Background

Spinal Muscular Atrophy (SMA) is a collection of hereditary neuromuscular illnesses characterized by motor neuron degeneration in the spinal cord and lower brainstem which results in progressive muscle weakening and atrophy. SMA is caused predominantly by a genetic mutation in the survival motor neuron 1 (SMN1) gene which produces a protein required for motor neuron survival. The severity of SMA is determined by the specific mutation and quantity of functional SMN protein generated by a linked gene. 

Based on the severity and age of onset there are many forms of SMA: 

Type 1 SMA:  It is also known as Werdnig-Hoffmann disease and is the most severe type and usually appears during the first six months of life. 

Type 2 SMA: Between the ages of 6 and 18 months most symptoms often start to show. Children with Type 2 SMA usually have less severe muscular weakness and may never be able to walk independently. 

Type 3 SMA: It is also referred to as Kugelberg-Welander disease. Symptoms develop only after 18 months of age and can manifest in terms of muscle weakness and fatigue. 

Type 4 SMA: This is the least severe type of the condition and the symptoms generally develop during adulthood. 

Epidemiology

SMA is a rare genetic disorder that can present with severe and potentially fatal complications. Based on demographic factors as well as geographical areas where SMA is common. It is estimated to occur in as many as one in every 6,000 live births or even one in every 10,000 live births. 

SMA is an autosomal recessive disease and results from mutations involving the survival of motor neurons 1 (SMN1) gene. For the disorder to be inherited to a kid, both parents must possess a copy of the gene which is mutated. SMA severity depends on the quantity of copies of a similar gene referred to as SMN2. The chances of a patient developing a mild form of SMA are determined by the number of copies of SMN2 they carry. 

Anatomy

Pathophysiology

In 1995 the researchers found the possibility of survival motor neuron (SMN) gene, a disorder linked with spinal muscular atrophy (SMA). Every individual has two copies of the SMN gene, known as SMN1 and SMN2. Because of mutation or rearrangements the SMN1 gene on chromosome 5q is deleted/converted homozygously in nearly 95% of SMA cases. While SMN2 produces only 10% of the full-length SMN protein as compared to SMN1 where all SMA patients retain at least one copy of this gene. This genetic structure offers a therapeutic strategy to overcome the shortage of SMN1 gene through enhancing the copy number of SMN2. 

Etiology

It is an inherited disorder characterized by absence of survival motor neuron (SMN) protein which is vital for motor neurons to function effectively. The specified condition results from an autosomal recessive pattern which implies that the two parents must have a mutant SMN1 gene. The amount of functional SMN protein is decreased because on both copies of the SMN1 gene mutations are present, and the severity of the illness depends on the mutations. Another gene present is the SMN2 which produces the SMN protein but only it lacks exon 7 and this makes the protein to be unstable and degrades within a short span of time. 

Genetics

Prognostic Factors

Motor function 

Respiratory function 

Clinical History

It leads to gradual deterioration of motor neurons and muscle atrophy and muscular dystrophy. 

The time of onset differs for each type: There are three developmental stages these include early childhood (Type 1), late childhood to maturity (Type 2) and early infancy (Type 3). 

Possible complications could relate to nutrition and respiration especially when the conditions are severe. 

Cognitive function remains intact with signs mainly affecting motor function. 

Gene therapies and disease-modifying drugs have resulted in better therapeutic outcomes for most clinical interventions. 

Physical Examination

Muscle strength and tone 

Deep tendon reflexes 

Joint Contractures 

Respiratory function 

Nutritional assessment 

Age group

Associated comorbidity

Associated activity

Acuity of presentation

Differential Diagnoses

Congenital Muscular Dystrophy 

Disorders of Carbohydrate Metabolism 

Amyotrophic Lateral Sclerosis 

Congenital Myopathies 

Muscular  

Emergent Management of Myasthenia Gravis 

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

SMA Treatments that Modify Disease 

Gene Replacement Therapy (Zolgensma): An injection of a virus containing a functional copy of the SMN1 gene. It has been authorized for use in children with SMA, including SMA Type 1. 

