Neuromuscular Diseases: Causes, Types and Treatments

The Neuromuscular Diseases (NMS) are a set of more than 150 neurological diseases of genetic origin, although each one responds to a different mechanism. Their nature is progressive and they are all characterized by the loss of strength in the muscles.

They are chronic and cause a great disability in the people who suffer them, affecting in their day to day life as well as in their quality of life. MMS may appear at any time in life, but more than 50% of them are from childhood onset.

Currently, it is estimated that in Spain more than 60,000 people suffer from one of these diseases. In addition, NMS are classified within the group of Rare Diseases, due to their low prevalence.

Each of these diseases affects few people, but if we add the total number of people affected by this set of diseases, we see how they affect a considerable group of the population.

Etiology of neuromuscular diseases

The causes for the occurrence of Neuromuscular Diseases are multiple, they can be classified according to whether they are genetic or acquired.

Genetics

The disease occurs as a consequence of the alteration of a certain gene that will vary according to which ENM is. In this type, there are often several people affected in the same family. There are different types of genetic inheritance.

1. Autosomal dominant: The gene that carries the disease is in the autosomes (pairs of chromosomes) and its effect is not compensated by the normal gene that corresponds to it. That is, in these cases the disease develops.

2. Autosomal recessive : The normal gene compensates for the effect of the anomalous gene. In this case, the person may or may not present the symptomatology.

3. Recessive linked to sex : The genetic defect is found in the pair of chromosomes that determines sex. In the case of being in the X, the men will present the disease. Therefore, women can be carriers and, nevertheless, do not present the symptomatology. In these cases, the severity of the disease will vary depending on the degree of penetrance and whether more genes are involved in the mechanism of the disease.

Acquired

Its transmission is not genetic. The mechanisms are diverse:

1. Immune source or autoimmune base : The immune system attacks one's own Cells Of the body because it does not recognize them.

2. Of infectious origin : Due to the action of an exogenous agent, such as viruses or parasites.

3. Of toxic-drug origin : They are produced by toxic exogenous, for example: some drugs, industrial or vegetable toxicants.

4. Of endocrine-metabolic origin : There are 3 main causes; Deficiency of essential nutrients or vitamins, absence / excess of certain hormones and the action of endogenous poisons produced by a malfunction.

Types

There are different types to classify NMS, according to the criteria that are followed (pathophysiological, clinical, form of transmission, etc.). I will then use the classification used by the Spanish Federation of Neuromuscular Diseases (ASEM). In this classification, those that are toxic are not listed.

1- Muscular Dystrophies (DM)

They usually affect the striated muscle and are due to a defect in the proteins that make up the muscle fiber. There are several types:

Dystrophinopathies

They receive this name because Dystrophin , One of the main proteins that maintain the muscle fiber, is affected. The main diseases that form this subgroup are:

• Duchenne muscular dystrophy . It begins around the 2-3 years and mainly affects the men. When it occurs in women, it manifests itself in a moderate way. It is perceived through problems in the gait, not able to run or jump. As the disease progresses, they stop walking, requiring certain supports. Contractures and scoliosis are common. They also suffer from cardiomyopathies and respiratory insufficiencies, which are some of the deadly causes.

The pharmacological treatment usually administered is the Corticosteroids At a time when the motor development gap is notorious, between 5 and 7 years.

• Becker's Muscular Dystrophy . It is very similar to that of Duchenne, but the symptomatology does not affect so invasively and, in addition, it appears later.

Congenital muscular dystrophies

They manifest from birth or with a few months of life. They are characterized by various symptoms, such as: hypotonia, weakness of muscles.

