About SMA
SMA (spinal muscular atrophy) is a hereditary condition that robs people of physical strength by weakening the motor nerve cells in the spinal cord, taking away the ability to walk, eat, or breathe. It is the top one hereditary cause of death for babies. SMA is caused by a mutation in the survival motor neuron gene 1 (SMN1).
Spinal muscular atrophy (SMA) causes muscle weakening and progressive loss of mobility. It is caused by degeneration in the nerve cells (motor neurons) connecting the brain and spinal cord to the body’s muscles. As the link between the nerves and muscles breaks broken, the muscles necessary for actions such as crawling, walking, sitting up, moving the head and even swallowing, grow gradually weaker and shrink (atrophy)
The illness is caused by a genetic mutation in the SMN1 gene, which encodes SMN, a protein widely expressed in all eukaryotic cells and important for survival of motor neurons. Lower levels of the protein results in loss of function of neuronal cells in the anterior horn of the spinal cord and subsequent system-wide muscle wasting (atrophy).
Spinal muscular atrophy appears in varying degrees of severity, which all share in common increasing muscle loss and movement limitation. Proximal muscles and lung muscles are impacted initially. Other body systems may be impacted as well, particularly in early-onset types of the condition. SMA is the most common hereditary cause of newborn death. Spinal muscular atrophy is an inherited illness and is passed on in an autosomal recessive manner.
SMA develops throughout a wide range of severity, affecting infants to adults. The disease spectrum is widely categorised into 3–5 kinds, in accordance either with the age of beginning of symptoms or with the highest accomplished milestone of motor development.
TYPES OF SMA
GENETICS
DIAGNOSIS
TREATMENT AND CURE
TYPES OF SMA
Types of SMA
SMA is classified into four categories due to the wide variation in disease severity amongst affected individuals. SMA type I, type II, type III, and type IV are the names given to these. The age at which symptoms first manifest, the degree of associated muscle weakness, and the child’s maximum motor function are used to identify the kind of SMA.
SMA Type I (Werdnig–Hoffmann disease)
Children that are unable to sit independently are considered to have the most severe form of SMA. Usually, it is noticeable during the first several months following delivery (0–6 months). Weak trunk mobility and floppy limbs are among the symptoms. In addition, they will struggle to breathe, hold their head up, and feed and swallow. They could require a feeding tube or help breathing. Rapid muscular deterioration brought on by Type 1 SMA often results in recurrent respiratory infections and death by the time a child is two years old.
SMA Type II(Dubowitz disease)
Between the ages of seven and eighteen months, SMA type 2 symptoms start to show. SMA type 2 is diagnosed in children who at some point were strong enough to hold sitting position, and some may even have learned how to stand, but they never develop the capacity to walk independently. There is a wide range in the rate of advancement. Similar to those with SMA type 1, individuals with SMA type 2 frequently experience swallowing difficulties and are more vulnerable to respiratory infections as a result of respiratory muscle weakness. A wheelchair or other mobility device is also necessary for them because of their developing muscle weakness. They can, however, survive to become teenagers and adults if given proper care. Stronger SMA 2 patients might be able to work, and some even establish families.
SMA Type III (Kugelberg–Welander disease)
This type’s initial symptoms may manifest between the ages of 18 months and early adulthood. Individuals with Type 3 SMA are able to walk and stand, but they may find it difficult to run, climb stairs, or get up from a sitting posture. They run a higher risk of respiratory infections and may also have mild muscular impairment. They could require a wheelchair later in life to get about. The life expectancy of most Type 3 SMA patients is nearly normal.
SMA Type IV
SMA type 4 is hardly common. This uncommon kind of SMA typically doesn’t show symptoms until the second or third decade of life. Adults with Type 4 SMA are able to walk, although they typically have slowly increasing muscle weakness along with other classic symptoms of SMA.
Overview of SMA clinical classification
| SMA Type | Usual age of symptoms | Impact of muscle weakness on sitting / walking |
| Type 1 | Younger than 6 months | Unable to sit or roll independently |
| Type 2 | 6 – 18 months | Able to sit but not walk independently |
| Type 3 | 18 months – 3 years | Able to walk, though may lose this ability over time. |
| Type 4 | Over 18 years | Mild walking difficulties |
Adapted from Tillmann et al. 2018
GENETICS
Genetics
A genetic neuromuscular illness that runs in families is called SMA.Gene variations or “faults” are the root cause of genetic disorders.
Genes associated with SMA:
The SMN1 gene: SMA is brought on by a mutation in the Survival Motor Neuron Gene 1 (SMN1), which is an uncommon alteration or “flaw” in the gene. Two copies of the SMN1 gene are found in a healthy individual. This gene generates a protein known as survival motor neuron protein, or SMN protein, which is essential to the operation of the nerves that regulate our muscles. Lack of it causes those nerve cells to malfunction and eventually die, which results in crippling and frequently deadly muscle paralysis.
Two defective copies of the SMN1 gene are present in SMA patients. In order to have healthy lower motor neurons, they are therefore unable to create adequate SMN protein.
