#SpinalMuscularAtrophyAwarenessMonth “An SMA diagnosis can bring a lot of uncertainty. Many factors can impact what having SMA will mean for you or your family. These factors include what type of SMA you or your child have and what type of treatment and care you choose to pursue. Every family has the right to receive support. They have the right to ask questions. They have the right to refuse or request certain treatment and care or to change their mind. They have the right to make decisions in accordance with their own values and priorities.” CureSMA, Make today a breakthrough Founded 1984 as Families of SME – Support. Research. Hope. https://www.curesma.org/
What is Spinal Muscular Atrophy (SMA)?
Spinal muscular atrophy (SMA) refers to a group of hereditary diseases that can damage and kill specialized nerve cells in the brain and spinal cord (motor neurons).
SMA is usually caused by a mutation in the survival motor neuron gene 1 (SMN1). In a healthy person, this gene produces a protein that is critical to the function of the motor neurons that control movement in the arms, legs, face, chest, throat, and tongue, as well as skeletal muscle activity, such as speaking, walking, swallowing, and breathing. Individuals with SMA produce low levels of survival motor neuron (SMN) protein. Without this protein, those nerve cells cannot properly function and eventually die, leading to debilitating and sometimes fatal muscle weakness. However, SMA does not affect a person’s ability to think, learn, and build relationships with others.
The classification of Spinal Muscular Atrophy (SMA)
Historically, when no other than supportive therapy was available, SMA was characterized and divided into five types of SMA: Types 0, 1, 2, 3, and 4. This historical description is based on the age that symptoms began and how severe they impact the child be describing highest physical milestone such as sitting, standing, walking that was achieved.
Following the approval of the first disease-modifying medicines for SMA, the historical classification of SMA fails to adequately reflect the new generation of infants and children with SMA who were treated early in life. In addition, by screening more infants are being diagnosed and treated before they show symptoms. Individuals achieve more physical milestones and abilities because of treatment than history would suggest.
As a result, although presenting the historical classification, the indicated symptoms and consequences only represent the untreated situation.
SMA Type 0
is very rare and very severe. Symptoms begin prior to birth and are seen as decreased fetal movement in the weeks prior to delivery. At birth, the infant has severe weakness and often difficulty breathing and feeding and may have joint contractures and heart problems. These infants historically survived a few months.
SMA Type 1 (Werdnig-Hoffman disease or infantile-onset SMA)
is the most common (60%) and a severe form. It becomes usually evident before 6 months of age. The most severely affected babies face many physical challenges, including muscle weakness and trouble breathing, coughing, and swallowing. Historically they often needed breathing assistance and a feeding tube. If not treated, Type 1 can be fatal early on in life and many affected children die before age 2.
SMA TYPE 2
is usually diagnosed after six months of age, but before two years of age. The first sign is often a delay in meeting motor milestones (crawling, sitting, standing, walking) or failing to meet milestones entirely. Children usually can sit without support but are unable to stand or walk without help. Often, they need a wheelchair. Children may also have respiratory difficulties. Life expectancy is reduced but most individuals live into adolescence or young adulthood.
SMA TYPE 3 (Kugelberg-Welander disease or juvenile SMA)
is usually diagnosed after 18 months of age and before three years of age. However, SMA Type 3 can be diagnosed as late as the teenage years. Children can walk independently but may have difficulty doing so or when running, rising from a chair, or climbing stairs. Other complications may include curvature of the spine, contractures, and respiratory infections. With treatment, most individuals can have an average lifespan.
SMA TYPE 4
is very rare–less than 1% of all diagnosed cases. It usually develops after 21 years of age, and it leads to mild motor impairment.
The classification of Spinal Muscular Atrophy (SMA)
The most common forms of SMA are caused by a mutated or missing gene known as the survival motor neuron gene 1 (SMN1) on chromosome 5. People living with SMA have insufficient levels of the SMN protein, which leads to loss of motor neurons in the spinal cord and causes weakness and wasting of the skeletal muscles.
