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Spinal Muscular Atrophy

Type 2 (intermediate SMA)


What is Spinal Muscular Atrophy Type 2?

Spinal muscular atrophy (SMA) is a genetic condition which affects the nerves that control muscle movement – the motor neurons.

It is named 'spinal' because most of the motor neurons are located in the spinal cord. 'Muscular' is in the name because it primary affects the muscles which don’t receive signals from the motor neurons. ‘Atrophy’ is the medical term for wasting away or getting smaller, which is what generally happens to muscles when they’re not active.

There is wide variability in age of onset, symptoms and rate of progression of SMA and it is often classified into types 1 to 4 based on the physical milestones achieved. Please see the document ‘Spinal Muscular Atrophy – an overview’ for a brief description of the different types.

Babies usually start to show symptoms of SMA type 2 between the ages of seven and 18 months. They are able to eventually sit unsupported but are usually not able to stand without support. Despite a set pattern of weakness, each person is different in the extent to which they are affected. Some children with SMA type 2 live well into adulthood and others are weaker and have shorter lives.

Intellect is normal and it is often observed that children with SMA are bright, alert and responsive.

SMA is a relatively common 'rare disorder' approximately 1 in 6000 babies born are affected, and about 1 in 40 people are genetic carriers.

In this factsheet:
• What are the symptoms of SMA type 2?
• What Causes SMA type 2?
• How is SMA type 2 diagnosed?
• What can we expect for the future?
• What research is being done?
• I am a carrier of the SMA gene - what can I do?
• Further information
• Glossary

What are the symptoms of SMA type 2?

The symptoms of SMA type 2 include:
• Muscle weakness and poor muscle tone
• The legs tend to be weaker than the arms
• Some children have swallowing and feeding difficulties
• Increased susceptibility to respiratory tract infections
• Scoliosis (curvature of the spine)
• Deformities of the hands, feet and chest may develop in childhood
• Joints may be affected by tendon contractures which reduce movement of the limbs

The onset of the symptoms of SMA type 2 is usually between the ages of seven and 18 months. Parents often notice that milestones such as sitting are delayed. These children do eventually develop the ability to sit unsupported but they may need some help to get into a sitting position. Some children with SMA type 2 are able to crawl or stand with assistance or bracing, but they usually never walk.

Weakness of the spinal muscles results in scoliosis (curvature of the spine) which may require bracing and eventually surgery. Shortening of the muscle (contractures) can restrict movement especially around the hip, knee and ankle joints. Usually the muscles used in chewing and swallowing are not significantly affected early on. The muscles of the chest wall are affected, causing poor breathing function and susceptibility to respiratory infections and complications.

Sometimes muscle weakness can seem to be non-progressive, but in most cases weakness and disability will slowly increase. Severe illness with prolonged periods of relative immobility, putting on excessive weight or growth spurts may contribute to deterioration in function.

There is a wide variation in symptoms. Severity and prognosis depends on the age of diagnosis and while some people with type 2 SMA die prematurely, many (especially if diagnosed after the age of 18 months) may live into adulthood.

Children with SMA type 2 are bright and alert and it is important that they receive all the available opportunities to develop their intellectual capacities to their fullest extent.

Is there a treatment?

Unfortunately, there is currently no specific treatment for SMA. However, research for a treatment is moving forward at a fast pace (please see below) and there are things that can be done to support the child and their family so that they can achieve the maximum quality of life.

A multidisciplinary team of healthcare professionals will be needed to manage the symptoms of SMA. The team may include specialists in neurology, genetics, palliative care, respiratory medicine, physiotherapy, occupational therapy, speech and language therapy and gastrointestinal /dietetics. A care coordinator may be available to help you manage care with all of these professionals.

Physiotherapy and occupational therapy
A physiotherapist can prescribe stretching exercises to help prevent shortening of muscles (contracture) which can limit the movement of joints. Orthotics, such as wrist or ankle splints can also be used to help prevent contractures. Eventually an orthopaedic surgeon may need to operate on contractures once they are no longer responding to physiotherapy and splinting. A physiotherapist can also teach respiratory exercises and chest physiotherapy which is very important to reduce the effect of chest infections when there is difficulty in coughing.

