Spinal Muscular Atrophy
Disease Details
Family Health Simplified
- Description
- 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.
- Type
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Spinal muscular atrophy (SMA) is typically classified into four main types based on the age of onset and severity of symptoms:
1. **Type 1 (Werdnig-Hoffmann disease)**: This is the most severe form and presents in infancy.
2. **Type 2**: This form presents in early childhood and is intermediate in severity.
3. **Type 3 (Kugelberg-Welander disease)**: This form presents in later childhood or adolescence and is milder.
4. **Type 4**: This is the adult-onset form and is the least severe.
The type of genetic transmission for SMA is **autosomal recessive**. This means that an affected individual inherits two copies of the mutated gene, one from each parent. The most commonly affected gene in SMA is the **SMN1** (Survival Motor Neuron 1) gene. - 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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The onset of spinal muscular atrophy (SMA) can vary depending on the type:
- Type 0: Prenatal onset, symptoms appear before birth.
- Type 1 (Werdnig-Hoffmann disease): Onset is before 6 months of age.
- Type 2: Onset occurs between 6 and 18 months of age.
- Type 3 (Kugelberg-Welander disease): Onset usually occurs after 18 months and can present in childhood or adolescence.
- Type 4: Adult-onset, typically in the second or third decade of life.
"SMA-NA" or "not applicable" may refer to a case where specific onset information is not applicable or unreported. - Prevalence
- Spinal muscular atrophy (SMA) is a rare genetic disorder. The estimated prevalence of SMA is approximately 1 in 10,000 live births.
- Epidemiology
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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. Here are key points about its epidemiology:
- **Prevalence**: SMA affects approximately 1 in 10,000 live births globally.
- **Carrier Frequency**: The carrier frequency for the defective gene (SMN1 gene on chromosome 5) is about 1 in 50 people in various populations.
- **Types**: SMA is categorized into several types (0, 1, 2, 3, and 4) based on the age of onset and severity, with Type 1 (Werdnig-Hoffmann disease) being the most common and severe form.
- **Ethnic Variability**: SMA occurs in all ethnicities, but the prevalence and carrier frequency may vary slightly between different populations.
Please clarify if you were looking for something specific under "nan," as it could be a typo or abbreviation needing further context. - Intractability
- Spinal muscular atrophy (SMA) has traditionally been considered a challenging disease to manage due to its genetic nature and progressive course. However, recent advances in treatments such as gene therapy (Zolgensma), antisense oligonucleotides (Spinraza), and small molecule therapy (Evrysdi) have significantly improved outcomes. While these treatments do not cure SMA, they can slow disease progression and improve quality of life. Thus, SMA is becoming increasingly manageable rather than intractable, though challenges remain, particularly with access to and the long-term efficacy of these treatments.
- Disease Severity
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For spinal muscular atrophy (SMA):
Disease Severity:
SMA is typically classified into several types based on the age of onset and the severity of symptoms:
- **Type 0**: The most severe form, evident before birth, often leading to severe weakness and respiratory failure at birth or shortly after.
- **Type 1 (Werdnig-Hoffmann disease)**: Onset within the first 6 months of life, characterized by severe muscle weakness, poor muscle tone, and difficulty breathing and swallowing. It is often fatal within the first two years of life.
- **Type 2**: Onset between 6 and 18 months, characterized by moderate severity. Individuals can sit without support but typically cannot walk unaided. Life expectancy varies but many live into adolescence or adulthood with supportive care.
- **Type 3 (Kugelberg-Welander disease)**: Onset after 18 months and into early adulthood, characterized by milder symptoms. Individuals can walk but may lose this ability over time. Life expectancy is near normal with appropriate management.
- **Type 4**: Adult onset, characterized by mild to moderate muscle weakness. It is the least severe form, and individuals typically have a normal life expectancy.
Nan:
SMA is caused by mutations in the SMN1 gene, which is crucial for motor neuron survival. The severity of the disease is also influenced by the number of copies of the SMN2 gene, which can partially compensate for the loss of SMN1. More copies of SMN2 are generally associated with a milder disease course. - Healthcare Professionals
- Disease Ontology ID - DOID:12377
- Pathophysiology
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Spinal muscular atrophy (SMA) is a genetic disorder characterized by progressive muscle weakness and atrophy due to the degeneration of motor neurons in the spinal cord and brainstem.
