Hereditary Spastic Paraplegia
Disease Details
Family Health Simplified
- Description
- Hereditary spastic paraplegia is a group of inherited disorders characterized by progressive weakness and stiffness of the leg muscles.
- Type
- Hereditary spastic paraplegia (HSP) can be transmitted through various genetic inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked inheritance.
- Signs And Symptoms
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Symptoms depend on the type of HSP inherited. The main feature of the disease is progressive spasticity in the lower limbs due to pyramidal tract dysfunction. This also results in brisk reflexes, extensor plantar reflexes, muscle weakness, and variable bladder disturbances. Furthermore, among the core symptoms of HSP are also included abnormal gait and difficulty in walking, decreased vibratory sense at the ankles, and paresthesia.
Individuals with HSP can experience extreme fatigue associated with central nervous system and neuromuscular disorders, which can be disabling. Initial symptoms are typically difficulty with balance, stubbing the toe or stumbling. Symptoms of HSP may begin at any age, from infancy to older than 60 years. If symptoms begin during the teenage years or later, then spastic gait disturbance usually progresses over many years. Canes, walkers, and wheelchairs may eventually be required, although some people never require assistance devices. Disability has been described as progressing more rapidly in adult onset forms.More specifically, patients with the autosomal dominant pure form of HSP reveal normal facial and extraocular movement. Although jaw jerk may be brisk in older subjects, there is no speech disturbance or difficulty of swallowing. Upper extremity muscle tone and strength are normal. In the lower extremities, muscle tone is increased at the hamstrings, quadriceps and ankles. Weakness is most notable at the iliopsoas, tibialis anterior, and to a lesser extent, hamstring muscles.
In the complex form of the disorder, additional symptoms are present. These include: peripheral neuropathy, amyotrophy, ataxia, intellectual disability, ichthyosis, epilepsy, optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing.Anita Harding classified the HSP in a pure and complicated form. Pure HSP presents with spasticity in the lower limbs, associated with neurogenic bladder disturbance as well as lack of vibration sensitivity (pallhypesthesia). On the other hand, HSP is classified as complex when lower limb spasticity is combined with any additional neurological symptom.This classification is subjective and patients with complex HSPs are sometimes diagnosed as having cerebellar ataxia with spasticity, intellectual disability (with spasticity), or leukodystrophy. Some of the genes listed below have been described in other diseases than HSP before. Therefore, some key genes overlap with other disease groups. - Prognosis
- Although HSP is a progressive condition, the prognosis for individuals with HSP varies greatly. It primarily affects the legs although there can be some upperbody involvement in some individuals. Some cases are seriously disabling whilst others leave people able to do most ordinary activities to an ordinary extent without needing adjustments. The majority of individuals with HSP have a normal life expectancy.
- Onset
- Hereditary spastic paraplegia (HSP) includes a group of inherited disorders characterized primarily by progressive spasticity and weakness of the lower limbs. The onset of HSP can vary widely, ranging from infancy to late adulthood, depending on the specific genetic mutation involved.
- Prevalence
- Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive weakness and spasticity of the lower limbs. The prevalence of HSP is estimated to be around 1.2 to 9.6 per 100,000 individuals, though it can vary somewhat by population and geographical region.
- Epidemiology
- Worldwide, the prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people. A Norwegian study of more than 2.5 million people published in March 2009 has found an HSP prevalence rate of 7.4/100,000 of population – a higher rate, but in the same range as previous studies. No differences in rate relating to gender were found, and average age at onset was 24 years. In the United States, Hereditary Spastic Paraplegia is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health which means that the disorder affects less than 200,000 people in the US population.
- Intractability
- Hereditary spastic paraplegia (HSP) is considered intractable. It is a group of genetic disorders characterized by progressive weakness and spasticity (stiffness) of the legs. There is currently no cure, and treatment focuses on managing symptoms and improving quality of life through physical therapy, medications to relieve symptoms, and occasionally surgical interventions.
- Disease Severity
- For hereditary spastic paraplegia, the severity of the disease can vary significantly depending on the type and genetic mutation involved. Some individuals may experience mild symptoms and progress slowly, while others may have more severe manifestations and a quicker progression. Symptoms generally include progressive spasticity and weakness of the lower limbs, which can lead to difficulty walking and maintaining balance.