Less common SMA forms are caused by changes in other genes including the
- VAPB gene on chromosome 20
- DYNC1H1 gene on chromosome 14
- BICD2 gene on chromosome 9
- UBA1 gene on the X chromosome
Except in rare cases, SMA is inherited in an “autosomal recessive manner”.
A Brief Excurse in Genetics: Dominant, Recessive, and Consanguineous
Nearly everyone — with rare exceptions — is born with 23 pairs of chromosomes that were passed down from parents through combinations of their 46 chromosomes. On these chromosomes, around 20.000 genes determine how we look like, and whether we have a risk for developing a disease.
X and Y, the two most popularly known chromosomes, are part of the 23rd pair of chromosomes. They’re also called the sex chromosomes because they determine what biological sex you’re born with.
The rest of the 22 pairs are called autosomes. They’re also known as autosomal chromosomes.
On our chromosomes, around 20.000 genes determine how we look like, and whether we have a risk for developing a disease. As we have chromosome pairs, for autosomal genes we always have two copies of the same gene, one on each chromosome. When you will get children, one copy will come from the mother and one copy will come from the father.
Within the 22 autosomes there are two categories of genes that pass on different traits and conditions from your parents. These categories are called autosomal dominant and autosomal recessive.
Autosomal dominant
Let us think about a mutated gene A resulting a disease B. If this disease is inherited “autosomal dominant”, you only need one of these genes A to be passed onto you from either parent to develop that disease B.
Autosomal recessive
Let us think about a mutated gene C resulting a disease D. If this disease is inherited “autosomal recessive”, you need one mutated gene C from your mother plus one mutated gene C from the father.
If you receive a normal gene C from your father and a normal gene C from your mother, you will not get disease D and will not pass the disease D to your children.
If you receive a normal gene C from one of you parents and a mutated gene C from the other, you will not get disease D, but you will carry the mutated gene C and there is a 50% chance you will pass it to each of your children.
If you have both mutated genes C, you will suffer from disease D. You will give a muted gene C to all of your children.
If two persons who both carry one mutated gene C – perhaps without knowing it – get children, they may give them either their normal or their mutated gene C. Statistically, there is a 25% chance, that a child gets two mutated genes C and will suffer from disease D.
Carrier in a population
If there are few persons in a population how carry a mutated gene, the chance two “carrier” meet, marry and get children with an autosomal recessive disease is low. When there are more carriers in a population, the risk gets higher and autosomal recessive diseases get more frequent. If there is no known genetic disorder in the family, first cousin marriages usually double the risk of autosomal recessive genetic disorders compared to of totally unrelated parents. While consanguineous marriages are culturally and socially favored and constitute 20–50% of all marriages is some regions, genetic counselling is offered to families with known genetic disease traits.
How likely is SMA
According to the Centre for Arab Genomic Studies, the SMA prevalence in Gulf Cooperation Council (GCC) populations is thought to be at least 50 times higher than in the US, with more than 50 cases per 100,000 live births. This means, that one in every 2000 babies is borne with SMA in the GCC.
Additionally, various studies conducted in the MENA region reported incidence of SMA to range from 10 to 193 per 100,000 births, and the incidence is almost 40-fold higher than in the western world.
The carrier frequency is also estimated to be higher. In the MENA region, around one in 20 individuals carry the mutated SMN1 gene.
Diagnosing SMA
Mutations or deletions (loss of the whole gene) of the SMA1 gene can be detected by a blood test. This test identifies at least 95 percent of SMA Types I, II, and III. It can also be used to reveal if a person is a carrier.
Treating SMA
Individuals with SMA fail to produce survival motor neuron (SMN) protein in sufficient quantities due to the mutation in the survival motor neuron gene 1 (SMN1). Without this protein, motor neuron cells shrink and ultimately die.
Until 2016, treatment consisted entirely of symptom management and preventing complications for as long as feasible. Now, disease-modifying therapies are available. They can influence the disease’s progression.
One method for treating SMA is to increase the quantity of survival motor neuron protein in the body. This is often referred to as a “SMN-based” or “SMN-enhancing” approach.
