Spinal muscular atrophy

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Classification according to ICD-10
G12.0 Infantile spinal muscular atrophy, type I (Werdnig-Hoffmann type)
G12.1 Other inherited spinal muscular atrophy
childhood form, type II
Kugelberg-Welander type
adult form
G12.9 Spinal muscular atrophy, unspecified
ICD-10 online (WHO version 2019)

The spinal muscular atrophy (SMA) is a muscle wasting , by a progressive decline of motor neurons in the anterior horn of the spinal cord is caused. It occurs rarely (1 in 10,000 births). The decline in these so-called 2nd motor neurons means that impulses are not passed on to the muscles . The result is paralysis with the characteristics of muscle wasting (atrophy) and reduced muscle tension . If cranial nerves are affected, there are also restrictions in swallowing, chewing and speaking functions. This is referred to as Kennedy type spinobulbar muscular atrophy (SBMA) or progressive bulbar paralysis .

The following findings can be obtained:

If spinal muscular atrophy is suspected, genetic tests are now the diagnostic standard.

Classification according to severity

The SMA is divided into different degrees of severity from type I to type IV:

SMA Type I - Werdnig - Hoffmann (Acute Infantile SMA)

  • By definition, free sitting is never learned
  • The disease begins in utero or during the first 3 months of life
  • Death usually occurs in the first two years of life due to respiratory failure or infection

SMA type II - chronic infantile SMA - Dubowitz (intermediate SMA):

  • Free sitting is learned, walking without help is never possible
  • The disease usually begins in the first year of life
  • limited life expectancy

SMA Type III - Kugelberg - Welander (Juvenile SMA)

  • Walking without help is possible
  • IIIa: start <3 years
  • IIIb: start> 3 years
  • Mild course
  • Life expectancy not significantly reduced

SMA Type IV - Adult SMA

  • Onset of illness> 30 years
  • Different progression
  • Normal life expectancy

Historical background

The term “ progressive spinal muscular atrophy” dates back to 1893 and was coined by the Heidelberg neurologist Johann Hoffmann . The most malignant form, infantile progressive spinal muscular atrophy, was named after the Graz neurologist Guido Werdnig , who described two boys with the disease in 1891, and Johann Hoffmann. The much benign progressive juvenile progressive spinal muscular atrophy was named after the Stockholm neurologists Eric Kugelberg and Lisa Welander . In 1956 they differentiated the disease from muscular dystrophies . William R. Kennedy described X-linked recessive bulbospinal muscular atrophy in 1968.

Occurrence and frequency

Like the other neuromuscular diseases , spinal muscular atrophies are relatively rare. With regard to the most common form, the infantile form, a frequency of 1 per 25,000 births is recorded, with regard to the juvenile form, a frequency of 1 per 75,000 births.

Symptoms

In spinal muscular atrophy is diseases that motor on the demise of nerve cell (the second-motor neuron , alpha motor neuron , anterior horn cell) in the spinal cord are based. This leads to a loss and weakness of the muscles . In healthy people, muscle fibers contract through activation by nerve fibers ( innervation ). As a result, the muscle becomes shorter, depending on the number of muscle fibers involved, it tenses, movement occurs. Muscle fibers that are not properly addressed ( innervated ) by the diseased nerve fibers do not contract.

Just as the whole muscle becomes lank when not in use, e.g. For example, if an arm is immobilized in a cast for a few weeks after a broken bone , the individual muscle fibers become weak if they are not activated by nerve cells. Since it is not the muscle that becomes diseased, but the nerve cells that control it, this is called muscle atrophy in contrast to muscular dystrophy, where the muscle becomes diseased. The disease reduces the strength and endurance of the muscle. Repair mechanisms run in parallel. Muscle fibers that are no longer supplied by a nerve fiber can also be supplied by a shoot of a preserved nerve fiber. The nerve fiber obtained sprouts close to the muscle fiber and forms a branch that forms a new connection with the muscle fiber ( motor end plate ). This increases the number of muscle fibers supplied (innervated) by a nerve fiber.

In the infantile form of spinal muscular atrophy (Werdnig, Hoffmann) a distinction is made between an acute and an intermediate form. The acute form begins before birth in the womb : children show decreased muscle tone at birth , i. H. decreased muscle tension. The spontaneous movements are reduced. The children do not learn to keep their heads free or to sit freely. They die from breathing difficulties in the first two to three years. In the intermediate form, the weakness sets in in the first months and years of life. Skills learned such as walking and standing are lost again. Curvatures of the spine and deformities of the chest occur. A third of the children experience their tenth birthday, some patients also survive the 20th year of life. The disease is inherited as an autosomal recessive trait. The affected gene location is usually the SMN gene - the long arm of chromosome 5 (5q11.2-13.3).

