease (LBD), corticobasal degeneration (CBD), and even SWEDDS (if it exists at all!). And always lurking in the shadows, waiting to catch the neurologist out, are dystonic tremor and essential tremor.

Marking Parkinson's. EMSL on Flikr. https://www.flickr.com/photos/emsl/4704802544
Marking Parkinson’s. EMSL on Flikr. https://www.flickr.com/photos/emsl/4704802544

 

These PD mimics challenge and intrigue neurologists in equal measure. They contribute to the delayed and missed diagnosis of PD in 20% of cases. Are there shortcuts out there to improve our diagnostic accuracy? A simple test perhaps? Maybe some biomarker? Here are 6 budding contestants.

1. Dopamine transporter (DAT) scans

Dopamine. John Lester on Flikr. https://www.flickr.com/photos/pathfinderlinden/211882099/in/photolist-jHXaD
Dopamine. John Lester on Flikr. https://www.flickr.com/photos/pathfinderlinden/211882099/in/photolist-jHXaD

DAT scans are now in general, even if not universal, use. They help to distinguish PD from conditions such as essential tremor or drug-induced Parkinsonism. DAT scans are however expensive, and they do not distinguish PD from many of its other mimics such as MSA, PSP, (you know the roll call). There are indications that DAT scans may be normal in cases of PD. We therefore clearly need better, cheaper (and newer!) PD biomarkers than DAT scans.

2. Cerebrospinal fluid (CSF) biomarkers

© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
© Nevit Dilmen [CC BY-SA 3.0 or GFDL], via Wikimedia Commons
Perhaps the answer is in a spinal tap or lumbar puncture (LP). A lumbar puncture is a simple but dreaded test. It is however useful for giving us access to the cerebrospinal fluid (CSF) that bathes the brain and spinal cord. Analysis of the CSF often gives the game away in many neurological disorders. It is not surprising therefore that researchers looked at a panel of nine CSF biomarkers that may identify PD. The paper, published in the JNNP, suggests that there may be biomarker roles for neurofilament light chain (NFL), soluble amyloid precursor protein (sAPP), and α-synuclein (of course). CSF α-synuclein is the focus of another paper in BioMedCentral which reports that one form, oligomeric α-synuclein, is the one to watch out for.

Another set of CSF biomarkers is related to blood vessel formation (angiogenesis). I came across this in a paper in Neurology titled Increased CSF biomarkers of angiogenesis in Parkinson disease. The authors are referring to vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and VEGFR-2. Others are placental growth factor (PlGF), angiopoietin 2 (Ang2), and interleukin-8. Enough to keep researchers busy for a while.

3. Peripheral blood biomarkers

Even the most compliant patient would prefer to have a blood test rather than a spinal tap. Thankfully there are some blood-based biomarkers in the offing. One set are called α-synuclein blood transcripts (SNCA transcripts). The authors of an article published in the journal Brain report that SNCA transcripts are consistently reduced in the blood of people with early PD. The accompanying editorial however cautions on the utility of these SNCA transcripts because low levels are also seen in some people who do not have PD. The true value of SNCA transcripts may lie in their ability to predict cognitive decline, but how many people really want to know that?

Other potential blood based biomarkers mentioned are uric acid and epidermal growth factor (EGF).

4. Retinal optical coherence tomography (OCT)

CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=525623
CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=525623

Even better than blood and spinal fluid biomarkers would be something totally painless. And to the rescue comes retinal optical coherence tomography (OCT). OCT uses light waves to take pictures of the retina. This allows measurement of the size of different parts of the retina; the area of interest in PD is called the foveal pit. A paper in Movement Disorders reports that OCT is a sensitive marker of PD. The authors show that the foveal pit in PD has a unique form; it is shallow in the superior-inferior and the nasal-temporal slopes. Perhaps neurologists will soon be running to ophthalmologists, cap-in-hand, to save their blushes.

5. Salivary gland α-synuclein

Public Domain, https://commons.wikimedia.org/w/index.php?curid=1074079
Public Domain, https://commons.wikimedia.org/w/index.php?curid=1074079

 

Back to painful biomarkers I’m afraid, all in aid of clinching an early diagnosis you must understand. This time it’s salivary gland biopsy. Some eager researchers took biopsy samples of the submandibular salivary glands of people with early PD. They then looked for, and found, α-synuclein in about 75% of them. Their paper is published in Movement Disorders titled Peripheral Synucleinopathy in Early Parkinson’s Disease: Submandibular Gland Needle Biopsy Findings. Unfortunately  20% of control subjects without PD also had α-synuclein in their salivary glands. Could these people have pre-manifest PD? We must await larger and longer studies before we start needling away at the salivary glands of the worried-well.

