Motor neuron disease

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Motor neuron disease
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spinal diagram
Specialty Neurology

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. [1] [2] They include amyotrophic lateral sclerosis (ALS), [3] [4] progressive bulbar palsy (PBP), pseudobulbar palsy, progressive muscular atrophy (PMA), primary lateral sclerosis (PLS), and monomelic amyotrophy (MMA), as well as some rarer variants resembling ALS.

Contents

Motor neuron diseases affect both children and adults. [5] While each motor neuron disease affects patients differently, they all cause movement-related symptoms, mainly muscle weakness. [6] Most of these diseases seem to occur randomly without known causes, but some forms are inherited. [2] 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. [7]

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. [2] Currently, there are no approved treatments for the majority of motor neuron disorders, and care is mostly symptomatic. [2]

Signs and symptoms

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. ALS clinical picture.png
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.

Signs and symptoms depend on the specific disease, but motor neuron diseases typically manifest as a group of movement-related symptoms. [6] 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. [2] [6] 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. [6]

Motor neuron diseases are seen both in children and in adults. [2] 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. [2] The clinical course depends on the specific disease, but most progress or worsen over the course of months. [6] Some are fatal (e.g. ALS), while others are not (e.g. PLS). [2]

Patterns of weakness

Various patterns of muscle weakness occur in different motor neuron diseases. [6] 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: [6] [9]

  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. [6] 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. [2] [6]

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. [2] It is thought that environmental, toxic, viral, or genetic factors may be involved. [2]

DNA damage

TARDBP (TAR DNA-binding protein 43), also referred to as 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. [10] 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. [10]

Associated risk factors

In adults, men are more commonly affected than women. [2]

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.[ citation needed ]

Classification

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). 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. As discussed above, 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. [11]

All types of MND can be differentiated by two defining characteristics: [6]

  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. [6]

UMNs are motor neurons that project from the cortex down to the brainstem or spinal cord. [12] LMNs originate in the anterior horns of the spinal cord and synapse on peripheral muscles. [12] 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.

TypeUMN degenerationLMN degeneration
Sporadic MNDs
Sporadic amyotrophic lateral sclerosis (ALS)*Yes [6] Yes [6]
Primary lateral sclerosis (PLS)*Yes [6] No [6]
Progressive muscular atrophy (PMA)*No [6] Yes [6]
Progressive bulbar palsy (PBP)*Yes [11] Yes, bulbar region [11]
Pseudobulbar palsyYes, bulbar region [6] No [6]
Monomelic amyotrophy (MMA)NoYes
Inherited MNDs
Familial amyotrophic lateral sclerosis (ALS)*Yes [6] Yes [6]

Tests

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. [15]

Prognosis

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

TypeMedian survival time
from start of symptoms
Amyotrophic lateral sclerosis (ALS)2–5 years [13] [16]
Primary lateral sclerosis (PLS)8–10 years [13]
Progressive muscular atrophy (PMA)2–4 years [13]
Progressive bulbar palsy (PBP)6 months – 3 years [16]
Pseudobulbar palsyNo 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. [2] [5] [17] In the United Kingdom and Australia, the term motor neuron(e) disease is used for amyotrophic lateral sclerosis, [3] [4] although is not uncommon to refer to the entire group. [18] [19]

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. [1] 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), [20] which is the definition followed in this article.

See also

Related Research Articles

Neuromyotonia (NMT) is a form of peripheral nerve hyperexcitability that causes spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. NMT along with Morvan's syndrome are the most severe types in the Peripheral Nerve Hyperexciteability spectrum. Example of two more common and less severe syndromes in the spectrum are Cramp Fasciculation Syndrome and Benign Fasciculation Syndrome. NMT can have both hereditary and acquired forms. The prevalence of NMT is unknown.

Benign fasciculation syndrome

Benign fasciculation syndrome (BFS) is characterized by fasciculation (twitching) of voluntary muscles in the body. The twitching can occur in any voluntary muscle group but is most common in the eyelids, arms, hands, fingers, legs, and feet. The tongue can also be affected. The twitching may be occasional to continuous. BFS must be distinguished from other conditions that include muscle twitches.

Riluzole Medication used to treat amyotrophic lateral sclerosis

Riluzole is a medication used to treat amyotrophic lateral sclerosis. Riluzole delays the onset of ventilator-dependence or tracheostomy in some people and may increase survival by two to three months. Riluzole is available in tablet and liquid form.

Fasciculation Muscle contraction

A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as much as 70% of people experiencing them. They can be benign, or associated with more serious conditions. When no cause or pathology is identified, they are diagnosed as benign fasciculation syndrome.

Lower motor neurons (LMNs) are motor neurons located in either the anterior grey column, anterior nerve roots or the cranial nerve nuclei of the brainstem and cranial nerves with motor function. All voluntary movement relies on spinal lower motor neurons, which innervate skeletal muscle fibers and act as a link between upper motor neurons and muscles. Cranial nerve lower motor neurons control movements of the eyes, face and tongue, and contribute to chewing, swallowing and vocalization. Damage to the lower motor neurons can lead to flaccid paralysis, absent deep tendon reflexes and muscle atrophy.

Spinal and bulbar muscular atrophy

Spinal and bulbar muscular atrophy (SBMA), popularly known as Kennedy's disease, is a progressive debilitating neurodegenerative disorder resulting in muscle cramps and progressive weakness due to degeneration of motor neurons in the brainstem and spinal cord.

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 nerve cells that control voluntary muscle movement degenerate and die, causing weakness in the muscles they control.

