Motor neurone disease

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Motor neurone disease is a relentless progressive neurodegenerative disease of motor neurons and their associated microglia. It is classically a disease of motor nerves, UMN and LMN only, with no sensory symptoms although it is now known that close to 50% have cortical involvement[1] Also known as MND, motor neuron disease or amyotrophic lateral sclerosis (ALS) with the later term becoming more common due to the new understanding that this is not solely a disease of motor neurons and the old understanding that there are distinct phenotypes with different prognosis and obviously no cortical involvement.

Prevalence of about 6/100,000. Most cases are apparently sporadic due to genetic penetration issues, but up to 10% of cases are clearly familial (see familial amyotrophic lateral sclerosis). Of the familial variety, about 20% of cases are associated with mutations in the superoxide dismutase 1 (SOD1) gene. Another 2-6% are associated with mutations in the TDP43 gene. The association with a region of chromosome 9p21 adjacent to the exons for C9ORF72 has proved to be important in an ever increasing proportion of all cases. Activation of a retrovirus gene may be important in up to 10%[2]. These associations are being rapidly explained down to gene level and a check of the latest literature may be useful as the genetics are rapidly being understood with better characterisation of a large study population being expected in 2018.

It is more common in athletes and males. Possible role of excitotoxins including cycad nuts (methylaminoalanine), chickling peas, seaweed and shell fish interacting with the genetic factors.

Contents

Aetiology

In most sporadic cases, the pathogenesis appears to be a TDP-43 proteinopathy. Fragments of this protein become aberrantly hyperphosphorylated and ubiquitinated, resulting in deposition of these fragments and neurodegeneration. It is possible that TDP-43 protein misfolding generates a prion like cascade. The familial forms are generally associated with non-TDP-43 mutations, of which several have now been identified and are listed in the familial amyotrophic lateral sclerosis article which is also reproduced at the end of this article for convenience. It is known that SOD1 aetiology variants which is not associated with TDP-43 proteinopathy can have the SOD1 abnormal protein transmitted between neurons. Mice models reveal that SOD1 expression in the motor neuron can determine the onset of the disease and the separate issue of how SOD1 is expressed by the microglia can determine the progression of the disease.[3]

Increased genetic risk is associated with mutations of:

Classification

Three main types exist, depending on the motor neurone type affected:

  • Upper motor neurone - Primary Lateral Sclerosis (very rare - 0.01 per 100,000)
  • Lower motor neurone - Progressive Muscle Atrophy, and Spinal Muscle Atrophy
  • Mixed upper and lower MN - Amyotrophic Lateral Sclerosis

Symptoms

In the older patient, usually presents with noticeable weakness or increasing clumsiness. Other variants, exist. These include those evident around birth, with floppy infant, or failure to thrive.

Signs

Different clinical patterns all of which can coexist

  • Progressive muscle atrophy
  • Weakness
  • Wasting
  • Fasiculations
  • Progressive bulbar palsy
  • Dysphagia
  • Nasal regurgitation
  • Altered speech
  • Aspiration
  • Wasted fasiculating tongue
  • Amyotrophic lateral sclerosis
  • Emotional disorder (eg pathological laughing and crying) [5]

Diagnosis

  • Presence of each of the following:
    1. LMN signs in at least 2 limbs
    2. UMN signs in at least one region
    3. Progression of disease as increasing symptomatic impairment by history
    4. Absence of:
    • Sensory signs
    • Neurogenic sphincter abnormalities
    • Other CNS disease
      • Excluding evidence from psychometric testing as this will be abnormal in the 50% odd who we now know to have cortical involvement which historically was not tested for unless frontotemporal dementia was present and was usually hidden when it had become gross in the others by the loss of speech and written communication due to motor neurone disease.
    • Other PNS disease
  • Blood tests:
    • CK
    • Lyme serology
    • Serum electrophoresis
    • Porphyria screen
    • Anti-ACh antibodies
    • HIV test
    • Genetics
      • Increasingly this is being found useful but the complexities when variants are associated with increased risks of othe neurological disease and the typical incomplete penetrance mean very careful counselling of both patients and the non expert clinician is required.
  • Imaging:
    • MRI brain and/or cervical spine
  • Muscle biopsy:
    • No role in diagnosis, other than exclusion of primary muscle disorder.

