Hereditary spastic paraplegia (all)

Overview

Hereditary Spastic Paraplegia (HSP) refers to a diverse group of inherited neurological disorders that mainly affect the spinal cord. The hallmark feature of HSP is progressive spasticity (stiffness) and weakness in the legs, leading to difficulties with movement and balance [PMID:33675001]. While the primary symptoms are in the lower limbs, some forms of HSP, known as 'complex' HSP, can involve other parts of the nervous system or other body systems.

HSP is a progressive condition, meaning symptoms tend to worsen over time, though the rate of progression varies significantly among individuals and different types of HSP. The condition is often classified into 'pure' forms, where neurological symptoms are confined to the lower limbs, and 'complex' forms, which include additional features such as intellectual disability, epilepsy, or problems with other senses [PMID:32761895].

Symptoms & clinical features

The main symptoms of HSP centre around changes in leg movement. Individuals typically experience a gradual onset of muscle stiffness (spasticity) in the legs, particularly in the quadriceps and calf muscles. This spasticity can make walking difficult, leading to a characteristic 'scissoring' gait where the legs cross over each other, or a 'tip-toe' gait due to tight calf muscles.

Along with stiffness, there is also progressive weakness in the legs, which can make it challenging to lift the feet and clear obstacles. This can result in frequent tripping and falls. Other common symptoms include hyperreflexia (overactive reflexes), clonus (involuntary, rhythmic muscle contractions), and sometimes bladder problems. In complex forms of HSP, symptoms can extend beyond the legs and may include ataxia (problems with coordination), peripheral neuropathy (nerve damage outside the brain and spinal cord), intellectual impairment, or other neurological features.

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Affected organs

The primary organ affected in HSP is the spinal cord, specifically the long nerve fibres (axons) that run from the brain down to the legs. These nerve pathways are responsible for controlling voluntary movement and relaying sensory information. In HSP, these axons gradually degenerate, particularly their longest parts, which explains why the legs are predominantly affected [PMID:33675001].

In complex forms of HSP, other parts of the nervous system can also be affected, such as the cerebellum (involved in coordination), peripheral nerves, or even the brain, leading to a wider range of symptoms impacting intellect, vision, or hearing.

Brain

Central nervous system involvement

Cellular impact

Mechanism at cellular level

Risks & severity

The severity and progression of HSP vary widely, even among individuals with the same genetic cause. Symptoms can begin at any age, from infancy to late adulthood, with juvenile and adult-onset forms being common. While HSP is progressive, it is generally not considered a life-limiting condition, and most individuals have a normal life expectancy. However, the condition can significantly impact mobility and quality of life.

Walking difficulties can range from mild unsteadiness to requiring walking aids like sticks, frames, or wheelchairs as the condition progresses. The exact prevalence of HSP is not well established, but research suggests it affects approximately 2 to 6 individuals per 100,000 in the general population. Factors influencing severity include the specific gene involved and individual genetic variations [PMID:32761895].

Genetic causes

HSP is caused by pathogenic variants (changes) in a number of different genes. These genes are involved in various cellular processes vital for the health and function of nerve cells, particularly the long nerve fibres in the spinal cord. For example, variants in the *SPG4* gene, which codes for a protein called spastin, are a common cause of autosomal dominant HSP [PMID:32761895]. Spastin is involved in microtubule dynamics, which are crucial for maintaining the structure and transport systems within nerve cells. When spastin doesn't function correctly, it can lead to axon degeneration.

Other genes, such as *SPG11*, are associated with autosomal recessive forms of complex HSP. The *SPG11* gene produces a protein called spatacsin, which plays a role in vesicle trafficking and autophagy - processes essential for clearing cellular waste and maintaining nerve cell health. Faults in this gene can lead to axonal degeneration and a more widespread impact on the nervous system. The *SPG7* gene, encoding paraplegin, is another gene linked to autosomal recessive HSP, where the protein is involved in mitochondrial function, critical for cellular energy production.

• SPG11
  SPG11 vesicle trafficking associated, spatacsin
• SPG4
  spastin
• SPG7
  SPG7 matrix AAA peptidase subunit, paraplegin

Inheritance pattern

HSP can be inherited in different ways, most commonly as an autosomal dominant or autosomal recessive condition. When HSP is inherited in an autosomal dominant pattern, only one copy of the altered gene is needed to cause the condition. This means that if one parent has the condition, there is a 50% chance that each child will inherit the altered gene and develop HSP. Both males and females are affected equally.

In autosomal recessive inheritance, an individual must inherit two copies of the altered gene - one from each parent - to develop the condition. Parents who each carry one copy of the altered gene are typically unaffected and are called carriers. With each pregnancy, there is a 25% chance of the child inheriting both altered copies and developing HSP, a 50% chance of being a carrier, and a 25% chance of inheriting two normal copies of the gene. Both inheritance patterns mean that other family members may also be affected or be carriers.

Diagnosis & testing

Diagnosing HSP typically begins with a detailed clinical assessment by a neurologist, including a thorough medical history and neurological examination to identify characteristic symptoms like spasticity and weakness. Other tests such as nerve conduction studies, electromyography, and MRI scans of the brain and spinal cord may be performed to rule out other conditions and assess the extent of neurological involvement.

Genetic testing is crucial for confirming a diagnosis of HSP and identifying the specific causative gene. This is usually carried out through NHS Genomic Medicine Service (GMS) pathways, often following a referral from a clinical geneticist or neurologist. The relevant NHS National Genomic Test Directory R-codes (e.g., R51 for Hereditary Spastic Paraplegia) guide which tests are appropriate. Genetic counselling is often offered before and after testing to discuss the implications of a diagnosis for the individual and their family.

Management & lifestyle

While there is currently no cure for HSP, management focuses on alleviating symptoms and improving quality of life. Treatment is primarily supportive and often involves a multidisciplinary team. Physiotherapy is a cornerstone of management, aiming to maintain muscle strength, flexibility, and mobility, as well as to help manage spasticity and prevent contractures (permanent muscle shortening). Occupational therapy can help individuals adapt to daily activities and suggest assistive devices.

Medications may be prescribed to reduce spasticity, such as baclofen or tizanidine, which can help ease muscle stiffness and pain. Regular follow-up with a neurologist is important to monitor disease progression and adjust management strategies as needed. Access to genetic counsellors can help families understand the inheritance pattern and implications for future planning. Lifestyle adjustments, including regular exercise and maintaining a healthy weight, may also contribute to overall well-being.

UK care pathway

In the UK, individuals suspected of having HSP are typically referred through their GP to a neurologist for initial assessment. If HSP is suspected, further referral to a clinical genetics service is common. These services can arrange for genetic testing through the NHS Genomic Medicine Service (GMS) pathways, using specific R-codes from the National Genomic Test Directory. Genetic counsellors are an integral part of this pathway, providing support and information regarding genetic testing, inheritance patterns, and the potential impact on families. They can also help patients navigate available resources and support networks.

Related conditions

Several conditions can present with symptoms similar to HSP, making accurate diagnosis important. These include other neurological disorders that cause spasticity, such as multiple sclerosis, cerebral palsy, or certain types of motor neuron disease. Distinguishing HSP from these conditions often relies on careful clinical assessment, imaging studies, and importantly, genetic testing. Conditions like Charcot-Marie-Tooth disease, a peripheral neuropathy, can sometimes have overlapping features, but typically present with more prominent sensory loss and different patterns of muscle weakness.

Frequently asked questions