Motor Neurone Disease

Familial forms of Motor neurone disease (MND)

Motor neurone disease is a progressive neurodegenerative disorder that attacks nerves of the brain and spinal cord which gradually inhibits nerve signals from reaching the muscles. This leads to muscle weakness and visible muscle atrophy. As the disease progresses actions such as walking, gripping, swallowing and breathing become increasingly difficult, and eventually impossible. In this article I will be discussing the hereditary forms of MND known as familial motor neurone disease and the symptoms related.

Symptoms of MND

Symptoms of motor neurone disease usually develop slowly and subtly over time and typically fall into 3 stages, the initial stage, advanced stage and the end stage. In two-thirds of cases first symptoms occur in the arm or leg known as limb-onset disease. This can be categorised by a weakened grip or tripping up due to muscle weakness; this can often be accompanied by fasciculation’s (muscle twitching) or muscle cramps. Bulbar-onset disease occurs in around a quarter of cases, this affects the muscles of the throat required for swallowing and speech. Advanced symptoms can display visible muscle atrophy due to the wearing away of muscle from inactivity. Limb function gradually becomes worse due to severe weakness leading to a person becoming unable to move. Joint aches and pain develop due to spasticity; this is a condition where the muscles become stiff and rigid. Breathing becomes progressively difficult as the nerves that control the respiratory muscles become more damaged which can leave a person short of breath after simple day to day tasks. End stage symptoms takes the disease into its final stages. A person will suffer increasing body paralysis and significant shortness of breath to which then non-invasive breathing assistance isn’t enough to compensate for the loss of normal lung function. Sufferers of MND usually become drowsy before falling into a deep sleep where they usually die peacefully.

 

Mentally aware

As MND affects only motor neurones a person’s cognitive function is not lost, meaning they are aware of their condition and symptoms. Although in around 15% of cases people with MND may also suffer with frontotemporal dementia; symptoms include difficulty with planning, concentration and use of language. Some people have additional symptoms that are not directly caused by MND but relate to the reality of living with the disease. These may include anxiety, depression and insomnia.

 

What causes MND?

According to the MND association around 5-10% of cases are caused by hereditary genetic factors known as familial motor neurone disease. Although a person may have a genetic mutation, this alone does not cause the disease but does increase the likelihood of development. There are four major genetic mutations associated with MND. A genetic mutation occurs when the instructions carried within the gene become scrambled in some way which may lead to the body’s processes not functioning accordingly.

One third of the 5-10% have a mutation in the C9ORF72 gene found on chromosome 9. Normal transcription of this gene encodes for a protein found in many tissues including the brain, although its function is unknown. The protein is found in the presynaptic terminals of neurons and in the fluid that surrounds the nucleus. The gene contains a region of 6 DNA nucleotides (the building blocks of DNA) of four guanines and two cytosines and can be repeated several times or just once. When this nucleotide sequence is repeated too many times, in a mutation called a hexanucleotide, it can cause the amyotrophic lateral sclerosis (ALS) form of MND (DeJesus-Hernandez M 2011). It’s not known for certain how many repeats cause MND but it is believed to be over 30. The hexanucleotide mutation has been found to reduce the amount of protein produced by the C9ORF72 gene, which may alter and interfere with the cells’ function; although it is unclear how this protein causes the disease. Mutations in this gene are also responsible for frontotemporal dementia (FTD) although again it is still unclear why some develop MND, FTD or both (Chio, A. et al 2012).

Another gene known to cause MND is the SOD1 gene located on chromosome 21. This gene, under normal function, encodes for an enzyme called superoxide dismutase (SOD) which is abundant in many cells throughout the body. The role of superoxide dismutase is responsible for the breakdown of toxic charged oxygen molecules, called superoxide molecules, by its binding to copper and zinc. The production of these molecules is a by-product of normal functioning cells, although a build-up of them internally can cause the cell damage (Rakhit R. 2006). There are at least 170 mutations of the SOD1 gene known to cause MND. One particular mutation is the changing of an amino acid alanine to valine which causes the enzyme SOD to gain new, but harmful, properties. Researchers are unclear as to why the cells that are affected in MND are sensitive to the SOD1 mutation but it is believed to be due the increased level of toxic free radicals or the formation of aggregates (clumps) of misfolded SOD that cause cell death (Shaw, B. 2007).

The gene TARDBP located on chromosome 1 is responsible for the production of a protein called transactive response DNA binding protein 43 kDa (TDP-43). This protein is found in most tissues and is responsible in regulating transcription (the first step in the production of new proteins) by binding to DNA and mRNA. TDP-43 cuts and rearranges the amino acid building blocks of proteins in different ways leading to the formation of different versions of certain proteins in a process known as alternative splicing. There are around 50 mutations in this gene known to cause MND which affect the region of the TDP-43 that is responsible for the alternative splicing process. The mutations are thought to cause the proteins to misfold and aggregate within motor neurons. Again it is unclear the reasons why motor neurons die and to whether a build-up of aggregated TDP-43 is the cause of death or a by-product of the dying cell (Buratti, E. 2008). The onset of frontotemporal dementia is also associated with mutations in this gene.

Found on chromosome 16, the FUS gene is also responsible in assisting transcription processes by producing a protein called Fused in Sarcoma (FUS). The FUS assists messenger RNA out of the nucleus to be further processed into a mature protein and also helps repair mistakes in DNA. There are around 50 mutations in this gene that can cause MND by interfering with the transport of mRNA which is likely to cause aggregates of FUS within neurons. People who have the FUS gene mutation tend to develop the disease at an earlier age and have a decreased life expectancy. Like the previous 3 genes, mutations in this gene may also cause frontotemporal dementia (Hewitt, C. 2010).

Conclusion

There is currently no cure for motor neuron disease. Extensive research is underway to discover further details about what causes the disease and to find potential life changing medications. The only drug available that has shown to extend survival by two to three months on average is Riluzole which slows the progressive damage to cells by reduction to glutamate sensitivity. Other treatments include physiotherapy to ease cramps, Baclofen medication to ease muscle stiffness, Amitriptyline or botulin injections to stop saliva drooling, and percutaneous endoscopic gastrostomy tube for food intake when dysphagia (swallowing) becomes too difficult. None of these treatments cure MND but may to help improve quality of life.

 

 

 

 

References

http://www.mndassociation.org/

Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Chio, A. et al 2012

 

Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. DeJesus-Hernandez M et al 2011

 

Structure, folding, and misfolding of Cu,Zn superoxide dismutase in amyotrophic lateral sclerosis. Rakhit R1Chakrabartty A. 2006

 

How do ALS-associated mutations in superoxide dismutase 1 promote aggregation of the protein? Shaw BF1Valentine JS.

 

Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease. Buratti E1Baralle FE.

 

Novel FUS/TLS mutations and pathology in familial and sporadic amyotrophic lateral sclerosis. Hewitt C1Kirby JHighley JRHartley JAHibberd RHollinger HCWilliams TLInce PGMcDermott CJShaw PJ.

 

Author: Laura Ellis

Editor: Rosemary Porter

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