6. Intestinal tract α-synuclein

What if the answer is not in the salivary glands? Then we should be really afraid because α-synuclein has popped up in …the intestines. A review paper in Movement Disorders describes this in the brilliantly titled Gut Feelings About α-Synuclein in Gastrointestinal Biopsies: Biomarker in the Making? Another paper published in PLOS One takes things further, reporting an association between intestinal α-synuclein with increased gut permeability. I’ll make no further comments on the gut; not with the threat of cameras and scopes going up all sorts of body openings.

α-synuclein staining of a Lewy body. By Marvin 101 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521
α-synuclein staining of a Lewy body. By Marvin 101Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=7533521

Below is a link to an open access article in Movement Disorders with more potential PD biomarkers

Are there any other biomarkers out there? Please leave a comment.

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neurochecklists-image

What precisely is the driver for essential tremor?

Neurologists do not break into a sweat when they make the diagnosis of essential tremor (ET). Theoretically, at least, they shouldn’t. Essential tremor presents with an obvious shaking of the hands when performing tasks; this is unlike the tremor of Parkinson’s disease which is typically at rest. Neurologists also have handy evidence-based treatment guidelines which recommend medications such as Propranolol and Primidone.

tremors. Daniel Chong Kah Fui דניאל 張家輝 on Flikr. https://www.flickr.com/photos/dckf/281301724/in/photolist-qRKcJ
tremors. Daniel Chong Kah Fui דניאל 張家輝 on Flikr. https://www.flickr.com/photos/dckf/281301724/in/photolist-qRKcJ

 

Essential tremor is however anything but straightforward. Tremor is a feature of many other medical and neurological diseases. Neurologists also know that essential tremor may mimic Parkinson’s disease and dystonic tremor. To muddy the waters further, essential tremor also has non-motor symptoms such as cognitive difficulties. And to add to the frustration, the touted evidence-based treatments, when tolerated, rarely work well enough. These twists and turns that accompany essential tremor are the reasons a review article in Practical Neurology labelled it ‘deceptively simple‘. This deception extends to the core puzzle in essential tremor-what causes it? Here are two tantalising suggestions which attempt to answer this question.

Is essential tremor a neurodegenerative disease?

L1070037. haemin kim on Flikr. https://www.flickr.com/photos/kimhaemin/1347409143/in/photolist-344PN8
L1070037. haemin kim on Flikr. https://www.flickr.com/photos/kimhaemin/1347409143/in/photolist-344PN8

 

Neurodegeneration is the usual suspect when neurologists are looking for ‘a cause’. With essential tremor the focus has been on the cerebellum, the part of the brain that co-ordinates movements. This is logical because tremor is a classical symptom of diseases of the cerebellum. This link, circumstantial as it is, has led researchers to interrogate the cerebellum in essential tremor. In doing this they also wondered if the problem is neurodegenerative. The logic behind this line of thinking is explained in a paper published in JAMA Neurology in 2009 titled, Essential tremors: a family of neurodegenerative disorders? 

B0006224 Purkinje cells in the cerebellum. Ludovic Collin / Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/6880271296
B0006224 Purkinje cells in the cerebellum. Ludovic Collin / Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/6880271296

 

Pursuing this lead, some researchers have tried to hone down on which of the different types of cerebellar cells is involved in essential tremor. Writing in the journal Movement Disorders, the authors are convinced that the seat of neurodegeneration in essential tremor is the Purkinje cell. Purkinje cells are unique cerebellar cells which are vulnerable to all sorts of insults. The researchers in this case demonstrated significantly fewer Purkinje cells in the brains of people with essential tremor than in control subjects without the disease. And they attributed this pathology to neurodegeneration (what else?). The answer to a long-standing riddle, or a hasty conclusion?

Purkinje cell Saguaro. Anita Gould on Flikr. https://www.flickr.com/photos/anitagould/3427285447
Purkinje cell Saguaro. Anita Gould on Flikr. https://www.flickr.com/photos/anitagould/3427285447

 

Is essential tremor a channelopathy?

