Is Motor Neurone Disease Hereditary?

Motor neurone disease (MND) is a rare neurological condition that progressively damages the motor neurones that make up part of the nervous system. MND can affect people of all ages, but most commonly appears in people aged between 60 and 70. Our understanding of what causes the progressive diminishing of motor neurone function is limited. In most people, MND does not have a genetic cause. However, in some cases, having a relative with MND, or a related condition called frontotemporal dementia, can increase your likelihood of developing the condition. In this article, we will discuss the genetic risk of inheriting MND, and what can be done if you believe you're at risk of developing the condition. 

What is Motor Neurone Disease?

Motor neurone disease (MND) occurs when motor neurones, which are specialist nerve cells in the brain and spinal cord that control muscle movement, progressively lose function. MND is an example of progressive neurodegeneration and causes the muscles to weaken, stiffen and waste. MND encompasses a group of progressive neurological disorders. This group includes conditions such as amyotrophic lateral sclerosis, progressive bulbar palsy, primary lateral sclerosis, progressive muscular atrophy, Kennedy’s disease, post-polio syndrome, and spinal muscular atrophy.

Motor neurones control important muscle activity, such as walking, speaking, swallowing, breathing, and gripping. People with MND will find these activities increasingly difficult as the disease progresses, and they may eventually become impossible to complete. MND becomes more debilitating over time as neurodegeneration spreads to other parts of the body. MND is an incredibly rare condition. It affects an estimated two in every 100,000 people each year in the UK. MND has a very low prevalence, and at any time there are only around 5,000 people living with MND in the UK. 

Signs and symptoms

Symptoms of MND develop gradually and become increasingly noticeable over time. Symptoms begin over weeks and months and usually appear initially on only one side of the body. Some early symptoms may include:

• Slurred speech (dysarthria)- this may further develop into difficulty swallowing.
• A weak grip - this may cause you to drop things, or struggle with completing tasks such as doing up buttons and taking the lids off jars.
• Weakness in your legs or ankles - you may find climbing stairs more difficult, or trip more often. This may also result in someone dragging their leg, or a “foot-drop”. 
• Weight loss - specifically in your arm or legs, as muscles may become thinner over time.
• Muscle cramps and twitches. 
• Emotional lability and changes in thinking and behaviour - this may include difficulty controlling laughter or crying in inappropriate situations.
• Breathing problems - this can lead to breathlessness and fatigue.

Eventually, a person with MND may lose the ability to move. Communicating, breathing, and swallowing may also become difficult as the condition worsens. 

When to see a doctor

You should book an appointment to see a doctor if you think you may be experiencing early symptoms of MND. MND is a rare and unlikely diagnosis, but it is important to get an early diagnosis to get the right support and care you need.

You should also visit your healthcare provider if you have a close relative with MND or frontotemporal dementia, and are worried about being at risk of developing MND. It is likely that your doctor will refer you to genetic counselling to discuss your genetic risk and the tests you can take.

Diagnosis

Diagnosing MND can be a long and difficult process. There is no single test used to diagnose the disease, and several different health conditions present similar symptoms. Therefore, a neurologist will often conduct a series of tests to help rule out other possible conditions. This may include; blood tests, brain scans, electrophysiological tests to measure the activity in your nerves and muscles, and a spinal tap (otherwise known as a lumbar puncture) to test spinal fluid. 

Clinical course

MND affects everyone differently, and not everyone experiences the same symptoms with the same rate of progression. Therefore, the clinical course of the disease is difficult to accurately predict. MND is life-shortening and there is currently no cure. However, symptoms can be managed to ensure the best quality of life possible. 

Prognosis varies depending on the age of symptom onset and the type of MND. Some types of MND, such as Kenedy’s disease or primary lateral sclerosis, progress very slowly and are usually not fatal.

Life expectancy

MND has severe life-shortening effects - 50% of people diagnosed with MND have a life expectancy of three years from the onset of symptoms. However, some people with MND live for many years after diagnosis, with patients seen to live for up to 10 years post-diagnosis, and in some instances even longer. 

Living with MND is extremely challenging, and it cannot be stopped or reversed. However, there are certain therapies, equipment, and medications that can help manage symptoms. 

Causes and risk factors - who can develop MND and why?

The cause of MND is not clearly understood. It is thought that different factors may trigger the disease for each person. Environmental, toxic, and viral factors may play a role in the development of sporadic (non-inherited) MND.

