Acta Scientific Medical Sciences

Mini ReviewVolume 1 Issue 2

Genotype-Phenotype Correlation in Spinal Muscular Atrophy

Isa Abdi Rad1,2*

1 Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
2 Department of Medical Genetics, Urmia University of Medical Sciences, Urmia, Iran

*Corresponding Author: Isa Abdi Rad, Professor of Neurogenetics, Department of Medical Genetics, Motahari Teaching Hospital, Urmia, West Azerbaijan, Iran.

Received: July 03, 2017; Published: July 15, 2017

Citation: Isa Abdi Rad. “Genotype-Phenotype Correlation in Spinal Muscular Atrophy”. Acta Scientific Medical Sciences 1.2 (2017).

Abstract

  Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative lower motor neuron disease with an incidence of 1/6000-1/10000 world-wide and characterised by symmetrical muscle weakness. Based on the age at onset and clinical severity, SMA classified clinically into the following types: SMA 0 (prenatal onset), SMA I (Werdnig-Hoffmann disease with onset before age 6 months), SMA II (Dubowitz disease with onset between age 6 and 18 months), SMA III (Kugelberg-Welander disease with onset after age 18 months), and SMA IV (onset after age 18 years). All types of SMA are the result of mutations in survival motor neuron (SMN1) gene and infantile type is the second leading genetic cause of death in infants. Although, mutations in SMN1 gene are essential for pathogenesis of the SMA, copy number variation in SMN2 gene and modification by some are genes such as NAIP, SERF1A and PLS3 determine the age of onset and the severity of disease in its phenotypic continuum.

Keywords: SMA; SMN; NAIP; Spinal Muscular Atrophy; Werdnig-Hoffmann; Kugelberg-Welander

Introduction

  Spinal muscular atrophy (SMA), with an incidence of 1/6000- 1/10000 world-wide [1] is the most common childhood genetic lower motor neuron disease characterized by symmetrical muscle weakness with significant phenotype variability. Based on the age at onset and clinical severity, SMA classified clinically into the following types: SMA 0 (prenatal onset), SMA I (Werdnig-Hoffmann disease with onset before age 6 months), SMA II (Dubowitz disease with onset between age 6 and 18 months), SMA III (Kugelberg-Welander disease with onset after age 18 months), and SMA IV (onset after age 18 years). All types of SMAs are the result of mutation in the survival motor neuron 1 (SMN1) gene and the severity of SMAs related to the copy number of SMN2 gene and modification with some other genes. SMN gene located on 5q11.2-q13.3 chromosomal region [2,3], and this region is a duplicated area of approximately 500 kb, where, at least four genes (SMN, NAIP, SERF1 and GTF2H2) are duplicated. Each of these duplicated genes has a telomeric and a centromeric copy.

  SMN gene has two homologue copies, SMN1 (telomeric copy) and SMN2 (centromeric copy), which differ by only eight nucleotides (five are intronic and three are exonic, located within exons 6, 7, and 8) [4-7].

   One of the coding sequence of SMN2 that differs from that of SMN1 by a single nucleotide (840 C > T) results in alternative splicing of exon 7 [5], which consequently leads to reduced amount of full length transcripts [3], which is insufficient to counteract the development of SMA. So, SMA is caused by low levels of SMN protein rather than the complete absence of SMN [8,9]. Although, mutations in SMN1 gene are essential for pathogenesis of the SMA, copy number variation in SMN2 gene and modification by some are genes such as NAIP, SERF1A and PLS3 determine the age of onset and the severity of disease in its phenotypic continuum.

SMN1 gene:

   SMN1 gene was introduced as a candidate gene for SMA in 1995 [4,10,11]. Reduced levels of SMN result in degeneration of α motor neurons in the spinal cord, leading to muscle atrophy and weakness in SMA patients [12]. SMN is a housekeeping protein involved in small nuclear ribonucleoprotein biogenesis, neuromuscular junction formation, axonal growth, and transport of RNA along axons [13-15].

