Spinal Muscular Atrophy

Spinal Muscular Atrophy

What is Spinal Muscular Atrophy (SMA)?

Spinal muscular atrophy (SMA) is a group of inherited disorders characterized by weakness and wasting (atrophy) in muscles used for movement (skeletal muscles). It is caused by a loss of specialized nerve cells, called motor neurons that control muscle movement. The loss of motor neurons leads to progressive muscle weakness and atrophy in the muscles closest to the trunk of the body (proximal muscles) such as the shoulders, hips and back. These muscles are necessary for crawling, walking, sitting up and head control. The muscle weakness usually worsens with age. The more severe types of SMA can affect muscles involved in feeding, swallowing and breathing.

What are the different types of SMA?

There are many types of spinal muscular atrophy that are caused by changes in the same genes. The types differ in age of onset and severity of muscle weakness; however, there is overlap between the types.

SMA type 0

SMA type 0 is the most severe form of the disease and is characterized by decreased fetal movement, joint abnormalities, difficulty swallowing and respiratory failure. These children often do not survive past infancy due to respiratory failure.

SMA type 1

SMA type 1 (also called Werdnig-Hoffmann disease) is the most common type of SMA and is also a severe form of the disease. Infants with SMA type 1 experience severe weakness before 6 months of age and never sit independently. Most affected children die before two years of age due to respiratory failure but survival may be dependent on the degree of respiratory function.

SMA type 2

The onset of weakness in SMA type 2 (also called Dubowitz disease) patients is usually between 6 and 12 months. Affected children are able to sit independently early in development but are unable to walk even 3 meters independently. The life span of individuals with spinal muscular atrophy type II varies, but many people with this condition live into their twenties or thirties.

SMA type 3

Patients with SMA type 3 (Kugelberg-Welander syndrome) learn to walk but fall frequently and have trouble walking up and down stairs at 2-3 years of age. People with spinal muscular atrophy type III typically have a normal life expectancy.

SMA type 4

The onset of muscle weakness for those with SMA type 4 is after age 10 years; these patients usually are ambulatory until age 60 years. People with spinal muscular atrophy type IV have a normal life expectancy.

How common is SMA?

Spinal muscular atrophy affects 1 per 5,000 to 10,000 people worldwide. Spinal muscular atrophy type I is the most common type, accounting for about half of all cases. Types II and III are the next most common and types 0 and IV are rare. However, carrier frequency is more common and estimated at approximately 1 in 25-50 persons

How does SMA affect the body?

The SMN1 and SMN2 genes both provide instructions for making a protein called the survival motor neuron (SMN) protein. Most people with spinal muscular atrophy are missing a piece of the SMN1 gene, which impairs SMN protein production. Mutations in the SMN1 gene cause all types of spinal muscular atrophy described above. The number of copies of the SMN2 gene modifies the severity of the condition and helps determine which type develops. In people with spinal muscular atrophy, having multiple copies of the SMN2 gene is usually associated with less severe features of the condition that develop later in life. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.

How is SMA inherited?

Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means both copies of the SMN1 gene in each cell have mutations. In most cases, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In rare cases, a person with spinal muscular atrophy inherits an SMN1 gene mutation from one parent and acquires a new mutation in the other copy of the gene that occurs during the formation of reproductive cells (eggs or sperm) or in early embryonic development. In these cases, only one parent is a carrier of the SMN1 gene mutation.

How is SMA diagnosed?

The diagnosis of SMA is suspected when symptoms are present and the diagnosis can be confirmed with molecular genetic testing. Molecular genetic testing is used to determine if a mutation is present in the SMN1 gene. neurophysiologic studies and muscle biopsy were used for diagnosis, but these tests are no longer necessary unless SMN gene testing is normal.

Carrier testing for SMA is available using a molecular genetic test in which the number of copies of the SMN1 gene is determined.

Genetic counseling is recommended for affected individuals and their families.

What are the therapies for SMA?

Care for individuals with SMA is symptomatic and includes physical therapy, occupational therapy, monitoring of respiratory function and nutritional status, orthotics and adaptive equipment. Respiratory support for SMA1 using a breathing machine called BiPAP (bi-level positive airway pressure) has been shown to increase comfort and life expectancy in some affected children. Novel therapies have emerged lately, showing promising results.

Standard therapies

The management of children with spinal muscular atrophy starts with the diagnosis and classification into 1 of the 5 categories. Health issues specific to spinal muscular atrophy are as follows:

Pulmonary management: Children with SMA1 can survive beyond 2 years of age when offered tracheostomy or noninvasive respiratory support.

An intermittent positive-pressure breathing device (mechanical in-exsufflator) has proven effective.

Nutrition: Bulbar dysfunction is universal in SMA1 patients. Early gastrostomy should be considered as part of the management of such patients. The bulbar dysfunction eventually becomes a serious problem for spinal muscular atrophy II patients and only very late in the course of disease for spinal muscular atrophy III patients.

Scoliosis: Scoliosis is a major problem in most SMA2 patients and in half of SMA3 patients.

The vertical expandable prosthetic titanium rib (VEPTR) was approved by the Food and Drug Administration (FDA) in 2004 as a treatment for thoracic insufficiency syndrome (TIS) in pediatric patients and helps that the lungs can grow and fill with enough air to breathe. The length of the device can be adjusted as the patient grows.

Hip dislocation: Hip dislocation is another orthopedic concern in patients with spinal muscular atrophy. If the hip dislocation is asymptomatic, surgery is not indicated.

Behavior issues: Compared to siblings and normal controls, patients with spinal muscular atrophy were quite well adjusted. Concern was, however, raised about unaffected siblings, who had a 2 to 3-fold higher rate behavioral problems than normal children.

Sleep disorders: Sleep-disordered breathing may develop prior to respiratory failure. Night-time use of continuous positive airway pressure with a nasal mask may be helpful.

Novel therapies

In 2017, Spinraza (nusinersen) was FDA-approved as the first drug to treat children and adults with SMA. Spinraza is an injection administered into the fluid surrounding the spinal cord.

In 2019, FDA approved Zolgensma (onasemnogene abeparvovec-xioi) for the treatment of children less than two years of age with SMA. Zolgensma is an adeno-associated virus vector-based gene therapy that targets the cause of SMA. The vector delivers a fully functional copy of human SMN gene into the target motor neuron cells. A one-time intravenous administration of Zolgensma results in expression of the SMN protein in a child’s motor neurons.

In 2020, FDA approved the first oral treatment for the disease. The drug is called Evrysdi (risdipla) and contains a survival of motor neuron 2-directed RNA splicing modifier for gene SMN2. It can be administered throughout the person’s lifetime aged 2 monthw and beyond.

More drugs are on the way and are, currently (2021) on different stages of clinical trials

How do you check for SMA antenatally?

 Antenatal diagnosis for SMA, checking the baby that is, is considered when both partners are carriers of the disease. Antenatal diagnosis is performed after checking both parents by CVS or amniocentesis from the 11th week of pregnancy onwards.

Checking the parents is performed by a blood sample. We then check for the number of copies of the SMN1 gene. In case both parents are carriers of the disease, the antenatal testing of the fetus is necessary to find out if the baby is healthy.