Survival Motor Neuron Spinal Muscular Atrophy
Disease Details
Family Health Simplified
- Description
- Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the degeneration of motor neurons, leading to muscle weakness and atrophy.
- Type
- Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder.
- Signs And Symptoms
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The symptoms vary depending on the SMA type, the stage of the disease as well as individual factors. Signs and symptoms below are most common in the severe SMA type 0/I:
Areflexia, particularly in extremities
Overall muscle weakness, poor muscle tone, limpness or a tendency to flop
Difficulty achieving developmental milestones, difficulty sitting/standing/walking
In small children: adopting of a frog-leg position when sitting (hips abducted and knees flexed)
Loss of strength of the respiratory muscles: weak cough, weak cry (infants), accumulation of secretions in the lungs or throat, respiratory distress
Bell-shaped torso (caused by using only abdominal muscles for respiration) in severe SMA type
Fasciculations (twitching) of the tongue
Difficulty sucking or swallowing, poor feeding - Prognosis
- In the absence of pharmacological treatment, people with SMA tend to deteriorate over time. Recently, survival has increased in severe SMA patients with aggressive and proactive supportive respiratory and nutritional support.If left untreated, the majority of children diagnosed with SMA type 0 and 1 do not reach the age of 4, recurrent respiratory problems being the primary cause of death. With proper care, milder SMA type I cases (which account for approx. 10% of all SMA1 cases) live into adulthood. Long-term survival in SMA type I is not sufficiently evidenced; however, as of 2007 advances in respiratory support seem to have brought down mortality.In untreated SMA type II, the course of the disease is slower to progress and life expectancy is less than the healthy population. Death before the age of 20 is frequent, although many people with SMA live to become parents and grandparents. SMA type III has normal or near-normal life expectancy if standards of care are followed. Type IV, adult-onset SMA usually means only mobility impairment and does not affect life expectancy.
- Onset
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Spinal Muscular Atrophy (SMA) onset can vary depending on the type:
- **Type 0:** Onset is prenatal (before birth).
- **Type 1 (Werdnig-Hoffmann disease):** Onset is usually within the first 6 months of life.
- **Type 2:** Onset typically occurs between 6 and 18 months of age.
- **Type 3 (Kugelberg-Welander disease):** Onset often manifests after 18 months and into early adulthood.
- **Type 4:** Onset occurs in adulthood, typically after age 21.
"nan" usually stands for "not a number," which might indicate missing or invalid data, but it does not apply to SMA onset. - Prevalence
- The prevalence of spinal muscular atrophy (SMA) varies, but it is estimated to affect approximately 1 in 6,000 to 1 in 10,000 live births globally.
- Epidemiology
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Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the loss of motor neurons, leading to muscle weakness and atrophy. The disorder is caused by mutations in the survival motor neuron (SMN) gene. In terms of epidemiology:
1. **Incidence**: SMA has an estimated incidence of about 1 in 6,000 to 1 in 10,000 live births.
2. **Carrier frequency**: Approximately 1 in 40 to 1 in 60 people are carriers of the SMA gene mutation.
3. **Prevalence**: The prevalence of SMA varies by type:
- **Type 1 (severe)**: This is the most common form, representing about 50-60% of all SMA cases.
- **Type 2 (intermediate)**: Accounts for around 27%.
- **Type 3 (mild)**: Makes up about 13-20%.
- **Type 4 (adult-onset)**: Very rare.
4. **Geographic distribution**: SMA affects individuals worldwide, with no significant differences in occurrence based on racial or ethnic background.
Understanding the epidemiology of SMA is crucial for targeting early diagnosis and therapeutic interventions. - Intractability
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Spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of motor neurons, leading to muscle weakness and atrophy. Although SMA is a severe and often debilitating condition, significant progress has been made in its treatment.
SMA is not completely intractable. Therapeutic approaches have emerged in recent years:
1. **Nusinersen (Spinraza)** - This is an antisense oligonucleotide that modifies the splicing of the SMN2 gene to increase the production of functional SMN protein.
2. **Onasemnogene abeparvovec (Zolgensma)** - A gene therapy that delivers a functional copy of the SMN1 gene to motor neurons.
3. **Risdiplam (Evrysdi)** - An oral medication that also targets the SMN2 gene to boost production of the SMN protein.
These treatments can significantly improve symptoms and quality of life, especially if administered early. However, they do not cure the disease, and ongoing management and supportive care are typically required. - Disease Severity
-
Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by progressive muscle weakness and atrophy. The severity of SMA can vary widely, and it's classified into different types based on the age of onset and the highest physical milestones achieved.
