Clinical Features:

The main Clinical features of SMA are muscle weakness and the death of muscle cells. In 1992 at International Consortium on Spinal Muscular Atrophy the SMA is clinically classified into 4 phenotypes based on the age of onset and highest motor function achieved¹⁰.

SMA type 0 – Most severe than a classical form of SMA with prenatal-onset spinal muscular atrophy. It can cause intrauterine death, asphyxia, and the early death of a neonatal baby. Weakness and swallowing difficulty more than type1. On survey found that infants with type 0 SMA may suffer from areflexia, facial dysplasia, and joint contractures. If it is not treated then life span is reduced and death within 3 months after birth^11-12.

SMA type 1 – It is known as werdnig-hoffman disease. It is a classical and severe type of spinal muscular atrophy. More than 50% of patients diagnosed with this type of SMA and onset of clinical signs developed before age of 6 months or also developed prenatal onset. Decreased breastfeeding, Prolong feeding, or cough while feeding is the first signs of progressive weakness in SMA type 1 infants. They never acquire the ability to sit unsupported. Present with profound hypotonia, poor head control with craniofacial abnormalities like chewable difficulty due to flaring of the upper incisors associated with masticatory muscle weakness^13,14. Spinal Muscular Atrophy type 1 is most commonly associated with pharyngeal swallowing problems and tongue fasciculation’s. Intercostal muscles are weakened so, sparing of diaphragm takes place and it produces bell-shaped chest and breathing of muscles of this type is called "belly breathing^15-16. Facial bones also get weakened. If there are no interventions are provided to an infant with SMA type1 they usually develop respiratory failure so, 80% of infants die within the first year but do not survive beyond 2 years¹⁷. Some patients of SMA type 1 developed cardiac defects¹⁸.

SMA type 2 – It is the Intermediate form of SMA in which infants learn to sit without any support but do not acquire the ability to walk independently. The age of onset is 7-18 months. The most common clinical signs of SMA type 2 patients are Joint contractures and Kryphoscoliosis in 12 months of life. The absence of deep tendon reflex and fine tremors on the tip are also common. Feeding problems are more frequently reported in SMA type 2 patients. By examination found that the patient swallows food without chewing, with Difficulty in mouth opening with hypotonia and areflexia. The survival rate of SMA type 2 is 99% and 69% after 5 years and 25 years, respectively which is more than SMA type 1. Mental conditions are normal^19,20.

SMA type 3 – It is a mild form of SMA also known as Kugelberg-Welander disease includes mixed patients with clinical signs. The age of onset is greater than 18 months. They achieve control of motor function and are able to sit and stand independently in their adulthood. They are present with weakness of legs more than arms. The leg weakness may force for a wheelchair in their childhood. On examination found that secondary myopathy and moderate elevation of serum creatine kinase were found in SMA 3 patients. After the age of 40 years ability to walk is reduced. Survival expectancy and mental conditions are not affected in this type²¹.

SMA type 4 – It is the mildest form of SMA. Patients have adult-onset greater than 18 years able to walk in adulthood similar to type 3 without any nutritional and respiratory problems²².

Molecular Genetics SMA

Genetics of SMA was unknown it was a question mark that how a defect in one gene can cause much more severity but in 1995 discovery by melki laboratory that SMA was caused by homozygous deletion of SMN1 gene on chromosome 5q13.1Two forms of SMN gene that exist in each allele of humans are Telomeric copy (SMN1) and Centromeric copy (SMN2). SMN, neuronal apoptosis inhibitor protein NAIP, SERF, and GTFH2 are the genes present in centromeric and telomeric copy²³. These two genes have a difference of five nucleotides at exon 7 and 8. Due to these differences, SMN2 failed C to T transition at position 6 of exon 7. It leads to exclusion of exon 7 in transcripts and the formation of trauncated protein which is non-functional or unstable. Nearly all SMA Patients possess one or more copies of the SMN2 gene which can at least produce 10-15% fully functional SMN protein^24,25. Thus there is an inverse relationship between the number of SMN2 genes and clinical severity of disease (n1 of T.A). In SMA 1 patients have two or three copies of the SMN2 gene in SMA type 2 patients have three or more copies of the SMN2 gene in SMA type 3 patients have 3 to 8 SMN2 genes. The number of SMN2 genes is greater than 4 then the average normal SMN protein will be 23%. If the 40% of normal SMN2 protein is present in the body irrespective of the SMN1 gene then the patient will be symptomless²⁶.