  Approximately, 95% - 98% of all types of SMA patients show homozygous deletion of SMN1 exon 7 [16,17]. Only 2 - 5% of SMA patients are compound heterozygous with a deletion of exon 7 and a point mutation [18-22]. Homozygous subtle mutations are very rare in patients with SMA [23,24].

SMN2 gene:

  Depending on the copy number of the gene, SMN2 produces a reduced amount of full length transcripts [3], which is insufficient to prevent the development of SMA. So, the severity of SMA is related to the reduced levels of SMN protein rather than the complete absence of SMN [8,9]. Approximately 5% of normal individuals do not carry the SMN2 gene [4].

  The number of SMN2 copies (arranged in tandem in cis configuration on each chromosome) ranges from zero to five that can be detected using quantitative PCR and MLPA methods [25,26]. Copy number variation or gene dosage can also be determined via MAPH technique [27]. The presence of three or more copies of SMN2 is associated with a milder phenotype [28-31]. Even, unaffected patients with a homozygous deletion of the SMN1 gene, with four or five SMN2 copies, have been reported [32].

  As, there is a significant relationship between the clinical phenotype and SMN2 copy number, SMN2 can be considered as an important SMA-modifying gene [33]. A nucleotide variation in exon 7 of the SMN2 gene (c.859G > C) has been described as a positive phenotype modifier in SMA patients, that is, found in SMA patients with a lower SMN2 copy number than expected according to their phenotypes [34-36]. So, considering this nucleotide variation in the SMN2 gene, it seems that all copies of the SMN2 genes don’t have a similar protective effect..

Other genes in the 5q13.2 region:

  NAIP (neuronal apoptosis inhibitory protein) and SERF1A (small EDRK-rich factor 1A) genes have been suggested as possible SMA modifier genes. These genes are deleted in approximately 50% of the patients with severe SMA [10,33,37,38]. In a recent study, NAIP and SERF1A copy number showed a positive correlation with the SMA phenotype, where, NAIP genes was absent in nearly 73% of type I SMA and in only a few cases with type II and III disease, and SERF1A was absent in the 35% of type I SMA and in only one case with type II [39].

  Higher frequency of homozygous deletion of SMN1 gene in severe type I SMA suggests involvement of NAIP deletion in the SMA phenotype. Deletion in the NAIP gene can worsen the prognosis independent of the number of SMN2 copy numbers [40-42]. NAIP gene is an apoptosis inhibitor, thus its deletion may result in the loss of spinal motor neurons.

Plastin 3 (PLS3) gene:

  Recent documents revealed that PLS3, located on chromosome Xq23 and highly expressed in the spinal cord, can play a role as a positive modifier of SMA phenotype [43,44]. PLS3 is a Ca2+ dependent F-actin-binding protein that plays an important role in axon development, cell polarity and migration [45,46].

  PLS3 can fully protect against SMA in SMN1-deleted individuals carrying 3 - 4 SMN2 copies, where, SMN2 products is insufficient to counteract the development of SMA.

  It has been revealed that in some rare families with unaffected homozygous SMN1-deleted females, the expression of PLS3 was higher than in their affected counterparts. The protective modifier effect of PLS3 may be due to its axon genesis role [47] that can rescue the axonal growth defects [48].

SMA type 0:

  SMA Type 0 or congenital SMA (sometimes classified as SMA type Ia) is the most severe type with prenatal onset [49-51]. The presence of only one copy of SMN2 has been described mostly in patients with congenital SMA or severe neonatal forms [52,53]. No patient has been reported with a homozygous deletion of both SMN1 and SMN2 genes, and this may be due to in utero lethality of this condition.

SMA type I (Werdnig-Hoffmann disease):

  Type I SMA is a severe type which shows generalized muscle weakness and hypotonia with onset in the first six months of life. Patients with affected Type I SMA never sit without aid and generally die of respiratory failure before two years of age [54]. Type 0 or congenital SMA sometimes classified as SMA type Ia, where, the classical form of the disease with onset after the neonatal period considered as type Ib, and patients with head control as type Ic [49,55]. Approximately, all SMA type I patients have two copies of SMN2 gene regardless of subtypes Ib and Ic [33,39].

