Editing Motor neuron diseases

{{short description|Group of neurological disorders affecting motor neurons}}
{{about|a group of muscle-wasting disorders|the disease amyotrophic lateral sclerosis, also known as motor neuron(e) disease|Amyotrophic lateral sclerosis}}
{{Use dmy dates|date=March 2023}}
{{Infobox medical condition
| name            = Motor neuron disease
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| field           = [[Neurology]]
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'''Motor neuron diseases''' or '''motor neurone diseases''' ('''MNDs''') are a group of rare [[neurodegenerative]] disorders that selectively affect [[motor neuron]]s, the cells which control [[voluntary muscles]] of the body.<ref name=El2008/><ref name="NINDS2014">{{cite web|title=Motor Neuron Diseases Fact Sheet: National Institute of Neurological Disorders and Stroke (NINDS)|url=http://www.ninds.nih.gov/disorders/motor_neuron_diseases/detail_motor_neuron_diseases.htm|publisher=ninds.nih.gov|url-status=dead|archive-url=https://web.archive.org/web/20140413093035/http://www.ninds.nih.gov/disorders/motor_neuron_diseases/detail_motor_neuron_diseases.htm|archive-date=13 April 2014|access-date=7 November 2010}}</ref> They include [[ALS|amyotrophic lateral sclerosis]] (ALS),<ref name="NHS">{{cite web |title=Motor neurone disease – NHS |url=https://www.nhs.uk/conditions/motor-neurone-disease/ |website=nhs.uk |access-date=24 October 2020 |language=en |date=15 January 2018}}</ref><ref name="healthdirectAU">{{cite web | author = Healthdirect Australia |title=Motor neurone disease (MND) |url=https://www.healthdirect.gov.au/motor-neurone-disease-mnd |website=healthdirect.gov.au |access-date=24 October 2020 |language=en-AU |date=17 April 2020}}</ref> [[progressive bulbar palsy]] (PBP), [[pseudobulbar palsy]], [[progressive muscular atrophy]] (PMA), [[primary lateral sclerosis]] (PLS), [[spinal muscular atrophy]] (SMA) and [[monomelic amyotrophy]] (MMA), as well as some rarer variants resembling ALS.

Motor neuron diseases affect both children and adults.<ref name=":14" /> While each motor neuron disease affects patients differently, they all cause movement-related symptoms, mainly [[muscle weakness]].<ref name=":7" /> Most of these diseases seem to occur randomly without known causes, but some forms are inherited.<ref name="NINDS2014" /> Studies into these inherited forms have led to discoveries of various [[gene]]s (e.g. ''[[SOD1]]'') that are thought to be important in understanding how the disease occurs.<ref name=":2">{{Cite book|title=Clinical and molecular aspects of motor neuron disease| vauthors = Cooper-Knock J, Jenkins T, Shaw PJ |isbn=9781615044290|location=San Rafael, California (1537 Fourth Street, San Rafael, CA 94901 USA)|oclc=860981760|name-list-style=vanc|date = 2013-09-01}}</ref>

Symptoms of motor neuron diseases can be first seen at birth or can come on slowly later in life. Most of these diseases worsen over time; while some, such as ALS, shorten one's life expectancy, others do not.<ref name="NINDS2014" /> Currently, there are no approved treatments for the majority of motor neuron disorders, and care is mostly symptomatic.<ref name="NINDS2014" />