1. **SMA Type 1 (Werdnig-Hoffmann Disease):**
- **Age of Onset:** Before 6 months
- **Symptoms:** Severe muscle weakness, poor muscle tone, difficulty breathing and swallowing
- **Prognosis:** Most severe form; life expectancy is typically less than 2 years without intervention
2. **SMA Type 2 (Intermediate):**
- **Age of Onset:** 6 to 18 months
- **Symptoms:** Moderate to severe muscle weakness; children can sit but may not stand or walk independently
- **Prognosis:** Variable life expectancy; many live into adolescence or adulthood
3. **SMA Type 3 (Kugelberg-Welander Disease):**
- **Age of Onset:** After 18 months, into early adulthood
- **Symptoms:** Mild to moderate muscle weakness; individuals can stand and walk, but mobility may decline over time
- **Prognosis:** Normal life expectancy but with potential for significant disability
4. **SMA Type 4 (Adult-Onset):**
- **Age of Onset:** Adulthood
- **Symptoms:** Mild to moderate muscle weakness, primarily affecting proximal muscles (those closer to the body's center)
- **Prognosis:** Normal life expectancy with varying degrees of motor impairment
Nanotechnology: Currently, there isn't a direct connection between SMA treatment and nanotechnology. However, research in molecular biology and potential future applications may explore innovative interventions using nanotechnology to deliver genetic therapies more effectively. - Healthcare Professionals
- Disease Ontology ID - DOID:0060160
- Pathophysiology
- Spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of motor neurons in the spinal cord. This leads to muscle weakness and atrophy. The pathophysiology of SMA is primarily due to mutations in the survival motor neuron 1 (SMN1) gene. These mutations result in a deficiency of the SMN protein, which is essential for the maintenance and function of motor neurons. The lack of SMN protein leads to the degeneration of motor neurons, causing the progressive muscle weakness observed in SMA patients.
- Carrier Status
- Carrier status for spinal muscular atrophy (SMA) refers to individuals who have one copy of a mutated SMN1 gene and one normal copy. Carriers typically do not show symptoms of the disease but have a 50% chance of passing the mutated gene to their children. If both parents are carriers, there is a 25% chance with each pregnancy that the child will have SMA, a 50% chance that the child will be a carrier, and a 25% chance that the child will be unaffected and not a carrier. Genetic testing can determine carrier status.
- Mechanism
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Survival motor neuron spinal muscular atrophy (SMA) is a genetic disorder characterized by the loss of motor neurons in the spinal cord, leading to muscle wasting and weakness.
**Mechanism:**
SMA is primarily caused by mutations in the SMN1 (Survival Motor Neuron 1) gene on chromosome 5q13. This gene is crucial for the production of the survival motor neuron (SMN) protein, which is essential for the maintenance and function of motor neurons.
**Molecular Mechanisms:**
1. **SMN Protein Deficiency:** Mutations in the SMN1 gene result in decreased levels of the SMN protein. This deficiency impairs the maintenance and function of motor neurons, leading to their degeneration and subsequent muscle atrophy.
2. **Backup Gene (SMN2):** Humans have a nearly identical backup gene called SMN2. However, SMN2 primarily produces a truncated, less functional version of the SMN protein due to a critical single nucleotide change that affects mRNA splicing. The level of functional SMN protein produced by SMN2 is not sufficient to fully compensate for the loss of SMN1 function.
3. **Motor Neuron Vulnerability:** Motor neurons are particularly sensitive to low levels of SMN protein. The reduced availability of SMN protein disrupts essential cellular processes in motor neurons, including RNA processing, axonal transport, and motor neuron development, leading to their death.
Understanding these mechanisms is crucial for developing therapeutic strategies aimed at increasing SMN protein levels or function to mitigate the effects of SMA. - Treatment
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Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the loss of motor neurons in the spinal cord, leading to muscle weakness and atrophy. The treatment for SMA includes:
1. **Nusinersen (Spinraza)**: An antisense oligonucleotide that helps increase the production of the SMN protein, essential for motor neuron survival.
2. **Onasemnogene abeparvovec (Zolgensma)**: A gene therapy that delivers a healthy copy of the SMN1 gene, which can result in long-term improvement and survival.
3. **Risdiplam (Evrysdi)**: An oral medication that also increases SMN protein levels by modifying SMN2 gene splicing.
Additionally, supportive care such as respiratory support, physical therapy, nutritional support, and assistive devices are crucial in managing SMA symptoms and improving quality of life. - Compassionate Use Treatment
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For Spinal Muscular Atrophy (SMA), particularly focusing on gene therapy targeting the Survival Motor Neuron (SMN) gene, compassionate use and experimental treatments include:
1. **Compassionate Use Treatment:**
- **Zolgensma (onasemnogene abeparvovec-xioi):** This gene therapy can sometimes be accessed through compassionate use programs for patients who do not qualify for clinical trials and are in severe need.
- **Spinraza (nusinersen):** An antisense oligonucleotide therapy that increases SMN protein production from the SMN2 gene and may be available under compassionate use for patients not eligible otherwise.
2. **Off-Label or Experimental Treatments:**
- **Risdiplam (Evrysdi):** An oral SMN2 splicing modifier approved for all SMA types, also used in experimental combinations with other therapies.
