AN AYURVEDIC MANAGEMENT OF SPINAL MUSCULAR ATROPHY (SMA) – A CASE STUDY

Spinal Muscular Atrophy (SMA) is the second leading genetic disorder inherited in the autosomal recessive pattern due to the absence of the SMN1 gene characterized by loss of motor neurons and progressive muscle wasting, often leading to dependent life and decreased life span. In Ayurveda, this condition can be considered as Kulaja Vyadhi wherein the patient’s Mamsa and Snayu is affected by Vata. This can be regarded as Mamsa-Snayugata Sarvanga Vata. It is said that Prakruta Vata dosha is the life, it is the strength, it is the sustainer of the body, it holds the body and life together. If it is Vikruta it produces Sankocha, Khanja, Kubjatva, Pangutva, Khalli and Soshana of Anga. So, in this disease aggravated Vata does the vitiation of Mamsa and Snayu thus leading to Soshana of both, resulting in Stambha, Nischalikarana of Avayava. A 21years female patient was admitted to our I.P.D with c/o of reduced strength in all four limbs leading to the inability to walk and to maintain erect posture during standing and sitting positions. Based on Ayurvedic principles the patient was initially subjected to Avaranahara Chikitsa followed by Brimhana line of management. Keywords: Mamsagata vata, Snayugata vata, Sarvanga vata, Spinal muscular atrophy (SMA)

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Case Study on Ayurvedic Management of Spinal Muscular Atrophy (SMA)

International Journal of Ayurvedic Medicine ◽

10.47552/ijam.v9i3.1142 ◽

2018 ◽

Vol 9 (3) ◽

pp. 225-230

Author(s):

Krishna Santoshi M ◽

Krishnaiah N

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Muscular Atrophy ◽

Genetic Disorder ◽

The Body ◽

Treatment Modalities ◽

Smn1 Gene ◽

Hands And Feet ◽

Autosomal Recessive Pattern

Spinal Muscular Atrophy (SMA) is the second leading genetic disorder inherited in autosomal recessive pattern due to absence of SMN1 gene characterized by loss of motor neurons and progressive muscle wasting, often leading to dependent life and decreased life span. In Ayurveda, SMA can be considered as a type of janma jaata Vata vikara as it has been mentioned that: “Tatra va gati gandhanayoriti vata” that means all the movements of the body are controlled by vata. In Vata vyadhi Lakshanas, few symptoms like Anganam sosha (Atrophy or emaciation of limbs), Sankocha (Contraction), Kanja, Pangulya, Kubjatva (Lameness of hands and feet, hunch-back and shortness), are considered, few of which are also observed in the Spinal Muscular Atrophy. A 2yrs female patient was admitted in our I.P.D who was a known case of SMA II presented with complaints of inability in sitting for longer time without support, unable to stand and walk even with support. Through Ayurvedic principles we have treated adopting various vata hara treatment modalities & also with few palliative treatments as per the need in view of enhancing the quality living.

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Clinical features and genetics in non-5q spinal muscular atrophy caused by acid ceramidase deficiency

Journal of Medicine and Life ◽

10.25122/jml-2021-0147 ◽

2021 ◽

Vol 14 (3) ◽

pp. 424-428

Author(s):

Mihaela Axente ◽

◽

Elena-Silvia Shelby ◽

Andrada Mirea ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Muscular Atrophy ◽

Smn1 Gene ◽

Progressive Degeneration ◽

Whole Exome ◽

Uncertain Significance ◽

Progressive Myoclonic Epilepsy ◽

Ceramidase Deficiency ◽

Next Generation Sequencing Ngs

Spinal muscular atrophy (SMA) is a spectrum of genetically and clinically heterogeneous diseases leading to the progressive degeneration of peripheric motor neurons with subsequent muscle weakness and atrophy. More than 95% of the cases of SMA are represented by homozygous mutations of the SMN1 gene (5q-SMA). Because this disease represents the leading cause of death due to a genetic cause and due to the availability of genetic therapies which can now save the life of the patient and stop the progress of the disease, early diagnosis is crucial. This report presents the case of a 13-year-old patient admitted to our hospital in 2018 who presented a phenotype typical to 5q-SMA. Next-generation sequencing (NGS) and Sanger sequencing of the SMN1 gene were performed, and a negative result was obtained. Consequently, we continued testing using whole-exome sequencing and discovered three mutations in the ASAH1 gene (one pathogenic and two variants of uncertain significance). Pathogenic mutations in the ASAH1 gene are responsible for spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) and Farber disease, which overlapped with our patient’s phenotype. Currently, there are 45 SMA cases caused by mutations in the ASAH1 gene reported worldwide; however, the present case is the first reported in Romania.

