Spinal Muscular Atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by progressive muscle weakness and atrophy. It affects both males and females with an incidence rate of approximately 1 in 11,000 and a carrier frequency of 1 in 40. SMA was the most commonest single gene disorder leading to infant mortality prior to the FDA approval of disease-modifying treatments. 

Affected individuals with SMA have a homozygous loss of function of the survival motor neuron gene SMN 1. SMA has been classified into types 0–4 based on symptoms, severity and genotypes. Symptoms for all types of the conditions emerge at different stages.

SMA Inheritance 

SMA is an autosomal recessive neuromuscular disorder. Our genes are present in pairs, with one copy inherited from each parent. Carriers are those with one non-functional copy of the gene for SMA. They do have no symptoms, but can pass the non-functioning gene to their offspring. An individual must inherit two non-functioning SMA genes, one from each parent to have symptoms of SMA. If both parents are carriers, there is a 25 percent risk of having an affected baby in each pregnancy. 

Genetic Counseling

Genetic counseling is recommended for 

• Those who are married in relation –Consanguineous marriage 
• Those who have a positive family history with SMA or a family member known to be a carrier 
• An individual without a family history of SMA can be a carrier for this condition as well. About 1 in 40, regardless of ethnic background are also carriers of SMA.

Genetic testing  for spinal muscular atrophy

Carrier testing can be done through a simple blood test. With 95% of affected individuals having a homozygous deletion of SMN1 exon 7, screening for the loss of exon 7 is the first tier in diagnostic testing. Multiplex ligation-dependent probe amplification (MLPA) is one of the most popular methods used as an initial test as it is convenient, highly sensitive and capable of determining both SMN1 and SMN2 copy number and it aids in the identification of types of SMA. Another 5% of cases will be caused by other mutations in the SMN1 gene. 

They are compound heterozygotes and have been shown to have a variety of different types of SMN1 mutations including missense mutations, nonsense mutations, splice site mutations, insertions and small deletions. There are rare SMA-affected patients with a single copy of SMN1 and an unidentified second mutation.

Carrier status for spinal muscular atrophy

An SMA carrier is an asymptomatic person with a functional copy of SMN1 on one chromosome. Most SMA carriers have an SMN1 deletion on one chromosome and one functional SMN1 copy on the other (1 + 0) classical carrier. If you are a carrier for SMA, your partner must undergo carrier testing as well. If your partner's test is negative, the chance to have an affected child is extremely low. 

If your partner is also a carrier for SMA, there is a 25 percent risk of having a baby with SMA in each pregnancy. If two parents with no family history of SMA are found to be carriers with routine screening, it is not possible to predict whether they are at risk of having children with the severe form of SMA or one of the less severe forms of SMA. 

Accordingly, parents of a SMA cases are not always carriers and a small proportion of them are considered as de novo or germinal mosaic cases. In that scenario explain the final risk for a given couple. Usually SMA carrier testing implies the performance of a quantitative method that detects one copy of SMN1 in classical 1/0 carriers. A small proportion of carriers 3–4% have two SMN1 copies in cis and none in the other allele 2/0 carriers.

SMN1 testing in minor asymptomatic siblings

For asymptomatic siblings of SMA children, genetic testing is offered for age groups more than 18 years. Therefore, genetic counselling is given when they reach reproductive age to ensure that the decision to undergo a genetic test is taken by themselves with adequate information and understanding. If the sibling has one mutated SMN1 copy, then carrier testing must be offered to the partner also. Once the partner also confirms as a carrier, then explained the risk of 25 % to their offspring .

Confidentiality of Genetic Report   

It is confidential. A genetic Counselor/Geneticist can provide guidance about the disclosure of genetic report after getting patients consent.

Prenatal testing for Carriers 

Detailed genetic counselling is given by Geneticist/Genetic counselor. Carrier screening must be done before pregnancy.Prenatal Diagnosis is possible by performing Chorionic villus sampling (CVS) at 11 to 13 weeks or Amniocentesis at 16 to 20 weeks to determine if the fetus is affected or not.

Other options can be offered 

In Intrauterine insemination (IUI), sperm from a donor who is not a carrier would be used.

In vitro fertilization (IVF) with their own eggs or sperm/ can use donor eggs or sperm. 

Tests can be done on the embryo before it is transferred to the uterus to see if the fetus has SMA or not. This is called Preimplantation Genetic Diagnosis(PGD).

Treatment for spinal muscular atrophy

Food and Drug Administration (FDA) has approved the use of Spinraza, Risdiplam and Zolgensma. Aim of therapy this is to increase functional SMN protein in the body.The trajectory of the disease is now changing due to the success of novel therapies to improve motor function in SMA patients.

Spinraza is the first approved drug for SMA treatment in 2016. Nusinersen(Spinraza) increases the expression levels of the SMN protein using an antisense oligonucleotide to alter splicing of the SMN2 transcript. It helps to increases the amount of full-length SMN, the protein that is depleted in patients with SMA.In 2019, the U.S. Food and Drug Administration approved the gene therapy Zolgensma, which alters the underlying genetic cause of spinal muscular atrophy and helps to stop the disease’s progression. Onasemnogene abeparvovec (Zolgensma) is a gene therapy that utilizes an adeno-associated virus serotype 9 vector to increase low functional SMN protein levels. Neither Zolgensma nor Spinrazais manufactured in India ,so parents import them with the help of clinicians after getting special government approvals.

Risdiplam is a small molecule that alters SMN2 splicing in order to increase functional SMN protein. It has been approved by Drug Controller General of India(DCGI) in 2021. Government of Kerala has started  issuing Risdiplam for children less than 5 years of age since July 2022 .Clinical follow up and Neurological assessment demonstrate that SMA children can attain developmental milestones after receiving treatment, which are never normally attained in untreated SMA patients and in late onset patients.

In conclusion, the emergence of new and effective treatments encourage the consultants to rethink and take decision on new therapies that   can make adramatic improvement on patients quality of life.

Future of SMA

Therapies need to be given within the newborn period for maximum benefit and  before the loss of motor neurons. It can achieved by identifying the SMA infants through Newborn screening. The most beneficial response to SMA treatments has been documented in the  treatment of  presymptomatic SMA cases. Newborn screening and adequate pre-test genetic counseling are essential for providing  precise information to the families. Newborn screening for SMA has been shown to be successful in treating SMA infants before the loss of motor neurons. In utero SMA treatment with Zolgensma could improve survival and neurologic outcomes in future. We can assess the acceptance of parents with SMA for prenatal diagnosis, fetal therapies with gene therapy being favoured, and clinical trials. Future research and follow up are needed to understand the long-term effects of the therapies alone or in combination.