Spinal Muscular Atrophy

The Spinal Muscular Atrophies are a spectrum of genetically inherited disorders. They all result in progressive lower motor neurone weakness and can be classified according to the age of symptom onset using the International Spinal Muscular Atrophy (SMA) Consortium classification system:¹

• Spinal Muscular Atrophy Type I (Acute infantile, Werdnig-Hoffman disease)²
• Spinal Muscular Atrophy Type II (Chronic infantile)³
• Spinal Muscular Atrophy Type III (Chronic juvenile, Kugelberg-Welander disease)⁴
• Spinal Muscular Atrophy Type IV (Adult onset)⁵

However, there are "long-term" survivors who do not comply with these classification criteria by age of onset or age of death.⁶ There are also a number of other rare SMA variants including SMA with Respiratory Distress (SMARD1).

SMA Type 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.
• The gene defect is on chromosome 5q and the implicated gene is called survival motor neurone gene 1 (SMN1).
• 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.¹
• 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.⁷

SMA Type IV

• Has a number of different inheritance patterns.
• It can be autosomal recessive or autosomal dominant (i.e. only one parent needs to pass it on).
• It may also be non-hereditary and due to mutations in the SMN gene.⁸
• 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 11q13.⁹

• SMA is the second most common lethal autosomal recessive disease in Caucasians after cystic fibrosis.¹⁰
• The international incidence of SMA is 7.8-10 cases per 100,000 live births.¹
• Carrier frequencies in the UK are 1 case per 60-80,000 individuals.¹
• SMA Type II is the most common form.

• 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.¹
• 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

Spinal Muscular Atrophy 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. May be deformities of limbs/joints at birth from in utero hypotonia. May be a history of reduced fetal movements in utero.
• Mortality/morbidity: Median survival 7 months, 95% die before 18 months.¹

Spinal Muscular Atrophy 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. May be finger tremor. Musculoskeletal deformities, respiratory failure. Pseudohypertrophy of gastrocnemius muscle.
• Mortality/morbidity: Can survive into 20s. Death is usually secondary to respiratory infection.

Spinal Muscular Atrophy Type III

• Age of onset: > 18 months
• Features: A milder disorder. Slowly progressive proximal weakness. Difficulty with more complex motor skills, e.g. climbing stairs. May have gastrocnemius pseudohypertrophy. Chewing and swallowing may be affected later.
• Mortality/morbidity: Can have normal life span.

Spinal Muscular Atrophy Type IV

• Age of onset: Usually mid-30s.
• Features: Similar to Type III but tends to be less severe.
• Mortality/morbidity: Can have normal life span.

Spinal Muscular Atrophy with Respiratory Distress Type 1(SMARD1)

• Age of onset: 1-6 months
• Features: Similar to SMA Type I-IV but predominant symptom is severe respiratory distress due to involvement of the diaphragm muscles. Respiratory problems are generally first symptoms. Distal muscle weakness. Sensory and autonomic nervous systems may also be involved.⁹

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.

• Motor neurone disease
• Primary lateral sclerosis
• Muscular dystrophy
• Congenital myopathies
• Disorders of carbohydrate metabolism (Glycogen Storage Diseases)
• Myasthenia gravis
• Poliomyelitis

Blood tests

• Creatine kinase: Usually normal in SMA Type I, normal or slightly raised in other types.

• Can be carried out pre or postnatally

• 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

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

• There is no current drug treatment or cure.
• Gene therapy is under clinical trial. Drugs including valproate and phenylbutyrate have been shown to stimulate SMN2 gene activity and help to improve symptoms but further clinical trials are needed.^11,12
• A multidisciplinary approach to supportive and palliative treatment is needed.
• In one study, > 70% of Type I and Type II patients needed assistance in mobility and self-care.⁶
• Focus should be on quality of life.
• Splints and braces may be needed for limbs.
• Physiotherapy and special seats and wheelchairs can help to minimize 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.

• Spinal deformity
• Joint contractures
• Respiratory infection
• Respiratory failure

• Mechanical ventilation can prolong survival in some children with SMA Type I.¹³
• Some studies have shown an inconsistency in the offering of ventilatory support to patients with SMA Type I.¹⁴
• Should affected individuals be offered ventilatory support when there is no current cure for the disease?
• What are the quality of life issues? A recent ruling refused permission for an 18 month old boy to be taken off a ventilator that was keeping him alive due to the fact that he continued to have a "relationship with his family".¹⁵
• There are financial and therefore social cost implications for mechanical ventilation.
• Anecdote and clinical judgement tend to guide doctor's decision making with regards to the use of mechanical ventilation in SMA Type I. However, doctors need to be cautious when making their own predictions of a patient's quality of life. Care providers often do not share the same perception of the patient's quality of life as doctors.¹⁶
• What role should the family have in decision making? A family's concept of quality of life needs to be explored. The family needs to be fully informed and supported.¹⁷

• There is a 25% risk that each offspring of two carrier parents is 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 (pre-natal 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.
• Research has shown that non-invasive analysis through testing of circulating fetal cells in the mother's blood may also be possible in the future.¹⁸