It is important for SMA-affected children to be in an upright position at the earliest possible age. Standing is important in development as it allows for better respiratory function, improved bowel function, and greater mobility. Getting children into an upright position as much as possible, or tolerated, throughout the day is extremely beneficial. This may require advocacy on the part of the parents to encourage the use of standing aids in the classroom as well as at home.

There are several options to consider when choosing the appropriate standing aid:
• A standing frame and/or parapodium.
• A standing wheelchair is ideal for added mobility and independence.
• Bracing: Reciprocating Gait Orthosis (RGO’s) and weight bearing Knee Ankle Foot Orthosis (KAFO’s) usually work well for children with SMA Type 2, and in some instances, children have been able to take some steps.

Young children who have difficulty sitting and who are unable to walk will often need assistance in finding stable positions for play and mobility. An appropriate pram can be obtained while later on a small wheelchair will be more appropriate. A motorised wheelchair can be considered as early as three years of age and occasionally younger.

After becoming a full-time wheelchair user, children are prone to develop progressive scoliosis (curvature of the spine). The physiotherapist will discuss correct posture and bracing, if necessary, to minimise the progression of curvature. However surgery is usually required eventually (see below).

An occupational therapist can help overcome problems associated with activities of daily living and enable children to make the most of their abilities. This includes help with:
• Self-care activities including dressing, bathing, toileting and car transportation.
• Kindergarten and school activities including writing, cutting, pasting etc.
• Play and leisure activities.

The occupational therapist may teach the child a different way of performing an activity or provide adapted equipment e.g. large handled cutlery, specially designed scissors or a bath chair. They will also recommend modifications to the home or school e.g. installation of ramps, widening of doorways and also work with teachers to ensure successful integration to school.

It is advised that people with SMA type 2 do as much physical activity as is comfortable (without overdoing it) in order to maintain general physical and psychological health and well-being. Hydrotherapy can also be of excellent benefit as freedom of movement not possible on land can be enjoyed.

With appropriate mobility aids even the youngest children can take an active part in family and social activities. Most children with SMA type 2 are capable of being educated in mainstream schools, if that is what their parents want, and will have much to contribute to others.

Respiratory health and nutrition
Breathing problems are less common and less severe in children with SMA type 2 than those with type 1 but if left untreated this can lead to a poorer quality of life. Breathing difficulties, particularly at night, can go unnoticed at first - signs to look out for are headaches, difficulty sleeping at night, excess sleepiness during the day, poor concentration, and chest infections. Doctors will use a variety of tests to monitor the breathing so that it can be decided when intervention is required.

Portable, effective ventilation devices are now available which can greatly improve quality and length of life. Some children require more breathing support, especially with colds, and sometimes just at night. There are several types of ventilator to consider which will be explained by your doctor.

A weak cough during respiratory infections can make it difficult to clear mucus from the airways. Chest physiotherapy and devices such as the “CoughAssist” are available to help with this.

Respiratory infections can be life threatening, so in case of illness a plan of action should be put in place. Rapid access to specialist medical care providers should be arranged. Routine immunizations, including influenza vaccine, are also recommended.

There is a tendency for children with muscle weakness to become overweight because of reduced energy requirements at a time when appetite remains normal. Prevention of excessive weight gain is important so that extra load isn’t placed on the muscles. A nutritionist can help with this.

On the other side of the coin, some children may have difficulty with swallowing food, making them at risk for aspiration or choking and they might not be able to consume adequate amounts of food for a balanced diet. Monitoring of the diet by a nutritionist might be necessary in this case. Care should be taken that long periods of fasting do not occur when unwell, as this can be very serious and life threatening.

Spinal surgery
Due to weakness of the muscles supporting the bones of the spinal column, scoliosis (curvature of the spine) often develops in children who are full-time wheelchair users. If this becomes severe it can cause discomfort and adversely affect breathing. An operation can be done to straighten the spine and prevent further deterioration.