Occasionally, they have: eye malformations, muscular retractions, and even malformations in the white matter that is lodged in the brain. The mode of inheritance is variable. They stand out in this group:

• Musculoskeletal dystrophies due to merosin deficiency . It is due to the absence of merosin in the muscles. It can be detected during the prenatal stage through analysis of chorionic villi. They present delayed motor development.
• Fukuyama congenital muscular dystrophy . It is characterized by a cerebral malformation and also includes: dystrophy in the skeletal muscles, severe intellectual deficit, epilepsy and motor difficulties. From the age of 10, heart problems and swallowing suffocation are common and in many cases fatal.
• Walker Syndrome - Warburg , Also known as MEB (Muscle - Eye - Brain) syndrome. It is the most serious type of these dystrophies. Children who suffer from it usually die before 3 years of age. At birth, symptoms of severe and generalized muscle hypotonia are detected. Psychomotor development is very poor and, in addition, suffer convulsions and eye problems. Its genetic inheritance is an autosomal recessive type and the prognosis of the disease will vary depending on the cerebral involvement.

Emery-Dreifuss Muscular Dystrophy

It usually manifests around the age of 20 years and the clinical triad includes: 1) multiple contractures of childhood onset that impair the joints to limit their movements, 2) slow progression muscle weakness and atrophy, and 3) cardiac abnormalities that can reach Cause sudden death of the patient. Inheritance can be linked to the X chromosome, dominant or recessive.

Muscle Dystrophies of Waistlines (LGMD)

This name responds to a group of diseases that, within neuromuscular diseases, form the most heterogeneous group. Usually, they are divided by the type of inheritance, whether it is autosomal or recessive. Both respond to failures in the muscles related to the pelvic and scapular waist. The autosomal type are the mildest and the most severe recessive.

Muscular dystrophy

It is one of the most frequent and usually occurs in youth, although this may be later. In addition, the degree of penetrance is variable and, therefore, the symptomatology will vary from one person to another.

It is characterized by progressive muscle weakness with involvement in the muscles of the face, shoulders and arms. The progression of the disease is usually slow, although after periods of stability, episodes can occur in which the progression of the disease is very rapid.

This type of dystrophy does not affect the life expectancy of the people who suffer it, although it does affect their quality of life.

Oculopharyngeal Muscular Dystrophy

The symptomatology begins, usually, from the 40 years of age. There is progressive weakness of the muscles of the face and neck, therefore, tending to fall of the eyelids and Dysphagia (Difficult to swallow food).

These symptoms can be treated through surgical procedures. In more severe cases of this dystrophy, people who suffer from it have problems walking or performing certain exercises, such as going up and down stairs. Sometimes they may require a wheelchair.

Bethlem myopathy

Only 100 cases have been described throughout the literature. It is autosomal recessive type, is due to lack of type VI collagen, and its progress is usually progressive type. It occurs throughout the first decade of life.

Important muscle retractions occur in the elbows and phalanges. Their progress is toward muscle weakness in the proximal (rather than the distal) and extensor (rather than flexor) muscles.

Sarcoglicanopathies. They are due to the absence of the sarcoglycan gene, located on chromosome 17. They are similar to the muscular dystrophy of the waists and, in addition, they study with hypertrophy of the calves and macroglosia (they have the tongue has a bigger size than normal). There are different types, the most severe are affected their gait and the milder, are characterized by chronic fatigue.

Distal myopathies

This group of Neuromuscular Diseases are of autosomal recessive or dominant inheritance. They mainly affect the distal musculature of the lower limbs. Within the distal myopathies, we find:

Welander distal myopathy

It is the most common. It usually occurs at age 50, although unusually, it has been described in people aged 30 years. Symptoms begin with muscle weakness in the hind limbs, especially in the extensor muscles of the wrist and fingers. Usually presented asymmetrically.

Its progression is slow and, as it progresses, affects the lower limbs. Rarely, it affects proximally.

Markesbery-Griggs Distal Myopathy

This type occurs in adults over 40 years. It begins by affecting the anterior part of the muscles of the legs and then in the arms of the extensor muscles of the fingers and the wrist. Twenty years after the onset of symptoms, the ability to walk is often lost.

Distal myopathy of the Miyoshi type

It appears in young people from 15 to 35 years and affects the back of the legs, the upper limbs are not affected.

These patients often complain of pain in the calves, not being able to be on tiptoe and also climb stairs. The progression of this myopathy is very variable.