Pathophysiology:
SMA is primarily caused by mutations or deletions in the survival motor neuron 1 (SMN1) gene, which leads to insufficient production of SMN protein. This protein is essential for the maintenance and function of motor neurons. Without adequate levels of SMN protein, motor neurons deteriorate and die, resulting in muscle wasting and weakness. The severity of SMA varies and is classified into several types (Type 0 through Type 4), largely based on the number of copies of the SMN2 gene, a nearly identical gene that can partially compensate for the loss of SMN1.
Nan:
The term "nan" is unclear in this context. If "nan" refers to anything specific like a measurement unit, term, or abbreviation related to SMA, please provide more details for an accurate response. - Carrier Status
- For spinal muscular atrophy (SMA), carrier status refers to an individual who carries one copy of the mutated gene (SMN1) but typically does not show symptoms of the disease. SMA is inherited in an autosomal recessive manner, which means that both copies of the SMN1 gene need to be mutated for an individual to exhibit symptoms. Carriers have one normal copy and one mutated copy of the gene.
- Mechanism
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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 wasting and weakness. The primary molecular cause of SMA is the mutation or deletion of the survival motor neuron 1 (SMN1) gene.
### Mechanism
1. **Genetic Defect:** The primary defect in SMA is a mutation or deletion in the SMN1 gene located on chromosome 5q13.
2. **Motor Neuron Degeneration:** The loss of function in the SMN1 gene results in reduced levels of the SMN protein, which is critical for the survival and maintenance of motor neurons.
3. **Muscle Weakness:** The degeneration of motor neurons leads to muscle atrophy and weakness, particularly in the proximal muscles (those closest to the body center).
### Molecular Mechanisms
1. **SMN Protein Deficiency:** The SMN protein is vital for the assembly of small nuclear ribonucleoproteins (snRNPs) in the spliceosome, a complex responsible for pre-mRNA splicing. Reduced SMN levels impair snRNP assembly, leading to defects in mRNA splicing and processing.
2. **Alternative SMN2 Gene:** Humans have a nearly identical copy of the SMN1 gene called SMN2, but a single nucleotide difference leads to the predominant production of a truncated and less stable SMN protein. Although SMN2 can partially compensate for the lack of SMN1, it is often insufficient.
3. **Accumulation of Aberrant mRNAs:** The deficiency in functional SMN protein causes the accumulation of unspliced or improperly spliced mRNAs, leading to cellular dysfunction and ultimately the apoptosis of motor neurons.
4. **Neuromuscular Junction (NMJ) Defects:** Impaired SMN protein levels disrupt the formation and maintenance of NMJs, exacerbating muscle weakness and atrophy.
5. **Axonal Transport Defects:** SMN protein deficiency affects axonal transport, leading to disrupted signaling between neurons and muscles.
Understanding these mechanisms helps in developing targeted therapies, such as SMN1 gene replacement, SMN2 splicing modifiers, and other neuroprotective strategies. - Treatment
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For spinal muscular atrophy (SMA), treatment options include:
1. **Gene Therapy:** Onasemnogene abeparvovec (Zolgensma) delivers a functional copy of the SMN1 gene to motor neurons.
2. **Antisense Oligonucleotides:** Nusinersen (Spinraza) modifies the splicing of the SMN2 gene to increase production of the SMN protein.
3. **Small Molecule Therapy:** Risdiplam (Evrysdi) enhances SMN2 gene expression and increases SMN protein levels.
Other supportive treatments may include physical therapy, respiratory care, nutritional support, and orthopedic interventions to manage symptoms and improve quality of life. - Compassionate Use Treatment
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Compassionate use treatment, off-label, and experimental treatments for Spinal Muscular Atrophy (SMA) include several approaches:
1. **Compassionate Use Programs**: These programs provide access to investigational drugs for patients who have no other treatment options. Companies like Novartis have run such programs for Zolgensma (onasemnogene abeparvovec), a gene therapy, prior to its formal approval.