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SAM68 is a physiological regulator of SMN2 splicing in spinal muscular atrophy

The Journal of Cell Biology ◽

10.1083/jcb.201502059 ◽

2015 ◽

Vol 211 (1) ◽

pp. 77-90 ◽

Cited By ~ 16

Author(s):

Vittoria Pagliarini ◽

Laura Pelosi ◽

Maria Blaire Bustamante ◽

Annalisa Nobili ◽

Maria Grazia Berardinelli ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neurons ◽

Messenger Rna ◽

Muscular Atrophy ◽

Splicing Factors ◽

Hnrnp A1 ◽

Smn1 Gene ◽

Smn2 Gene ◽

Physiological Regulator

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by loss of motor neurons in patients with null mutations in the SMN1 gene. The almost identical SMN2 gene is unable to compensate for this deficiency because of the skipping of exon 7 during pre–messenger RNA (mRNA) processing. Although several splicing factors can modulate SMN2 splicing in vitro, the physiological regulators of this disease-causing event are unknown. We found that knockout of the splicing factor SAM68 partially rescued body weight and viability of SMAΔ7 mice. Ablation of SAM68 function promoted SMN2 splicing and expression in SMAΔ7 mice, correlating with amelioration of SMA-related defects in motor neurons and skeletal muscles. Mechanistically, SAM68 binds to SMN2 pre-mRNA, favoring recruitment of the splicing repressor hnRNP A1 and interfering with that of U2AF65 at the 3′ splice site of exon 7. These findings identify SAM68 as the first physiological regulator of SMN2 splicing in an SMA mouse model.

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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 ◽

10.18388/abp.2009_2521 ◽

2009 ◽

Vol 56 (1) ◽

Cited By ~ 18

Author(s):

Maria Jedrzejowska ◽

Michał Milewski ◽

Janusz Zimowski ◽

Janina Borkowska ◽

Anna Kostera-Pruszczyk ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Autosomal Recessive ◽

Clinical Symptoms ◽

Muscular Atrophy ◽

Neuromuscular Disorder ◽

Smn1 Gene ◽

Gender Influence ◽

Gene Copies ◽

Smn2 Gene ◽

Naip Gene

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations of the SMN1 gene. It is characterized by significant phenotype variability. In this study, we analyzed possible phenotype modifiers of the disease - the size of the deletion in the SMA region, the number of SMN2 gene copies, as well as the effect of gender. Among the factors analyzed, two seem to influence the SMA phenotype: the number of SMN2 gene copies and a deletion in the NAIP gene. A higher number of SMN2 copies makes the clinical symptoms more benign, and the NAIP gene deletion is associated with a more severe phenotype. The influence of gender remains unclear. In a group of 1039 patients, 55% of whom were male, the greatest disproportion was in the SMA1 (F/M = 0.78) and SMA3b (F/M = 0.45) forms. In SMA1 a deletion in the NAIP gene was seen twice as frequently in girls compared to boys. In three patients, we observed genotypes atypical for the chronic forms of SMA: two patients with SMA3a and 3b had a deletion of the NAIP gene, and a third patient with SMA2 had one copy of the SMN2 gene.

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AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy

Human Molecular Genetics ◽

10.1093/hmg/ddz188 ◽

2019 ◽

Vol 28 (22) ◽

pp. 3742-3754 ◽

Cited By ~ 7

Author(s):

E Villalón ◽

R A Kline ◽

C E Smith ◽

Z C Lorson ◽

E Y Osman ◽

...

Keyword(s):

Mouse Model ◽

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Muscular Atrophy ◽

Genetic Disorder ◽

Premature Death ◽

Survival Motor Neuron ◽

Motor Neuron Diseases ◽

Smn Protein

Abstract Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.

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Genomic Variability in the Survival Motor Neuron Genes (SMN1 and SMN2): Implications for Spinal Muscular Atrophy Phenotype and Therapeutics Development

International Journal of Molecular Sciences ◽

10.3390/ijms22157896 ◽

2021 ◽

Vol 22 (15) ◽

pp. 7896

Author(s):

Matthew E. R. Butchbach

Keyword(s):

Spinal Muscular Atrophy ◽

Motor Neuron ◽

Motor Neurons ◽

Muscular Atrophy ◽

Survival Motor Neuron ◽

Smn1 Gene ◽

Spinal Motor Neurons ◽

Copy Numbers ◽

Smn Protein ◽

High Degree

Spinal muscular atrophy (SMA) is a leading genetic cause of infant death worldwide that is characterized by loss of spinal motor neurons leading to muscle weakness and atrophy. SMA results from the loss of survival motor neuron 1 (SMN1) gene but retention of its paralog SMN2. The copy numbers of SMN1 and SMN2 are variable within the human population with SMN2 copy number inversely correlating with SMA severity. Current therapeutic options for SMA focus on increasing SMN2 expression and alternative splicing so as to increase the amount of SMN protein. Recent work has demonstrated that not all SMN2, or SMN1, genes are equivalent and there is a high degree of genomic heterogeneity with respect to the SMN genes. Because SMA is now an actionable disease with SMN2 being the primary target, it is imperative to have a comprehensive understanding of this genomic heterogeneity with respect to hybrid SMN1–SMN2 genes generated by gene conversion events as well as partial deletions of the SMN genes. This review will describe this genetic heterogeneity in SMA and its impact on disease phenotype as well as therapeutic efficacy.

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