Brief overview
- What is spinal muscular atrophy? A group of muscle weakness diseases. They are due to the death of certain nerve cells in the spinal cord that control muscles (motor neurons). Therefore, SMAs are categorized as motor neuron diseases.
- What are the different forms? In the case of hereditary spinal muscular atrophies with a genetic defect on chromosome 5 (5q-associated SMA), physicians primarily distinguish between the five forms of SMA type 0 type 4 or, according to symptoms, non-sitter, sitter and walker. There are also sporadic forms whose heritability is not certain.
- Frequency: Rare disorder; inherited SMA affects about one newborn in 7000.
- Symptoms: Muscle twitching, progressive muscle weakness, muscle wasting, paralysis. Courses differ depending on the form of SMA.
- Causes: Hereditary spinal muscular atrophies type 1-4 are a result of a gene defect on chromosome 5, more specifically on the SMN1 gene. As a result, the body lacks a special protein, the SMN protein. This deficit damages the motor neurons in the spinal cord.
- Treatment: Gene replacement therapy or drug administration of splicing modulators are possible. Accompanying physiotherapy, speech therapy, pain therapy and psychotherapy. If necessary, spinal surgery. Treatment plan depends on SMA form.
- Prognosis: In hereditary proximal SMA, new treatment options have a causal effect and can positively influence the course of the disease. Early initiation of treatment is critical. Treatments are not yet available to every patient. Untreated, children with type 1 SMA usually die within the first two years. Life expectancy with type 3 and type 4 hardly or not reduced.
What is spinal muscular atrophy?
In spinal muscular atrophies (SMA), certain nerve cells in the spinal cord die. They normally control muscles, which is why experts call these nerve cells motor neurons. Accordingly, SMA belong to the so-called motor neuron diseases.
Physicians distinguish between different forms of spinal muscular atrophy. By far the largest group is hereditary SMA, in which the muscles close to the trunk (proximal) are affected. They are based on a specific genetic defect. About one in 7000 newborns develops the disease.
Spinal muscular atrophy is a rare disease overall. Nevertheless, it is the second most common autosomal recessive inherited disease. It is also considered the most common cause of death of an infant or young child due to a genetic defect.
What are the different forms of spinal muscular atrophy?
Physicians distinguish hereditary forms of SMA from sporadic forms. Another classification of spinal muscular atrophy refers primarily to the muscle groups that are affected first. Thereby there are
- Proximal SMA: These form the largest SMA group, accounting for about 90 percent. The symptoms start at the muscles close to the trunk, i.e. proximally.
- Non-proximal SMA: Here, more distant muscle groups, such as those in the hands and feet, are affected first (distal SMA). In the further course, these SMA can also spread to muscles close to the middle of the body.
Proximal spinal muscular atrophies
Hereditary proximal spinal muscular atrophies are mostly diseases based on a specific genetic defect (5q-associated SMA, defect on chromosome 5). These are in turn divided into five different forms (sometimes only types 1 to 4 are mentioned). The classification is based on the time at which the first symptoms appear and on the course of the disease.
Spinal muscular atrophy type 0
SMA type 0 is the term used when unborn or newborn children develop the disease by the seventh day of life. The unborn child is conspicuous, for example, because it hardly moves in the womb. Affected newborns have difficulty breathing immediately after birth, and their joints are barely mobile. As a rule, the children die before the age of six months due to their respiratory weakness.
Spinal muscular atrophy type 1
The muscle weakness affects the entire body – doctors also speak of a “floppy infant syndrome”. Most untreated children with SMA type 1 die before the age of two.
Spinal muscular atrophy type 2
This form of SMA is also called “intermediate spinal muscular atrophy” or “chronic infantile SMA.” First symptoms typically appear before 18 months of age. Affected individuals have a sometimes significantly shortened life expectancy.
Spinal muscular atrophy type 3
It is also called “juvenile spinal muscular atrophy” or “Kugelberg-Welander disease”. This SMA usually begins after the age of 18 months and before early adulthood. Muscle weakness is milder than in type 1 or 2, and affected individuals have only a slightly reduced life expectancy.
If the symptoms occur before the onset of the third year of life, doctors refer to this as SMA type 3a. After that, they refer to it as SMA type 3b.
Spinal muscular atrophy type 4
The transitions between the various forms are fluid. In some cases, this makes it difficult to make a clear distinction. Also, some genetic predispositions play an important role in the severity of the respective disease.
In addition, newer therapies influence how spinal muscular atrophy actually progresses. Medical experts have therefore developed a classification based on the patient’s symptoms and abilities:
Non-Sitters: Affected individuals are unable to sit independently or at all. This mainly includes those affected by SMA type 1 and type 2. In rare cases, this also affects patients with advanced-stage SMA type 3.
Sitter (able to sit): Affected individuals can sit independently for at least ten seconds without propping themselves up. Most often, these are children and adolescents with SMA type 2 or 3, but SMA 1 patients can also be “sitters” if they have been treated with the new therapeutic approaches.
Other spinal muscular atrophies
There are other forms of spinal muscular atrophy besides these proximal ones. These include, for example, rarer distal spinal muscular atrophies that are also hereditary. In these, symptoms typically begin in muscle groups further away from the body.
In sporadically occurring SMA, heredity is not confirmed. In addition, no familial clustering can be established. In the literature, these include:
- Hirayama type (juvenile distal SMA, disease around the age of 15, affects arm muscles, usually stops even without therapy and may even improve)
- Vulpian-Bernhard type (also known as “flail-arm” syndrome with onset in the shoulder girdle, usually after the age of 40)
- Duchenne-Aran type (initially affects hand muscles, spreads to trunk, usually after age 30)
- Peroneal type (“flail-leg” syndrome, first affecting lower leg muscles)
- Progressive bulbar paralysis (speech and swallowing disorders, affects about 20 percent of patients with amyotrophic lateral sclerosis)
Spinobulbar Muscular Atrophy
Spinobulbar or bulbospinal muscular atrophy (Kennedy type, Kennedy syndrome) is an inherited disorder. It often begins in young to middle adulthood. This particular form of SMA is inherited in an X-linked recessive manner and therefore only affects males (since males only have one X chromosome, in females the second, healthy X chromosome predominates and would compensate for the defect).
The usual symptoms are muscle weakness in the muscles close to the body in the legs and arms or shoulders, as well as in the tongue and throat muscles. As a result, affected individuals have problems speaking and swallowing. They also complain of tremors, muscle cramps and twitching. Affected men also often have atrophied testicles and are infertile. In addition, the mammary glands enlarge (gynecomastia).
Spinobulbar muscular atrophy usually progresses slowly. Life expectancy is hardly limited.
How can spinal muscular atrophy be recognized?
Symptoms of Infantile Spinal Muscular Atrophy Type 1
In SMA type 1, symptoms already appear in the first six months of life. Generalized muscle weakness – i.e. weakness affecting the entire body – occurs. In addition, the tension of the muscles against each other decreases. Physicians refer to this as muscle hypotonia.
In newborns, this muscle weakness is initially manifested by a typical leg posture reminiscent of a lying frog (frog leg posture). The legs are bent, the knees are bent outwards and the feet are bent inwards. Independent lifting or holding of the head is also usually not possible.
At an advanced age, children with SMA type 1 cannot sit or walk independently. Many children are also unable to speak, as the tongue muscles may also be affected.
Often there is also an increasing curvature of the spine (scoliosis). The forward bent and crouched posture causes further breathing problems. Characteristic is very rapid and shallow breathing (tachypnea).
Symptoms of Intermediate Spinal Muscular Atrophy Type 2
Spinal muscular atrophy type 2 usually does not produce its first symptoms until between the seventh and 18th months of life. Affected children can sit independently, but usually do not learn to stand or walk. Muscle weakness progresses more slowly overall than in type 1.
In SMA type 2, similar symptoms to those of the severe infantile form also appear over time, such as a deformation of the spine. The joints stiffen due to shortened muscles and tendons (contractures). Other signs include trembling of the hands and muscle twitching of the tongue.