Nerve conduction velocity

Nerve conduction velocity (CV) is an important aspect of nerve conduction studies. It is the speed at which an electrochemical impulse propagates down a neural pathway. Conduction velocities are affected by a wide array of factors, including age, sex, and various medical conditions. Studies allow for better diagnoses of various neuropathies, especially demyelinating diseases as these conditions result in reduced or non-existent conduction velocities.

Neuromuscular disease

Neuromuscular disease is a broad term that encompasses many diseases and ailments that impair the functioning of the muscles, either directly, being pathologies of the voluntary muscle, or indirectly, being pathologies of nerves or neuromuscular junctions.

Progressive muscular atrophy

Progressive muscular atrophy (PMA) is a very rare subtype of motor neuron disease (MND) that affects only the lower motor neurons. PMA is thought to account for around 4% of all MND cases. This is in contrast to amyotrophic lateral sclerosis (ALS), the most common form of MND, which affects both the upper and lower motor neurons, or primary lateral sclerosis, another rare MND variant, which affects only the upper motor neurons. The distinction is important because PMA is associated with a better prognosis than classic ALS.

Progressive bulbar palsy (PBP) is a medical condition. It belongs to a group of disorders known as motor neuron diseases. PBP is a disease that attacks the nerves supplying the bulbar muscles. These disorders are characterized by the degeneration of motor neurons in the cerebral cortex, spinal cord, brain stem, and pyramidal tracts. This specifically involves the glossopharyngeal nerve (IX), vagus nerve (X), and hypoglossal nerve (XII).

Amyotrophic lateral sclerosis Neurodegenerative disease characterized by progressive muscular weakness

Amyotrophic lateral sclerosis (ALS): also known as Lou Gehrig's disease in Canada and the United States, as motor neurone disease (MND) in Australia, Ireland, New Zealand, South Africa, and the United Kingdom, and Charcot disease in francophone countries; is a neurodegenerative neuromuscular disease that results in the progressive loss of motor neurons that control voluntary muscles.

Multifocal motor neuropathy (MMN) is a progressively worsening condition where muscles in the extremities gradually weaken. The disorder, a pure motor neuropathy syndrome, is sometimes mistaken for amyotrophic lateral sclerosis (ALS) because of the similarity in the clinical picture, especially if muscle fasciculations are present. MMN is thought to be autoimmune. It was first described in the mid-1980s.

Upper motor neuron syndrome (UMNS) is the motor control changes that can occur in skeletal muscle after an upper motor neuron lesion.

Facial Onset Sensory and Motor Neuronopathy syndrome is an extremely rare disease characterised by sensory and motor loss beginning in the face and spreading to involve an increasingly larger area including the upper arms. Details of the disease, and in particular its aetiology, are currently subject to debate, mainly because FOSMN syndrome is so rare. FOSMN was first described in four patients in 2006 and subsequently in a further six patients but so far, these ten represent the only reported cases.

Ozanezumab is a monoclonal antibody designed for the treatment of ALS and multiple sclerosis.

Multisystem proteinopathy (MSP) is a dominantly inherited, pleiotropic, degenerative disorder of humans that can affect muscle, bone, and/or the central nervous system. MSP can manifest clinically as classical amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), or as a combination of these disorders. Historically, several different names have been used to describe MSP, most commonly “inclusion body myopathy with early-onset Paget disease and frontotemporal dementia (IBMPFD)” or “inclusion body myopathy with frontotemporal dementia, Paget’s disease of bone, and amyotrophic lateral sclerosis (IBMPFD/ALS).” However, IBMPFD and IBMPFD/ALS are now considered outdated classifications and are more properly referred to as MSP, as the disease is clinically heterogeneous and its phenotypic spectrum extends beyond IBM, PDB, FTD, and ALS to include motor neuron disease, Parkinson’s disease features, and ataxia features. Although MSP is rare, growing interest in this syndrome derives from the molecular insights the condition provides into the etiological relationship between common age-related degenerative diseases of muscle, bone, and brain.

Christopher Edward Dennistoun Shaw MBChB, MD, FRACP, FRCP (Hon), FMedSci, FANA is Professor of Neurology and Neurogenetics at the Institute of Psychiatry, Psychology and Neuroscience, King's College London. He is also Head of the Department of Basic and Clinical Neuroscience, Director of the Maurice Wohl Clinical Neuroscience Institute at King's College London and an Honorary Consultant Neurologist and Neurogeneticist at King's College Hospital. His major research interest is in the genetic, molecular and cellular basis of motor neuron diseases such as amyotrophic lateral sclerosis (ALS).

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. MMA is reported most frequently in Asia but has a global distribution. It is typically marked by insidious onset of muscle atrophy of an upper limb, which plateaus after two to five years from which it neither improves nor worsens. There is no pain or sensory loss associated with MMA. MMA is not believed to be hereditary.

Research on amyotrophic lateral sclerosis has focused on animal models of the disease, its mechanisms, ways to diagnose and track it, and treatments.

References

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  14. Duleep, Anuradha; Shefner, Jeremy (1 February 2013). "Electrodiagnosis of Motor Neuron Disease". Physical Medicine and Rehabilitation Clinics of North America. 24 (1): 139–151. doi:10.1016/j.pmr.2012.08.022. ISSN   1047-9651. PMID   23177036.
  15. "NIH: ninds: Motor Neuron Diseases Information Page". 27 March 2019. Retrieved 18 November 2019.
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  20. "8B60 Motor neuron disease". ICD-11 for Mortality and Morbidity Statistics. World Health Organisation.
Classification
D