Pathophysiology of Sma:

SMA is a autosomal recessive genetic neuromuscular disorder with progressive muscle wasting due to mutation in the SMN1 gene, deficiency in SMN protein, and loss of motor neurons, 3D illustration. As SMAis caused due to deletion of SMN1 (Survival motor neuron gene1) or homozygous mutation of SMN1, It is also categorized as aNeurodegenerative disease²⁷. This type of disease causes memory and cognitive impairment affecting a person's ability to move, speak andbreathe²⁸. SMN1 and SMN2 are the two homozygous genes, present on the chromosome region 5q13. SMN1 gene is telomeric and SMN2 iscentromeric gene. Both SMN genes code nine exon RNA, but SMN2produces transcript without exon²⁹. The results produced truncated and unstable proteinSMN. As a result, the major product of SMN2 will be the severity of the disease. The lack of the SMN1 protein leads to degeneration of motor neurons in the ventral horn of the sp inal cord²⁵.Another reason for SMA is neuronal apoptosis inhibitory protein (NAIP) present in thesame 5q13 region. This gene has neuroprotective effects and acts as anegative regulator of motor neuron apoptosis. It is postulated thatdeletion of NAIP leads to severity of SMA³⁰.

Fig.2. Pathophysiology of Spinal Muscular Atrophy

Diagnosis And Treatments SMA:

Fig No 3: Diagnosis of Spinal Muscular Atrophy is done by physical examination of patient, medical history of patient and genetic testing. Survival motor neuron 1 (SMN1) genotype has great effect on Electromyography (EMG). Treatments of Spinal muscular atrophy are symptomatic or disease modifying treatments.

Therapeutic Approaches:

There is no cure for SMA. Treatment consists of managing the symptoms and preventing complications.SMA are categorized into two parts one is SMN dependent therapies In which target SMN2 site for treatment by three approaches a) by inducing the expression of SMN2 b) RNA based therapy c) by stabilizing the SMN protein. The second approach is SMN independent therapy like stem cell therapy and by altering neuromuscular junctions etc. Although there is no specific cure for SMA these approaches can help patients to live more life.

SMN dependent therapies:

The clinical severity of the disease depends on the SMN2 gene copy number and having inverse relation between them so, for the development of therapeutic approaches SMN2 gene site has the main focus. And also SMN protein is produced by gene therapy³¹.

a) Inducing expression of SMN2:

Histone deacetylases i.e. HDACs remove acetyl moiety and repress expression of a gene by chromatin condensation. Thus, inhibitors of Histone deacetylase induce gene transcription by reassembling chromatin fibers which can produce complete SMN proteins and help the patient³². Sodium butyrate, Valproic acid, and phenylbutyrate are various Histone Deacetylase inhibitors that are analyzed in animal models and clinical trials and they show their potential therapeutic effect and are also tolerated by patients. But, the clinical benefits of HDAC inhibitors are disappointing and no clinical improvement in the patient^33-35. A study on other HDAC inhibitors, Suberoylanilidehydroxamic acid LBH589, and Trichostatin A showed SMN2 gene induction in animal models and cell culture^36-37. Besides these, prolactin which is lactation harmone and these drugs can cross the blood-brain barrier through their receptors and activate the JAK2 or STAT5 pathway which also controls SMN2 regulation. Prolactin (PRL) proved to increase milk volume in lactating deficient mothers and it can be used in the immediate case of SMA due to its therapeutic potential and safety³⁸.

b) RNA-based therapy:

Modification in SMN2 splicing to support inclusion of exon 7 to RNA transcript which can increase expressions of SMN2 proteins is another approach for the treatment of SMA. It is found that the antibiotic aclarubicin induces the inclusion of exon 7 to mRNA transcript to increase the full length of SMN transcript³⁹. Antisense oligonucleotides i.e. ASOs are newer RNA molecules developed that can bind to exon and can enhance or disturb splicing. ASOs are complementary to SMN2 pre-RNA transcript which inhibits the 3' splice site of exon 8 and thus increases the length of SMN transcript and SMN protein. ASOs not able to cross the blood-brain barrier^40-42.

c) SMN protein stabilization:

The class of antibiotics aminoglycosides prevent the mutation of stop codon before maturation and allow it to go through translation and significantly increases the level of SMN protein in fibroblasts of patients. It is found that tobramycin and amikacin expeditiously increase SMN protein letargetedlevels in patients^43,
44.

SMN Independent therapies:

Stem cell therapy-This therapy treats the motor neuron by replacing lost motor neurons and supporting existing neurons. Primary murine neural stem cells and embryonic stem cell-derived neural stem cells are helping to support and replace the motor neurone. Stem cell therapy is effective in SMA type I⁴⁵.

Gene therapy:

It is one of the supportive therapy can be used to treat spinal muscular atrophy. Self-complementaryadeno-associated virus (scAAV) vector 8 and 9 used which can carry SMN1 cDNA and treat the animalmodel of SMA. Result found that it increase the life span of patient as compared to non-treated patient. But, some challenges are also addressed before it comes into clinical management^46-48.

Rho-kinase inhibitor:

Rho kinase is essential pathway of actin dynamics which has essential activity in SMN deficient cells. Rho-kinase inhibitors help to decrease severity of spinal muscular atrophy by altering neuromuscular junction it leads to increasing life span of patients⁴⁹.

Aromatherapy:

Is the practice of using essential oils fortherapeutic benefits, improving psychological or physical well-being⁵⁰.

Yoga:

Studies show that exercise increases protein synthesis. Therefore, higher protein intake, combined with routine yoga practice, should contribute to maintenance of muscle by offsetting muscle losses and enhancing the body's ability to build muscle at the same time⁵¹.

Cowpathy therapy:

This kind of treatment is called Panchgavya therapy, Panchgavya represents milk, urine, dung, ghee, and curd, derived from cow. You can recover from muscle atrophy by exercising regularly and eating a healthy diet. You may start seeing improvement after a few months, but it may take much longer for you to fully recover your strength. There is no any evidence that Cowpathy therapy is helpful in treatment of SMA, but this therapy relief body pain in Spinal Muscular Atrophy⁵².

Music therapy:

Is appropriate and enjoyable for clients with muscular dystrophy, there is no cure for SMA, music therapy treatment consists of managing the symptoms and complications of SMA.Music activates multiple areas of the brain, including the motor cortex which is an area of the brain that's responsible for physical movement^53-55.

Progressive Muscle Relaxation therapy:

It involves tensing and then relaxing your muscles, one by one. This helps you release physical tension, which may ease stress and anxiety. This method often helps people get to sleep during SMA⁵⁶.

Ayurvedic Management of Spinal Muscular Atrophy:

Ayurvedic medicinal plants and their constituents play the important role on body⁵⁷, in Ayurveda, SMA can be considered as a type of “Tarawa gati gandhanayoriti vata” that means all the movements of the body are controlled by vata. In Vata vyadhiLakshanas, few symptoms like Anganamsosha (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. Through Ayurvedic principles we can treat Spinal Muscular Atrophy adopting various vata hara treatment modalities and also with few palliative treatments as per the need.

Treatment Protocol^58-60:

· Abhyangam- Is an ancient relaxing massage technique originating in Ayurveda for 14 days.

· ShashtikaShaliPindaSweda- Is form of sweat inducing massage treatment mainly to provide strength and rejuvenate the tissues and also to provide relief from pain, inflammation, and stiffness (catch) associated with bone, joint, neuromuscular and or musculoskeletal pains, improve muscle strength.

· MeruVasti- It special massage therapy especially designed to treat acute back pain and innumerable disorders by using ayurvedic oils and steam bath.