In juvenile progressive spinal muscular atrophy (Kugelberg, Welander) the same gene location is affected as in infantile forms. The disease usually begins in childhood and adolescence with weaknesses in the pelvic girdle muscles . Therefore, the first thing you notice is the cumbersome climbing stairs. It later spreads to the rest of the muscles, but remains close to the core . The shoulder girdle is affected first. Due to the weaknesses in the muscles close to the trunk, the disease was long considered to be a muscular dystrophy of the limb belt type , i.e. a muscle disease. Sometimes an apparently strong calf is noticeable - this does not have more intact muscle fibers, but fat and connective tissue . One then speaks of a pseudohypertrophy (apparent thickening). The CK , a muscle enzyme , is also often significantly increased, so that a primary muscle disease is suggested. The electromyographic examination (EMG) and even the muscle biopsy can give indications of a primary muscle disease. As a rule, the signs of a neurogenic disease, i.e. a disease primarily of the nerves, but with EMG and biopsy, should point in the right direction. Hardly any other disease leads to controversial diagnoses as often as juvenile pseudomyopathic muscular atrophy (Kugelberg, Welander). In addition to the weakness, contractures of the joints and foot deformities ( archesus , equinus ) also occur. Some of the patients will need a wheelchair over time .

There are also adult forms of spinal muscular atrophy (occurring in adulthood). They start in adulthood and are slow to progress. If they start with weaknesses and muscular atrophy of the hand muscles, one speaks of the Aran-Duchenne type. This is sometimes confused with the Duchenne type of muscular dystrophy. Both diseases have nothing in common. If the foot lifters are weak first, the peroneal type is spinal muscular atrophy, and the Vulpian- Bernhardt type starts with the shoulder muscles .

The X-linked bulbospinal muscular atrophy Kennedy develops in the third to fifth decade of life with weaknesses in the muscles in the mouth area and swallowing disorders as well as weaknesses in the muscles near the trunk. Affected men often have an enlarged breast.

Progressive bulbar paralysis is a disease that mostly affects speech and swallowing muscles. The muscles of the arms and legs are spared. Charcot still described this form of disease as a separate disease, years later the French neurologist Dejerine regarded progressive bulbar paralysis as amyotrophic lateral sclerosis , since weaknesses in the arm and leg muscles were usually noticeable as the disease progressed .

Motor neuron diseases are also often referred to as spinal muscular atrophies affect the second motor neuron. This term is used in Anglo-American countries. It is imprecise because it includes all diseases of the first and second motor neurons. As a rule, this includes spinal and amyotrophic lateral sclerosis .

Diagnosis

The diagnosis of spinal muscular atrophy is made taking into account the anamnesis (description of the development of the functional disorders and similar changes in the family by the patient), the detailed physical-neurological examination and additional technical examinations. The measurement of the nerve conduction velocity ( electroneurography ) and the muscle currents ( electromyography , EMG) are particularly noteworthy. In particular, multifocal motor neuropathy should be used for the differential diagnosis . There are conduction blocks in different areas of the nerves. Since this disease is susceptible to specific therapy , it is important not to overlook this differential diagnosis.

Additional examinations

Any additional examinations that may be necessary

treatment

Gene therapy

The increasing understanding of the molecular causes of many neuromuscular diseases increased diagnostic accuracy. One treatment approach is based on “repairing” a tiny part of the genetic make-up. The defective gene is switched off with an antisense oligonucleotide (ASO) (“gene silencing”). During DNA reading, messenger RNA (mRNA) is formed in the cell nucleus. This serves as a blueprint for protein formation. As false mRNA building blocks in the nerve cells, synthetically produced ASOs prevent the reading of the defective gene.

At the end of 2016, an ASO drug was approved in the USA ( Spinraza , active ingredient: Nusinersen ). EU approval followed in 2017. The developer Adrian R. Krainer from the Cold Spring Harbor Laboratory received the lavish Breakthrough Prize in Life Sciences for 2019 . Treatment costs $ 750,000 the first year and $ 375,000 in subsequent years. The results initially available for children were also confirmed for adults up to the age of 65 in 2019.

In 2018, Novartis filed for approval for a novel gene therapy . An infusion of AVXS-101 should provide an additional 13 years of life in good health. As with the similarly acting, approved Tisagenlecleucel (product name Kymriah ), the price is only payable in the event of success. AVXS-101 ( generic name : Onasemnogen abeparvovec ) was 2019 under the name preparations Zolgensma approved in the US. The price is around two million dollars for a single dose designed to save life and avoid expensive follow-up treatments. It is one of the most expensive drugs in the world per dose , but is said to save costs in the long term compared to long-term treatment for hundreds of thousands of dollars per year.

rehabilitation

The aim of rehabilitation for neuromuscular diseases is to improve and maintain independence in mobility. Treatment is best provided by an interdisciplinary team of doctors , nurses , physiotherapists (formerly physiotherapists), occupational therapists , speech therapists , psychologists and social workers .

Outpatient therapies such as physiotherapy , occupational therapy and lopopedia are necessary to maintain existing skills. Inpatient treatment measures (rehabilitation) with a duration of approx. Four to six weeks are urgently recommended in order to improve latent abilities and muscular functions and to favorably influence the course.

Muscular weakness is the cause of the clinical problems of spinal muscular atrophy. There are well-controlled studies examining the effects of exercise and training on muscle strength in neuromuscular disorders. In slowly progressing neuromuscular diseases, a 12-week training session with moderate resistance resulted in an increase in strength of 4 to 20% without negative effects. In the same patient group, training with vigorous resistance for 12 weeks showed no additional benefit, but evidence of weakness due to overuse in some patients. There is evidence that the therapeutic procedures for the various neuromuscular diseases are differently effective.

With rapidly progressing neuromuscular diseases, the risk of increased weakness due to excessive training is high. Training should be more with the aim of improving the function, not primarily with the aim of strengthening. Patients with neuromuscular disorders should not exercise to exhaustion and should be informed of warning signs of overuse. These include a feeling of weakness within 30 minutes after the exercise or muscle pain 24 to 48 hours after the exercise. Other warning signs include muscle spasms , heaviness in your arms and legs, and persistent shortness of breath.

Nevertheless, through training with light to moderate aerobic stress such as walking, swimming and driving on the ergometer, an improvement in muscular endurance and the performance of the cardiovascular system and thus a reduction in weakness is possible. The training increases physical performance, helps to maintain a favorable body weight , to reduce pain caused by improper stress and to improve depressive moods.

In a number of neuromuscular diseases, contractures, i.e. stiffening of the joints and scoliosis, i.e. curvatures of the spine, are common. Patients must be checked regularly for this, especially if they are wheelchair dependent and the strength of the core muscles has decreased. Careful stretching of the affected joints is necessary.

In individual cases , orthoses , i.e. devices for stabilization, can improve the function of joints. The foot lifter orthosis, often called a peroneal splint, can make walking easier if the foot lifter is weak.

Improving endurance is an important goal, as is stretching shortened muscles to prevent contractures. Physiotherapy also aims to improve blood circulation and metabolism . The orthostasis functions, i.e. the ability to maintain the circulation when standing, to avoid osteoporosis and poor posture , are further goals of physiotherapy.

Physiotherapy is also necessary for pulmonary disorders to train the muscles and to make it easier to cough.

Occupational therapy focuses on the arms and trunk. One of the domains of occupational therapy is the provision of aids such as grippers, wheelchairs, lifting aids, and raised toilet seats. Likewise, the Beüben everyday tasks relevant (ADL = Activities of daily living; Engl. ) Another important sector.

Physical therapy includes massages , heat and cold therapy ( thermotherapy ), balneotherapy (bath therapy) and electrotherapy .

Massages loosen tense muscles, improve tone, blood circulation and nutrition of the muscles ( trophic improvement ) through kneading, flexing, stroking, vibrations and connective tissue massage .

Thermotherapy (heat and cold therapy) offers opportunities to also help relax muscles. These include overheating baths, saunas , packs ( mud , mud) and hot rolls. Local cryotherapy, i.e. cold, can be used for localized irritation of the joints, for example due to incorrect stress.

Electrotherapy is mainly used for pain therapy and to stimulate muscle groups. Nerves and muscles are stimulated by low and medium frequency currents.

The use of exponential current as a low-frequency current method is used to stimulate muscle fibers that are no longer supplied by nerves, so-called denervated muscle fibers. Intact muscle fibers supplied by nerves are stimulated by surge current. Both types of current can be useful in neuromuscular diseases to address muscles, possibly to improve blood circulation, to give the patient back the feeling of movement.

