Multiple Sclerosis (IMSGC, 2019) – Is MS genetic?

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Is MS genetic? A sample MS report from Nebula Genomics
Is MS genetic? A sample report of MS genetic variants from Nebula Genomics

Additional Information

What is MS? (Part 1 of is MS genetic?)

Multiple sclerosis (MS) or encephalomyelitis disseminata (ED) is a chronic inflammatory neurological autoimmune disease with very different forms of progression, depending on the area of nerve damage, the extent, and the severity of the disease. Specifically, it attacks the myelin sheaths in the brain and spinal cord of the central nervous system (CNS). Myelin sheaths are insulating layers that protect nerves. The attacks cause the myelin sheath to become inflamed in small patches (plaques or lesions), which can be seen on an MRI scan. Disruption of messages sent along the nerves causes MS symptoms.

Biological effects of disease in neurons
The biological changes in MS. BruceBlaus. Attribution-Share Alike 4.0 International

There are two main types of MS: primary progressive MS, in which the disease is characterized by worsening neurological functions without relapses or remissions, and relapse-remitting MS, in which symptoms tend to occur in distinguishable episodes, or relapses. Secondary progressive MS follows an initial relapsing-remitting course.

The exact causes of the disease have not yet been clarified despite research efforts. In MS, many (multiple) inflammatory demyelination foci are scattered in the white matter of the brain and spinal cord, presumably caused by the attack of the body’s own immune cells on the myelin sheaths of the nerve cell processes. Since the centres of demyelination can occur throughout the entire CNS, multiple sclerosis can cause almost any neurological symptom. Visual disturbances and blurred vision can eventually lead to blindness and disorders of eye movements (internuclear ophthalmoplegia), but are not specific for multiple sclerosis. 

Along with epilepsy, MS is one of the most common neurological diseases in young adults. There is no cure for the disease, but its course can often be influenced favorably by various measures. Multiple sclerosis does not necessarily lead to severe disabilities.

Is MS genetic?

Although the exact cause of MS is unknown, most experts believe that a combination of genetic and environmental factors act as a trigger for the characteristic immune-mediated damage. 

As of October 2013, 110 genetic variations have been identified that occur more frequently in MS patients than in the general population and may contribute to a predisposition to multiple sclerosis. That number is around 200 in 2020. Although each of these variations alone represents only a very low risk for the development of MS, together they account for about 20 percent of the genetic components of the disease. 

Among other things, polymorphisms of genes involved in the interleukin signaling pathway are thought to be involved. Many of the gene variants found are directly related to the immune system. Some of them could also be identified as genetic risk factors in autoimmune diseases such as diabetes type 1 or Crohn’s disease. 

According to the National Multiple Sclerosis Society, the general population’s risk of developing MS is about 1 in 750 – 1000. In identical twins, if one twin has MS the risk that the other twin will develop MS is about 1 in 4. The risk of developing MS is also increased when other first degree relatives (parents, siblings and children) have MS, but far less than in identical twins.

Research is ongoing to better understand genetic risk and other factors that contribute to the development of MS.

Non-genetic risk factors (Part 3 of Is MS genetic?)

Multiple non-genetic factors have been suspected to bring on MS. Some of the most researched factors are described below. 

Infection 

Numerous viruses (including Epstein-Barr virus and human herpes virus 6) have been attributed a possible role in the development of disease. In fact, an immune reaction against the Epstein-Barr virus is more frequently detectable in children with multiple sclerosis in particular than in children who do not suffer from the disease. Bacterial pathogens (including chlamydia, spirochaetes, rickettsia and Streptococcus mutans) have also been associated with the development of multiple sclerosis.

Vitamin D

Growing evidence suggests that vitamin D plays an important role in MS. Low vitamin D levels in the blood have been identified as a risk factor for the development of MS. Some researchers believe that sun exposure (the natural source of Vitamin D) may help to explain why people who live closer to the equator are less likely to develop MS. The theory is that living closer to the equator results in more sunlight (and thus vitamin D exposure) year-round. Vitamin D is important for overall immune health.

