Motor neuron diseases or motor neurone diseases (MNDs) are a group of rare

neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

disorders that selectively affect

motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirectl ...

s, the cells which control

voluntary muscles Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...

of the body. They include

amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...

(ALS),

progressive bulbar palsy Progressive bulbar palsy (PBP) is a medical condition. It belongs to a group of disorders known as motor neuron diseases. Lapiedra 2002 PBP is a disease that attacks the nerves supplying the bulbar muscles. These disorders are characterized by the ...

(PBP),

pseudobulbar palsy Pseudobulbar palsy is a medical condition characterized by the inability to control facial movements (such as chewing and speaking) and caused by a variety of neurological disorders. Patients experience difficulty chewing and swallowing, have in ...

progressive muscular atrophy Progressive muscular atrophy (PMA), also called Duchenne–Aran disease and Duchenne–Aran muscular atrophy, is a disorder characterised by the degeneration of lower motor neurons, resulting in generalised, progressive loss of muscle function. P ...

(PMA),

primary lateral sclerosis Primary lateral sclerosis (PLS) is a very rare neuromuscular disease characterized by progressive muscle weakness in the voluntary muscles. PLS belongs to a group of disorders known as motor neuron diseases. Motor neuron diseases develop when the n ...

(PLS),

spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...

(SMA) and

monomelic amyotrophy Monomelic amyotrophy (MMA) is a rare motor neuron disease first described in 1959 in Japan. Its symptoms usually appear about two years after adolescent growth spurt and is significantly more common in males, with an average age of onset between 1 ...

(MMA), as well as some rarer variants resembling ALS. Motor neuron diseases affect both children and adults. While each motor neuron disease affects patients differently, they all cause movement-related symptoms, mainly

muscle weakness Muscle weakness is a lack of muscle strength. Its causes are many and can be divided into conditions that have either true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, includi ...

. Most of these diseases seem to occur randomly without known causes, but some forms are inherited. Studies into these inherited forms have led to discoveries of various

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s (e.g. ''

SOD1 Superoxide dismutase u-Zn'' also known as superoxide dismutase 1 or hSod1 is an enzyme that in humans is encoded by the ''SOD1'' gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. It is implicated in apoptosis, fam ...

'') that are thought to be important in understanding how the disease occurs. 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. Currently, there are no approved treatments for the majority of motor neuron disorders, and care is mostly symptomatic.

Signs and symptoms

Signs and symptoms depend on the specific disease, but motor neuron diseases typically manifest as a group of movement-related symptoms. 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 Exertion is the physical or perceived use of energy.Newton's Third Law, Elert, Glenn. “Forces.” ''Viscosity – The Physics Hypertextbook'', physics.info/newton-first/. Exertion traditionally connotes a strenuous or costly ''effort'', resulting ...

), difficulty breathing when lying down (

orthopnea Orthopnea or orthopnoea is shortness of breath (dyspnea) that occurs when lying flat, causing the person to have to sleep propped up in bed or sitting in a chair. It is commonly seen as a late manifestation of heart failure, resulting from fluid ...

), or even

respiratory failure Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...

if breathing muscles become involved. Bulbar symptoms, including difficulty speaking (

dysarthria Dysarthria is a speech sound disorder resulting from neurological injury of the motor component of the motor–speech system and is characterized by poor articulation of phonemes. In other words, it is a condition in which problems effectively ...

), difficulty swallowing (

dysphagia Dysphagia is difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, in some contexts it is classified as a disease#Terminology, condition in its own right. It may be a sensation that suggests difficulty in the passag ...

), and excessive saliva production (

sialorrhea Hypersalivation, or ptyalism, also known as sialorrhea or hypersialosis is the excessive production of saliva. It has also been defined as increased amount of saliva in the mouth, which may also be caused by decreased clearance of saliva.Medscape ...

), can also occur. Sensation, or the ability to feel, is typically not affected. Emotional disturbance (e.g.

pseudobulbar affect Pseudobulbar affect (PBA), or emotional incontinence, is a type of emotional disturbance characterized by uncontrollable episodes of crying, laughing, anger or other emotional displays. PBA occurs secondary to a neurologic disorder or brain inj ...

) and cognitive and behavioural changes (e.g. problems in word fluency, decision-making, and memory) are also seen. There can be lower motor neuron findings (e.g. muscle wasting, muscle twitching), upper motor neuron findings (e.g. brisk reflexes,

Babinski reflex The plantar reflex is a reflex elicited when the sole of the foot is stimulated with a blunt instrument. The reflex can take one of two forms. In healthy adults, the plantar reflex causes a downward response of the hallux (flexion). An upward re ...

Hoffman's reflex Hoffmann's reflex (Hoffmann's sign, sometimes simply "''Hoffmann's''", also finger flexor reflex) is a neurological examination finding elicited by a reflex test which can help verify the presence or absence of issues arising from the corticospina ...

, increased muscle tone), or both. Motor neuron diseases are seen both in children and adults. 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. The clinical course depends on the specific disease, but most progress or worsen over the course of months. Some are fatal (e.g. ALS), while others are not (e.g. PLS).

Patterns of weakness

Various patterns of muscle weakness occur in different motor neuron diseases. 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: # 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. Some have just lower or upper motor neuron findings, while others have a mix of both. Lower motor neuron (LMN) findings include muscle

atrophy Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations (which can destroy the gene to build up the organ), poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply t ...

and

fasciculation A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more serio ...

s, and upper motor neuron (UMN) findings include

hyperreflexia Hyperreflexia is overactive or overresponsive bodily reflexes. Examples of this include twitching and spastic tendencies, which indicate upper disease of the upper motor neurons and the lessening or loss of control ordinarily exerted by highe ...