SMA type II (Dubowitz disease):

  The onset of symptoms in SMA type II occurs between 6 and 18 months. Patients can sit but unable to walk without aid [54]. Depending on the respiratory involvement and management of the complications they can reach adolescence and even adult age.

  Most SMA type II patients have three copies of SMN2 gene [33]; however, rarely SMA type II patient with only one copy of the SMN2 gene has been reported [41].

SMA type III (Kugelberg-Welander):

  Patients with Kugelberg-Welander disease or juvenile SMA are able to walk and the lifespan is generally not reduced [54]. SMA type III classified into two types of IIIa with onset before three years of age and IIIb with onset between three and 20 years of age. The probability of being able to walk after 10, 20 and 40 years of age is 73%, 44% and 34%, respectively, in SMA IIIa, and 97%, 89% and 67% in SMA IIIb [56,57].

  SMA type III patients generally have three or four SMN2 copies [33,39]. The presence of four copies of the SMN2 gene is more frequent in type IIIb than in type IIIa SMA [58,39]. SMA type III patients with more than three SMN2 copies show better motor function over time regardless of age at onset [30]. However, the influence of SMN2 copy number is not strict, e.g., three SMN2 copies have been detected in both SMA I and SMA III. One explanation may be that all SMN2 copies are not functionally equivalent [59].

SMA type IV (Adult SMA):

  SMA type IV is a less common form of the disease and its symptoms manifest between 20 and 30 years of age with a normal life expectancy [50,60,61]. The high copy number of SMN2 in types IV SMA, generally more than three copies, can partially compensate for the absence of SMN2 product [28], and more than four copies of SMN2, even 6 copies, are also reported in milder type or type IV SMA [25,58,62]. Since, general population has an average of one or two copies of SMN2 gene, greater copy number in the mild form of SMA probably result from the conversion of SMN2 into SMN2 gene [63].

Phenotypic Discordances:

  Usually, siblings affected with SMA are very similar in their clinical presentations, in terms of age at onset and the progression of disease. However, in rare cases, phenotypic discordances can be seen in the SMA patients, that is, individuals are asymptomatic or mildly affected despite carrying the same SMN1 mutations as their affected siblings, which suggests the effect of genetic modifiers [47].

  Phenotypic discordances have been reported between haploidentical siblings with milder forms in adulthood i.e. SMA type III. Patients with severe forms (type I and type II) tended to show fairly similar phenotypic presentation [32]. The Phenotypic discordances could be due to the presence of genetic phenotypic modifiers other than SMN2 that may act in early life. For instance, PLS3 has higher expression in unaffected SMN1-deleted individuals in comparison with their affected siblings [47]. PLS3 is an important factor for the process of axonogenesis through increasing the level of F-actin, so defects in the axonogenesis may be the major cause in the pathogenesis of SMA [47].

Gender Effect:

  The influence of gender on the phenotype of SMA remains unclear; however, it seems to play a role in the severity of disease. In a study on 1039 SMA patients, the overall ratio of females to males was F/M = 0.82, and the gender disproportion was higher for milder forms, that is, F/M ratio for SMA3b was 0.45 [41].

  Milder forms of SMA, with the onset at the age of over 3 years, were seen approximately twice as frequently in males than females, and it is suggested that estrogens may play as a protective role in milder forms in females [41,64]. Also, asymptomatic cases with biallelic mutation of the SMN1 gene have been reported more frequently in women than in men [41,65,66]. On the other hand, the more severe genotype, that is, NAIP gene deletion and the presence of two SMN2 copies, was observed more frequently in female than males [41,67].

Summary

  All types of SMA result from mutations in SMN1 gene and its significant variations in the age of onset and the severity of clinical symptoms are due to modifier genes. Full-length product of SMN1 is necessary for lower motor neuron function and loss of SMN1 is essential to the pathogenesis of SMA, while SMN2 copy number modifies the severity of phenotype. No correlation exists between the loss of SMN1 exon 7 and the severity of disease, that is, the homozygous exon 7 deletion is observed with the same frequency in all phenotypes. It seemed that a large deletion including neighbouring genes such as NAIP and SERF1A cause the severe phenotypes of SMA. And also, PLS3 gene, located on chromosome Xq23, can play a role as a positive modifier of SMA phenotype.