- **Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF):** These neurotrophic factors are being researched for their potential in neural protection and repair.
- **Valproic Acid and Hydroxyurea:** These drugs have shown some promise in increasing SMN protein levels but are not widely accepted as standard treatments.
- **Stem Cell Therapy:** Experimental studies are looking into the potential of stem cells to regenerate or repair motor neurons.
Patients should consult with a healthcare provider to consider these options, as approaches may vary based on individual clinical circumstances. - Lifestyle Recommendations
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Lifestyle recommendations for individuals with Spinal Muscular Atrophy (SMA):
1. **Physical Therapy**: Regular physical therapy can help maintain muscle strength and flexibility.
2. **Assistive Devices**: Use of wheelchairs, braces, and other assistive devices to aid mobility.
3. **Respiratory Care**: Regular monitoring of respiratory function, and use of devices like cough assist machines if needed.
4. **Nutritional Support**: Ensuring a balanced diet to maintain overall health; may include supplements as advised by a healthcare provider.
5. **Safe Environment**: Creating a safe home environment to prevent falls and injuries.
6. **Regular Check-Ups**: Ongoing medical evaluations to monitor disease progression and manage complications.
7. **Activity Modification**: Engage in activities that are suitable for your level of ability to avoid overexertion.
8. **Emotional Support**: Seeking counseling or support groups for emotional and psychological well-being.
These recommendations should be tailored to the individual’s specific needs and in consultation with healthcare professionals. - Medication
- Nusinersen (marketed as Spinraza) is used to treat spinal muscular atrophy. It is an antisense nucleotide that modifies the alternative splicing of the SMN2 gene. It is given directly to the central nervous system using an intrathecal injection. Nusinersen prolongs survival and improves motor function in infants with SMA. It was approved for use in the US in 2016, and for use in the EU in 2017.Onasemnogene abeparvovec (marketed as Zolgensma) is a gene therapy treatment which uses self-complementary adeno-associated virus type 9 (scAAV-9) as a vector to deliver the SMN1 transgene. The therapy was first approved in the US in May 2019 as an intravenous formulation for children below 24 months of age. Approval in the European Union, Japan and other countries followed, albeit often with different approval scopes.Risdiplam (marketed as Evrysdi) is a medication taken by mouth in liquid form. It is a pyridazine derivative that works by increasing the amount of functional survivor motor neuron protein produced by the SMN2 gene through modifying its splicing pattern. Risdiplam aims to increase the amount of SMN protein so that there is enough protein to sustain the peripheral nervous system tissues which are usually the most damaged by SMA. Risdiplam was first approved for medical use in the United States in August 2020 and has since been approved in over 30 countries.
- Repurposable Drugs
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For Spinal Muscular Atrophy (SMA) associated with mutations in the survival motor neuron (SMN) gene, repurposable drugs include:
1. **Valproic Acid (VPA)** - An anticonvulsant and mood-stabilizing drug that has been explored for its potential to increase SMN protein levels.
2. **Salbutamol (Albuterol)** - A bronchodilator used in asthma that has shown some promise in improving motor function in SMA patients.
3. **Celecoxib** - A COX-2 inhibitor usually used for pain and inflammation, which has been studied for its ability to enhance SMN gene expression.
4. **Metformin** - A diabetes medication that has shown potential neuroprotective effects and is being investigated for SMA.
These drugs are under various stages of research and clinical trials to determine their efficacy and safety for treating SMA. - Metabolites
- Survival motor neuron (SMN) protein deficiency is central to spinal muscular atrophy (SMA). Metabolites related to SMA have been studied to understand disease pathology and progression. Key metabolites often examined include amino acids, acylcarnitines, and fatty acids. However, the specifics can vary widely among different research studies, and a clear, consistent metabolic signature has yet to be fully established. Elevated levels of certain metabolites like glutamate and alterations in the tricarboxylic acid (TCA) cycle intermediates have been observed in some studies.
- Nutraceuticals
- For Spinal Muscular Atrophy (SMA), there is no specific approval for nutraceuticals as a treatment. Nutraceuticals, which include dietary supplements and functional foods, may support general health but should not replace standard treatments such as FDA-approved medications like Spinraza, Zolgensma, or Evrysdi. Always consult healthcare providers before adding any supplement to your regimen.
- Peptides
- Survival Motor Neuron (SMN)-related Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the loss of motor neurons, leading to muscle wasting and weakness. It is caused by mutations in the SMN1 gene, which are critical for the production of the SMN protein necessary for motor neuron survival. SMA treatments often focus on increasing SMN protein levels or improving motor neuron function. Peptides have not been a primary focus in SMA treatment; instead, current therapies like Spinraza (nusinersen) use antisense oligonucleotides to modify SMN2 gene splicing, and gene therapies like Zolgensma deliver functional copies of the SMN1 gene. Nanotechnology has potential applications in targeted drug delivery for SMA, but it is still an emerging area of research.