All people with SMA have at least one, and often multiple, copies of a second gene known as survival motor neuron gene 2 (SMN2) or the “SMA back-up gene.” SMN2 also produces SMN protein, albeit in substantially smaller quantities than the SMN1 gene.
Many SMN-enhancing medications target the SMN2 gene, which produces more usable SMN protein. Other SMN-enhancing techniques work to replace the function of or repair the mutated SMN1 gene.
Nusinersen (Spinraza™)
The U.S. Food and Drug Administration (FDA) approved nusinersen (Spinraza™) as the first drug approved to treat children and adults with SMA. The drug is designed to increase production of the SMN protein, which is critical for the maintenance of motor neurons.
Onasemnogene abeparovec-xioi (Zolgensma ™)
The FDA approved onasemnogene abeparovec-xioi (Zolgensma ™) gene therapy for children less than two years old who have infantile-onset SMA. A safe virus delivers a fully functional human SMN gene to the targeted motor neurons, which in turn improves muscle movement and function and survival.
Risdiplam (Evrysdi)
The FDA approved the orally administered (a pill taken) drug risdiplam (Evrysdi) to treat patients aged two months of age and older with SMA.
Clinical Trials
In addition to the approved treatments, several more are being investigated in clinical trials. If you or your therapeutic team want to check for ongoing clinical trials that might fit your circumstances, have a look at:
Timing is Key
Regardless of the type of treatment chosen, persons with SMA should begin therapy as soon as feasible after diagnosis. This is especially important for SMN-enhancing treatments. When SMN levels are low, motor neurons finally die. Once lost, these neurons cannot be regained. Beginning therapy as soon as possible is the only approach to prevent or halt motor neuron degeneration.
Treatment for babies identified through newborn screening should ideally begin before they develop SMA symptoms. In clinical trials of SMN-based therapies, babies and children who started treatment sooner had better outcomes than those who started later.
Supportive Care
Physical therapy, occupational therapy, and rehabilitation may help to improve posture, prevent joint immobility, and slow muscle weakness and atrophy. Stretching and strengthening exercises may help reduce contractures, increase range of motion, and keeps circulation flowing. Some individuals require additional therapy for speech and swallowing difficulties.
Supports or braces, orthotics, speech synthesizers, and wheelchairs are examples of assistive devices that can help promote functional independence.
Proper diet and calorie intake are required to maintain weight and strength while avoiding prolonged fasting. Individuals who are unable to chew or swallow may require the installation of a feeding tube. Non-invasive ventilation at night can help with breathing while sleeping. Some people may need assisted ventilation during the day due to muscle weakness in the neck, throat, or chest.
Palliative Care
Palliative care does not mean “doing nothing.” Palliative care involves reducing or calming symptoms while not curing the underlying ailment. Palliative care is an interdisciplinary strategy that brings together medical professionals from a variety of fields, including medicine, nursing, social work, spiritual care, and numerous therapies. Palliative care aims to give comfort while also preserving quality of life on a physical, psychological, social, emotional, and spiritual level.
Quality of Life is Counting
There are options to consider after receiving a spinal muscular atrophy (SMA) diagnosis. No matter what options you choose, a focus on quality of life should be part of your care plan. This will assist you in making decisions that are best and are consistent with your personal values and beliefs.
Patient Stories – A Beacon of Hope
The new therapeutic approaches, while not a cure, demonstrate new measurable motor milestones, such as head control, sitting, crawling and even standing for infants with SMA type 1.
In a Phase I clinical trial of 15 patients up to 6 months of age, at the study cutoff all the children were at least 20 months old, and none required permanent mechanical ventilation. In comparison, only 8% of patients in a historical group survived to the same age without permanent mechanical ventilation.
Among the 12 infants who received high dose in the clinical trial, 11 were able to achieve head control. Nine were able to roll at least 180 degrees from the back to both the left and right and could sit unaided for at least 30 seconds, something normally never seen in babies with SMA type 1.
Have a look at the stories of the brave little fighters for life:
