Is Motor Neurone Disease Genetic?

Contents

For the large majority of Motor Neurone Disease cases, there are no known genetic components. However, for 5-10% of cases there is a family history, and therefore a potential genetic relationship to the disease and/or related conditions.

What is Motor Neurone Disease (MND)?

Motor Neurone Disease (MND) is a severely life-shortening disease of the nervous system. MND attacks the motor neurons and gradually breaks them down, leading to muscle weakness that progressively worsens over time. 

Motor neurons are a type of nerve cell responsible for sending electrical messages throughout our body, allowing us to move. In MND, when motor neurons start to deteriorate, these electrical messages can no longer travel throughout the body. As a result, voluntary movements become increasingly difficult. Over time, muscles become thinner and begin to break down due to lack of use; this is known as “atrophy”. As MND progresses, people lose the ability to walk, talk, swallow, and eventually breathe. MND significantly shortens the life expectancy of patients and eventually leads to death. 

Some well-known types of MND include:

  • Amyotrophic Lateral Sclerosis (ALS): The most common type of MND (also known as Lou Gehrig’s disease.) It develops quicker than other forms. Patients living with ALS will experience muscle weakness, muscle wasting, speech and swallowing difficulties, and muscle spasms. 
  • Progressive Muscular Atrophy (PMA): A less common form of MND and often develops at a slower rate than ALS. Patients living with PMA do not tend to experience muscle spasms. However, some patients with PMA can go on to develop ALS. 
  • Primary Lateral Sclerosis (PLS): PLS is a much rarer type of MND. Patients with PLS experience spasticity (muscle tightness) but do not suffer from muscle wasting or muscle twitching. 
  • Progressive Bulbar Palsy (PBP): A type of MND that largely impacts the throat muscles, tongue and face. It mainly causes problems in speech, swallowing, coughing, and throat clearing. Patients living with PBP may also experience changes in emotional expression; PBP can affect the expression of emotions, resulting in patients laughing or crying in inappropriate situations (known as emotional lability). 

Signs and Symptoms 

The first signs and symptoms of MND can happen gradually and may not be immediately obvious. The majority of patients first experience the symptoms after the age of 40 (with MND being most common in people aged between 50-70 years).1 The first signs can vary from person to person. However, early symptoms often include: 

  • Muscle weakness (e.g. weakened legs or ankles causing trips and falls, and difficulty in climbing the stairs) 
  • Slurred speech or difficulties speaking
  • Difficulty swallowing 
  • Muscle cramping and twitching
  • Involuntary contractions of the muscle - are known as fasciculations. (These can be felt as flickers and twitches beneath the skin)
  • Stiffness in the legs, feet, arms, or hands 
  • Weakened grip (e.g. dropping items, difficulty adjusting buttons or gripping objects) 
  • Losing weight (gradual thinning of arms and legs)
  • Difficulty in control over laughter (and/or crying) in inappropriate circumstances

As MND progresses, these symptoms worsen, leading to more severe: 

  • Speaking difficulties

The majority of people living with MND struggle with speech. Early symptoms such as slurred speech become increasingly worse, and it may become more difficult for others to understand them. In late stages, it is common for patients to depend on technology to communicate.

  • Breathing difficulties  

In later stages of MND, the muscles required for breathing become paralysed. It is common for patients to use various medical devices to facilitate breathing at night. The most common cause of death for patients with MND is respiratory failure in the final stages of the disease.6

  • Eating problems

As patients develop issues with swallowing, they can then experience dehydration and malnutrition as a result. There is also an increased likelihood of liquid, food, or excess saliva getting into the lungs, which in some cases can cause pneumonia.6

  • Dementia 

Some MND patients experience cognitive difficulties, such as problems with decision-making and memory, which can lead to a diagnosis of dementia.6

Patients typically do not experience pain in the earlier stages of MND, and it remains uncommon in the later stages. The condition does not impact sensory perception or bladder control. 

Causes and Risk Factors 

The exact causes of MND are unknown. As a result, understanding the risk factors involved remains similarly tricky. Like many diseases, it is believed that a combination of genetics, environmental and lifestyle factors contribute to development. 

  • Genetics: Inherited MND, otherwise known as ‘familial MND’, only accounts for a small proportion of cases; most cases have no or little genetic involvement (known as ‘sporadic MND’).3
  • Lifestyle and Environment: There is known to be a link between lifestyle factors and MND.3 Possible lifestyle and environmental risk factors include: 
  • High levels of intensive exercise
  • Environmental toxin exposure, e.g. heavy metal exposure, agricultural chemical exposure 
  • Smoking: The development of ALS has been linked to smoking, with the greatest risk being in women – particularly post-menopause.6  
  • Military service
  • Electrical and/or mechanical trauma

However, there has been conflicting evidence of the links between these risk factors and the development of MND – some studies state there is a link, and others show no correlation. Because of these mixed results, it is not possible to provide definite advice to reduce the risk of MND. 

Diagnosis and Treatment

Diagnosis of MND can be more difficult in the early stages of the disease. Additionally, many symptoms of MND are similar to other diseases; therefore, it is important to rule these out before making a final diagnosis. There are several different tests that identify MND: blood tests, tests assessing the function of electric activity in your nervous system using electromyography (EMG) techniques, brain and spine scans (e.g. Magnetic Resonance Imaging scans that generate detailed photographs of the brain and spinal cord), and a spinal tap (a.k.a. lumbar puncture) to run tests on the spinal fluid. 

Regarding MND treatment, there are no current cures for MND. However, there are several treatments that aim to slow the progression of the disease and target specific symptoms in order to make daily life more manageable for patients. Treatments are comprised of medications and other non-pharmaceutical therapies, including: 

  • Physiotherapy and specialised exercises (maintaining muscle activity and strength and minimising muscle stiffness) 
  • Occupational therapy and specialised clinics (help to manage everyday tasks that may become more difficult)
  • Dietary advice 
  • Speech and language therapy (helping slurred speech symptoms) 
  • Riluzole (the only drug treatment available specifically for MND life expectancy benefits)
  • Medications that relieve muscle stiffness, cramps, and spasticity, and reduce difficulties with saliva-related symptoms
  • Patients with breathing problems may be treated with assisted ventilation or oxygen therapy
  • Psychological and social-emotional support for the patient and their caregivers 

Prognosis

MND is a condition that gets progressively worse over time. It is known to significantly reduce life expectancy and eventually lead to death. However, the mortality rate varies significantly among patients; half of those with the disease have a life expectancy of three years - whilst others may live for up to a decade and, in rarer cases, over a decade.4 Most frequently, patients with MND have a life expectancy of 2-3 years from symptom onset.9 Riluzole, a drug treatment specific to MND, increases life expectancy by an average of 3-4 months.9 Due to the incurable nature of MND, the remainder of the treatment aims to treat symptoms, making daily life more manageable for patients. Respiratory function (breathing ability) is known to significantly indicate both quality of life and survival rates in MND patients. As such, treating respiratory function and breathing problems is a critical component of care.9 

Inherited MND

The question of heredity in MND is a very common question and concern. Research in this area is ongoing; however, it is currently understood that MND is thought to arise due to a complex collection of factors, including environment, lifestyle and genetics. Most MND cases occur without any family history of MND, but between 5-10% of MND cases are familial.9 

Frequency

MND is an uncommon disease. Reported incidences vary between 0.6 and 2.4 per 100,000 persons every year.5 The lifetime risk of someone developing any type of MND is approximately 1 in 1,000. It is the third most common neurodegenerative disease in adults and tends to develop in later life, with an average onset between 55-60 years.9 

Approximately 1 in 15 individuals diagnosed with MND has ‘familial MND’, varying between 5-10%.9 ‘Familial MND’ means patients have a relative with MND or frontotemporal dementia (a related condition). Other instances of MND, where no known family member is diagnosed, are known as ‘sporadic MND’. Sporadic MND accounts for the majority of MND diagnoses (around 10%).5

Some studies find higher instances of MND diagnosis in men. For example, one study found that MND incidence was 54% higher in men than in women, with 2.6 MND diagnoses per 100,000 persons per year in women and 3.9 in men. For both sexes, MND diagnosis peaked between 75-79 years. 

Genetics

As with most neurological disorders, MND is believed to arise due to a combination of environment, lifestyle and genetics. However, in familial MND (when a patient with an MND diagnosis is aware of another family member with the same diagnosis or a diagnosis of a related condition), particular faults in genes may have contributed to the development of the disease. There are 4 common faults in genes of patients with familial MND: C9orf72, SOD1, FUS and TARDBP. 

Carrying one of these faulty genes does not necessarily lead to the development of MND, despite the fact that sometimes people talk about MND ‘running in the family.’ Individuals carrying these faulty MND-related genes frequently develop typically into adulthood and later life without any progression of the disease. 

Those with sporadic MND may be concerned about ‘passing down’ the condition and increasing the risk of MND for their children. However, studies thus far suggest that the overall risk for their children remains extremely low – increasingly only slightly compared to children of parents without MND. As the absolute lifetime risk of an MND diagnosis is approximately 0.3%, a slight increase in risk still means that the chances of developing MND for anyone with a relative with MND remain extremely low.7 Indeed, every person has 2 copies of every gene. Thus, individuals carrying a faulty MND-related gene have a 50% chance of passing this gene to their children – these genes are not necessarily passed down. 

If you would like to explore further information about the roles of genetic factors in causing MND or have concerns regarding your own risk of MND due to a family member’s diagnosis, you should seek advice from your doctor. It may be possible to get advice from a neurologist or a Clinical Genetics consultant. 

Genetic Testing and Insurance

Genetic testing can be run to check whether there are any faults in the 4 common faulty genes in patients with familial MND (C9orf72, SOD1, FUS and TARDBP). These faults are present in any of these 4 genes. Individuals who do carry a faulty version of MND-related genes may still live as long as others without developing MND or frontotemporal dementia. Because of this, testing family members who do not have MND symptoms is not recommended as it can cause unnecessary distress and worry.7

In addition to the 4 MND-related genes already established, there are a growing number of additional genes associated with the development of MND. At present, there are over 20 different MND-related faulty genes discovered. However, these additional MND-related gene faults are very rare, and there is presently no routine genetic testing available to identify them.8

Current Research 

As the causes are still unclear, MND is an area of active research investigating potential causes and effective treatment options.