Symptoms of Juvenile Spinal Muscular Atrophy Type 3
Over the course of several years, performance decreases: At first, the affected person finds it difficult to engage in sporting activities or climb stairs, but eventually also to carry shopping bags, for example. After many years, spinal muscular atrophy type 3 makes walking and any other exertion difficult or impossible, even in older patients.
Overall, however, the symptoms are less pronounced than in the other two forms of the disease, type 1 and type 2, and the quality of life is hardly restricted for many affected persons over a long period of time.
Symptoms of adult spinal muscular atrophy type 4
This very rare form of progressive muscle atrophy begins in adulthood, often after the third decade of life. It initially affects the leg and hip muscles. As the disease progresses, the muscle weakness also spreads to the shoulders and arms.
The clinical picture is similar to that of juvenile SMA type 3, although the progressive muscle weakness is even slower than in SMA type 3.
What causes spinal muscular atrophy?
Genetic defect
In most cases, spinal muscular atrophy is a hereditary disease (hereditary SMA). The cause of the typical proximal forms of SMA is a defective piece of information in the genetic material of the affected person. In this case, the so-called SMN1 gene on chromosome 5 is not functional.
The SMN1 gene carries the information – i.e. the blueprint – for the vital protein molecule called SMN. SMN stands for “Survival (of) Motor Neuron”. Without the SMN protein molecule, motor neurons perish over time.
It is true that there is also a related SMN2 gene in the body, which in principle is able to “compensate” for the non-functional SMN1 genetic information. But this usually happens only to a small extent. This means that a loss of function of the SMN1 gene (untreated) usually cannot be completely compensated by an intact SMN2 gene copy.
Autosomal recessive and autosomal dominant inheritance
The genetic information of a human being exists in duplicate. Consequently, each person also has two copies of the SMN1 gene – one from the father and one from the mother. Proximal spinal muscular atrophies of childhood are typically inherited in an autosomal recessive manner.
About every 45th person is a carrier of this predisposition for SMA. A couple in which both partners are carriers has a 25% risk of having a child with the disease.
In a few cases in adolescence, especially spinal muscular atrophies of adulthood also follow an autosomal dominant mode of inheritance. In the case of a dominant inheritance, a defective gene already asserts itself – and affected individuals become ill. However, this is not the case with the gene defect on chromosome 5 already mentioned. These 5q-associated SMA are always inherited in an autosomal recessive manner.
Inheritance in other forms of SMA
Non-proximal spinal muscular atrophies can also be inherited. The spinobulbar special form (Kennedy type) is inherited recessively via a sex chromosome, the X chromosome (affected here are the gene variants that contain the blueprint of docking sites for male sex hormones). In sporadic forms, on the other hand, the inheritance is not certain. Exactly why the second motor neurons perish is hardly known in this case.
Examinations and diagnosis
Taking the medical history (anamnesis)
For every illness, the doctor first asks about the symptoms that have occurred and the previous course of the illness. In the case of babies and small children, the parents report on changes and abnormalities in their child’s behavior. Particularly in the case of hereditary diseases, the doctor also focuses on the family’s history of the disease.
Physical examinations
Basically, a doctor detects abnormalities in motor development by physically examining the child. He tests, for example, whether the children can hold their heads upright independently, sit or move their arms or legs independently (depending on their age).
In older children and adults with suspected spinal muscular atrophy, complementary physical stress and function tests take place. In these tests, the doctor checks how much strength the affected person can muster and for how long he or she can maintain it. He also examines endurance.
Genetic testing
The most reliable method of detecting (hereditary) spinal muscular atrophy is genetic analysis. Doctors look for evidence of an altered (mutated) SMN1 gene, as well as for the number of SMN2 copies present. SMN2 gene copies may occur in greater numbers and can then partially compensate for the defective SMN1 gene.
Since fall 2021, blood testing for hereditary SMA (5q-associated) is part of newborn screening. The costs for the screening are covered by the statutory health insurance. In most cases, blood drops are taken from the heel of the newborn within the first three days of life.
In general, (hereditary) SMA should be diagnosed and treated as early as possible. Thus, depending on the form and available treatment, motor development can be positively influenced before the motor neurons of the spinal cord have been irreparably damaged.
