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The Importance of Genetic testing for Spinal Muscular Atrophy

M3 India Newsdesk Aug 17, 2017

Spinal Muscular Atrophy (SMA) is the second most common autosomal recessive disorder and one of the major causes of infant mortality.







It has a very high carrier frequency of almost 1:40-1:60. In a Pan-ethnic study which included 976 Asian Indians, the carrier frequency for Indians was 1:52. Because of this high carrier frequency and the prevalence of consanguinity, the burden of the disease is particularly high in India. In India SMA remains highly under-diagnosed moreover even with a positive family history carrier detection is not done for at-risk individuals. Since most genetic disorders cannot be cured but only prevented it becomes imperative to diagnose index cases, perform carrier detection and risk analysis, so as to enable informed choice after appropriate counseling. The availability of molecular assays both for diagnosis and carrier detection has made this easily possible.

Classification and Symptoms

SMA is caused by degeneration of anterior horn cells of the spinal cord predominantly the muscles of the extremities closest to the trunk are most severely affected. SMA is clinically classified into three subgroups: acute (type 1), intermediate (type 2) and mild (type 3)

Type I: Werdnig Hoffman disease, characterized by onset of severe muscle weakness and hypotonia in the first few months of life and inability to sit or walk. Fatal respiratory failure occurs before 2 years of age.

Type II: Proximal muscle weakness before 18 months of age, the ability to sit but not walk unaided and survival beyond 4 years of age.

Type III: Kugelberg- Welander disease, characterized by proximal muscle weakness after the age of 2, the ability to walk independently until the disease progresses and survival into adulthood.

How is SMA caused?

SMA of all types is associated with homozygous mutation in the survival of motor neurone 1 gene (SMN 1). There are two homologue copies of the SMN gene, SMN1 (or telomeric copy) and SMN2 (or centromeric copy) (5q12.2-q13.3) these genes are arranged in tandem on each chromosome. Both SMN1 and SMN2 contain nine exons and are very similar, their sequences differ only in five nucleotides. However, the nucleotide difference of clinical significance is the c. 840C>T change in exon 7 between SMN1 and SMN2. This change results in disruption of the exon splicing enhancer sequence. The SMN1 produces a full length protein whereas SMN2 produces transcript which is lacking exon 7. The lack of full length SMN1 protein is responsible for the clinical phenotype of SMA, often exon 8 is also deleted along with exon 7 in the SMN1 gene. Only in one series of cases, it has been reported that the patient had a deletion in exon 8 and exon 7 was intact. Data from India indicates almost 73% of SMA1 patients had both exon 7 and exon 8 deletion along with deletion in the exon 5 of NAIP gene. Concomitant deletion of NAIP exacerbates the disease severity. Isolated exon 8 deletion has been reported till date in only one case from India with a manifestation of optic atrophy as an unusual phenotype .

Diagnosis of SMA

Physicians encountering children with hypotonia and weakness should maintain a high index of suspicion for the diagnosis of SMA. The weakness is usually symmetrical and more proximal than distal. Sensation is preserved. Tendon reflexes are absent or diminished. Weakness in the legs is greater than in the arms. The first diagnostic test for a patient suspected to have SMA should be the SMN1 gene deletion test, which involves testing for exon 7 and exon 8 deletions in the SMN1 gene.

Genetic Testing

Genetic testing by molecular methods is not only the most rapid and sensitive method to confirm the diagnosis but also the testing allows for further invasive investigations such as electromyography and muscle biopsy to be avoided.

Approximately 95-98% of patients with the clinical diagnosis of SMA lack both copies (homozygous deletion) of SMN1 exon 7 (and exon 8 in the majority of cases). Since isolated exon 8 deletion has also been indicated to occur resulting in varied phenotype it is critical that the testing laboratory should include both exon 7 and exon 8 deletion.

However a minority of SMA patients (2-5%), may be compound heterozygous, e.g. carry an SMN1 deletion of exon 7 (and exon 8) on one of their alleles and an intragenic point mutation of the SMN1 gene on the other allele. Point mutations may be dispersed all over the SMN1 gene.

Carrier Testing

Carrier testing for SMA should be offered to asymptomatic individuals with a confirmed or suspected family history of SMA. Given the 1/40 –1/60 carrier frequency of SMA, population carrier screening has recently been recommended by the ACMG (American College of Medical Genetics).

Carrier status cannot be identified with a qualitative PCR technology but requires determining the gene dosage or gene copy: carriers will possess one SMN1 copy and non-carriers will have two SMN1 copies and occasionally have three SMN1 copies.

The multiplex ligation probe assay (MLPA) technology is able to detect copy number of specific genomic loci and therefore is the method of choice for carrier status in clinical and prenatal settings. One limitation of MLPA is that it cannot detect the 2+0 carriers, individuals with 2 SMN copies on one allele and 0 copies on the other allele.

MLPA is often used also in diagnosis of index cases to help understand the type of SMA and the probable prognostication as it helps know the number of SMN2 gene copies also. The disease severity is inversely correlated with the number of SMN2 copies.

Prenatal Diagnostic Test

Prenatal genetic testing is advised for subsequent pregnancies in case there has been a previous child with SMA/family history of SMA. Even if the female has tested negative on carrier detection analysis, however, due to the possibility of gonadal mosaicism (some of the germline cells i.e egg cells/ova may have the mutation), it is critical to perform genetic testing on the fetal material by chorionic villus biopsy or amniocentesis. MLPA is the choice of test for prenatal testing.


Till 6 months ago no treatment was available for SMA and disease management was based on supportive care, as per the functional status of the individual. In December 2016 there was a significant breakthrough that has brought hope to several families affected by SMA. Nusinersen became the first FDA approved drug used in treating this disorder. Nusinersen is an antisense oligonucleotide which modulates alternate splicing of the SMN2 gene, functionally converting it into SMN1 gene, thus increasing the level of SMN protein in the CNS. It is administered directly to the central nervous system (CNS) using intrathecal injection. However, this drug is currently unavailable in India.


  1. Sugarman et al, EJHG 2012; 20: 27–32
  2. Gambardella et al, Ann Neurol 1998; 5:836-9
  3. Dastur RS et al, Neurol India 2006; 54:255-9.
  4. Maiti et al, JPGM 2012; 58:294-5.
  5. Ottesen et al, Translational Neuroscience 2017; 8 (1): 1-6.

Contributed by Dr Aparna Bhanushali, PhD, Research Scientist & Senior Manager, R&D, SRL Limited and Dr B R Das, PhD Advisor & Mentor-R&D, Molecular Pathology & Clinical Research Services, SRL Limited

Disclaimer-The information and views set out in this article are those of the author(s) and do not necessarily reflect the official opinion of M3 India. Neither M3 India nor any person acting on their behalf may be held responsible for the use which may be made of the information contained therein.

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