The surgical team, particularly the anaesthesiologist, must thoroughly understand SMA. People with SMA can have dangerous reactions to the muscle-relaxing drugs often used during surgery. Doctors will use alternative drugs to avoid this.

The timing of spinal surgery is tricky. Doctors generally like to wait until maximum spinal growth has been achieved because that allows a simpler surgical technique to be used. On the other hand, if respiratory status is deteriorating, surgery often can’t wait until growth is complete.

What Causes SMA type 2?

SMA is a genetic condition caused by changes to a gene called 'survival motor neuron 1' (SMN1) which is located on chromosome number 5. For an individual to have SMA, they need to inherit two altered SMN1 genes - one from their mother and one from their father). This is what is called an 'autosomal recessive’ inheritance pattern.

The parents of an individual with SMA each carry one copy of the altered SMN1 gene, and are known as ‘carriers’, but they typically do not show signs and symptoms of the condition. Their other ‘good’ copy of the SMN1 gene is enough to keep the motor neurons healthy. In order for carrier parents to have a child affected by SMA, both parents must pass the altered SMN1 gene on to their child. If both parents are carriers the likelihood of a child inheriting the disorder is 25 percent, or 1 in 4. About 1 in every 40 people is a carrier of the altered gene that causes SMA.

The SMN1 gene change (often called a mutation) usually involves the entire gene being missing or occasionally some of the code of the gene is altered so that the gene doesn’t work. The role of the SMN1 gene in the body is the production of a protein called ‘Survival of Motor Neuron’ (SMN). If this protein isn’t produced in sufficient amounts motor neurons start to die. Motor neurons are nerve cells in the spinal cord which send out nerve fibres to muscles throughout the body and control their movement.

But why do some people have less severe types of SMA? This is primarily due to the presence of another similar gene called SMN2. This gene produces several different versions of the SMN protein; however, it only produces a small amount of the full size and functional version. Some people have more copies of the SMN2 gene which results in significant amounts of full-length SMN protein being made. As a general rule, children with SMA type 2 have more than two SMN2 gene copies (usually three) and as a result the condition isn’t as severe as SMA type 1 but insufficient amounts of SMN protein are produced to protect the motor neurons completely.

SMA severity also may depend on levels of other proteins that people naturally produce in their body. These are called ‘disease modifiers’. Two such proteins that have been identified so far are ‘plastin 3’ and ‘ZPR1’. Patients who naturally produce higher amounts of these proteins tend to have less severe symptoms, but more research is required to fully understand this.

How is SMA type 2 diagnosed?

SMA type 2 is usually diagnosed between the ages of seven and 18 months. If symptoms and a physical examination suggest that a baby might have SMA the first diagnostic test to be done is a blood test which looks for the presence or absence of the SMN1 gene. In approximately 95% of patients with SMA there is complete absence of the SMN1 gene.
If the genetic test shows that the SMN1 gene is present, further physical examination is done to look for symptoms indicative of rare types of SMA caused by mutations in other genes.

Other laboratory tests may also be done to rule out other neuromuscular conditions, which may include:
• Electromyography (EMG) which measures the electrical activity of muscle. Small recording electrodes (needles) are inserted into the patient's muscles, usually the arms and thighs, while an electrical pattern is observed and recorded.
• Nerve conduction velocity test (NCV) is performed to help assess how well the nerves are functioning in response to an electrical stimulus. Small shocks are repeatedly administered to help assess nerve integrity and function.
• A blood test for the muscle enzyme ‘creatine kinase’– a positive result may indicate a muscular dystrophy.
• Occasionally, doctors may request a muscle biopsy.

If these tests suggest a motor neuron disease, then further genetic testing for SMN mutations should be pursued. In two to five percent of patients with SMA the SMN1 gene is not missing but some of the code of the gene is changed rendering it inactive. Testing for this type of mutation is more complicated so it may take some time to obtain a result.