· There is a wide range of complementary therapies that people used to maintain positive mental, physical health and wellbeing which include yoga, taichi, relaxation and therapeutic massage.

Table No.2 Treatment Protocol in Spinal Muscular Atrophy

Sr. No	Treatment	Process	Purpose
1	Snehana	Abhyangam for 14 days with Mahanarayanatailam, Dhanwantharamtailam, ksheerabalatailam.	Massage with warm oil, reduce muscle stiffness, promoting circulation, healing, relaxation
2	Swedana	ShashtikaShaliPindaSwedamfor 14 days	Provide strength, Relief from pain, stiffness associated with bone, improve muscle strength.
3	Vasti	Madhu, saindhavam, satapushpa, gomutraBalamoolaqwatha, Dashamoola qwatha, ashwagandha, rasna, mahanarayanataila, Ksheerabalatailafor 11 days	Vasti is one of the panchakarma procedures for purpose of management of pain as analgesic, anti-inflammatory, antioxidant, anti-rheumatic, and reduces stress and anxiety.
4	Meruvasti	Maha vishagarbha Tailam + Ksheerabala Tailam for 14 days	Meruvasti used in Ayurvedic Treatment of Disease due to vata dosha, Stiffness, Tightness in back and limb
5	Physiotherapy	Physiotherapist to follow on the progression of Orthotics, Splinting, Taping, Management of contractures, Exercise and activity	Physiotherapy helps restore movement and function when someone is affected by injury, illness or disability.

Internal Medication:

Table No 3. Internal Medication in Spinal Muscular Atrophy

Sr. No	Treatment	Purpose
1	Bruhat vata chintamaniRas-½ tab three times in a day	It is used in the treatment of Vata Dosha
2	Tab. YogarajaGuggulu-½ three times in a day	As Anti-inflammatory properties that can help provide relief from joint pain
3	Pravalabhasma 10mg+Trivanga bhasma 5mg+Yasti churnam 200mg three times in a day with honey	Improves Strength and Immunity, Management of bone metabolic disorders
4	BalaMoolaqwatha 15ml two times a day	For purpose of management of pain.

CONCLUSIONS:

A tremendous amount of translational work is progressing rapidly towards the pre-clinical stage in the SMA Field. Clearly, obstacles will exist. Blood–brain barrier penetrationis an impediment for all CNS disorders.⁵¹However, a number of major challenges remain that demand the development of a more detailed understanding of the molecular mechan-isms underlying SMA in order to deliver the next gen-eration of therapies that will be required to supplement current and future SMN-targeted therapies.Critically, clinical trials are assessing a number ofapproaches aimed at increasing the amount of full-length SMN protein, including histone deacetylase inhibitors and antisense oligonucleotide based modulation of SMN 2. Stem cell therapy and neuroprotective strategies are also ofinterest. Developing a further understanding of the patho-physiological processes during the chronic plateau phase of SMA will be critical in determining the success of potentialdisease-modifying therapies.³Ayurvedic treatment for SMA is primarily aimed at arresting / slowing down the progress of the illness and helping alleviate the symptoms. According to Neuroplasticity Central Nervous System have the ability to repair their neurons by axonal sprouting to take over the function of damaged neurons. we can conclude - Ayurvedic treatment is helpful for a better management of SMA.

ACKNOWLEDGMENT:

The authors would like to acknowledge Dr. Ashwini R. Madgulkar, Principal, AISSMS College of Pharmacy, Pune, for her encouragement and guidance.

CONFLICTS OF INTEREST:

No conflict of interest was declared by the authors. The authors alone are responsible for the content and writing of the paper.

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DOI: 10.52711/2321-5836.2022.00042

SMA type	Clinical Severity	Also named as	Highest motor function achieved	Age of onset
0	Most severe	--------	Not any(can cause early death)	After birth
1	Severe	Werdnig-Hoffmann disease	Never sit	0-6 months
2	Intermediate	SMA, Dubowitz type	Sit but never stand	7-18 months
3	Mild	Kugelberg-Welander disease	Stand and Walk	Greater than 18 months
4	Milder	----------	Walk during adulthood	Adulthood