- Healthcare Professionals
- Disease Ontology ID - DOID:2476
- Pathophysiology
- The major feature of HSP is a length-dependent axonal degeneration. These include the crossed and uncrossed corticospinal tracts to the legs and fasciculus gracilis. The spinocerebellar tract is involved to a lesser extent. Neuronal cell bodies of degenerating axons are preserved and there is no evidence of primary demyelination. Loss of anterior horn cells of the spinal cord are observed in some cases. Dorsal root ganglia, posterior roots and peripheral nerves are not directly affected.HSP affects several pathways in motor neurons. Many genes were identified and linked to HSP. It remains a challenge to accurately define the key players in each of the affected pathways, mainly because many genes have multiple functions and are involved in more than one pathway.
- Carrier Status
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Hereditary spastic paraplegia (HSP) is typically inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The carrier status depends on the specific genetic mutation and inheritance pattern:
1. **Autosomal Dominant HSP**: A single copy of the altered gene, inherited from one affected parent, is sufficient to cause the condition. Carriers of an autosomal dominant mutation are typically affected by the disease.
2. **Autosomal Recessive HSP**: Two copies of the mutated gene, one from each parent, are necessary to develop the condition. Individuals with only one copy of the mutated gene are carriers and usually do not show symptoms.
3. **X-linked HSP**: The mutated gene is located on the X chromosome. Men (with one X and one Y chromosome) are usually affected if they inherit the mutation, while women (with two X chromosomes) can be carriers. Female carriers of an X-linked HSP mutation might have mild symptoms or might be asymptomatic.
If you need specific details about a particular type of HSP, genetic counseling is recommended. - Mechanism
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Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized primarily by progressive stiffness and contraction (spasticity) and weakness of the lower limbs. The condition is caused by the degeneration of corticospinal tract neurons.
### Mechanism:
- **Clinical Mechanism**: The primary mechanism involves degeneration of long motor neurons, particularly in the corticospinal tracts and posterior columns of the spinal cord. This neuronal damage leads to spasticity and muscle weakness, predominantly affecting the lower extremities.
### Molecular Mechanisms:
1. **Gene Mutations**: HSP is associated with mutations in various genes (more than 70 identified), which encode proteins involved in diverse cellular activities. Some notable genes include SPG4 (spastin), SPG3A (atlastin-1), and SPG7 (paraplegin).
2. **Spastin (SPG4)**: This gene encodes a microtubule-severing protein critical for maintaining microtubules, which are essential for axonal transport. Mutations here can disrupt microtubule dynamics and impair axonal transport, leading to axonal degeneration.
3. **Atlastin-1 (SPG3A)**: This protein is involved in endoplasmic reticulum (ER) shaping and fusion. Mutations can impair ER function and distribution, affecting the axonal integrity and leading to neurodegeneration.
4. **Paraplegin (SPG7)**: This protein is a part of the mitochondrial metalloprotease complex, crucial for mitochondrial function and maintaining mitochondrial DNA integrity. Mutations can lead to mitochondrial dysfunction, contributing to axonal degeneration.
5. **Axonal Transport Deficits**: Many of the proteins implicated in HSP are involved in the maintenance of axonal transport, endosomal trafficking, and mitochondrial function. Deficits in these systems can lead to the progressive degeneration of long axons in corticospinal tracts. - Treatment
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No specific treatment is known that would prevent, slow, or reverse HSP. Available therapies mainly consist of symptomatic medical management and promoting physical and emotional well-being. Therapeutics offered to HSP patients include:
Baclofen – a voluntary muscle relaxant to relax muscles and reduce tone. This can be administered orally or intrathecally. (Studies in HSP )
Tizanidine – to treat nocturnal or intermittent spasms (studies available )
Diazepam and clonazepam – to decrease intensity of spasms
Oxybutynin chloride – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
Tolterodine tartrate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems
Cro System – to reduce muscle overactivity (existing studies for spasticity )
Botulinum toxin – to reduce muscle overactivity (existing studies for HSP patients)
Antidepressants (such as selective serotonin re-uptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) – for patients experiencing clinical depression
Physical therapy – to restore and maintain the ability to move; to reduce muscle tone; to maintain or improve range of motion and mobility; to increase strength and coordination; to prevent complications, such as frozen joints, contractures, or bedsores. - Compassionate Use Treatment
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Hereditary Spastic Paraplegia (HSP) currently lacks a definitive cure, and treatment primarily focuses on managing symptoms and improving quality of life. Compassionate use treatment and off-label or experimental treatments for HSP can include:
1. **Baclofen** - Often used off-label to reduce muscle spasticity.
2. **Tizanidine** - Another muscle relaxant used off-label for spasticity management.
3. **Intrathecal Baclofen Pump** - Delivered directly to the spinal cord for severe spasticity cases.