Further examinations in SMA
In addition, doctors arrange for blood tests. If spinal muscular atrophy is present, certain parameters may be altered: For example, the level of creatine kinase (CK, a typical muscle enzyme) is elevated.
In addition, because SMA can limit respiratory function, physicians check lung function. If possible, they measure the lungs’ capabilities using spirometry. To detect nocturnal oxygen deficiency, polysomnography is useful. Here, they monitor important parameters such as heart rate and oxygen saturation while patients sleep.
Treatment of spinal muscular atrophy
The treatment of spinal muscular atrophy is complex. For a long time, causal therapy was not possible for any form of SMA. However, thanks to advances in medical research, there are new treatment options to fundamentally help sufferers with proximal SMA (SMN gene defect on chromosome 5).
In other respects, physicians focus on alleviating symptoms and providing the best possible support to affected individuals (e.g., physical therapy, respiratory therapy, psychotherapy, surgery if necessary).
Drug therapy
The goal is to enable the patient’s body to independently produce sufficient amounts of SMN protein, which is crucial for motor neurons.
The following treatment options are available for spinal muscular atrophy:
- Splicing modulators (nusinersen, risdiplam): These drugs directly interfere with the processing of messenger RNA molecules. In doing so, they strengthen those processes that deliver a higher amount of SMN protein from the intact SMN2 gene.
- Gene replacement therapy (Onasemnogene Abeparvovec): This therapy directly interferes with the human genome. The defective copy of the SMN1 gene is replaced by an externally delivered, functional gene construct in the affected cells.
Splicing modulators
In the case of an SMN1 gene defect, the SMN protein can also be produced by the body as a substitute from the related SMN2 gene. The replacement SMN2 gene “steps in”, but this is not sufficient. The reason is that the SMN2 proteins are usually too short and are rapidly degraded.
For this purpose, the SMN2 gene in the genome is first read. A preliminary SMN2 messenger RNA is produced. It must be further processed, among other things, by a process known as splicing. Only then does the mature messenger RNA emerge. Special cell complexes, the ribosomes, finally read the mature messenger RNA and thus produce SMN2 protein. And it is precisely this protein that is shortened and unstable, is rapidly degraded and thus cannot take over the function of SMN1.
To change this, the active substances nusinersen and risdiplam influence the further processing of the preliminary messenger RNA. As a result, these so-called splicing modulators ultimately increase the amount of usable SMN proteins – and can thus ensure an adequate supply.
Nusinersen
The drug nusinersen is a so-called “antisense oligonucleotide” (ASO). It was approved by the European Medicines Agency in 2017. ASOs are artificially produced and specially adapted RNA molecules. They bind to SMN2 messenger RNA in a targeted and precisely fitting manner. In this way, they prevent their incorrect further processing in the human cell.
Nusinersen is administered through a procedure called lumbar puncture. This means the drug is injected into the spinal canal with a syringe. This therapy is repeated at regular intervals of several months. In the first year of treatment, patients receive six doses, then three doses annually.
Patients usually tolerate the drug well. Nusinersen leads to a more favorable course of the disease. Studies showed that mobility improved in many patients: sitting freely and turning the body independently was possible in many cases. Side effects and complications are due to the lumbar puncture (e.g. headaches, infections of the meninges).
Risdiplam
The European Medicines Agency approved risdiplam in March 2021 as the third drug for 5q-associated SMA (type 1-3 or one to four SMN2 gene copies). Risdiplam is taken daily as a dissolved powder by mouth or feeding tube. The exact dose is calculated according to age and body weight.
According to studies, risdiplam improves infants’ chance of survival and their likelihood of achieving important developmental milestones. For example, 12 of 41 infants treated with the drug for one year were able to sit unassisted for at least five seconds. This was not possible without treatment. In patients from two to 25 years of age treated with risdiplam, overall motor skills improved.
Common side effects of risdiplam include gastrointestinal discomfort, skin rash, fever and urinary tract infections.
Gene replacement therapy
Another approach to treating proximal spinal muscular atrophy relies on so-called gene replacement therapy. The defective SMN1 gene – the starting point of progressive SMA – is “replaced” with a new functional gene copy.
