Spinal muscular atrophy

What is spinal muscular atrophy?

Spinal muscular atrophy is characterised by slowly progressive muscle weakness and atrophy of the limb muscles associated with motor neurone loss in the spinal cord. Bulbar muscular atrophy affects the bulbar and facial muscles with motor neurone loss in the brainstem.¹

The spinal muscular atrophies (SMAs) are a spectrum of genetically inherited disorders. They all result in progressive lower motor neurone weakness. The gene defect is on chromosome 5q and the implicated gene is called survival motor neurone gene 1 (SMN1).

SMAs can be classified according to the age of symptom onset using the International Spinal Muscular Atrophy Consortium Classification System:²

• SMA type I (acute infantile, Werdnig-Hoffmann disease).³

• SMA type II (chronic infantile).⁴

• SMA type III (chronic juvenile, Kugelberg-Welander syndrome).⁵

• SMA type IV (adult onset).⁶

However, there are 'long-term' survivors who do not comply with these classification criteria by age of onset or age of death.⁷ There are also a number of other SMAs not linked with the SMN gene.

Pathophysiology^{2 8}

Spinal muscular atrophy (SMA) types I-III

• Inheritance is autosomal recessive.

• Affected individuals have two copies of the altered gene.

• Those who carry one copy are usually unaffected carriers. Hence, there is often no family history.

• Loss of this gene results in loss of function of specific proteins required for RNA processing.

• This abnormal RNA processing seems to have a toxic effect on the lower motor neurones and results in their progressive degeneration in the spinal cord and also in the brainstem motor nuclei of cranial nerves V, VII, IX and XII.

• The body has an almost identical copy of the SMN1 gene - the SMN2 gene.

• About 95% of those with SMA have the SMN1 gene defect. About 50% of those more severely affected show a deletion in the second gene as well.⁹

SMA type IV

• Has a number of different inheritance patterns.

• It can be autosomal recessive or autosomal dominant (ie only one parent needs to pass it on).

• It may also be non-hereditary and due to mutations in the SMN gene.⁶

• There is an X-linked recessive form known as bulbo-SMA, or Kennedy's syndrome (daughters who inherit the gene become carriers and sons who inherit it show the symptoms).

SMA with respiratory distress (SMARD1)

• Inheritance is autosomal recessive due to mutations in the IGHMBP2 gene on chromosome 11q13.¹⁰

How common is spinal muscular atrophy? (Epidemiology)

• The estimated incidence is between 1 in 6,000 and 1 in 10,000 live births and the carrier frequency is between 1 in 40 and 1 in 60.²

• SMA type II is the most common form.

Symptoms of spinal muscular atrophy (presentation)^{3 4 5 6}

• SMA generally presents with muscle weakness and wasting. The limbs, respiratory and bulbar muscles and brainstem can be affected.

• Intellect is preserved and people with SMA often have above-average IQ.

• General clinical signs are that of lower motor neurone weakness:
  

  • Flaccid weakness (muscles soft and floppy).

  • Hypotonia.

  • Reduced or absent tendon reflexes.

  • Normal or absent plantar reflexes.

  • Muscle fasciculation.

  • Muscle atrophy.

SMA type I

• Age of onset: <6 months.

• Features: the most severe form. Severe muscle weakness, hypotonia (no support of head when pulled up from lying to sitting; floppy when held in ventral suspension), poor suck and swallow reflexes, respiratory failure. Ocular and facial muscles and cerebral function are preserved. There may be deformities of limbs/joints at birth from in utero hypotonia. There may be a history of reduced fetal movements in utero.

• Mortality/morbidity: median survival is 7 months - 95% die before 18 months.

SMA type II

• Age of onset: 6-18 months.

• Features: developmental motor delay (delay in sitting, standing). Can usually eventually sit unsupported. Some can crawl or stand but these abilities may reduce as body weight increases. There may be finger tremor. Musculoskeletal deformities, respiratory failure. Pseudohypertrophy of gastrocnemius muscle.

• Mortality/morbidity: although remains a severe condition that may shorten life expectancy, improving care standards mean longer, more productive lives are possible for the majority of people.

SMA type III

• Age of onset: >18 months.

• Features: a milder disorder. Slowly progressive proximal weakness. Difficulty with more complex motor skills - eg, climbing stairs. May have gastrocnemius pseudohypertrophy. Chewing and swallowing may be affected later.

• Mortality/morbidity: can have a normal lifespan.

SMA type IV

• Age of onset: usually mid-30s.

• Features: similar to type III but tends to be less severe.

• Mortality/morbidity: can have a normal lifespan.

SMA with respiratory distress type 1(SMARD1)

• Age of onset: 1-6 months.

• Features: similar to SMA types I-IV but the predominant symptom is severe respiratory distress due to involvement of the diaphragm muscles. Respiratory problems are generally the first symptoms. Distal muscle weakness. Sensory and autonomic nervous systems may also be involved.

Bulbo-SMA, or Kennedy's syndrome

• Age of onset: 20-40 years.