== Signs and symptoms ==
[[File:ALS clinical picture.png|thumb|325x325px|A man with [[amyotrophic lateral sclerosis]] (ALS). (A) He needs assistance to stand. (B) Advanced atrophy of the tongue. (C) There is upper limb and truncal muscle atrophy with a positive [[Babinski sign]]. (D) Advanced [[thenar muscle]] atrophy.<ref>{{Cite web|title=Patient with amyotrophic lateral sclerosis (ALS) (case {{!}} Open-i|url=https://openi.nlm.nih.gov/detailedresult.php?img=3996815_bmjopen2013004353f02&query=amyotrophic+lateral+sclerosis&it=xg&lic=by&req=4&npos=5|website=openi.nlm.nih.gov|url-status=dead|archive-url=https://web.archive.org/web/20181215225214/https://openi.nlm.nih.gov/detailedresult.php?img=3996815_bmjopen2013004353f02&query=amyotrophic+lateral+sclerosis&it=xg&lic=by&req=4&npos=5|archive-date=15 December 2018|access-date=2018-12-12}}</ref>]]
Signs and symptoms depend on the specific disease, but motor neuron diseases typically manifest as a group of movement-related symptoms.<ref name=":7">{{cite journal | vauthors = Statland JM, Barohn RJ, McVey AL, Katz JS, Dimachkie MM | title = Patterns of Weakness, Classification of Motor Neuron Disease, and Clinical Diagnosis of Sporadic Amyotrophic Lateral Sclerosis | journal = Neurologic Clinics | volume = 33 | issue = 4 | pages = 735–748 | date = November 2015 | pmid = 26515618 | pmc = 4629510 | doi = 10.1016/j.ncl.2015.07.006 }}</ref> They come on slowly, and worsen over the course of more than three months. Various patterns of muscle weakness are seen, and muscle cramps and spasms may occur. One can have difficulty breathing with climbing stairs ([[exertion]]), difficulty breathing when lying down ([[orthopnea]]), or even [[respiratory failure]] if breathing muscles become involved. [[Bulbar]] symptoms, including difficulty speaking ([[dysarthria]]), difficulty swallowing ([[dysphagia]]), and excessive saliva production ([[Hypersalivation|sialorrhea]]), can also occur. Sensation, or the ability to feel, is typically not affected. Emotional disturbance (e.g. [[pseudobulbar affect]]) and cognitive and behavioural changes (e.g. problems in word fluency, decision-making, and memory) are also seen.<ref name="NINDS2014" /><ref name=":7" /> There can be lower motor neuron findings (e.g. muscle wasting, muscle twitching), upper motor neuron findings (e.g. brisk reflexes, [[Plantar reflex|Babinski reflex]], [[Hoffmann's reflex|Hoffman's reflex]], increased muscle tone), or both.<ref name=":7" />

Motor neuron diseases are seen both in children and adults.<ref name="NINDS2014" /> Those that affect children tend to be inherited or familial, and their symptoms are either present at birth or appear before learning to walk. Those that affect adults tend to appear after age 40.<ref name="NINDS2014" /> The clinical course depends on the specific disease, but most progress or worsen over the course of months.<ref name=":7" /> Some are fatal (e.g. ALS), while others are not (e.g. PLS).<ref name="NINDS2014" />

=== Patterns of weakness ===
Various patterns of muscle weakness occur in different motor neuron diseases.<ref name=":7" /> Weakness can be symmetric or asymmetric, and it can occur in body parts that are distal, proximal, or both. According to Statland et al., there are three main weakness patterns that are seen in motor neuron diseases, which are:<ref name=":7" /><ref>{{cite journal | vauthors = Barohn RJ, Amato AA | title = Pattern-recognition approach to neuropathy and neuronopathy | journal = Neurologic Clinics | volume = 31 | issue = 2 | pages = 343–361 | date = May 2013 | pmid = 23642713 | pmc = 3922643 | doi = 10.1016/j.ncl.2013.02.001 }}</ref>

# Asymmetric distal weakness without sensory loss (e.g. ALS, PLS, PMA, MMA)
# Symmetric weakness without sensory loss (e.g. PMA, PLS)
# Symmetric focal midline proximal weakness (neck, trunk, bulbar involvement; e.g. ALS, PBP, PLS)

=== Lower and upper motor neuron findings ===
Motor neuron diseases are on a spectrum in terms of upper and lower motor neuron involvement.<ref name=":7" /> Some have just lower or upper motor neuron findings, while others have a mix of both. Lower motor neuron (LMN) findings include muscle [[atrophy]] and [[fasciculation]]s, and upper motor neuron (UMN) findings include [[hyperreflexia]], spasticity, muscle spasm, and abnormal reflexes.<ref name="NINDS2014" /><ref name=":7" />

Pure upper motor neuron diseases, or those with just UMN findings, include PLS.<ref>{{cite book | vauthors = Emos MC, Agarwal S | chapter = Neuroanatomy, Upper Motor Neuron Lesion |date=2022 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK537305/ | title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30725990 |access-date=2022-06-24 }}</ref>

Pure lower motor neuron diseases, or those with just LMN findings, include PMA.<ref>{{Cite web |title=Progressive Muscular Atrophy – an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/neuroscience/progressive-muscular-atrophy |access-date=2022-06-24 |website=sciencedirect.com}}</ref>

Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS.<ref>{{Cite web |title=Motor Neuron Diseases Fact Sheet {{!}} National Institute of Neurological Disorders and Stroke |url=https://www.ninds.nih.gov/health-information/patient-caregiver-education/fact-sheets/motor-neuron-diseases-fact-sheet |access-date=2022-06-24 |website=ninds.nih.gov}}</ref>

== Causes ==
Most cases are sporadic and their causes are usually not known.<ref name="NINDS2014" /> It is thought that environmental, toxic, viral, or genetic factors may be involved.<ref name="NINDS2014" />