, spasticity, muscle spasm, and abnormal reflexes. Pure upper motor neuron diseases, or those with just UMN findings, include PLS. Pure lower motor neuron diseases, or those with just LMN findings, include PMA. Motor neuron diseases with both UMN and LMN findings include both familial and sporadic ALS.

Causes

Most cases are sporadic and their causes are usually not known. It is thought that environmental, toxic, viral, or genetic factors may be involved.

DNA damage

TARDBP TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene. Structure TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...

(TAR DNA-binding protein 43), also referred to as TDP-43, is a critical component of the

non-homologous end joining Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. NHEJ is referred to as "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology direct ...

(NHEJ) enzymatic pathway that repairs DNA

double-strand breaks DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dama ...

in pluripotent

stem cell In multicellular organisms, stem cells are undifferentiated or partially differentiated cells that can differentiate into various types of cells and proliferate indefinitely to produce more of the same stem cell. They are the earliest type o ...

-derived motor neurons. TDP-43 is rapidly recruited to double-strand breaks where it acts as a scaffold for the recruitment of the

XRCC4 DNA repair protein XRCC4 also known as X-ray repair cross-complementing protein 4 or XRCC4 is a protein that in humans is encoded by the XRCC4 gene. In addition to humans, the XRCC4 protein is also expressed in many other metazoans, fungi and in ...

DNA ligase DNA ligase is a specific type of enzyme, a ligase, () that facilitates the joining of DNA strands together by catalyzing the formation of a phosphodiester bond. It plays a role in repairing single-strand breaks in duplex DNA in living organ ...

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 Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most com ...

patients’ spinal cord specimens there is significant double-strand break accumulation and reduced levels of NHEJ.

Associated risk factors

In adults, men are more commonly affected than women.

Diagnosis

Differential diagnosis can be challenging due to the number of overlapping symptoms, shared between several motor neuron diseases. 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.

Classification

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. All types of MND can be differentiated by two defining characteristics: # Is the disease sporadic or inherited? # Is there involvement of the

upper motor neuron Upper motor neurons (UMNs) is a term introduced by William Gowers in 1886. They are found in the cerebral cortex and brainstem and carry information down to activate interneurons and lower motor neurons, which in turn directly signal muscles t ...

s (UMN), the

lower motor neuron Lower motor neurons (LMNs) are motor neurons located in either the anterior grey column, anterior nerve roots (spinal lower motor neurons) or the cranial nerve nuclei of the brainstem and cranial nerves with motor function (cranial nerve lower mo ...

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 In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

, or

X-linked Sex linked describes the sex-specific patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, ...

. Some disorders, like ALS, can occur sporadically (85%) or can have a genetic cause (15%) with the same clinical symptoms and progression of disease. UMNs are motor neurons that project from the cortex down to the brainstem or spinal cord. LMNs originate in the anterior horns of the spinal cord and synapse on peripheral muscles. 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.

Tests

Cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...

(CSF) tests: Analysis of the fluid from around the brain and spinal cord could reveal signs of an infection or inflammation. *

Magnetic resonance imaging Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio wave ...

(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). *

Electromyogram Electromyography (EMG) is a technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an instrument called an electromyograph to produce a record called an electromyogram. An electromyog ...

(EMG) &

nerve conduction study A nerve conduction study (NCS) is a medical diagnostic test commonly used to evaluate the function, especially the ability of electrical conduction, of the motor and sensory nerves of the human body. These tests may be performed by medical specia ...

(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 Reinnervation is the restoration, either by spontaneous cellular regeneration or by surgical grafting, of nerve supply to a body part from which it has been lost or damaged. See also * Denervation * Neuroregeneration Neuroregeneration refers t ...

of the muscle, as the remaining motor neurons attempt to fill in for lost motor neurons. * By contrast, the NCS in these patients is usually normal. It can show a low

compound muscle action potential The compound muscle action potential (CMAP) or compound motor action potential is an electromyography investigation (electrical study of muscle function). The CMAP idealizes the summation of a group of almost simultaneous action potentials from se ...

(CMAP), which results from the loss of motor neurons, but the

sensory neuron Sensory neurons, also known as afferent neurons, are neurons in the nervous system, that convert a specific type of stimulus, via their receptors, into action potentials or graded potentials. This process is called sensory transduction. The cell ...

s should remain unaffected. *

Tissue biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a diseas ...

: 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. Please refer to the articles on individual disorders for more details.

Prognosis

The table below lists life expectancy for patients who are diagnosed with MND.

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''. In the United Kingdom and Australia, the term ''motor neuron(e) disease'' is used for amyotrophic lateral sclerosis, although is not uncommon to refer to the entire group. While MND refers to a specific subset of similar diseases, there are numerous other diseases of

s that are referred to collectively as "motor neuron disorders", for instance the diseases belonging to the

spinal muscular atrophies Spinal muscular atrophies (SMAs) are a genetically and clinically heterogeneous group of rare debilitating disorders characterised by the degeneration of lower motor neurons (neuronal cells situated in the anterior horn of the spinal cord) and ...

group. However, they are not classified as "motor neuron diseases" by the 11th edition of the

International Statistical Classification of Diseases and Related Health Problems The International Classification of Diseases (ICD) is a globally used diagnostic tool for epidemiology, health management and clinical purposes. The ICD is maintained by the World Health Organization (WHO), which is the directing and coordinating ...

(ICD-11), which is the definition followed in this article.

References

External links

* * {{DEFAULTSORT:Motor neuron disease Motor neuron diseases Rare diseases Systemic atrophies primarily affecting the central nervous system