Category : Neurology
Understanding a Rare Neuromuscular Disease
Spinal muscular atrophy (SMA) is a genetic disorder that causes muscle weakness and atrophy. It is characterized by the progressive loss of motor neurons, which are the nerve cells that control muscle movement. These neurons control voluntary muscle movements, including those involved in walking, swallowing, and breathing. Without sufficient SMN protein, motor neurons deteriorate and die, leading to progressive muscle wasting. This autosomal recessive disorder is caused by a homozygous deletion or mutation in the 5q13 SMN1 gene; however, the severity is partly affected by the number of copies of a backup gene called SMN2, which also codes for the same protein in much smaller amounts.
Epidemiology and Prevalence
Being an autosomal recessive disorder, SMA forms one of the rare disorders with The carrier frequency is approximately 1 in 50 in the general population, but it can be higher in certain ethnic groups or populations with a high degree of consanguinity. SMA affects approximately 1 in 10000 live births globally, while in India the estimates suggests a prevalence of 1 in 7,000 to 10,000 live births.
Classification and Types of SMA
SMA is classified into five major types based on the age of onset and the maximum motor function achieved:
- Type 0 (Prenatal SMA): This is the rarest and most severe form, presenting during pregnancy. It is characterized by decreased fetal movement, joint contractures, severe weakness at birth, and respiratory failure. Infants usually survive only a few days or weeks.
- Type 1 (Werdnig-Hoffmann Disease): Onset occurs before six months of age. Infants are unable to sit unassisted and often have difficulty swallowing and breathing. Without intervention, most children with Type 1 SMA do not survive beyond two years.
- Type 2: This intermediate form manifests between six and eighteen months. Children can sit but cannot walk independently. They may develop scoliosis and respiratory complications, but can survive into adolescence or adulthood with proper supportive care.
- Type 3 (Kugelberg-Welander Disease): Onset occurs after eighteen months or in early childhood. Individuals can walk but may lose this ability later in life. Life expectancy is usually normal.
- Type 4: This adult-onset form of SMA appears in the second or third decade of life. It causes mild to moderate muscle weakness and has the slowest progression. Most individuals maintain their independence throughout life.
Clinical Features and Symptoms
The symptoms of SMA vary widely depending on the type, but all forms share a common feature of progressive muscle weakness.
Diagnosis and Genetic Testing
Early and accurate diagnosis is crucial for timely intervention. The following steps are involved in the diagnostic process:
- Clinical Evaluation: Based on symptoms such as hypotonia, absent reflexes, and motor developmental delay.
- Electromyography (EMG): Shows denervation patterns indicative of motor neuron disease.
- Muscle Biopsy (rarely used now): Reveals group atrophy of muscle fibers.
- Genetic Testing (Gold Standard):
- Confirms diagnosis by detecting homozygous deletion of exon 7 in the SMN1 gene using methods like MLPA (Multiplex Ligation-dependent Probe Amplification) or quantitative PCR.
- Determines SMN2 copy number, which helps predict disease severity and guides treatment.
- Carrier Screening: Recommended for couples planning pregnancy, especially with family history.
Treatment Options
Until recently, SMA was managed only through supportive care employing Physiotherapy to maintain muscle strength, orthopedic interventions for scoliosis and joint contractures, providing respiratory support through non-invasive ventilation, cough assist devices of required, and occupational and speech therapy as needed.
However, breakthroughs in molecular medicine have led to disease-modifying treatments.
- Zolgensma (Onasemnogene Abeparvovec)
- A gene therapy that delivers a functional copy of the SMN1 gene via an AAV9 viral vector.
- One-time intravenous infusion.
- Most effective when administered early in life, preferably before symptom onset.
- Approved in India (2021) but extremely costly (approx. ₹16–18 crore).
- Spinraza (Nusinersen)
- An antisense oligonucleotide administered via intrathecal injection.
- Modifies SMN2 gene splicing to produce more functional SMN protein.
- Requires lifelong administration every four months.
- Evrysdi (Risdiplam)
- An oral medication that also modifies SMN2 splicing.
- Easier to administer and more accessible, especially in developing countries.
- Recently introduced in India and can be used across age groups.
Prevention and Prenatal Diagnosis
Prevention strategies are vital in reducing the burden of SMA:
- Carrier Screening: Especially in high-risk couples or communities. Detects SMN1 deletions in prospective parents.
- Prenatal Testing: Via chorionic villus sampling (CVS) or amniocentesis if both parents are carriers.
- Preimplantation Genetic Testing for Monogenic Disorders (PGT-M): Used with IVF to select embryos without SMA.
- Public Awareness Campaigns: Promote early diagnosis, screening, and reduce stigma.
Government Policies and Support in India
Recognizing the burden of rare diseases, the Indian government launched the National Policy for Rare Diseases (NPRD) 2021. This policy provides a framework for diagnosis, treatment, and support for rare diseases including SMA.
Key features of NPRD 2021:
- SMA is included in Group 1 diseases, which are treatable with one-time curative therapies.
- Financial assistance up to ₹50 lakh per patient through crowdfunding and Corporate Social Responsibility (CSR) partnerships.
- Centers of Excellence (CoEs) have been designated across India to provide diagnosis and treatment for rare diseases.
- Collaboration with NGOs like Cure SMA India, ORDI, and Rett Syndrome Foundation to support patients and families.
Despite these efforts, access to high-cost treatments remains a significant challenge, and many families rely on crowdfunding platforms.
Author:
Dr. Jyothi M N,
Senior Project Associate,
Department of Medical Genetics,
JSS Medical College, JSS AHER