Differentials

Mimic syndromes

Treatment

  • Supportive
  • Education and counselling
  • Hydration
  • Skin care
  • PEG feeding
  • Riluzole - glutamate release inhibitor
    • Inactivates voltage dependent sodium channels
    • In SOD1 defective mice, delays median time to death
    • Two trials may demonstrate delay in time to tracheostomy or death on riluzole
      • This is not statistically significant
    • Does produce early increase in survival
  • Non-invasive ventilation is beneficial and increases survival by about 7 months with good bulbar function[6].

Inherited motor neuron disease

There are a large number of genetic conditions that explain the 10% with clearly inherited familial amyotrophic lateral sclerosis. There is an interesting overlap with the genetics of frontotemporal dementia[7] and sporadic motor neurone disease. The characterised genetic types include:

In the past spinal muscular atrophy‎ in its various forms was considered by some a form of genetic motor neuron disease. There is indeed some overlap as with repeat expansions in the ATXN2 gene.

References

  1. Nidos A, Kasselimis DS, Simos PG, Rentzos M, Alexakis T, Zalonis I, Zouvelou V, Potagas C, Evdokimidis I, Woolley SC. Frontotemporal Dysfunction in Amyotrophic Lateral Sclerosis: A Discriminant Function Analysis. Neuro-degenerative diseases. 2016 ; 16(3-4):140-146.(Print-Electronic) (Link to article – subscription may be required.)
  2. Douville RN, Nath A. Human Endogenous Retrovirus-K and TDP-43 Expression Bridges ALS and HIV Neuropathology. Frontiers in microbiology. 2017 ; 8:1986.(Electronic-eCollection) (Link to article – subscription may be required.)
  3. Boillée S, Yamanaka K, Lobsiger CS, Copeland NG, Jenkins NA, Kassiotis G, et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science. 2006;312(5778):1389-92. (Direct link – subscription may be required.)
  4. Dunckley T, Huentelman MJ, Craig DW, Pearson JV, Szelinger S, Joshipura K, Halperin RF, Stamper C, Jensen KR, Letizia D, Hesterlee SE, Pestronk A, Levine T, Bertorini T, Graves MC, Mozaffar T, Jackson CE, Bosch P, McVey A, Dick A, Barohn R, Lomen-Hoerth C, Rosenfeld J, O'connor DT, Zhang K, Crook R, Ryberg H, Hutton M, Katz J, Simpson EP, Mitsumoto H, Bowser R, Miller RG, Appel SH, Stephan DA. Whole-genome analysis of sporadic amyotrophic lateral sclerosis. The New England journal of medicine. 2007 Aug 23; 357(8):775-88.(Link to article – subscription may be required.)
  5. McCullagh S, Moore M, Gawel M, Feinstein A. Pathological laughing and crying in amyotrophic lateral sclerosis: an association with prefrontal cognitive dysfunction. Journal of the neurological sciences. 1999 Oct; 169(1-2):43-48.(Print) (Link to article – subscription may be required.)
  6. Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet neurology. 2006 Feb; 5(2):140-7.(Link to article – subscription may be required.)
  7. Fontana F, Siva K, Denti MA. A network of RNA and protein interactions in Fronto Temporal Dementia. Frontiers in molecular neuroscience. 2015; 8:9.(Epub) (Link to article – subscription may be required.)
  8. Jonsson PA, Graffmo KS, Andersen PM, Brännström T, Lindberg M, Oliveberg M, et al. Disulphide-reduced superoxide dismutase-1 in CNS of transgenic amyotrophic lateral sclerosis models. Brain : a journal of neurology. 2006;129(Pt 2):451-64. (Direct link – subscription may be required.)
  9. Hadano S, Kunita R, Otomo A, Suzuki-Utsunomiya K, Ikeda JE. Molecular and cellular function of ALS2/alsin: Implication of membrane dynamics in neuronal development and degeneration. Neurochem Int 2007.(Epub ahead of print) (Direct link – subscription may be required.)
  10. Kwiatkowski TJ, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science (New York, N.Y.). 2009 Feb 27; 323(5918):1205-8.(Link to article – subscription may be required.)
  11. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science (New York, N.Y.). 2009 Feb 27; 323(5918):1208-11.(Link to article – subscription may be required.)
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