The SMN2 gene: The production of SMN protein is also regulated by a second gene. This gene is called the Survival Motor Neuron 2 (SMN2), or the “back-up gene” for SMA.
There is a significant single base (nucleotide) variation between SMN2 and SMN1. This results in the majority of the SMN protein that the SMN2 gene produces to lack a minor portion of the gene, known as Exon 7. Only roughly 10% of the SMN protein, which is derived from SMN2, is thought to be functional.
In contrast to most genes, SMN2 can have different amounts of copies on different chromosomes in different individuals.
Given that the amount of SMN protein produced by an individual has been associated with the severity of SMA, there is a broad correlation between an individual’s SMA copy number (or “SMN2 copy number”) and the likelihood of experiencing severe symptoms. Less severe SMA symptoms are typically linked to higher SMN2 copy numbers. On the basis of the SMN2 copy number alone, however, precise predictions on the Type or severity of SMA cannot be made. This is probably due to the moderating effect of additional genetic variables.
Inheritance of these Genes
There are 23 pairs of chromosomes in humans. SMA is a recessive autosomal disorder. SMA, or the Survival Motor Neuron 1 (SMN1) gene, is found in the ‘q’ region of the fifth autosomal chromosome. The majority of individuals (>95%) suffering from the most prevalent types of SMA have deletions in SMN1 exon 7, which prevents the synthesis of SMN1 protein.
Maternal and paternal autosomal disorders are equally prevalent.
When SMA is an autosomal recessive condition:
Only two defective copies of the SMN1 gene must be inherited for a person to have SMA.
A person is a carrier but not unwell if they have one healthy copy of the gene and one defective copy. Although they do not exhibit any symptoms, their offspring may inherit the defective gene.
How will this affect the children?
Whether you or your spouse have SMA, or are carriers, will determine the likelihood that the children will either be carriers or have SMA. Every pregnancy has the same chances; a single child with SMA or a carrier does not affect the likelihood of having any more. The likelihood of each gene copy—whether it is functional or not—being passed on is the same. This occurs at random, much like a coin flip.
The odds for various families are displayed in the following diagrams.
A “non-carrier” is defined as an individual who does not have SMA and does not possess the defective gene for the purposes of the diagrams.
Autosomal recessive family 1: Both parents are carriers
For each pregnancy, the chances are:
- Child will not have SMA and won’t be a carrier: 1 in 4 chance (25%)
- Child will not have SMA but will be a carrier: 2 in 4 chance (50%)
- Child will have SMA: 1 in 4 chance (25%)
Autosomal recessive family 2: One parent is a carrier the other is a non-carrier
For each pregnancy, the chances are:
- Child will have SMA: not possible
- Child will not have SMA and won’t be a carrier: 2 in 4 chance (50%)
- Child will not have SMA but will be a carrier: 2 in 4 chance (50%)
DIAGNOSIS
DIAGNOSIS
SMA is usually diagnosed in one of three ways:
- Through genetic testing, after an infant or child shows symptoms of SMA
- Through a positive newborn screening result
- Through prenatal testing
Early Symptoms of SMA
When a child is notably weak or falls behind in reaching developmental milestones, a doctor may consider SMA. Delays in sitting up straight, rolling over, standing, or walking are a few examples of this.
To make an accurate diagnosis of SMA, more investigation and testing are required because there are other conditions that might induce weakness or a delay in reaching milestones.
When a physician suspects SMA, they could:
Order genetic testing through a blood sample, or
Refer the child to a neurologist who will also perform an examination, and then order genetic testing (again through a blood sample) to confirm the diagnosis.
A simple blood draw test can identify an estimated 95% of all SMA cases. The other 5% are caused by a rare mutation and must be identified through further testing.
Newborn Screening
A tiny sample of the newborn’s blood is obtained. After that, this sample is examined for several genetic disorders. Several states started screening newborns with SMA in 2018. In order to confirm the diagnosis of SMA in newborns, more testing is necessary if the screening results are positive.
When a newborn is screened, treatment can start before symptoms show up, when it may be most beneficial, according to study. See our Support & Care section for additional details on what to do in the event of a positive SMA screen.
Prenatal Testing
To find out if a fetus has inherited a genetic disease, prenatal testing is performed. If a kid is known to be at risk for SMA, some families may decide to proceed with this kind of testing after consulting with their physician. Two distinct tests could be applied:
- In amniocentesis, the most common form of prenatal testing, a very fine needle is inserted into the woman’s abdomen, and amniotic fluid is extracted. This fluid contains fetal DNA that can be tested for SMA. Amniocentesis can be performed after the 14th week of pregnancy, and is associated with a risk of miscarriage that may be as high as 1 in 200.
- Chorionic Villus Sampling can often be performed as early as the 10th week of pregnancy. Chorionic villi are small, finger-like structures that form the placenta. Chorionic villi contain fetal DNA that can be extracted and tested for SMA. CVS is associated with a risk of miscarriage that may be as high as 1 in 100.
Carriers of Spinal Muscular Atrophy
The SMN1 gene is present in two functional copies in most individuals. “Carriers” are those who have one working copy and one defective copy.