In the majority of cases, there is no genetic predisposition toward developing MND. However, in around 5% of cases, there is a family history of motor neuron disease, or a related neurological condition called frontotemporal dementia. This type of MND is called familial motor neuron disease. 

Treatment and support

Unfortunately, there is no known cure for MND. However, there are options available to help reduce the impact of the disease on a person's daily quality of life. Treatment aims to make the person feel comfortable and compensate for the loss of certain bodily functions.

This may include the use of a breathing mask to alleviate the symptoms of impaired breathing and weakness, and a feeding tube to maintain nutrition and mitigate problems with swallowing. Physical therapy and rehabilitation may also be recommended to help improve comfort and slow muscle weakness and atrophy. In some cases, medication can be prescribed to control excessive drooling. 

There is only one licensed drug used for treating MND in the UK called Riluzole. This will be recommended under the advice of a neurologist if appropriate. Riluzole may not be recommended as a treatment in some cases, such as primary lateral sclerosis (PLS), which has a slower disease progression. Riluzole is not a cure for MND, however, it has been seen to increase survival by an average of 2-4 months by slowing down the progression of the disease.¹

Inherited or Familial vs. Sporadic MND

MND is classified according to whether the loss of motor neuron function is inherited (familial) or sporadic. Most cases of MND would be classified as sporadic, where there is no family history of the condition and MND has not developed due to inheriting a mutated gene. In cases of inherited MND, it is most often caused by a single gene mutation.

Genomics and Genetics

Familial MND is usually inherited by one of the following genetic patterns:

• Autosomal dominant means that a person only needs to inherit one copy of the mutated gene from one of their parents to have the disease. 
• Autosomal recessive means that a person would have to inherit a mutated copy of the gene from each parent to have the disease. The parents will likely be asymptomatic.
• X-linked inheritance occurs in genetic conditions that are associated with genetic mutations on the X chromosome. A male carrying a genetic mutation on the X chromosome will always be affected by the condition, as males only carry one X chromosome. On the other hand, a female carrying a mutation in one gene, with a normal gene on her other X chromosome, will be a carrier of the disease and will generally not show any symptoms.² 

Everyone has two copies of each gene, and those carrying a fault in a gene resulting in MND have a 50% chance of passing the genetic mutation onto their offspring. 

Which genes?

There are a growing number of genes that have been associated with MND, with over 20 recognised to date. Some of the most common genes include:

• C9orf72 - repeat expansions of this gene have been found to cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.³ 
• SOD1 - mutations in this gene have been shown to cause MND.⁴
• FUS - mutations in the FUS gene on chromosome 16 have been shown to cause MND.⁵
• TARDBP - a gene that codes for an RNA/DNA binding protein that has been implicated in the development of MND.⁶

Genetic testing

Although there are no specific tests to diagnose MND, there are genetic tests that can be done to determine whether you carry a genetic mutation that could result in MND. Mutations in the four most common genes, C9orf72, SOD1, FUS, and TARDBP, associated with suspected familial motor neurone disease, can be easily tested for. Routine testing for some of the more rare genes thought to cause MND is not currently available.

If you are a carrier of the faulty gene, you may never experience the symptoms of MND or frontotemporal dementia, and live a long life without the disease. For this reason, it is not always recommended to undergo genetic testing as this may result in unnecessary stress. In some cases, people with concerns about passing MND on to their offspring with a family history of MND may want to consider screening their embryos for genetic mutations. This process would require in vitro fertilisation (IVF) to allow only the embryos without the faulty gene to be implanted. This is a rare and unusual situation and would need to be discussed in depth with your doctor and a genetic counsellor. 

Current research and clinical studies of inherited MND

There is a wide range of ongoing research aimed at preventing and curing MND, which includes finding better treatments and medicines, identifying genetic mutations, and discovering the causes of MND. 

Scientists are exploring the potential of gene therapy to interrupt motor neuron degeneration and slow the progression of the disease in models of spinal muscular atrophy and inherited ALS.⁷ These are two of the most common and fatal motor neurone diseases. Gene therapy is a method by which normal genes are introduced into chromosomes in place of missing or defective ones in order to reverse genetic disorders. 

Conclusion

In conclusion, motor neurone disease is a rare but incredibly debilitating, and often ultimately fatal, neurodegenerative disease. Whilst the majority of MND cases are sporadic, there is a small percentage of people who develop MND as a result of an inherited gene mutation. If you are worried about your risk of developing MND because someone in your family has MND or frontotemporal dementia, you should seek advice from your healthcare provider. Although there is currently no cure for motor neurone disease, gene therapies are proving promising in the clinical trial stages of research.