What can we expect for the future?

There is a wide range of variability in the symptoms and severity of SMA. This is crucial to remember when considering different aspects of an individual’s care. No two children will be exactly the same and thus treatment and care plans for each family should be tailored to meet their individual needs.

As with all forms of SMA, weakness increases over time. Today most doctors prefer not to make rigid predictions about life expectancy or weakness based strictly on age of onset because the lines between the different types are blurred. Anecdotal information shows that some people with SMA type 2 live into adolescence and others as late as the third or fourth decade.

SMA type 2 presents a daunting list of medical problems, however with good medical attention children and adults with this condition can anticipate a high-quality of life.

What research is being done?

It is an exciting time for SMA research with several clinical trials underway to test promising new potential treatments. Although clinical trials might not always involve children with SMA type 2, it is expected that if a therapy proves to be effective for one type it may also be applicable to SMA type 2.

Gene therapy
The aim of gene therapy for SMA is to introduce a healthy synthetic copy of the SMN1 gene into the motor neurons so that SMN protein can be made. Effective delivery of the gene to the difficult-to-access motor neurons has been considered an almost impossible challenge until very recently. Several research groups published results of experiments in 2010 and 2011 showing that a virus called ‘adeno-associated virus type 9’ (AAV9) is effective at delivering the SMN1 gene to the motor neurons of mice when injected into the blood stream. The gene therapy dramatically improved the life span and motor function of mice that had severe SMA.

In June 2014 a phase 1 clinical trial of this type of gene therapy for SMA was started by US company Avexis Inc. The trial will involve about nine SMA type 1 patients younger than nine months of age. More information about the trial is available on the clinicaltrials.gov website.

Utilising the SMN2 gene
Several research strategies involve manipulating the genetic instructions provided by the SMN2 gene so that more full-length SMN protein can be made. Some researchers are discovering potential drugs in what could be a considered a ‘trial and error’ approach – testing thousands of molecules to find any that increase production of SMN protein. Others are using a more targeted approach – specifically designing drugs to alter the way the SMN2 gene works.

One example of the former approach is a potential drug called RG 3039. Screening of over 500, 000 potential drugs by researchers in the USA discovered a type of compound that was capable of increasing the production of full-length SMN protein from the SMN2 gene. The composition of this compound was then optimised to produce the drug RG3039 which was tested in mice. It was shown to improve the lifespan and various disease symptoms including motor neuron survival in the mice. RG3039 is now being tested by Repligen Corporation in Phase 1 clinical trial in healthy volunteers to determine the safety and pharmacokinetics (see glossary below) of the drug. It is hoped that the information gained from these Phase 1 trials will aid in the future design of clinical trials of RG3039 in SMA patients. Pharmaceutical company Pfizer has now bought the licence to RG3039 and will continue the development and testing. RG3039 is also known by the names PF-06687859 and Quinazoline.

Using the more targeted approach is Isis Pharmaceuticals who are currently testing a potential drug called ISIS-SMNRx in clinical trial. ISIS-SMNRx is an antisense oligonucleotide (AONs) – small pieces of genetic material that can specifically manipulate the way that the genetic code is read. The aim of using AONs for SMA is to encourage the cells to produce more of the full length SMN protein from the SMN2 gene. Administration of ISIS-SMNRx to mice with SMA has previously been shown to target many neuromuscular symptoms leading to a large increase in survival.

Isis Pharmaceuticals has reported positive results part-way through two clinical trials f ISIS-SMNRx. The first of the ongoing trials aims to test two different doses of ISIS-SMNRx in infants with SMA type 1 and the second aims to test four different doses in children with the less severe types 2 and 3 SMA. In both studies the results are encouraging with the children faring better than the typical course of the disease. Importantly, ISIS-SMNRx has been well tolerated.

The ISIS-SMNRx trials involve only a small number of participants and assessments have only been made over a short time period, so further clinical trials will be needed to further assess the safety and effectiveness. However, the results so far are encouraging enough for plans to already be in place to start larger Phase 3 studies. More information on the ISIS clinical trials.