Carriers run the chance of having a kid with SMA even if they often do not exhibit the disease’s signs and symptoms.
One in every fifty persons carries the SMA gene. Until their child is born with SMA, the majority of carriers are unaware that they are carriers.
How is SMA Inherited?
SMA is an autosomal recessive genetic condition. This means that a child must inherit two non-working copies of the SMN1 gene, typically one from each parent, in order to have SMA.
When two parents are carriers, there is:
- A 25% chance that their child will be unaffected
- A 50% chance that their child will be a carrier
- A 25% chance that their child will have SMA
If only one parent is a carrier, the child is usually not at risk for SMA, though they do have a 50% risk of being a carrier. However, in very rare cases, spontaneous genetic changes in the SMN1 gene can occur during egg or sperm production. In this situation, only one parent will be a carrier. In addition, a small percentage of carriers have genetic changes that cannot be identified through current testing technology. In this case, it will appear as though the disease has been caused by a single carrier.
Carrier Testing
The only way to determine a person’s carrier status is through a DNA test. The DNA test is a straightforward process that starts with a blood test. About 95% of carriers in the general population can be found with this test. The detection rate is closer to 70% in African-American populations, though. This is due to the fact that African-American populations exhibit a difficult-to-detect mutation at a higher frequency than those of other races.
It is recommended by the American College of Obstetricians and Gynecologists that carrier screening for SMA and other genetic diseases be made available to all women who are pregnant or considering becoming pregnant. People who have a family history of SMA are also advised to get screened for carriers. It is very personal to decide whether or not to have genetic testing done, and we highly advise talking to a doctor or genetic counselor about it. As an alternative to a blood test, saliva testing is offered for carrier screening.
Reproductive Choices
For couples who are carriers, reproductive decisions can be sensitive. A number of options are available, such as prenatal testing, adoption, and pre-implantation genetic diagnosis (PGD). PGD screens embryos for genetic disorders and selects the unaffected embryos for implantation.
We believe that your family has the right to choose whatever option is best for you.
We help families understand their options and provide resources to support their decision-making process. We do not advocate any specific course of action, nor do we pressure families to choose one way or the other.
We encourage each family to discuss their situation with a an expert physician and a genetic counselor and only then take a final call.
TREATMENT AND CURE
TREATMENT AND CURE
Prior to 2016, there was no recognized treatment or cure for spinal muscular atrophy; the only things that could be done were to manage the symptoms and avoid consequences. On December 23, 2016, the US Food and Drug Administration (US FDA) authorized Spinraza as the first medication to treat spinal muscular atrophy in both adults and children.
The sole available medication for adults and children with SMA who are two months of age or older is Roche Pharmaceuticals’ Evrysdi (Risdiplam), which is now accessible in India. Launched in July 2021 for SMA, it is the only DCGI-approved medication available in India. Within 11 months of the US FDA’s initial clearance in August 2020, Evrysdi became available in India. Targeting the survival motor neuron gene 2 (SMN2), evrysdi (Risdiplam) causes the gene to produce more functional SMN protein. This helps children and adults with spinal muscular atrophy (SMA) restore their motor nerve and muscle function by raising the amounts of SMN protein throughout the body and central nervous system. Every day, it is taken orally at home.
A person needs to take erysdi for the rest of their lives.
The cost varies according to the individual’s age and weight, from Rs 22 lakhs to Rs 72 lakhs every year.
Treat SMA India is making a lot of effort to have this medication exempt from GST.
Intracerebral (IT) injections, which deliver drugs directly into the CSF fluid through the lower back, are how spinraza is administered. Four “loading doses” are administered to patients throughout the first two months of treatment. For the remainder of their lives, they will receive a maintenance dose every four months after those loading doses are finished.
The purpose of the medication is to boost the synthesis of the full-length SMN protein, which is essential for the upkeep of motor neurons.
Spinraza currently costs $750,000 (about Rs. 5 crores) for the first year and $375,000 (about Rs. 3 crores) for each additional year the patient lives. It is acceptable for all SMA types.
This drug is unavailable in India.
The only approved gene treatment for spinal muscular atrophy is called zolgensma. It is comprised of a synthetic SMN1 gene inserted into a virus that has been specifically designed. The virus “infects” the target cells with a functional copy of the SMN1 gene after being injected into the spinal cavity or veins.
The treatment was created by the American business AveXis, which is currently a Novartis subsidiary. On May 24, 2019, it was authorized for treatment in children with SMA under two years old in the United States. Trillions of carefully engineered viral particles, encased in a conventional viral shell (capsid) and carrying a synthetic SMN1 sequence (a transgene), are present in a single dosage of AVXS-101. These altered viruses “infect” neuronal cells with the SMN1 transgene once they are administered. After that, the transgene functions inside the cell to generate a reasonable amount of SMN protein in the same manner as an SMN1 gene would naturally. AVXS-101 thereby targets the underlying cause of spinal muscular atrophy, which is the SMN protein shortage.
The most costly medication ever, Novartis, set the price at $2.1 million (about Rs. 15 crores).
Under the Global Managed Access Program (GMAP), a small number of patients in India are receiving zologensma.