An electrical stimulation of denerved muscles is given with broad biphasic rectangular pulses, which stimulate peripherally paralyzed muscles with large surface electrodes. There are two variants. First, single twitches in the form of biphasic square pulses with 120 ms (60/60 ms) pulse duration and a subsequent pause of 400 ms - results in approx. 2 Hz for 10 s with a subsequent pause of 1 s. As soon as the electrical excitability of the muscle improves, one can try whether the muscle also reacts to tetanic cycles with 40 ms (20/20 ms) pulse width and a subsequent pause of 10 ms swelling 3 s, swelling pause 2 s. Stimulation current therapy devices with high output power are required to produce broad, biphasic square-wave pulses. These must have individually programmable current forms. These forms of current promote the restoration of the cell structures of denerved dystrophic muscles.

In the transcutaneous electrical nerve stimulation (TENS) is a pain therapy. Surface electrodes are glued to the skin. This creates a pleasant current that stimulates the rapidly conducting sensory nerve fibers. In the spinal cord, the influx of these impulses inhibits the pain of conducting slower fibers. The gate to pain is quasi closed. The impulses should be pleasant, not painful. The procedure is well tolerated. It is not used all the time, but several times a day for around 20 minutes, or a little longer if necessary. With constant use there would be a risk of tolerance development.

The galvanization is a pain reduction by direct current by means of joints (as Quergalvanisation) or throughout the body ( Stanger is headed, four cell). It also works to improve blood circulation. In the Stangerbad and four-cell bath, it depends on how the polarity is made, i.e. whether the cathode is attached to the top and the anode to the bottom of the body (ascending) or vice versa (descending). The activity level of the nerve cells in the spinal cord can be increased (ascending) or decreased (descending). If you want to increase the tension of the muscles in a flaccid paralysis such as a spinal muscular atrophy, an ascending switch is used.

Interference current is a medium-frequency method that has a massage-like effect and can thus loosen the muscles.

Shortwave ( diathermy ) is a high-frequency process that creates deep heat and thus also has a relaxing and loosening effect on the muscles.

Ultrasound therapy also leads to the generation of heat in the tissue, it improves blood circulation and metabolic processes.

Disorders of the lung function

Weaknesses in the chest wall muscles, the diaphragm and the abdominal muscles can lead to disorders of the lung function. The various neuromuscular diseases lead to these impairments to different degrees, depending on which muscle groups are affected. If the respiratory muscles are regularly affected, routine lung function tests should be carried out. Patients should be informed how to recognize a nocturnal breathing disorder . Above all, regular morning headaches , restlessness or nightmares at night, the feeling of waking up in the morning “as if worn out”, and an unrefreshing sleep must make one think of these problems. This can also lead to increased daytime sleepiness. In recent years there have been advances in the possibility of home ventilation , which is often only necessary at night . The devices today are small, quiet and not very stressful.

psychology

Depressive disorders are often observed in patients with neuromuscular diseases. The cause is often the coping with the illness, but there are often also problems with social integration and keeping a job. Self-help groups can provide important assistance here, and participation is highly recommended for patients. In Germany, the German Society for Muscle Sick People is very active in many regions. Members of the groups also provide assistance in solving social problems or in advising on aids.

Disease processing plays an important role in all diseases. It is often difficult to find a constructive attitude in dealing with the disease, especially with chronically progressive diseases. With a positive attitude, the patient can optimally take advantage of therapy options and opportunities. Discussion groups or individual psychological treatments, e.g. B. in the context of an inpatient rehabilitation, can be useful here.

It is also important to accompany from the beginning how the interaction with the social environment, the dependency on caregivers (family) and their own excessive demands affect, in order to enable the development of self-confidence and a constructive perspective on life.

In addition, relaxation methods such as autogenic training or progressive muscle relaxation according to Jacobson are used.

Orthopedic measures

The orthopedic measures at SMA include the prescription of wheelchairs with a lifting function and rails. In cooperation with occupational therapy , orthopedic treatment primarily aims at an early functional approach to avoid or delay secondary damage to the musculoskeletal system. She uses various measures from the physical circle, such as heat applications, baths and careful massages. The treatment of (painful) joint changes or misalignments can be done, for example, with orthoses . The function- preserving surgical measure is often only at the end of the therapeutic chain in orthopedics.

Tools

A number of aids can make coping with the impairments caused by the disease easier or even make it possible in the first place. These can include shower chairs, bathtub lifters, raised toilet seats, wheelchairs, ramps for wheelchairs, hospital beds, but also small aids such as grippers. Here it must be individually selected and compiled which aids are useful and necessary for the individual. Flexibly designed, corset-like, partially flexible bandages and soft-body jackets are also a relief for vital functions, especially in the case of scoliosis and / or lung problems, in which the remaining torso mobility is partially actively stabilized and the breathing function is facilitated with the help of abdomen and torso compression .