Oral and intravenous treatments for spinal muscular atrophy involve antisense oligonucleotide therapy in the form of Spinraza, which increases the mRNA levels of fully spliced SMN2 genes. Approved for SMA categories 1, 2 and 3. 

Symptomatic and supportive care include: 

Respiratory management involving invasive ventilation through a tracheostomy or non-invasive ventilation (NIV) should be given to treat respiratory muscle dysfunction. 

Special support for patients who have dysphagia or need help to eat includes, mouth care, feeding, nutritional support, dietary supplements and enteral tube feeding for patients who need a gastrostomy tube. 

Physical and Occupational Therapy for example Exclusive programs and activities to maintain joint movement, prevent deformity and enhance mobility. 

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

use-of-a-non-pharmacological-approach-for-treating-spinal-muscular-atrophy

• Physical therapy: It is an essential component of SMA care with an emphasis on preserving and developing mobility strength and flexibility. Stretching techniques such as range-of-motion and customized exercise regimens can assist to maintain joint function thereby avoiding the muscle contractures and improve general physical function.  
• Occupational therapy: Its goal is to improve ADLs or activities of daily living including grooming, clothing and taking care of oneself.  
• Respiratory therapy: It is essential for treating the respiratory issues brought on by SMA. 

Role of Gene Therapy in the treatment of Spinal Muscular Atrophy

Onasemnogene Abeparvovec (Zolgensma): Zolgensma is a virus-based gene therapy that increases the synthesis of SMN protein: By using adeno-associated viral vectors to deliver a functional copy of the SMN1 gene to motor neurons. It is administered as an intravenous solution or injection with the preferred administration being a single dose. It was seen in several clinical trials that this therapy is useful in bettering the motor function and survival proportions of SMA Type 1 kids. 

Role of SMN Splicing Modifiers

Risdiplam (Evrysdi): It is an oral medicine that altered the process of splicing in the tiny molecule known as SMN2. It enhances the quantity of functional SMN protein by promoting the incorporation of the seventh exon following the splicing of SMN2 pre-mRNA. It is considered more comfortable to take as it is ingested orally as opposed to other SMA therapies. The results of clinical trials indicate that it improves motor functions and life expectancy in SMA patients. 

use-of-intervention-with-a-procedure-in-treating-spinal-muscular-atrophy

• Scoliosis Surgery: Scoliosis in people with SMA is more frequent and those with severe types are likely to develop the condition. In some cases, when severe spinal curves need to be corrected or further progression of the curve prevented, surgical interventions like spinal fusion may be recommended. 
• Tracheostomy: Tracheostomy may be needed if the motor weakness of respiratory muscles leads to insufficient respiratory function. It is not easy to breathe so a hole in the trachea must be created and then it will be necessary to insert a tube. 
• Placement of Gastrostomy Tube: SMA patients can experience difficulties taking food through the mouth especially if they experience swallowing problems. In such circumstances feeding may be done, and adequate nutrition reached by passing a gastrostomy tube through the abdominal wall and into the stomach. 
• Videofluoroscopic Swallow Study (VFSS): In cases where there is concern of dysphagia, a VFSS that helps in the assessment of swallowing function and feeding recommendation may be conducted. 

use-of-phases-in-managing-spinal-muscular-atrophy

SMA is a life-long disease, for which diagnosis is specific and the intervention strategies include early management plans. Three clinical stages can be distinguished: early, consistent, and gradually increasing. These are primarily diagnostic and treatment planning and initial stabilization of symptoms. All the activities involving starting of disease modifying medicines to enhance the supportive care and further monitoring are done during the stable phase. 

There are three types of therapies including the acute therapy, chronic therapy, and maintenance. Nutrition and respiratory distress are some of the needs that are considered as emergent ones that should be met during the acute phase. Due to the continuous changes in chronic phase patient’s quality of life and long-term management, the chronic phase consists of ongoing disease modification, supportive care plans, and complex management across multiple specialties. In the maintenance phase, dosage schedule, therapy evaluation and required dose adjustments are to be done. 

Medication

Future Trends

Media Gallary

References

Spinal Muscular Atrophy:ncbi.nlm.nih