Bibliography

  1. Sugarman EA., et al. “Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of > 72,400 specimens”. European Journal of Human Genetics 20.1 (2012): 27-32.
  2. Melki J., et al. “Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q”. Nature 344.6268 (1990): 767-768.
  3. Brzustowicz LM., et al. “Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2- 13.3”. Nature 344.6266 (1990): 540-541.
  4. Lefebvre S., et al. “Identification and characterization of a spinal muscular atrophy-determining gene”. Cell 80.1 (1995): 155-165.
  5. Burglen L., et al. “Structure and organization of the human survival motor neurone (SMN) gene”. Genomics 32.3 (1996): 479-482.
  6. Chen Q., et al. “Sequence of a 131-kb region of 5q13.1 containing the spinal muscular atrophy candidate genes SMN,and NAIP”. Genomics 48.1 (1998): 121-127.
  7. Biros I and Forrest S. “Spinal muscular atrophy: untangling the knot?”. Journal of Medical Genetics 36.1 (1999): 1-8.
  8. Burghes AH and Beattie CE. “Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?”. Nature Reviews Neuroscience 10.8 (2009): 597-609.
  9. Prior TW. “Perspectives and diagnostic considerations in spinal muscular atrophy”. Genetics in Medicine 12.3 (2011): 145-152.
  10. Roy N., et al. “The gene for neuronal apoptosis inhibitory protein is partially deleted in individuals with spinal muscular atrophy”. Cell 80.1 (1995): 167-178.
  11. Lewin B. “Genes for SMA: Multum in Parvo”. Cell 80.1 (1995): 1-5.
  12. Merlini L., et al. “Motor function-muscle strength relationship in Spinal muscular atrophy”. Muscle and Nerve 29.4 (2004): 548-552
  13. McWhorter ML., et al. “Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding”. The Journal of Cell Biology 162.5 (2003): 919-931.
  14. Zhang HL., et al. “Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization”. Journal of Neuroscience 23.16 (2003): 6627-6637.
  15. Carrel TL., et al. “Survival Motor Neuron Function in Motor Axons Is Independent of Functions Required for Small Nuclear Ribonucleoprotein Biogenesis”. The Journal of Neuroscience 26.43 (2006): 11014-11022.
  16. Scheffer H., et al. “SMA carrier testing-validation of hemizygous SMN exon 7 deletion test for the identification of proximal spinal muscular atrophy carriers and patients with a single allele deletion”. European Journal of Human Genetics 8.2 (2000): 79-86.
  17. Ogino S and Wilson RB. “Genetic testing and risk assessment for spinal muscular atrophy (SMA)”. Human Genetics 111.6 (2002): 477-500.
  18. Parsons DW., et al. “Intragenic telSMN mutations: frequency, distribution, evidence of a founder effect, and modification of the spinal muscular atrophy phenotype by cenSMN copy number”. American Journal of Human Genetics 63.6 (1998): 1712-1723.
  19. Wirth B. “An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy”. Human Mutation 15.3 (2000): 228-237.
  20. Fraidakis MJ., et al. “Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain”. Neurology 78.8 (2012): 551-556.
  21. Ganji H., et al. “Detection of Intragenic SMN1 Mutations in Spinal Muscular Atrophy Patients with a Single Copy of SMN1”. Journal of Child Neurology 30.5 (2015): 558-562.
  22. Zabnenkova VV., et al. Russian Journal of Genetics 51 (2015):925.
  23. Kirwin SM., et al. “A homozygous double mutation in SMN1: a complicated genetic diagnosis of SMA”. Molecular Genetics and Genomic Medicine 1.2 (2013): 113-117.
  24. Rad IA., et al. “Homozygous Point Mutation in a Patient with Spinal Muscular Atrophy Type 1”. Journal of Genetic Disorders and Genetic Reports 5.3 (2016).
  25. Arkblad EL., et al. “Multiplex ligation-dependent probe amplification improves diagnostics in spinal muscular atrophy”. Neuromuscular Disorders 16.12 (2006): 830-838.
