LAUSR

To the Editor: Spinal muscular atrophy (SMA) is an autosomal recessive disorder (MIM #253300) with a pan-ethnic distribution. It is characterized by progressive degeneration of alpha motor neurons in the spinal cord, which results in severe proximal muscle weakness and paralysis. It is caused by a genetic defect in the SMN1 gene which encodes for SMN protein required for the survival of motor neurons. SMA is common in India as the number of diagnostic tests (2256) and prenatal diagnoses (1052) we have performed for this disorder from 1997 to date are the third highest among various molecular tests (next only to β-thalassemia and Duchenne muscular dystrophy). The landscape for SMA has changed dramatically after Nusinersen (Spinraza) and Zolgensma (gene therapy) were approved for use in United States and Europe. These therapies are highly efficacious, but their staggering costs makes them unaffordable for most patients in developing countries. Therefore, the traditional genetic approaches of carrier screening/prenatal/pre-implantation genetic diagnosis are invaluable to reduce the socio-economic burden of SMA. Knowledge about carrier rate helps to plan the services for prevention and management of this severely burdensome disorder. The study was approved by the local Institutional Ethics committee. Healthy pregnant women and their unrelated spouse attending the hospital clinics were enrolled after obtaining written informed consent. Only cases with no history of SMA or neuro-muscular disease in the family were included. Peripheral blood sample (3-4 mL in EDTA) was collected from 400 unrelated subjects. DNA was extracted from blood using the salt-precipitation method. Carrier screening was done by Multiplex Ligation dependent Probe Amplification (MLPA) using SALSA Probe-mix P060 from MRC Holland, as per the recommended protocol, and analyzed by CoffalyserNet software. The data obtained from analysis of 400 subjects are depicted in Table 1. Nine subjects had a heterozygous deletion of exons 7 and 8 in SMN1 gene [1 + 0 genotype], yielding a direct carrier rate of one in 44 (2.25%). However, the carrier frequency is probably higher than this, as there were 35 subjects having three copies [2 + 1 genotype] and two subjects having four copies [2 + 2 genotype] of SMN1 gene, indicating that 39 (4.87%) of 800 alleles analyzed have two copies of SMN1 gene on the same chromosome. Most of these subjects showing two copies of SMN1 gene will have 1 + 1 genotype while a few will have 2 + 0 genotype. MLPA and other techniques shows the number of copies but not their allelic distribution. Complete exclusion of carrier status is thus challenging. Studies from the West have shown carrier status of SMA in Asian Indians to be one in 51-71. 2,3 The carrier rate in the current study is 1 in 44, which is higher than that reported earlier. Caucasians and Ashkenazi Jews have higher carrier rates than Asians, Afro-Americans, and Hispanics. Carrier frequencies in Morocco, Iran and Saudi Arabia are higher than in European populations probably due to the increased consanguineous marriages. Carrier frequency reported in some other countries are China 1 in 50, Korea 1 in 47-55, Taiwan 1 in 48, Australia 1 in 49 and Poland 1 in 35. Based on the carrier frequency obtained in the current study (1 in 44), and assuming Hardy Weinberg balance the incidence of SMA was determined to be one per 7744 births, which means that about 3112 infants affected with SMA are born every year in India. The present study demonstrates that it is feasible to carry out carrier screening of pregnant women (estimated coast US $50) and prenatal diagnosis where both the partners are carriers, or preimplantation genetic diagnosis for those couples who can afford it. These reproductive options should also be offered to parents who have already given birth to a child with SMA. There are sufficient number of centers able to perform these techniques. However such a strategy should be initiated only after conducting a wide spread community awareness program. This would be a feasible and effective strategy for controlling this devastating disorder in India and other resource restricted countries.