Protecting motor neurons
Olesoxime (TRO19622) is a cholesterol-like compound being developed by Trophos, a French pharmaceutical company. Olesoxime has been shown to protect nerve cells from damage and improve neuronal growth and function, effects that could prove beneficial to SMA patients.

Following a successful phase 1 trial, Trophos conducted a larger phase 2 trial involving 165 people with SMA types 2 and 3, aged between three and 25 years. Results were announced in March 2014. The trial showed that loss of motor function was prevented in those taking olesoxime for two years while those taking the placebo had the typical progressive loss of motor function. Participants taking the olesoxime also had fewer of the medical complications that are normally associated with SMA such as lower respiratory tract infections. The safety of olesoxime was also confirmed and Trophos plans to file for regulatory approval in both the US and Europe as soon as possible. More information about the Olesoxime trial.

Ongoing searches for new drugs
There are many ongoing efforts to identify other new drugs for SMA, both in research institutions and by pharmaceutical companies. Companies involved include Novartis, Merck, Roche and PTC Therapeutics. In August 2013 PTC Therapeutics announced that it had selected and will continue to develop a candidate drug that has the potential to treat SMA.

Stem cells
Another treatment strategy that is being actively investigated in SMA is to use stem cells to replace the motor neurons that have died. SMA mice treated with stem cells displayed increased survival and improved mobility, as well as increased motor neuron number. Research is ongoing to understand the best type of stem cell to use, how to produce these cells in large numbers and how to control their development into motor neurons. California Stem Cell Inc. is particularly active in this area.

Research challenges
One of the big challenges of developing a therapy for SMA is proving that a therapy works. The severity of symptoms from one patient to the next is very variable which makes it difficult to measure whether a new drug works. In addition, SMA type 2 and type 3 patients often have stable muscle strength for months and years making the detection of meaningful changes difficult, whereas infants with SMA type 1 are often too sick to take part in muscle strength tests.

Preclinical research has shown that the timing of treatment may also be critical – early treatment, before too many motor neurons are lost, is likely to be most successful. The window of opportunity for treatment of people with SMA is not known which makes it difficult to plan clinical trials that will give positive results. If a successful treatment is found it may be beneficial for a newborn screening program for SMA to be introduced so that treatment can be started before symptoms appear and the motor neurons are lost.

NOTE: Research is moving forward at a fast pace, so this research summary may not be up-to-date at the time of reading. Feel free to contact MDA's Scientific Communications Officer for an update on the latest developments - kristina.elvidge@mda.org.au

I am a carrier of the SMA gene - what can I do?

If you find you are a carrier of the SMA gene, it is recommended that you seek the advice of a genetic counsellor. The genetic counsellor can help you to better understand the risks and chances of having a child with SMA. If you already have a child with SMA, the counsellor can discuss with you options that you may want to consider regarding future pregnancies.
Preimplantation genetic diagnosis (PGD) is an option that might be considered by some couples who are carriers of SMA. This involves using IVF to fertilise eggs outside the body and then testing the resulting embryos for the genetic mutation. Unaffected embryos are then chosen to be placed back in the woman’s womb. Another option is prenatal diagnosis – testing the foetus once the woman is pregnant. The couple then has the option whether or not to continue the pregnancy if the foetus is affected. Alternatively some couples may choose to use egg or sperm donors, or adopt a child.

Further information

Clinical trials – your questions answered
• A Family Guide to the Standards of Care for Spinal Muscular Atrophy is available in two different formats and 16 different languages
• Learn about patient registries and join the Australian Spinal Muscular Atrophy Registry
More research news on the MDA website
More research information from the Families of SMA in the USA
• For definitions of any terms that you are not familiar with please take a look at our glossary
• You can get regular updates by becoming a friend of the MDA Facebook page.

If you have any questions, please contact us at MDA:
Email: info@mda.org.au
Phone: (03) 9320 9555

Click here for PDF version

Updated 7 July 2014

 

 


 

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