===DNA damage===

[[TAR DNA-binding protein 43]] (TDP-43), is a critical component of the [[non-homologous end joining]] (NHEJ) enzymatic pathway that [[DNA repair|repairs DNA]] [[DNA damage (naturally occurring)|double-strand breaks]] in pluripotent [[stem cell]]-derived motor neurons.<ref name =Mitra2019>{{cite journal | vauthors = Mitra J, Guerrero EN, Hegde PM, Liachko NF, Wang H, Vasquez V, Gao J, Pandey A, Taylor JP, Kraemer BC, Wu P, Boldogh I, Garruto RM, Mitra S, Rao KS, Hegde ML | display-authors = 6 | title = Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 116 | issue = 10 | pages = 4696–4705 | date = March 2019 | pmid = 30770445 | pmc = 6410842 | doi = 10.1073/pnas.1818415116 | bibcode = 2019PNAS..116.4696M | doi-access = free }}</ref> TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the [[DNA repair protein XRCC4|XRCC4]]-[[DNA ligase]] protein complex that then acts to repair double-strand breaks. About 95% of ALS patients have abnormalities in the nucleus-cytoplasmic localization in spinal motor neurons of TDP43. In TDP-43 depleted human neural stem cell-derived motor neurons, as well as in sporadic [[amyotrophic lateral sclerosis|ALS]] patients' spinal cord specimens there is significant double-strand break accumulation and reduced levels of NHEJ.<ref name=Mitra2019/>

=== Associated risk factors ===
In adults, men are more commonly affected than women.<ref name="NINDS2014" />

== Diagnosis ==
Differential diagnosis can be challenging due to the number of overlapping symptoms, shared between several motor neuron diseases.<ref>{{Cite journal |last1=Statland |first1=Jeffrey M. |last2=Barohn |first2=Richard J. |last3=McVey |first3=April L. |last4=Katz |first4=Jonathan |last5=Dimachkie |first5=Mazen M. |date=2015 |title=Patterns of Weakness, Classification of Motor Neuron Disease & Clinical Diagnosis of Sporadic ALS |journal=Neurologic Clinics |volume=33 |issue=4 |pages=735–748 |doi=10.1016/j.ncl.2015.07.006 |issn=0733-8619 |pmc=4629510 |pmid=26515618}}</ref> Frequently, the diagnosis is based on clinical findings (i.e. LMN vs. UMN signs and symptoms, patterns of weakness), family history of MND, and a variation of tests, many of which are used to rule out disease mimics, which can manifest with identical symptoms.<ref>{{Cite web |title=Archive {{!}} Practical Neurology |url=https://pn.bmj.com/content/by/year |access-date=2022-06-24 |website=pn.bmj.com}}</ref><ref name=":12"/>

=== Classification ===
[[File:UMN vs LMN.png|thumb|296x296px|'''Corticospinal tract.''' Upper motor neurons originating in the primary motor cortex synapse to either lower motor neurons in the anterior horn of the central gray matter of the spinal cord (insert) or brainstem motor neurons (not shown). Motor neuron disease can affect either upper motor neurons (UMNs) or lower motor neurons (LMNs).]]
Motor neuron disease describes a collection of clinical disorders, characterized by progressive muscle weakness and the degeneration of the motor neuron on [[Electrophysiological techniques for clinical diagnosis|electrophysiological testing]]. The term "motor neuron disease" has varying meanings in different countries. Similarly, the literature inconsistently classifies which degenerative motor neuron disorders can be included under the umbrella term "motor neuron disease". The four main types of MND are marked (*) in the table below.<ref name=":8">{{Cite web|url=http://www.mndnsw.asn.au/about-mnd/what-is-mnd/44-mndforms.html|title=What forms does MND take?|website=mndnsw.asn.au|access-date=2018-12-11}}</ref>

All types of MND can be differentiated by two defining characteristics:<ref name=":7" />

# Is the disease sporadic or inherited?
# Is there involvement of the [[upper motor neuron]]s (UMN), the [[lower motor neuron]]s (LMN), or both?

Sporadic or acquired MNDs occur in patients with no family history of degenerative motor neuron disease. Inherited or genetic MNDs adhere to one of the following inheritance patterns: [[autosomal dominant]], [[Autosomal Recessive|autosomal recessive]], or [[X-linked]]. Some disorders, like ALS, can occur sporadically (85%) or can have a genetic cause (15%) with the same clinical symptoms and progression of disease.<ref name=":7" />

UMNs are motor neurons that project from the cortex down to the brainstem or spinal cord.<ref name=":4">{{Cite book|title=Neuroanatomy through clinical cases| vauthors = Blumenfeld H |date=2002 |publisher=Sinauer |isbn=087893060-4|location=Sunderland, Mass.|oclc=44628054}}</ref> LMNs originate in the anterior horns of the spinal cord and synapse on peripheral muscles.<ref name=":4" /> Both motor neurons are necessary for the strong contraction of a muscle, but damage to an UMN can be distinguished from damage to a LMN by physical exam.<ref>{{cite book | vauthors = Javed K, Daly DT | chapter = Neuroanatomy, Lower Motor Neuron Lesion |date=2022 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK539814/ |title = StatPearls |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30969636 |access-date=2022-06-24 }}</ref>

{| class="wikitable"
 ! Type !! UMN degeneration !! LMN degeneration
|-
| colspan="3" |'''Sporadic MNDs'''
|-
| Sporadic amyotrophic lateral sclerosis (ALS)* || Yes<ref name=":7" />|| Yes<ref name=":7" />
|-
|Primary lateral sclerosis (PLS)* || Yes<ref name=":7" />|| No<ref name=":7" />
|-
|Progressive muscular atrophy (PMA)* || No<ref name=":7" />|| Yes<ref name=":7" />
|-
|Progressive bulbar palsy (PBP)* || Yes<ref name=":8" />|| Yes, [[bulbar]] region<ref name=":8" />
|-
|Pseudobulbar palsy|| Yes, bulbar region<ref name=":7" />|| No<ref name=":7" />
|-
|Monomelic amyotrophy (MMA)
|No
|Yes
|-
| colspan="3" |'''Inherited MNDs'''
|-
|Familial amyotrophic lateral sclerosis (ALS)*
|Yes<ref name=":7" />
|Yes<ref name=":7" />
|}

=== Tests ===
* [[Cerebrospinal fluid]] (CSF) tests: Analysis of the fluid from around the brain and spinal cord could reveal signs of an infection or inflammation.<ref name=":12">{{cite journal | vauthors = Foster LA, Salajegheh MK | title = Motor Neuron Disease: Pathophysiology, Diagnosis, and Management | journal = The American Journal of Medicine | volume = 132 | issue = 1 | pages = 32–37 | date = January 2019 | pmid = 30075105 | doi = 10.1016/j.amjmed.2018.07.012 | s2cid = 51910723 }}</ref>
* [[Magnetic resonance imaging]] (MRI): An MRI of the brain and spinal cord is recommended in patients with UMN signs and symptoms to explore other causes, such as a tumor, inflammation, or lack of blood supply (stroke).<ref name=":12" />
* [[Electromyography|Electromyogram]] (EMG) & [[nerve conduction study]] (NCS): The EMG, which evaluates muscle function, and NCS, which evaluates nerve function, are performed together in patients with LMN signs.
* For patients with MND affecting the LMNs, the EMG will show evidence of: (1) acute denervation, which is ongoing as motor neurons degenerate, and (2) chronic denervation and [[reinnervation]] of the muscle, as the remaining motor neurons attempt to fill in for lost motor neurons.<ref name=":12" />
* By contrast, the NCS in these patients is usually normal. It can show a low [[compound muscle action potential]] (CMAP), which results from the loss of motor neurons, but the [[sensory neuron]]s should remain unaffected.<ref>{{cite journal | vauthors = Duleep A, Shefner J | title = Electrodiagnosis of motor neuron disease | journal = Physical Medicine and Rehabilitation Clinics of North America | volume = 24 | issue = 1 | pages = 139–151 | date = February 2013 | pmid = 23177036 | doi = 10.1016/j.pmr.2012.08.022 }}</ref>
* [[Tissue biopsy]]: Taking a small sample of a muscle or nerve may be necessary if the EMG/NCS is not specific enough to rule out other causes of progressive muscle weakness, but it is rarely used.

== Treatment ==
There are no known curative treatments for the majority of motor neuron disorders. 
Physiotherapy helps maintain movement and function when someone is affected by
disability, injury or illness. This is achieved through movement and exercise, manual
therapy, education and advice. Although physiotherapy can't reverse the effects of
MND, or Kennedy's disease, it can help maintain range of movement and comfort
for as long as possible.