  26. Scarciolla O., et al. “Spinal muscular atrophy genotyping by gene dosage using multiple ligation-dependent probe amplification”. Neurogenetics 7.4 (2006): 269-276.
  27. Armour JA., et al. “Gene dosage analysis by multiplex amplifiable probe hybridization”. Methods in Molecular Medicine 92 (2004): 125-139.
  28. Feldkotter M., et al. “Quantitative analyses of SMN1 and SMN2 based on real-time light Cycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy”. The American Journal of Human Genetics 70.2 (2002): 358-368.
  29. Soler-Botija C., et al. “Implication of fetal SMN2 expression in type I SMA pathogenesis: protection or pathological gain of function?”. Journal of Neuropathology and Experimental Neurology 64.3 (2005): 215-223.
  30. Swoboda KJ., et al. “Natural history of denervation in SMA: relation to age, SMN2 copy number, and function”. Annals of Neurology 57.5 (2005): 704-712.
  31. Zheleznyakova GY., et al. “Genetic and expression studies of SMN2 gene in Russian patients with spinal muscular atrophy type II and III”. BMC Medical Genetics 12 (2011): 96.
  32. Jedrzejowska M., et al. “Unaffected patients with a homozygous absence of the SMN1 gene”. European Journal of Human Genetics 16.8 (2008): 930-934.
  33. Noguchi Y., et al. “Telomeric region of the spinal muscular atrophy locus is susceptible to structural variations”. Pediatric Neurology 58 (2016): 83-89.
  34. Prior TW., et al. “A positive modifier of spinal muscular atrophy in the SMN2 gene”. American Journal of Human Genetics 85.3 (2009): 408-413.
  35. Bernal S., et al. “The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor”. Journal of Medical Genetics 47.9 (2010): 640-642.
  36. Vezain M., et al. “A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy”. Human Mutation 31.1 (2010): 1110- 1125.
  37. He J., et al. “Molecular analysis of SMN1, SMN2, NAIP, GTF2H2, and H4F5 genes in 157 Chinese patients with spinal muscular atrophy”. Gene 518.2 (2013): 325-329.
  38. Brkusanin M., et al. “Joint effect of the SMN2 and SERF1A genes on childhood-onset types of spinal muscular atrophy in Serbian patients”. Journal of Human Genetics 60.11 (2015): 723-728.
  39. Medrano S., et al. “Genotype-phenotype correlation of SMN locus genes in spinal muscular atrophy children from Argentina”. European Journal of paediatric Neurology 20.6 (2016): 910-917.
  40. Dastur RS., et al. “Correlation between deletion patterns of SMN and NAIP genes and the clinical features of spinal muscular atrophy in Indian patients”. Neurology India 54.3 (2006): 255-259.
  41. Jedrzejowska M., et al. “Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease”. Acta Biochimica Polonica 56.1 (2009): 103-108.
  42. Ahn EJ., et al. “Genotype-Phenotype Correlation of SMN1 and NAIP Deletions in Korean Patients with Spinal Muscular Atrophy”. Journal of Clinical Neurology (2016): 1-5.
  43. Heesen L., et al. “Plastin 3 is upregulated in iPSC-derived motoneurons from asymptomatic SMN1-deleted individuals”. Cellular and Molecular Life Sciences 73.10 (2015): 2089-2104.
  44. Hosseinibarkooie SM., et al. “The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype”. The American Journal of Human Genetics 99.3 (2016): 647-665.
  45. Pollard TD and Borisy GG. “Cellular motility driven by assembly and disassembly of actin filaments”. Cell 112.4 (2003): 453-465.
  46. Delanote V., et al. “versatile modulators of actin organization in (pa-tho) physiological cellular processes”. Acta Pharmacologica Sinica 26.7 (2005): 769-779.
  47. Oprea GE., et al. “Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy”. Science 320.5875 (2008): 524-527.
  48. Hao T., et al. “Survival motor neuron affects plastin 3 protein levels leading to motor defects”. Journal of Neuroscience 32.15 (2012): 5074-5084.
  49. Dubowitz V. “Very severe spinal muscular atrophy (SMA type 0): an expanding clinical phenotype”. European Journal of Paediatric Neurology 3.2 (1999): 49-51.
  50. MacLeod MJ., et al. “Prenatal onset spinal muscular atrophy”. European Journal of Paediatric Neurology 3.2 (1999): 65-72.
  51. Sarnat HB and Trevenen CL. “Motor neuron degeneration in a 20-week male fetus: spinal muscular atrophy type 0”. Canadian Journal of Neurological Sciences 34.2 (2007): 215-220.
  52. Watihayati MS., et al. “Combination of SMN2 copy number and NAIP deletion predicts disease severity in spinal muscular atrophy”. Brain and Development 31.1 (2009): 42-45.
  53. Parra J., et al. “Ultrasound evaluation of fetal movements in pregnancies at risk for severe spinal muscular atrophy”. Neuromuscular Disorders 21.2 (2011): 97-101.
  54. Munsat TL and Davies KE. “International SMA consortium meeting”. Neuromuscular Disorders 2 (1992): 423-428.
  55. Bertini E., et al. “134th ENMC International Workshop: outcome measures and treatment of spinal muscular atrophy. Naarden, The Netherlands”. Neuromuscular Disorders 15.11 (2005): 802-816.
  56. Zerres K., et al. “A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III): 569 patients”. Journal of the Neurological Sciences 146.1 (1997): 67-72.
  57. Rudnik-Schoneborn S., et al. “The predictive value of achieved motor milestones assessed in 441 patients with infantile spinal muscular atrophy types II and III”. European Neurology 45.3 (2001): 174-181.
  58. Wirth B., et al. “Mildly affected patients with spinal muscular atrophy are partially protected by an increased SMN2 copy number”. Human Genetics 119.4 (2006): 422-428.
  59. Harada Y., et al. “Correlation between SMN2 copy number and clinical phenotype of spinal muscular atrophy: three SMN2 copies fail to rescue some patients from disease severity”. Journal of Neuroscience 249.9 (2004): 1211-1219.
  60. Brahe C., et al. “Genetic homogeneity between childhoodonset and adult-onset autosomal recessive spinal muscular atrophy”. Lancet 346.8977 (1995): 741-742.
  61. Clermont O., et al. “SMN gene deletions in adult-onset spinal muscular atrophy”. Lancet 346 (1995): 1712-1713.
  62. Prior TW., et al. “Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2”. American Journal of Medical Genetics Part A 130A.3 (2004): 307-310.
  63. Burghes AH. “When is a deletion not a deletion? When it is converted?”. American Journal of Human Genetics 61.1 (1997): 9-15.
  64. Hausmanowa-Petrusewicz I., et al. “Chronic proximal spinal muscular atrophy of childhood and adolescence: sex influence”. Journal of Medical Genetics 21 (1984): 447-450.
  65. Helmken C., et al. “Evidence for modifying pathway in SMA discordant families: reduced SMN level decreases the amount of its interacting partners and Htra2-beta1”. Human Genetics 114.1 (2003): 11-21.
  66. Cusco I., et al. “SMN2 copy number predicts acute or chronic spinal muscular atrophy but does not account for intrafamilial variability in siblings”. Journal of Neurology 253.1 (2006): 21-25.
  67. Novelli G., et al. “A possible role of NAIP gene deletions in sex-related spinal muscular atrophy phenotype variation”. Neurogenetics 1.1 (1997): 29-30.

Copyright: © 2017 Isa Abdi Rad. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.



News and Events

  • Submission Timeline
    Last date for submission of articles is January 31, 2019.
  • Publication Certificate
    Authors will be issued a "Publication Certificate" as a mark of appreciation for publishing their work.
  • Best Papers of the Issue
    The Editors will elect one Best Article after each issue release. The authors of this article will be provided with a certificate of “Best Article of the Issue”.
  • Welcoming Article Submission
    Acta Scientific delightfully welcomes the authors for submission of articles towards the upcoming issue of respective journals.
  • Contact US