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Spinal Muscular Atrophy

Recognising SMA

This section of the Spinal Muscular Atrophy (SMA) Learning Zone will help you to recognise and diagnose SMA. Early diagnosis and intervention are linked to the best outcomes for patients.

Epidemiology of spinal muscular atrophy

Spinal muscular atrophy (SMA) is one of the leading causes of inherited infant mortality in the world.91,92 Recent studies which used genetic diagnosis estimate the incidence of SMA in Europe of 1 in every 3,900–16,000 live births.93

SMA incidence and prevalence vary across countries and within different communities due to parental consanguinity94 or high carrier frequencies in specific ethnicities.92,95

SMA is an autosomal, recessive condition. Most commonly, carriers have one copy of the functional SMN1 allele and one deleted (1+0). However, other carrier phenotypes with a higher number of SMN1 copies (2+0) or point mutations in one of the copies (1+1D) have also been reported. The carrier frequency is estimated to be between 1/40 to 1/100 and can vary in different ethnic groups.96–99

SMA is classified into different subtypes based on the age of onset, motor milestones achieved and SMN2 copy number. The Type I subtype is the most severe post-natal form of the disease and accounts for the majority of all incidences of SMA cases.96 The median life expectancy of untreated individuals with Type I is very short, about one year. As a consequence, the prevalence of Type I is lower (0.04 to 0.28 per 100,000) as compared to the 1–2 per 100,000 noted for all SMA subtypes.92 Patients with each SMA subtype can sometimes be referred to according to the relevant motor milestones achieved: Non-sitters for Type I, sitters for Type II, walkers/sitters for Type III and walkers for those with Type IV.

SMA Types.png

Find out more about the different types of SMA in the next page of the Learning Zone.


Symptoms and spinal muscular atrophy Types 0–IV

Spinal muscular atrophy (SMA) is classified based on the age of onset, motor milestones achieved and SMN2 copy number. Loss of motor functions together with whole-body complications can arise in SMA.

Type 0 SMA is associated with decreased foetal movements in utero, joint abnormalities, respiratory failure at birth and is fatal.101 SMA is further divided into subtypes classified in the order of decreasing severity as Type I, Type II, Type III and Type IV. In these subtypes, disease severity is inversely correlated with SMN2 copy number, with Type I SMA patients having the lowest SMN2 copy numbers compared to Type IV SMA patients (Table 1). Further stratification of each subtype also aids disease management and care.

Table 1. Types of SMA and features.102–106

Table 1. Types of SMA and features.102–106.png

Type I SMA, also referred to as Werdig Hoffman disease or acute infantile SMA, is the most severe form of the disease. Disease onset is within the first six months of life. Infants with Type I SMA exhibit extreme hypotonia and are unable to raise their head, sit, stand or walk independently. Cognitive abilities are unaffected. Additionally, they have problems with sucking or swallowing, which is accompanied with respiratory distress. Type I SMA is also associated with cardiovascular defects such as heart malformation, digital necrosis and vascular thrombosis. Life expectancy is extremely low, and infants die within the first two years of life, often due to respiratory failure.

Type II SMA, also known as intermediate SMA or Dubowitz disease, typically manifests between 6–18 months of life. Children with Type II SMA can sit independently or with little assistance. However, they are unable to stand or walk independently. Muscle weakness in SMA is symmetric and proximal muscles are most severely affected. Bulbar muscle weakness is also reported in Type II SMA. Respiratory muscle weakness in children with Type II SMA leads to difficulties in coughing and vulnerability to respiratory infections. They frequently develop scoliosis as the muscles that support their spine are also weak. Although the disease progression varies in this subtype, the overall life expectancy is reduced.

The onset of Type III SMA (Kugelberg-Welander disease or juvenile SMA) is after the first 18 months of life. Children with Type III SMA can sit, stand and walk independently but have a progressive loss of mobility. Type III can be further distinguished into Type IIIA and Type IIIB based on the age of onset and severity. Children with Type IIIA have an earlier onset and more severe loss of dexterity and muscle strength. There is also some evidence that Type IIIA have fewer copies of the SMN2 gene in comparison to Type IIIB.107

The onset of Type IV is varied but usually occurs in the second or third decade of life.91 It is the least prevalent and mildest form of the disease. Patients with Type IV are able to walk but develop progressive weakness in muscles slowly over time. Type III and Type IV SMA patients have a normal life expectancy, but the disease can have significant impact on the quality of life.


Diagnosis of spinal muscular atrophy

Clinical manifestations

Physical symptoms of SMA can vary widely based on disease severity. The most severe form of SMA (Type I) has an early onset, with early symptoms presenting within the first six months of life. Infants with SMA develop hypotonia and progressive weakness and wasting of muscles initially affecting legs more than arms, but eventually being generalised. Affected people also present with recurrent respiratory infections, difficulties breathing and respiratory distress, commonly requiring ventilator support. Other bulbar symptoms include difficulty swallowing and poor feeding. Babies with Type I SMA will never be able to sit independently14. Symptoms onset in Type II SMA  occur between 6–18 months, and although children can sit, they are unable to walk independently. They exhibit severe muscle weakness in the lower limbs, and develop progressive scoliosis over time. Patients with SMA may also present with tongue atrophy with fasciculations14. Eye movement and cognition are usually unaffected in SMA14.

There is growing evidence of SMA affecting systems other than skeletal muscle, such as the cardiovascular and gastrointestinal systems, especially in more severe disease8,11,108–110. Cardiovascular (such as intestinal vascular insufficiency, peripheral vascular disease and chronic vascular disease) or gastrointestinal (for example perinatal disorders of the digestive system, ascites and other interstinal obstruction) defects may in fact be present prior to first clinical signs of neuromuscular degeneration3. For more information on symptoms linked to different SMA subtypes, see the 'Symptoms and spinal muscular atrophy Types 0–IV' page in this section.

