Spinal Muscular Atrophy (SMA)
Spinal Muscular Atrophy (SMA) is a leading cause of infant mortality and is a group of inherited neurodegenerative disorders. It’s characterised by the progressive loss of lower motor neurons in the spinal cord and brainstem, leading to symmetrical, proximal muscle weakness and atrophy. Despite the severe physical symptoms, cognitive function remains normal. The UK’s National Institute for Health and Care Excellence (NICE) has updated its guidance on the use of new, disease-modifying therapies, which have revolutionised the management and prognosis of SMA.
Pathophysiology and Genetics
SMA is an autosomal recessive disorder caused by a mutation or deletion in the survival motor neuron 1 (SMN1) gene located on chromosome 5q13. The SMN1 gene produces a protein, SMN, that is crucial for the survival and function of anterior horn cells (motor neurons). The severity of the disease is influenced by the number of copies of a nearly identical gene, SMN2. The SMN2 gene produces a limited amount of functional SMN protein, and more copies of this gene lead to a milder phenotype.
Clinical Classification
SMA is classified into different types based on the age of onset and the highest motor milestone achieved.
Type 1 (Werdnig-Hoffmann Disease): The most severe form, with onset before 6 months of age. Infants are known as “non-sitters” as they never achieve the ability to sit independently. They present with profound hypotonia, absent reflexes, and tongue fasciculations. Death from respiratory failure or aspiration usually occurs by the age of two years.
Type 2 (Dubowitz Disease): An intermediate form with onset between 6 and 18 months. Children are “non-walkers,” as they can sit independently but never walk. They have progressive weakness, absent reflexes, and often develop scoliosis. Survival into adulthood is common.
Type 3 (Kugelberg-Welander Disease): A milder form with onset after 18 months. Children can walk independently initially but may lose this ability later in life. They have progressive proximal weakness and an abnormal gait. Survival into adult life is the norm.
Type 0: A rare and severe neonatal form with onset at birth, often with severe hypotonia and joint contractures (arthrogryposis). These infants are ventilator-dependent from birth and have a very poor prognosis.
Investigations and Management
Diagnosis: The gold standard for diagnosis is molecular genetic testing to identify the deletion or mutation in the SMN1 gene. Electromyography (EMG) may show abnormal fibrillation patterns, but genetic testing is confirmatory.
Management: The management of SMA is now a combination of supportive care and new, disease-modifying therapies.
Supportive Management
Multidisciplinary Team: Care is provided by a multidisciplinary team including a paediatric neurologist, respiratory physician, orthopaedic surgeon, and physical and occupational therapists.
Respiratory Care: This is a critical aspect of management. It includes non-invasive ventilation (CPAP/BiPAP) and, in some cases, a tracheostomy for prolonged mechanical ventilation.
Nutrition: Gastro-oesophageal reflux is common and can be managed with medication. A nasogastric or gastrostomy tube may be required to ensure adequate nutrition and prevent aspiration.
Orthopaedic Care: Management of scoliosis and other postural deformities with bracing or surgery is a key component of care.
Disease-Modifying Therapies
Nusinersen (Spinraza®): This is an antisense oligonucleotide that modifies the splicing of the SMN2 gene to produce more functional SMN protein. NICE has approved its use in the UK, and it is administered via intrathecal injection. It has shown significant improvement in motor milestones and survival in children with SMA types 1, 2, and 3.
Onasemnogene abeparvovec (Zolgensma®): This is a gene therapy that delivers a functional copy of the SMN1 gene. It is a one-time intravenous infusion. It has been approved by NICE for a specific group of children with SMA and has shown remarkable results.