Research on MND generally focuses on:

  • Identifying therapeutic targets - To understand the aetiology of MND, focusing on the underlying biochemical processes that lead to the illness so that we can learn how to intervene and stop the progression.
  • Understanding the clinical progression of MND - To generate a detailed and accurate understanding of how MND progresses in different patients. 
  • Developing treatment pipelines - Translating scientific findings in the lab into new potential treatments for patients is a pivotal focus of much MND research.
  • Improving the standards of care - To ensure that the patients living with MND and their families are informed of the clinical management of the disease.

Various scientific techniques, including animal and stem cell-based methods, are currently being used for research. Many researchers have specifically explored the potential use of stem cell therapy as a treatment for MND. However, there is currently no reliable evidence suggesting the use of stem cells as an effective MND treatment.10

Other research avenues include AI and new drug trials. Some researchers have been utilising artificial intelligence (AI) models, led by Stanford and Sheffield researcher Dr Sai Zhang, to help understand the possible causes of MND. In terms of new drugs, a new type of medication, antisense oligonucleotides, is currently undergoing testing in clinical trials (via large-scale studies to determine whether a drug is effective and safe for patients to use). This drug will target familial MND in particular.7

There are a number of prominent research groups that are dedicated to deepening our understanding of MND development and progression to better improve treatments. Some prominent examples include the My Name’5 Doddie Foundation and the Darby Rimmer MND Foundation supported by football player Stephen Darby (who was diagnosed with MND in 2018; read Stephen’s story here). 

To find out more about current MND research and how to get involved, you can visit these research pages

MND Association Register

The MND Association is an initiative to support research in MND, funding and promoting research with the ultimate goal of finding causes, treatments and a cure for MND. Their website provides accurate information on different aspects of MND, such as clinical information (e.g. symptoms, diagnoses, prognoses), the difference between inherited versus sporadic MND and current research activities. 

If you’d like to be directly involved, by registering with the MND Association, you allow the MND association to collect your data and details, which will help researchers work towards finding causes, treatments and cures for MND. 

Summary

MND is a group of conditions (including ALS, PMA, PLS and PBP) that result in the gradual breakdown of motor neurons, causing muscle weakness and movement difficulties that worsen with time. MND dramatically reduces the life expectancy of patients, though the exact prognosis varies between each individual. 

The cause of MND ultimately remains unknown. Though we know that genetics plays a role in the development of MND in some cases, the vast majority of MND cases occur without any family history of the disease.

There is currently no known cure for MND, and so there is still active research around the globe dedicated to understanding and treating the disease and ultimately finding a cure. Available treatments of MND focus on relieving symptoms, expanding life expectancy, and making everyday life more manageable and as comfortable as possible for patients.

References

  1. Brain & Spine Foundation. Motor neurone disease [Internet]. [cited 2022 May 12]. Available from: https://www.brainandspine.org.uk/our-publications/our-fact-sheets/motor-neurone-disease/
  2. NHS. Motor neurone disease [Internet]. [cited 2022 May 12]. Available from: https://www.nhs.uk/conditions/motor-neurone-disease/ 
  3. MND Association. About MND [Internet]. [cited 2022 May 12]. Available from: https://www.mndassociation.org/about-mnd/what-causes-mnd/
  4. NHS. NHSInform. MND Survival rate [Internet]. [cited 2022 May 12]. Available from: https://www.nhsinform.scot/illnesses-and-conditions/brain-nerves-and-spinal-cord/motor-neurone-disease-mnd#
  5. Alonso, et al. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol. 2009 Jun;16(6):745–751. Available from:<10.1111/j.1468-1331.2009.02586.x>
  6. Mayo Clinic. Amyotrophic lateral sclerosis [Internet]. [cited 2022 May 12]. Available from: https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/
  7. Oxford MND Centre | NHS. Is MND Hereditary? [Internet]. [cited 2022 May 12]. Available from:   https://www.ouh.nhs.uk/services/departments/neurosciences/neurology/mnd/support/is-mnd-hereditary.aspx#
  8. Sheffield MND Care and Research Centre. Is MND Hereditary? [Internet]. [cited 2022 May 12]. Available from:   https://sheffieldmndcarecentre.group.shef.ac.uk/support/hereditary/
  9. Rafiq, et al. Respiratory management of motor neurone disease: a review of current practice and new developments. Practical Neurology. 2012 Jun;12(3):166-76. Available from:<10.1136/practneurol-2011-000199>
  10. MND Association. Stem cell therapy [Internet]. [cited 2022 May 12]. Available from: https://www.mndassociation.org/research/our-research/using-animals-and-stem-cells/stem-cells/stem-cell-therapy/ 

Author: Molly Rowlands

PhD Candidate @ MRC Cognition & Brain Sciences Unit, University of Cambridge, England
Access Officer | Pembroke College GPC

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