Genetic testing

Genetic testing can confirm the diagnosis of SMA, identify SMA in pre-symptomatic individuals and inform the carrier status of at-risk parents (Figure 5). 


Figure 5. Diagnostic algorithm for spinal muscular atrophy.111 (Reproduced from Mercuri et al., 2011)..png

Figure 5. Diagnostic algorithm for spinal muscular atrophy.111 (Reproduced from Mercuri et al., 2011).
SMA, spinal muscular atrophy; SMN1, survival of motor neuron 1; SMN2, survival of motor neuron 2; NMD, neuromuscular disorders; EMG, electromyography; NCV, nerve conduction velocity; CK, creatine kinase levels; WES, whole exome sequencing; WGS, whole genome sequencing.

Genetic testing is performed at different times: 

  1. Prenatal screening when parents have a known carrier status 
  2. Screening of new born infants as part of a standard screening test 
  3. To establish the carrier status of an asymptomatic sibling in an at-risk family 

These screening tests are being encouraged especially with the advent of disease modifying therapies which target underlying genetics and exhibit improved efficacy with an earlier intervention.106 SMA is included in the recommended uniform screening panel for newborn infants in the USA.112

To detect homozygous deletions in SMN1, a simple and inexpensive method of PCR followed by restriction digestion is used. Most patients with SMA have a homozygous deletion of exon 7 and 8 in the SMN1 gene. However, in some cases, SMA symptoms may manifest even in patients heterozygous for SMN1. In these cases nucleotide sequencing of the entire SMN1 gene is performed to identify other loss of function mutations or deletions.96

Quantitative analysis of SMN1 and SMN2 using multiplex ligation-dependent probe amplification (MLPA) or quantitative PCR is the gold standard for genetic testing of SMA. These methods can determine the copy numbers of SMN1 and SMN2.113–116

Although the copy number of the SMN2 gene is not relevant for diagnosis, it is essential for prognosis and disease management.

Screening SMN2 copy number in pre-symptomatic patients facilitates disease management given its predictive potential for the age of onset and disease severity. SMN2 copy number is also a criterion for enrolment in clinical trials.14

Additional assessment of neuromuscular function

Besides genetic testing, certain biochemical and electrophysiological tests can help assess neuromuscular function in SMA.

  • Creatine kinase (CK) enzyme is enriched in skeletal muscles and leaks into the blood upon muscle damage. Therefore, serum creatine kinase levels may be elevated in SMA as a consequence of deterioration of the muscle tissues. However, since changes in CK levels are not always reported, the direct measurements of neuromuscular function may be more relevant.
  • Electromyography (EMG) evaluates the electrical activity of skeletal muscles. It is carried out together with nerve conduction velocity (NCV) study, which measures the speed with which electrical impulses are transmitted through the nerve. These techniques can be used to measure compound muscle action potential (CMAP).
    • The compound muscle action potential (CMAP) is the electrophysiological output from a muscle or group of muscles following supramaximal stimulation of a peripheral nerve. Ulnar CMAP values are most widely studied in SMA and correlate well with disease severity.14,111
    • The motor unit number estimation (MUNE) technique quantifies functional motor neurons/axons innervating a specific muscle. MUNE values are significantly lower in children with SMA and can even be sensitive to early deterioration of the motor unit pool before the manifestation of clinical symptoms.14,111

Although these tests do not provide a specific diagnosis of SMA, they can help monitor disease severity, progression, management and response to therapy.


Burden of disease

Spinal muscular atrophy (SMA) has a profound impact on the quality of life of affected patients, their families and caregivers. SMA also poses a considerable financial burden on society, costing millions per year.

Quality of life for patients and their carers

Parents and families of children with SMA experience significant emotional distress, and this also directly affects their careers and productivity. Individuals affected by SMA also struggle with anxieties about the progressive loss in mobility. This is particularly evident by the increased psychological assistance required by SMA Type II and Type III patients.98

Find out how patients with SMA Type II cope on a daily basis by watching these short videos.

Meet Katie, who describes the hopes and dreams for her daughter who is living with SMA Type 2 and has ambitions of going to college and living in a big city.

Meet Conor who has been living with SMA for 31 years and find out his view of a good and a bad day.

Meet Marni who has a strong can-do attitude but is worried that a deterioration in her arm strength will prevent her creativity.

Financial impact

There are very few studies on country-specific estimates of the financial burden of the disease. In Germany, it is estimated to be about €106.2 million per year.98 The burden of SMA differs by subtypes as measured by the cost of illness. SMA Type I and Type II are the most severe and present the highest cost of resources for disease management. 

In SMA I patients, the direct health care costs resulting from outpatient medical consultations and medical aids are the highest (€53,707/y per patient in Germany).98 Advances in disease management such as nutritional and pulmonary interventions may improve survival but add to the financial costs and do not cure the disease. Overall, the life expectancy of patients with SMA Type I is very low.

The direct medical costs for SMA Type II and III are lower in comparison to Type I. However, there are significant direct non-medical costs in SMA Type II.98,117,118 These arise from the increased cost for housing from structural alterations to support mobility, personal assistance with everyday activities and informal care. Parents are the primary carers in infants and children with SMA. Due to their severely decreased mobility, children with SMA Type II are heavily dependent on their families or social services for fulfilling their daily activities.

Advances in supportive care have certainly improved patient survival and quality of life, but significant unmet needs remain. Disease management requires a multidisciplinary approach that addresses the broad range of clinical phenotypes. In the next section of the Learning Zone, guidelines for disease management and treatment as well as ongoing clinical trials are provided.

Next Section: Treatment