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Neurologists have known for a long time that essential tremor has a strong genetic element. The diagnosis always feels more certain when there is another family member with tremor. The exact nature of this genetic link is however uncertain. Into this void comes a research paper suggesting that people with essential tremor may have abnormal cellular channels. Channels are proteins in the cell wall that let electrolytes like sodium and potassium in and out, and channelopathies are diseases that affect these channels. The authors of this paper studied a large essential tremor family who also suffer with epilepsy, a typical channel disorder. And the genetic tests they carried out revealed an abnormality in the SCN4A sodium channel. Correlation or causation? The mystery only deepens, I think.

tremor. Rufus Gefangenen on Flikr. https://www.flickr.com/photos/rufo_83/330164755/in/photolist-vbbtM
tremor. Rufus Gefangenen on Flikr. https://www.flickr.com/photos/rufo_83/330164755/in/photolist-vbbtM

 

As researchers dig deeper, they will have to decide if it’s neurodegeneration or channelopathy. Or perhaps both. This may then open the doors to better treatments for the disease, confining Propranolol and Primidone to the history books.

 

 

How is neurology stamping out the anguish of Duchenne?

Duchenne muscular dystrophy (DMD) is the most familiar of the inherited muscle diseases called muscular dystrophies. DMD is life limiting, but advances in care are enabling children born with this disease to survive well into adulthood. The disease is named after the French neurologist Guillaume Duchenne.

See page for author [CC BY 4.0], via Wikimedia Commons
See page for author [CC BY 4.0], via Wikimedia Commons

The foundation of long survival in DMD is close supervision of breathing and heart functions. DMD however affects much more than these vital functions, and it remains a challenging disease for families and management teams. Thankfully researchers are not resting on their laurels, working ever hard on heart-warming advances. Here are three.

STEROIDS

By Ring0 (Own work) [Public domain], via Wikimedia Commons
By Ring0 (Own work) [Public domain], via Wikimedia Commons
Steroids are now well-established in the treatment of Duchenne muscular dystrophy. What is new however is a better understanding of their benefits in DMD, together with clearer guidance on their use. This is contained in the recent practice guideline update summary: Corticosteroid treatment of Duchenne muscular dystrophy.

Published in the journal Neurology, this document shows how steroids help to improve muscle strength, maintain breathing functions, stabilise ambulation, prevent spinal deterioration (scoliosis), and delay onset of heart disease.

Is there more one could hope for? Yes, a lot more when it comes to genetic diseases.

IDEBENONE

Mitokondria. 140264jd on Flikr. https://www.flickr.com/photos/140264jd/6286783453/in/photostream/
Mitokondria. 140264jd on Flikr. https://www.flickr.com/photos/140264jd/6286783453/in/photostream/

 

Idebenone is not new to neurologists. Researchers at Newcastle have been investigating its vision-preserving effect in the mitochondrial disease called Leber’s hereditary optic neuropathy (LHON). Idebenone is thought to improve the activity of mitochondria, the energy-producing component of all cells. Idebenone has also been investigated in other neurological disorders such as Friedreich’s ataxia.

Perhaps as an indication of its growing importance, researchers have now looked at the effect of Idebenone in people with DMD, and they did this in two separate trials. DELPHI is published in the journal Neuromuscular Disorders as Idebenone as a novel, therapeutic approach for Duchenne muscular dystrophy. The authors reported benefit in both cardiac and respiratory function.

DELOS, the second trial, is published in Lancet Neurology and titled Efficacy of idebenone on respiratory function in patients with Duchenne muscular dystrophy not using glucocorticoids. The authors again reported similar benefits. For a synthesised take, see this useful review in Touch Neurology.

But is this enough for ambitious researchers? Of course not…not when you see the promise of gene editing.

GENE EDITING

Jazz Mouse. Richard Scott on Flikr. https://www.flickr.com/photos/richardmscott/2091183925
Jazz Mouse. Richard Scott on Flikr. https://www.flickr.com/photos/richardmscott/2091183925

 

I first came across this in Eureka Alert which proclaimed: Gene-editing technique successfully stops progression of Duchenne muscular dystrophy. The gene editing, or gene splicing, technique is called CRISPR. The research itself is published in the journal Science as In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.

The researchers used CRISPR technology to delete exon 23 from the Duchenne gene on the X chromosome. Exon 23 is the site of the fault that makes DMD patients unable to produce the muscle protein called dystrophin. By splicing this exon out, the researchers demonstrated an increase in the production of dystrophin. And this increase was significant enough to lead to an improvement in muscle strength.

OK, its only the humble mouse at the moment, but exon skipping therapy is clearly beckoning.

B0007267 Muscle Fibers. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814145089
B0007267 Muscle Fibers. Welcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814145089