The active ingredient Onasemnogene Abeparvovec (AVXS-101), which functions on this principle, received approval from the European Medicines Agency (EMA) in May 2020 for the treatment of infants and children.
With Onasemnogene Abeparvovec, a functional copy of the human SMN1 gene is introduced into the affected cells of the spinal cord and brain stem. This is accomplished by certain viruses that serve as a “ferry” for the new genetic material – so-called adeno-associated viral vectors (AAV vectors).
The vector gene constructs are administered once as an infusion via the vein into the bloodstream, from where they are distributed throughout the body. Due to a not yet fully developed blood-brain barrier in young children, these vectors can also enter the spinal cord tissue.
Through preferential binding of these vectors to special surface structures of the motor neurons, these preferentially take up the genetic material in order to subsequently produce the SMN protein on their own.
Treatment can improve motor function and lead to sustained developmental success (e.g. sitting, crawling and walking without support).
Age-appropriate motor development is generally only possible if gene therapy has been started before the first symptoms. Treatment is provided in specialized neuromuscular treatment centers.
Physiotherapy
Physiotherapy continues to be an important pillar of treatment for SMA. Not every form of SMA can be treated by novel treatment approaches. Regular exercise therapy is designed to maintain physical abilities and slow muscle deterioration.
The physical therapist passively moves through parts of the body that are already paralyzed. Active movements, on the other hand, are trained to support the mobility and strength of the muscles. In addition, massage or heat and cold treatments can help. These also serve to relax and, under certain circumstances, slow down further degeneration.
Depending on the needs of the patient, additional aids may be available. These include hard shell orthoses that support and stabilize joint mobility. Or support corsets to ensure a certain degree of trunk stability.
Speech therapy
Both physiotherapists and speech therapists support sufferers with targeted respiratory therapy.
Vaccinations
Since SMA usually affects breathing, affected persons should protect their respiratory tract as best as possible. Doctors make sure that affected persons have regularly refreshed vaccination protection, especially against pneumococcus, pertussis (whooping cough) and influenza.
In addition, preventive treatment with palivizumab against the RS virus (respiratory syncytial virus) can be useful in the first two years of life.
Pain-relieving treatment
Pain therapy plays an important role, especially in more advanced stages of the disease. Doctors use pain-relieving drugs to reduce the suffering of those affected.
Surgery
Since spinal muscular atrophy can lead to severe curvature of the spine (scoliosis), doctors sometimes consider surgery. In doing so, they stiffen the spine in a targeted manner.
Psychotherapeutic care
Neuromuscular diseases such as spinal muscular atrophy pose great psychological stress. Patients and family members process the diagnosis in psychotherapeutically guided individual and group sessions and develop strategies to better cope with the disease.
Self-help groups and patient advocacy groups also offer important support. They provide information, advice, and support to affected individuals and their relatives in coping with the challenges of SMA disease.
Palliative therapy
If SMA is very advanced, palliative counseling is advisable. Palliative care comprehensively accompanies affected persons in the last phase of life. The aim is to maintain the quality of life as best as possible, to alleviate physical and psychological suffering, and to minimize the social burden of the disease.
Chances of recovery from spinal muscular atrophy
The new treatment options by splicing modulators and gene replacement therapy hold great potential in the treatment of proximal SMA – especially with a (very) early start of treatment. However, data for a reliable long-term prognosis are still lacking. Only further studies and close drug safety monitoring can provide further certainty here in the next (months and) years. With the newer drugs, long-term control of the disease or even cure is at least conceivable.
SMA types 0 and 1 are generally a serious disease. Children who develop it have a very limited life expectancy (if untreated). The rapidly increasing muscle weakness throughout the body also affects breathing. The result is acute pneumonia and even respiratory failure. Affected children die within the first few years of life, in the case of SMA type 0 usually before the sixth month of life.
In SMA type 3, the prognosis is significantly better – especially if the first symptoms appear late. Over the course of several years, performance gradually deteriorates. In old age, a wheelchair or even permanent care may become necessary. However, life expectancy is hardly limited by spinal muscular atrophy type 3.
Adult spinal muscular atrophy (type 4) progresses even more slowly than type 3, and affected individuals usually have a normal life expectancy.