Is MS genetic? A map of MS caseload around the world
More cases of MS are recorded further away from the equator, suggesting that lack of sunlight and consistent Vitamin D may play a role. Lokal_Profil. Attribution-Share Alike 2.5 Generic

Smoking

The role of cigarette smoking in increased risk of MS has been researched for years. Smoking before the onset of the disease seems to significantly increase the risk. A meta-analysis showed a 1.2 to 1.5-fold increase in the risk of disease.

It is not yet known which pathological changes triggered by smoking can influence the development and progression of MS.

Obesity

Being extremely overweight in childhood seems to be a factor in the development of multiple sclerosis in adulthood. 

Microbiome

Various studies have shown that the microbiome has an influence on the immune system and on autoimmune diseases in general. Intestinal bacteria can dampen or activate the immune.

Epidemiology (Part 4 of Is MS genetic?)

According to a study funded by the National MS Society in 2019, nearly 1 million people are living with MS in the United States. Most people with MS are diagnosed between the ages of 20 and 50, although MS can occur in young children and older adults. While cases of MS are found in most ethnicities, it is most common in Caucasians of northern European ancestry.

Women are 2 to 3 times more likely to develop MS than men. MS is known to occur more frequently in areas that are farther from the equator. 

Characteristics and Symptoms (Part 5 of Is MS genetic?)

MS symptoms are widely varied among individuals, in both type and amount. Some of the more and less common primary symptoms of MS are:

Common symptoms:

  • Fatigue
  • Walking (gait) difficulties
  • Numbness or tingling
  • Spasticity
  • Weakness 
  • Vision problems and vision loss
  • Dizziness and vertigo
  • Bladder problems
  • Sexual problems
  • Bowel problems
  • Pain and itching
  • Cognitive changes
  • Emotional changes
  • Depression

Less common symptoms:

  • Speech problems
  • Swallowing problems
  • Tremure
  • Seizures
  • Breathing problems
  • Hearing loss
Summary of affected areas impacted by MS
Summary of Affected Areas Impacted By Multiple Sclerosis, Source

MS has different forms of progression and relapses are common. A relapse is defined as the occurrence of new or resurgence of already known clinical symptoms that last longer than 24 hours. To distinguish a new attack from a previous one, there must be at least 30 days between the two clinical events. 

The duration of a relapse is usually a few days to a few weeks. Depending on whether the symptoms that have occurred recede completely or only incompletely, one speaks of a complete or incomplete remission. So-called pseudo relapses occur in the context of a temperature increase or in conjunction with infections and can lead to a temporary worsening of clinical symptoms.

The first symptoms usually appear between the ages of 15 and 40. Some patients are also slightly younger. While the relapses usually subside completely at the beginning of the disease, neurological deficits are increasingly left behind in the later course of the disease after relapses. 

At the beginning of the disease, visual and sensory disturbances are frequently observed. It is not uncommon for the disease to begin with an isolated symptom.

Which symptom develops in a relapse depends on the respective localization of the active demyelinating focus in the central nervous system: For example, inflammation in the area of the optic nerve fibers causes visual disturbances that can manifest themselves as visual blur or milky haze and can also be accompanied by eye pain. 

One means of quantifying patient impairment is the use of the Expanded Disability Status Scale (EDSS). This scale is used to classify the current severity of the patient’s disabilities, with prior assessment of impairments in seven neurological systems. Looking at the entire course of the disease, it is fatigue, bladder dysfunction and motor system disorders such as paralysis and spasticity that often have the greatest impact on the lives of those affected.

Diagnosis (Part 6 of Is MS genetic?)

Your doctor will perform multiple types of tests to diagnose MS and rule out any other conditions including medical history, a neurologic exam, magnetic resonance imaging (MRI), spinal fluid analysis, and blood tests to rule out other conditions.

Sometimes, patients exhibiting MS symptoms will be diagnosed with clinically isolated syndrome (CIS). CIS presents the same symptoms as MS. Unlike MS, a CIS episode is a singular event while the latter is a lifelong disease. Patients with either condition will receive the same treatment. 

