Spinal Muscular Atrophy (SMA)

Original Editor - Evelin Milev Top Contributors - Evelin Milev, Jeremy Bryan, Nikhil Benhur Abburi, Lucinda hampton, Kim Jackson, Rucha Gadgil, Momina Khalid, Aminat Abolade, Rachael Lowe and Meaghan Rieke

Introduction

Spinal Muscular Atrophy (SMA) is a genetic condition under the scope of the neurodegenerative disorders and Motor Neurone Disease MND. It is characterised by degeneration of alpha motor neurons in the spinal cord that affects the control of voluntary muscle movement. The disease is characterised as an autosomal recessive condition with prevalence of approximate 1 in 6-10,000 births affected by SMA with a carrier frequency of 1 in 35-70. Classification of SMA type depends on the age of onset and the highest level of motor function achieved

Clinically Relevant Anatomy

SMA is caused by deficiency of a motor neuron protein called SMN (Survival Motor Neuron). This protein is essential for normal motor function and the lack of it is caused by genetic flaws on chromosome 5 in the gene SMN1. The neighbouring SMN2 gene can compensate some of the functions of SMN1 and this is where some of the pharmaceutical companies trying to develop a drug which can enhance the effect of SMN2.

Pathological Process

Spinal Muscular Atrophy is an autosomal recessive condition due in most cases to the homozygous deletion of the SMN1 gene. This means that both parents of the affected individual are only carriers of the affected gene. Therefore, they are not going to present with any symptoms of the disease and this is what makes SMA difficult to foreseen and apply preventable measures.

Clinical Presentation and Classification

Spinal Muscular Atrophy (SMA) is the second most common neuromuscular disorder of childhood. People affected by the mildest types of SMA have proximal weakness and impaired ambulation. Furthermore, fatigue is a symptom to present in almost every case of SMA which may also lead to impaired function and endurance. Current research in the area shows that there is good correlation between upper and lower limb function in patients with the disease. There are several types of SMA, which start at different ages and may present with various phenotype. <be>

Types of SMA

• SMA type I (Werdnig-Hoffmann disease) - affects babies less than six months old and is the most severe type of the disease. Sitting unsupported may never be achieved. Present with profound hypotonia, symmetrical flaccid paralysis, and no head control with poor spontaneous mobility and reduced antigravity movements of limbs.
• SMA type II - develops in babies between 7 and 18 months old. This type is less severe than type I and most children survive into adulthood and can live long, fulfilling lives. May achieve ability to sit unsupported but may not be able to walk independently. Joint contractures and kyphoscoliosis are very common along with fine tremors of upper extremities.
• SMA type III (Kugelberg-Welander disease) - appears after 18 months of age and is the least severe type affecting children. SMA type III has been divided into two further sub-categories: SMA IIIa and SMA IIIb - according to the time when the first symptoms of the condition appears (if before or after 3 years of age).
• SMA type IV - this type of SMA patients are diagnosed in adulthood and they present with only mild problems.

Diagnostic Procedures

Diagnoses could be made by prenatal screening or by gene panel investigation and/or muscle biopsy. Inthe early stages, the diagnosis may be suspected due to symptoms like floppiness and muscular weakness. Children with type I SMA can present with lack of head control, minimal to absent anti-gravity movements and severe respiratory complications.

The first steps in diagnosing someone with SMA would be by taking a full clinical examination and family history. A blood test might be required to look at the amount of creatine kinase (CK), an investigation to indicate if muscle damage has occurred. High levels of the CK in the blood is not damaging itself, but it is an important indicator of a muscle disorder condition. Electrophysiological tests such as electromyography (EMG), and nerve conduction study should be performed, if EMG suggests a motor neuron disease, then, further testing should be done.

Further investigation will probably include genetic testing as this is the most accurate way to diagnose if a patient has Spinal Muscular Atrophy.

Differential Diagnosis

Neuromuscular conditions:

• Duchenne Muscular Dystrophy
• Charcot-Marie-Tooth
• Amyotrophic Lateral Sclerosis

Congenital Myopathies:

• congenital myotonic dystrophy,
• congenital myasthenic syndromes,
• metabolic myopathies

Congenital disorders of the motor neuron and the peripheral nerve (congenital hypomyelinating neuropathy).

Non-Neuromuscular Conditions:

• Prader-Willi syndrome,
• acute hypoxic ischemic encephalopathy,
• neonatal sepsis and
• dyskinetic or metabolic conditions

The tools that can address these differential diagnostic possibilities beyond the clinical examination and a careful family history are CK determination, EMG/nerve conduction studies, MRI of the brain, muscle biopsy, and specific genetic or metabolic testing.

Outcome Measures

There are several outcome measures which can be used to detect changes in the natural history of the patients with SMA. These tools should be appropriate selected according to the age and severity of the disease.

• Six-Minute Walking Test (6MWT) - The Six-Minute-Walking-Test can be safely performed in ambulant patients with SMA. It has been proven to detect fatigue-related changes in this population of patients and also correlates with other established outcome measures for patients with spinal muscular atrophy.

• Revised Hammersmith Scale for SMA (RHS) - The RHS is predominantly used in patients with SMA type 2 and 3. In a combination with the WHO motor milestones, the scale can be more sensitive towards the description of SMA phenotype. The RHS has been designed to capture a wide range of abilities across a broad spectrum of SMA, from very young children to adolescents and adults.

• WHO Developmental Milestones - The WHO scales aims to link the growth of the child and the motor development in one single reference. The final version of the protocol includes six items: "Sitting without support", "Hands-and-knees crawling", "Standing with assistance", "Walking with assistance", "Standing alone", and "Walking alone". The WHO provides important information about a child's gross motor development in different cultural settings.

• Revised Upper Limb Module (RULM) for SMA - The RULM is specifically designed outcome measure for upper limb function in patients with Spinal Muscular Atrophy. The scale has shown good reliability and validity, which makes it a good choice for assessing arm function in children and adults with SMA.

Management / Interventions

Spinal Muscular Atrophy (SMA) is a severe genetic condition which requires precise diagnosis and extensive physiotherapy treatment in order to protect the muscles from rapid deterioration and development of contractures. The management of SMA must be as a part of a broad multi-disciplinary team which should include rehabilitation, spinal management, orthopaedics, nutritional and gastrointestinal management.

Recently, it has been stated that SMA might be a multi-organ disease and more detailed examination should be performed. Further recommendations have been made on pulmonary management and acute care issues in the severe forms of spinal muscular atrophy.

Medical Management:

• Neuroprotective Drugs like riluzole,
• Drugs to improve energy metabolism and
• Drugs affecting the gene expression of SMN

Gene Therapy:

Along with advances in the medical management, gene therapy approaches have been evaluated for SMA, using viral vectors to replace SMN1 gene.

Stem Cell Therapy: cellular replacement strategy in the treatment of SMA. However, this therapy is still in testing stages.

Cell replacement may be achieved by :

• Transplantation of stem cell-derived cells which have undergone maturation in vitro
• Activation of endogenous stem cells in the CNS

Physiotherapy

• Assessment of the patient with neuromuscular disease and particularly with SMA is of great importance. Looking at baseline function, joint range and power will assist the physiotherapist to follow on the progression of the condition.
• Orthotics
• Splinting
• Taping
• Management of contractures
• Exercise and activity

Respiratory Care

Many of the children and adults with Spinal Muscular Atrophy will be dependant on pulmonary management due to loss of muscle function. When a patient with SMA has a respiratory failure they need to be transferred on non-invasive positive pressure ventilation (NIV). In order, this to be implemented in the best possible way, a respiratory physiotherapist should be involved in the assessment and the management of pulmonary complications.

Airway clearance (chest physio) is best administered with the combination of Cough Assist and this should be the primary airway clearance therapy for all SMA patients with respiratory illness.

Suctioning is a critical part of the treatment and should be used in all patients with excessive secretions or in those with an ineffective cough.

The high-frequency chest wall oscillation (Vest) is another option for managing secretions. However, there is no evidence that the Vest improves airway clearance and secretions.

Non-invasive positive pressure ventilation (NIV) should be used for respiratory failure or to prevent chest wall distortion.

Continuous positive airway pressure (CPAP) should be used only when NIV is not tolerated or in the treatment of chronic respiratory failure.