Other therapy methods

The effect of valproic acid in the therapy of SMA is being tested at the Institute for Human Genetics at the University Hospital Cologne . Since valproic acid is an already approved anti-epileptic drug, testing it on affected patients is ethically justifiable and legal. The successes to date are very promising, with certain restrictions.

Social medical aspects

Various aspects can be discussed here. If, for example, the job is to be saved, applying for a workplace facility adapted to the disability and possibly agreeing on additional breaks can provide important support. The social workers can advise and support them with these problems. You know which cost units to ask for. Advice on the question of (partial) retirement can also provide important assistance. In the case of severely affected persons, the benefits under the Care Act or the Social Security Code IX must be known. Here, too, you have to know who to turn to as a victim.

Inpatient treatment measures (rehabilitation)

Regular outpatient treatments are usually required in order to continuously maintain skills at the most stable possible level. Inpatient rehabilitation is necessary in order to improve latent abilities and muscular functions, thereby influencing the course favorably. It should be done at regular intervals. If the disease requires it due to deterioration in functions, it can occur at shorter intervals, for example annually. With a corresponding application by the family doctor or the supervising neurologist , you can contact the responsible insurance provider. For working people, the responsible cost bearer is the pension insurance provider , i.e. BfA or LVA . If the rehabilitation measure is not about maintaining the ability to work, the health insurance company should usually be contacted.

Neuromuscular diseases are rare. It is therefore important that treatment takes place in a rehabilitation clinic that is well versed in the treatment of neuromuscular diseases. It is required that therapists regularly treat patients with neuromuscular disorders. The intensity and type of treatment differ significantly from treating other neurological diseases.

Spinal muscular atrophy with type 1 shortness of breath

The spinal muscular atrophy with dyspnoea type 1 (called SMARD1 , from English spinal muscular atrophy with respiratory distress ) was genetically elucidated in addition to the classic SMA as the second fore horn disease in infancy and toddler age and differs mainly in that the dyspnea is already apparent at the beginning of the disease .

Possible causes

Mutations in the IGHMBP2 gene

Veterinary medicine

Hereditary spinal muscular atrophy also occurs in some dog breeds (see Degenerative Myelopathies in Dogs ).

literature

  • Adele D'Amico, Eugenio Mercuri, Francesco D Tiziano, Enrico Bertini: Spinal muscular atrophy. In: Orphanet Journal of Rare Diseases. 2011, 6, p. 71. (PDF)
  • Christian L. Lorson, Hansjorg Rindt, Monir Shababi: Spinal muscular atrophy: mechanisms and therapeutic strategies. In: Human Molecular Genetics . 2010, Vol. 19, Review Issue 1, pp. R111-R118. doi: 10.1093 / hmg / ddq147
  • Helmut Kern, Ugo Carraro et al .: Home-Based Functional Electrical Stimulation Rescues Permanently Denervated Muscles in Paraplegic Patients With Complete Lower Motor Neuron Lesion. In: Neurorehabilitation and Neural Repair. 2010; 24 (8), pp. 709-721. (PDF)

Individual evidence

  1. ↑ https://www.aerztezeitung.de/medizin/krankheiten/seltene- Krankungen/article/963925/spinale-muskelatrophie-kostenfreier-gentest- sma.html
  2. ↑ Nusinersen / Spinraza® / 99/2017 , Pharmazeutische Zeitung.
  3. ↑ a b https://www.tagesschau.de/ausland/novartis-arznei-101.html
  4. ↑ Hagenacker T, Wurster CD, Günther R et al: Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study. , Lancet Neurol 2020; 19: 317-25
  5. ↑ How much can a human life cost , Tamedia , accessed: December 20, 2018
  6. ↑ Pharmaceutical company receives approval for the world's most expensive drug , Spiegel online, May 25, 2019.
  7. ↑ Are two million euros in drug costs too much? Spiegel online, November 15, 2019, accessed on November 18, 2019
  8. ↑ Helmut Kern, Ugo Carraro et al .: Home-Based Functional Electrical Stimulation Rescues Permanently Denervated Muscles in Paraplegic Patients With Complete Lower Motor Neuron Lesion. 2010.
  9. ↑ L. Brichta, E. Hahnen, K. Haug et al: Influence of valproic acid on the SMN2 protein level: A well-known substance as a possible therapy for spinal muscular atrophy . In: Yearbook of Neuromuscular Diseases . Arcis Verlag, 2004, ISSN  1435-4209 .