Imaging

The images of the brain and spinal cord obtained by magnetic resonance imaging (MRI) can be used to visualize inflamed and scarred tissue areas. With the aid of a contrast medium containing gadolinium, such as gadopentetate dimeglumine or gadoteric acid, acute disease foci can be detected. Periventricular (around the lateral ventricles) sites of inflammation in the medullary bed of the brain and so-called beam sites are typical of MS.

With MRI examination, both the spatial and temporal dissemination of the inflammatory foci in the brain and spinal cord can be detected. The McDonald criteria specify exactly how many sites of inflammation in which region of the CNS must be detectable in order to be able to speak of a positive MRI result with regard to spatial dissemination. The diagnosis of MS is usually not made solely on the basis of imaging findings.

MRI of a brain with MS
MRI of a brain with MS. (2015). “The Parallel Analysis of Phase Sensitive Inversion Recovery (PSIR) and Double Inversion Recovery (DIR) Images Significantly Improves the Detection of Cortical Lesions in Multiple Sclerosis (MS) since Clinical Onset”. PLOS ONE 10 (5): e0127805. DOI:10.1371/journal.pone.0127805. ISSN 1932-6203. (CC-BY-4.0)

Other tests

Lumbar puncture (spinal tap)

A lumbar puncture is recommended in cases of suspected disease. In 50% of the patients there is a slight increase of lymphocytic cells in the cerebrospinal fluid (CSF) and a chronic inflammatory process in the central nervous system is detectable in more than 95% of the patients. 

Evoked potential tests

These tests record the electrical signals produced by your nervous system in response to stimuli, either visual or electrical. In these tests, you watch a moving visual pattern, or short electrical impulses are applied to nerves in your legs or arms. Electrodes measure how quickly the information travels through your nerves.

In most people with relapsing-remitting MS, a diagnosis can be made based on a pattern of symptoms consistent with the disease and confirmed by brain imaging scans, such as MRI.

For others with an unusual pattern of symptoms, it can be hard to distinguish MS from other diseases. In addition to infectious diseases, other chronic inflammatory diseases must also be excluded. Other inflammatory demyelinating diseases (such as neuromyelitis optica, tropical spastic paraparesis or acute disseminated encephalomyelitis (ADEM)) must also be considered. Diseases of the metabolism or a vitamin B12 deficiency can also lead to similar symptoms as in MS. 

Treatment (Part 7 of Is MS genetic?)

According to the Mayo Clinic, there is no cure for MS. The goal of all therapeutic measures is to maintain the independence of the patient in everyday life by increasing recovery times from attacks, slowinging the progression of the disease and managing MS symptoms.

To treat attacks, patients can use either prescription corticosteroids to reduce nerve inflammation or they can elect to undergo plasma exchange, by which blood is removed from the mody, modified, and reinjected. 

For primary-progressive MS, ocrelizumab (Ocrevus) is the only medication approved by the U.S. Food and Drug Administration (FDA) as a disease modifying therapy. Those who receive this treatment are slightly less likely to progress than those who are untreated.

More options are available for persons with relapsing-remitting MS. Since much of the immune response occurs at the start of the disease, early and aggressive treatment with these therapies is associated with better outcomes. 

Injectable treatments that can alter the immune system’s attacks include interferon beta medications and glatiramer acetate (Copaxone, Glatopa). 

There are many oral and infusion treatments available:

Oral:

  • Fingolimod (Gilenya)
  • Dimethyl fumarate (Tecfidera)
  • Diroximel fumarate (Vumerity)
  • Teriflunomide (Aubagio)
  • Siponimod (Mayzent)
  • Cladribine (Mavenclad)

Infusion:

  • Ocrelizumab (Ocrevus)
  • Natalizumab (Tysabri)
  • Alemtuzumab (Campath, Lemtrada)

Besides medication, other strategies may be recommended to help alleviate symptoms, especially with regards to muscle and coordination challenges.

  • Physical therapy
  • Muscle relaxants
  • Medications to reduce fatigue
  • Medications to increase walking speed
  • Other medications for conditions such as depression, pain, and bladder control that are often associated with MS

Did you like this article? You can find more posts like this in the Nebula Research Library!