== Prognosis ==
The table below lists life expectancy for patients who are diagnosed with MND.
{| class="wikitable"
!Type
!Median survival time <br />from start of symptoms
|-
|Amyotrophic lateral sclerosis (ALS)
|2–5 years<ref name=":12" /><ref name=":10">{{cite web |url=https://imnda.ie/about-mnd/different-types-of-mnd/ |title=Different types of MND | work = Irish Motor Neurone Disease Association |access-date=2018-12-12}}</ref>
|-
|Primary lateral sclerosis (PLS)
|8–10 years<ref name=":12" />
|-
|Progressive muscular atrophy (PMA)
|2–4 years<ref name=":12" />
|-
|Progressive bulbar palsy (PBP)
|6 months – 3 years<ref name=":10" />
|-
|Pseudobulbar palsy
|No change in survival
|}

==Terminology==
In the United States and Canada, the term ''motor neuron disease'' usually refers to the group of disorders while amyotrophic lateral sclerosis is frequently called ''Lou Gehrig's disease''.<ref name=NINDS2014/><ref name=":14">{{Cite book |title=Clinical and molecular aspects of motor neuron disease | vauthors = Cooper-Knock J, Jenkins T, Shaw PJ |isbn=978-1-61504-429-0|location=San Rafael, California  |oclc=860981760|date = 2013-09-01}}</ref><ref name=":3">{{cite journal | vauthors = Shaw PJ | title = Molecular and cellular pathways of neurodegeneration in motor neurone disease | journal = Journal of Neurology, Neurosurgery, and Psychiatry | volume = 76 | issue = 8 | pages = 1046–1057 | date = August 2005 | pmid = 16024877 | pmc = 1739758 | doi = 10.1136/jnnp.2004.048652 | quote = Many doctors use the terms motor neuron disease and ALS interchangeably. }}</ref> In the United Kingdom and Australia, the term ''motor neuron(e) disease'' is used for amyotrophic lateral sclerosis,<ref name="NHS"/><ref name="healthdirectAU"/> although is not uncommon to refer to the entire group.<ref name=":15">{{cite web |url=https://www.mndassociation.org/wp-content/uploads/2015/02/an-introduction-to-mnd-booklet.pdf |archive-url=https://ghostarchive.org/archive/20221009/https://www.mndassociation.org/wp-content/uploads/2015/02/an-introduction-to-mnd-booklet.pdf |archive-date=2022-10-09 |url-status=live|title=An introduction to motor neurone disease (MND) |website=motor neurone disease association|date= 2015}}</ref><ref>{{Cite book  |title=Neurodegeneration| vauthors = Schapira AH, Wszolek ZK, Dawson TM, Wood NW |isbn=978-1-118-66191-8 |location=Chichester, West Sussex |oclc=958876527 | date = 2017-02-13 }}</ref>

While MND refers to a specific subset of similar diseases, there are numerous other diseases of [[motor neuron]]s that are referred to collectively as "motor neuron disorders", for instance the diseases belonging to the [[spinal muscular atrophies]] group.<ref name=El2008>{{cite book | vauthors = Ince PG, Clark B, Holton J, Revesz T, Wharton SB | chapter = Chapter 13: Diseases of movement and system degenerations | veditors = Greenfield JG, Love S, Louis DN, Ellison DW |title=Greenfield's neuropathology|date=2008|publisher=Hodder Arnold|location=London|isbn=978-0-340-90681-1 | volume = 1 |page=947|edition=8th|chapter-url=https://books.google.com/books?id=nrEWkAc7W7IC&pg=PA947}}</ref> However, they are not classified as "motor neuron diseases" by the 11th edition of the [[International Statistical Classification of Diseases and Related Health Problems]] (ICD-11),<ref>{{Cite web|url=https://icd.who.int/browse11/l-m/en#/http%3a%2f%2fid.who.int%2ficd%2fentity%2f661720689|title=8B60 Motor neuron disease|website=ICD-11 for Mortality and Morbidity Statistics|publisher=World Health Organisation}}</ref> which is the definition followed in this article.

== See also ==
* [[Spinal muscular atrophies]]
* [[Hereditary motor and sensory neuropathy|Hereditary motor and sensory neuropathies]]
* [[Stephen Hawking]]

== References ==
{{reflist}}

== External links ==
* {{Commons-inline}}
* {{NINDS|Motor-Neuron-Diseases|Motor neuron diseases}}
{{Medical resources
| DiseasesDB     = 8358
| ICD11          = {{ICD11|8B60}}
| ICD10          = {{ICD10|G12.2}}
| ICD9           = {{ICD9|335.2}}
| ICDO           =
| OMIM           =
| MedlinePlus    =
| eMedicineSubj  =
| eMedicineTopic =
| MeshID         = D016472
}}
{{CNS diseases of the nervous system}}

{{DEFAULTSORT:Motor neuron disease}}
[[Category:Motor neuron diseases|Motor neuron diseases]]
[[Category:Rare diseases]]
[[Category:Systemic atrophies primarily affecting the central nervous system]]