2. **Off-label Use of Medications**: Some medications approved for other conditions may be used off-label for SMA. For instance, Nusinersen (Spinraza) may be prescribed in ways not explicitly covered in its official guidelines to manage symptoms or for specific patient subgroups.
3. **Experimental Treatments**: These include a range of ongoing clinical trials investigating novel therapies. Examples include:
- **Risdiplam** (Evrysdi) before it received FDA approval for use in SMA.
- **Gene Therapy**: Beyond Zolgensma, other gene therapies are in development, focusing on delivering functional copies of the SMN1 gene.
- **Small Molecules**: New drugs aimed at modulating the SMN2 gene or interacting with other cellular pathways.
- **Antisense Oligonucleotides**: Research into new AONs similar to Spinraza continues, aiming to modify splicing of the SMN2 gene to increase production of functional SMN protein.
These treatments represent the broad spectrum of strategies paralleling standard care to address the underlying genetic causes and symptomatic manifestations of SMA. - Lifestyle Recommendations
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Lifestyle recommendations for individuals with spinal muscular atrophy (SMA) typically focus on maintaining mobility, managing symptoms, and improving quality of life. Key aspects include:
1. **Physical Therapy:** Regular sessions to strengthen muscles, maintain flexibility, and reduce the risk of joint contractures.
2. **Occupational Therapy:** Help with daily activities and the use of adaptive devices to enhance independence.
3. **Respiratory Care:** Techniques and devices to support breathing, such as cough assistance and ventilatory support if needed.
4. **Nutritional Support:** Ensuring adequate nutrition, which may involve working with a dietitian and addressing swallowing difficulties.
5. **Assistive Devices:** Use of wheelchairs, braces, or other mobility aids to promote movement and autonomy.
6. **Healthy Lifestyle:** Encouraging a balanced diet, hydration, and avoiding smoking or exposure to respiratory infections.
7. **Emotional and Social Support:** Access to counseling, support groups, and social activities to reinforce mental and emotional well-being.
Regular medical check-ups and a personalized care plan are essential to address the specific needs of individuals with SMA. - 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), some repurposable drugs have shown promise in research. Risdiplam (Evrysdi), previously used in clinical trials, was repurposed to treat SMA as it helps increase SMN protein levels by modifying SMN2 gene splicing. Nusinersen (Spinraza), though initially developed specifically for SMA, can be considered repurposed from its originally intended pharmaceutical mechanism.
Nanotechnology in SMA research is still emerging, with studies looking into nanoparticles for targeted drug delivery and gene therapy. Nanocarriers, for example, are being explored to improve the delivery of therapeutic agents to motor neurons, enhancing treatment efficacy while minimizing side effects. - Metabolites
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For spinal muscular atrophy (SMA), specific metabolites related to the condition have not been distinctly identified for diagnostic or therapeutic purposes. SMA is primarily diagnosed through genetic testing to identify mutations in the SMN1 gene. Metabolomic profiling for SMA is still an area of ongoing research and has not yet resulted in widely accepted biomarkers.
If you are referring to "nan", it might not be clear within this context. If you need more information about "nan", please provide additional context or clarify. - Nutraceuticals
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For spinal muscular atrophy (SMA), nutraceuticals are dietary supplements or food products that provide health and medical benefits, including the prevention and treatment of disease. Currently, there is limited clinical evidence to support the efficacy of nutraceuticals in the treatment of SMA. However, some patients may use supplements such as omega-3 fatty acids, antioxidants, and certain vitamins (e.g., vitamin D) to support overall health and potentially complement other treatments.
Consulting with healthcare professionals before starting any nutraceuticals is crucial for patients with SMA. - Peptides
- 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. Peptides in the context of SMA research and treatment often refer to synthetic or natural molecules that might have therapeutic potential, such as those involved in muscle repair or motor neuron protection. "Nan" commonly refers to "nanomolar," a unit of measurement for the concentration of substances like drugs or peptides. Researchers might study peptides at nanomolar concentrations to evaluate their efficacy in treating SMA.