• Features: bulbar and lower motor neurone weakness. Muscle cramps, facial fasciculations, hand tremor. Associated with type 2 diabetes and infertility.

Differential diagnosis

• Motor neurone disease.

• Primary lateral sclerosis.

• Muscular dystrophy.

• Congenital myopathies.

• Disorders of carbohydrate metabolism (glycogen storage diseases).

• Myasthenia gravis.

• Poliomyelitis.

Diagnosing spinal muscular atrophy (investigations)

Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis.¹¹

Blood tests

• Creatine kinase: usually normal in SMA type I; normal or slightly raised in other types.

Genetic testing

• Can be carried out prenatally or postnatally.

Electrophysiology testing

• Shows diminished nerve signals.

• Helps to differentiate from other neuromuscular disorders.

• Sensory nerve conduction is usually normal.

• Other more complex testing involving motor action potentials can also be performed.

Muscle biopsy

• Histology shows muscle fibre atrophy and can help to differentiate from other neuromuscular disorders.

Management of spinal muscular atrophy⁸

A multidisciplinary approach to supportive and palliative treatment is needed. The focus should be on the quality of life:

• Assistance with mobility and self-care .

• Splints and braces may be needed for limbs.

• Physiotherapy and special seats and wheelchairs can help to minimise joint contractures and scoliosis. Physiotherapy can also allow respiratory exercises.

• Respiratory support may be needed as the respiratory muscles become involved.

• Gastrostomy feeding may be needed as swallowing becomes affected.

For SMA type 1, aCohrane review concluded:¹²

• Based on the very limited evidence currently available regarding drug treatments for SMA type 1, intrathecal nusinersen probably prolongs ventilation-free and overall survival in infants with SMA type I.

• It is also probable that a greater proportion of infants treated with nusinersen than with a sham procedure achieve motor milestones and can be classed as responders to treatment on clinical assessments.

• The proportion of children experiencing adverse events and serious adverse events on nusinersen is no higher with nusinersen treatment than with a sham procedure, based on evidence of moderate certainty.

• It is uncertain whether riluzole has any effect in patients with SMA type I, based on the limited available evidence.

For SMA types II and III, a Cochrane review concluded:¹³

• Nusinersen improves motor function in SMA type II, based on moderate-certainty evidence.

• Creatine, gabapentin, hydroxyurea, phenylbutyrate, valproic acid and the combination of valproic acid and acetyl-L-carnitine probably have no clinically important effect on motor function in SMA types II or III (or both) based on low-certainty evidence.

• Olesoxime and somatropin may also have little to no clinically important effect but evidence was of very low-certainty.

New treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed.¹⁴

Three treatments that increase SMN protein levels in patients with SMA have provided incremental improvements in motor function and developmental milestones and prevented the worsening of SMA symptoms. While the therapeutic approaches with Spinraza®, Zolgensma®, and Evrysdi® have a clinically significant impact, they are not curative.¹⁵

NICE guidance on treatment options for spinal muscular atrophy¹⁶
In July 2021, NICE issued highly specialised technologies guidance for onasemnogene abeparvovec, recommending it as an option for treating babies with 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the SMN1 gene and a clinical diagnosis of type 1 SMA in babies who do not require permanent ventilation for more than 16 hours per day or a tracheostomy, only if:

• They are 6 months or younger; or

• They are aged 7-12 months, and their treatment is agreed by the national multidisciplinary team; and

• The company provides it according to the commercial arrangement.

In July 2019, NICE also issued technology appraisal guidance on the use of nusinersen for treating SMA.¹⁷ It recommended nusinersen as a treatment option, as long as the company provides it according to the commercial arrangement, for treating 5q SMA only if people have pre-symptomatic SMA, or SMA types 1, 2 or 3.

NICE guidance on risdiplam for treating spinal muscular atrophy¹⁸
NICE has recommended risdiplam as an option for treating 5q spinal muscular atrophy (SMA) in people 2 months and older with a clinical diagnosis of SMA types 1, 2 or 3 or with pre-symptomatic SMA and 1 to 4 SMN2 copies. However, it is recommended only if the conditions of the managed access agreement are followed.

Complications of spinal muscular atrophy

• Spinal deformity.

• Joint contractures.

• Respiratory infection.

• Respiratory failure.

Prognosis

Although SMA involves a wide range of disease severity and a high mortality and morbidity rate, recent advances in multidisciplinary supportive care have enhanced quality of life and life expectancy.¹⁹

Prevention of spinal muscular atrophy

• There is a 25% risk that each offspring of two carrier parents will be affected with the autosomal recessive inherited forms of SMA.

• Genetic testing can be done prenatally by amniocentesis and chorionic villus sampling to look for SMN gene deletions (prenatal genetic diagnosis). Parents can then decide to abort an affected fetus.

• IVF and pre-implantation genetic diagnosis can also be carried out if families have had a previous child affected by SMA. Embryos are tested to see if they are affected by SMA and unaffected embryos can be transferred to the uterus. Chorionic villus sampling may then be used later in the pregnancy to confirm that the growing fetus is unaffected.