Motor neuron diseases

Motor neuron diseases or motor neurone diseases (MNDs) are a group of rare neurodegenerative disorders that selectively affect motor neurons, the cells which control voluntary muscles of the body.<ref name=El2008/><ref name="NINDS2014">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> They include amyotrophic lateral sclerosis (ALS),<ref name="NHS">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="healthdirectAU">{{#invoke:citation/CS1|citation |CitationClass=web }}</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 genes (e.g. SOD1) that are thought to be important in understanding how the disease occurs.<ref name=":2">Template:Cite book</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

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Signs and symptoms depend on the specific disease, but motor neuron diseases typically manifest as a group of movement-related symptoms.<ref name=":7">Template:Cite journal</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 (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, Babinski 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>Template:Cite journal</ref>

1. Asymmetric distal weakness without sensory loss (e.g. ALS, PLS, PMA, MMA)
2. Symmetric weakness without sensory loss (e.g. PMA, PLS)
3. 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 fasciculations, 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>Template:Cite book</ref>

Pure lower motor neuron diseases, or those with just LMN findings, include PMA.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</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 repairs DNA double-strand breaks in pluripotent stem cell-derived motor neurons.<ref name =Mitra2019>Template:Cite journal</ref> TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the 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 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>Template:Cite journal</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=":12"/>

Classification

File:UMN vs LMN.png

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 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">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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

1. Is the disease sporadic or inherited?
2. Is there involvement of the upper motor neurons (UMN), the lower motor neurons (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, 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">Template:Cite book</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>Template:Cite book</ref>

Type	UMN degeneration	LMN degeneration
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
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">Template:Cite journal</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" />
• 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 neurons should remain unaffected.<ref>Template:Cite journal</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.

Type	Median survival time from start of symptoms
Amyotrophic lateral sclerosis (ALS)	citation	CitationClass=web }}</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">Template:Cite book</ref><ref name=":3">Template:Cite journal</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">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>Template:Cite book</ref>

While MND refers to a specific subset of similar diseases, there are numerous other diseases of motor neurons that are referred to collectively as "motor neuron disorders", for instance the diseases belonging to the spinal muscular atrophies group.<ref name=El2008>Template:Cite book</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>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> which is the definition followed in this article.

See also

• Spinal muscular atrophies
• Hereditary motor and sensory neuropathies
• Stephen Hawking

External links

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• Template:NINDS