Nonaka distal myopathy

It occurs in people who are in the 2nd or 3rd decade of life. Muscular weakness is present in the anterior part of the legs, these patients present with their feet fallen. More mildly, it affects the distal musculature of the upper limbs and, rarely, the flexor muscles of the neck.

3. Congenital myopathies

They are usually diagnosed after birth, since the development of these babies is not normative (lack of movement, unusual postures and / or not properly fed). This type of NMS is caused by a defect in muscle development. In this classification, we find:

• Congenital myopathy . It is characterized by severe hypotonia, accompanied by spontaneous movements in neonates. One case is estimated every 50,000 births. These babies have difficulty sucking and swallowing, also cardiorespiratory affectations. Survival after childhood is uncommon.
• Central core congenital myopathy . Its onset, too, is in childhood and is characterized by hypotonia and delayed motor development. It mainly affects the proximal areas and, seriously, the pelvic area. A strong progression usually does not suffer and the disability that produces is moderate.
• Centronuclear Congenital Myopathy . Linked to the X chromosome, it causes a very serious genotype in men who, together with the hypotonia, suffer external ophthalmoplegia (progressive weakness of the ocular muscles) and respiratory failures.
• Myotubular Congenital Myopathy . It is one of the most terrible, since it entails the death of the baby within a few weeks of life due to the involvement of the respiratory system.
• Congenital Myopathy with Minicores . It responds to a wide phenotypic variability, but the most common profile is the one that presents spinal rigidity, premature scoliosis and respiratory affectation. It can be accompanied, even, by cardiac symptomatology. In most cases, the progression of myopathy is slow and, therefore, the factor that becomes more relevant and marks the course of the disease is the degree of respiratory distress.

4- Steinert Myotonic Dystrophy

It is the most common of dystrophies, it is estimated that affects 1 / 20,000 inhabitants. It usually appears in adulthood. It is characterized by: myotonia and multiorgan damage, arrhythmias and / or cardiac conduction disorders, endocrine damage, sleep disorders And baldness.

The progression of the disease is usually slow and progressive. In these cases, life expectancy is reduced by cardiac and respiratory problems.

5 - Myopathies, Congenital

They manifest from birth or childhood. We find two types:

• Congenital myotonia . In this subtype, we find two. The autosomal recessive type is the Becker type (the most severe) and the autosomal dominant type is the Thomson type (the lightest). They affect 1 to 10 people per 100,000 and are characterized by slow muscle relaxation associated with hyperexcitability of muscle fibers.
• Chondrodistrophic myotonia , Also known as Schwartz-Jampel syndrome. This type is associated with growth problems and therefore, skeletal deformations are related. The appearance of the face is as if it were wrinkled and, also, it has ears with low implantation, anomalies of the external ear, etc.

6- Periodic family paralysis

Here, we differentiate between two types:

• Gamstorp episodic adynamia and Westphal disease . People who suffer from it suffer episodes of paralysis that are variable in frequency and duration. They are usually caused by: resting after exercising, ingesting a meal rich in sugars or salt, exposure to cold, a fever or physical or psychic trauma. Between crisis, there is usually no affectation. The number of crises is reduced and from 40-50 years, they disappear.
• Paramiotonía de Eulenburg . Very similar to the previous one. In this case, the affectation is stable over time, there are no crises.

7- Inflammatory muscular diseases

This group of neuromuscular diseases are of an acquired type, of immunological cause.

• Polyomyositis and Dermatomyositis . There are inflammations in the muscles and appear in childhood or in adulthood. In addition to muscle weakness in the proximal areas, eruptions appear on the face and upper trunk. If they do not receive the appropriate treatment, their progress is very fast and with a severe prognosis. We are faced with a type of NMS that are treatable, thanks to the Immunosuppressants .
• Inclusion body myositis . They are a group of inflammatory diseases of muscles with insidious onset in adulthood. They are characterized by muscular weakness and by having atrophied the flexor muscles of the hand and the bulbar muscles, that is why dysphagia is frequent. This type of NMS does not respond to drugs that have been tested. There are several types, the best known being Pompe disease, since it is the clinical manifestation that may appear in the infantile stage, with hypotonia and cardiac and hepatic affections, it is possible that the death occurs before the 3 years. In the juvenile form, its evolution is variable. During adulthood, its evolution is slow and, therefore, compatible with prolonged life. It is possible to treat it by replacing the defective protein in these patients.

8- Progressive Ossifying Myositis

This ENM produces a high degree of disability and causes a series of congenital malformations in the toes of the feet and also the ossification (they become bones) in extraskeletal areas. One case occurs every 2 million people.

Prenatal diagnosis is not possible; be alert for your symptoms as the symptoms are visible. Its evolution is marked by a series of episodes and crisis throughout the life.

9- Metabolic Myopathies

This name responds to a series of genetic diseases characterized by the difficulty in obtaining energy from the muscular fiber. All of them can be presented throughout childhood or adult life. We find different types:

• Mitochondrial Myopathies . They are not usually very disabling. It usually affects the muscles of the face, causing drooping of the eyelids and these patients usually present chronic fatigue.
• Muscle Lipidosis . They occur due to lipid storage. In this classification we find Gaucher disease, in its different degrees, characterized by enlargement of the liver and spleen.
• Muscle Glycogenosis . The myopathies of this type, usually go with muscle fatigue, cramps and pain after physical exertion.

10- Diseases of the Neuromuscular Union

• Myasthenia gravis . It is characterized by the affectation, of varying degrees, of the skeletal (voluntary) body muscles. The muscle weakness produced increases after periods of activity and decreases after rest. Nowadays, the life expectancy of people suffering from Myasthenia Gravis is not affected.
• Eaton-Lambert syndrome . It is an autoimmune disease, that is, the immune system of people suffering from this disease attacks the neurons. In this way, it hinders the release of Acetylcholine (This neurotransmitter produces impulses between nerves and muscles). This causes muscle weakness, in addition to lung tumors.
• Congenital myasthenic syndromes . They affect less than one person every 500,000. They cause an involvement in the synapse.
• Spinal amyotrophies . There are several, according to the degree of affectation and the moment of appearance, and all of them are of autosomal recessive inheritance. They consist of the loss or degeneration of the neurons of the anterior horn of the spinal cord . In this way, the nerve impulse is not produced properly, affecting the movements and muscle tone.

12- Hereditary Sensory-Motor Neuropathies

Also known as Charcot-Marie-Tooth disease . It has a prevalence of 28 people affected per 100,000 inhabitants.

The affectation of this disease is very variable. The most common symptoms are: asymmetrical muscular atrophy of legs and arms of distal affection and muscular weakness that will cause difficulties in the march. In addition, problems of sensitivity, different pains and foot cavo (anomalous elevation of the vault of the foot) can appear.

Treatments

As we have seen through classification, most of these diseases have no cure. The existing treatments are symptomatic, that is, they are aimed at palliate the symptomatology.

In Neuromuscular Diseases is very important multidisciplinary approach, in which different professionals from different branches, work in teams in a coordinated way and thus, address the situation of these patients.

Due to the degree of disability that can cause these diseases, in addition to the work of specialists and treatments, the technical aids that these people may require in their day to day life and that can improve their quality of life are especially relevant.

There are multiple and to choose the appropriate (s) to the needs of the person, it is very important to carry out an assessment of the capacities and dimensions in which it requires support, assessing the activities performed and their context.

Bibliography

1. Spanish Association against Neuromuscular Diseases (ASEM) and Association Française contre les Myophaties (AFM). Neuromuscular Diseases: 49 tabs.
2. Spanish Association against Neuromuscular Diseases (ASEM) and the Spanish Federation of Neuromuscular Diseases. Guide to Neuromuscular Diseases. Information and support for families.
3. Spanish Association against Neuromuscular Diseases (ASEM) and the Spanish Federation of Neuromuscular Diseases. Types of Neuromuscular Diseases. Classification.
4. Galician Association against Neuromuscular Diseases (ASEM Galicia). What are neuromuscular diseases.
5. Information portal for Orphan drugs and rare diseases: Orphanet.