4. **Botox (Botulinum Toxin)** - Used off-label to manage localized spasticity.
5. **Anticholinergic medications** - Sometimes used off-label to address bladder dysfunction, a common symptom in HSP.
6. **Gene Therapy** - Experimental research is ongoing to target specific genetic mutations causing HSP.
7. **Stem Cell Therapy** - Still in the experimental stage but shows potential for future treatment.
8. **Physical Therapy and Occupational Therapy** - Routinely employed to improve mobility and functionality, though not off-label or experimental.
9. **SPG Therapy** - Experimental treatments targeting specific genetic subtypes (e.g., SPG4 gene mutations).
Patients should discuss potential treatments with their healthcare providers to understand the benefits, risks, and availability. - Lifestyle Recommendations
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For hereditary spastic paraplegia (HSP), lifestyle recommendations include:
1. **Physical Therapy**: Engaging in regular physical therapy can help maintain muscle strength, improve mobility, and reduce spasticity.
2. **Exercise**: Low-impact exercises such as swimming, cycling, or yoga can be beneficial for overall fitness and flexibility.
3. **Assistive Devices**: Using braces, canes, walkers, or wheelchairs can assist with mobility and reduce the risk of falls.
4. **Healthy Diet**: A balanced diet rich in nutrients can support overall health and well-being.
5. **Avoiding Alcohol and Smoking**: These can have a negative impact on neurological health and overall physical condition.
6. **Regular Monitoring**: Regular check-ups with healthcare providers for monitoring the progression of symptoms and adjusting treatment plans as needed.
It's important for individuals with HSP to work closely with healthcare professionals to develop a personalized plan that meets their specific needs. - Medication
- Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spasticity and weakness of the legs. While there is no cure, medications can help manage symptoms. Baclofen, tizanidine, and dantrolene are commonly used to reduce muscle spasticity. Botulinum toxin injections may also be beneficial for some individuals. Physical therapy and other supportive treatments are important components of managing the condition. Regular follow-ups with a healthcare professional are necessary to tailor treatments to individual needs.
- Repurposable Drugs
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Hereditary spastic paraplegia (HSP) currently has no cure, but some drugs originally developed for other conditions may offer symptomatic relief or have potential benefits:
1. **Baclofen** - This muscle relaxant, traditionally used for multiple sclerosis and spinal cord injuries, can help manage spasticity in HSP patients.
2. **Tizanidine** - Another muscle relaxant, tizanidine, can also reduce spasticity.
3. **Gabapentin and Pregabalin** - These anticonvulsants can help with neuropathic pain associated with HSP.
4. **Botulinum Toxin (Botox)** - Though primarily used for cosmetic purposes and muscle spasticity in various conditions, it may alleviate localized spasticity.
5. **Dalfampridine (4-Aminopyridine)** - Initially developed for multiple sclerosis, research indicates potential in improving walking ability in HSP patients.
6. **Levodopa** - Traditionally used for Parkinson's disease, it might offer benefits for certain genetic types of HSP.
Consultation with a healthcare provider is essential before taking any medication. - Metabolites
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For hereditary spastic paraplegia (HSP), specific metabolic alterations are not well-defined as primary features of the disease. HSP primarily affects motor neurons, leading to progressive spasticity and weakness in the lower limbs. While metabolites are not typically a primary focus in HSP, researchers sometimes investigate metabolic pathways to understand the disease better.
However, abnormalities in lipid metabolism, mitochondrial function, and other cellular processes can be associated with certain subtypes of HSP. Detailed metabolic studies might reveal specific biomarkers or contribute to understanding the pathogenesis in particular genetic variants of HSP, but these findings can be subtype-specific and are not broadly generalized across all HSP patients. - Nutraceuticals
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Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive weakness and spasticity, particularly in the lower limbs. The focus of management is primarily on symptom relief and supportive care.
As of now, there are no nutraceuticals that have been definitively proven to either cure or significantly alter the course of HSP. Nutraceuticals refer to food-derived products that offer health benefits, but their efficacy in HSP remains investigational and not well-supported by rigorous clinical trials.
For the latest and most effective treatment options, it is advisable to consult with a healthcare provider who specializes in neuromuscular disorders. - Peptides
- Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive weakness and spasticity of the lower limbs. There is ongoing research into various treatment options, including the use of peptides and nanoparticles (nanomedicine). Peptides can potentially target specific pathways involved in the disease process, while nanoparticles can be used to deliver therapeutic agents directly to affected cells. However, these approaches are still largely experimental and not yet widely available as standard treatments for HSP.