Hereditary Spastic Paraplegia


Article title: Hereditary spastic paraplegia
Author: Tala Mohammad
Editors: Haneen Al-Abdallat,  Haneen A. Banihani
Reviewer: Ethar Hazaimeh

Keywords: Hereditary, Ataxia, Spastic, Motor, Neurodegenerative

Overview and epidemiology

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by motor neuron degeneration in the lower extremities,1 with relative sparing of the rest of the body.2 It is also known as Strumpell-Lorrain syndrome. HSPs are generally considered non-life-threatening but are linked with a poor quality of life.3 They can be classified as pure or complex,4 the latter associated with additional neurological features.2

HSP is further divided according to the mode of inheritance, phenotype, and pathophysiology.5 The disease may be autosomal dominant, recessive, X-linked, or a mitochondrial trait.2 Moreover, the familial form is twice as widespread as the sporadic form in 70% of autosomal dominant HSP.1 Almost 80 spastic paraplegia genes (SPGs) are present, with an incidence of up to 5 to 100,000 individuals worldwide.1

Table 1- HSP Classification 5

Pathogenesis and etiology

In HSP, motor neurons are the most affected, and their degeneration results in most of the clinical signs.6 Mutations often affect multiple pathways, ranging from the microtubule cytoskeleton to the mitochondrial compartment.6 Furthermore, two groups of structures are more commonly implicated following gene mutations; kinesin, spastin, and paraplegin.

Kinesin and spastin are associated with microtubule function, whereas others, such as paraplegin and HSP60, are implicated in mitochondrial function.7 Frequently, HSPs result from the degeneration of the longest neurons present in the pyramidal tract and dorsal columns.1 Hence, patients present with motor symptoms and ataxia. Currently, approximately 60 genetic types have been isolated.2 The nomenclature of HSP genotypes is grouped as SPGs, which stands for Spastic Paraplegia Genes, followed by the number of gene discoveries.8 Studies have shown that SPG11 is the most common autosomal recessive HSP genetic type.8 On another note, ataxia was a common presenting symptom in SPG7, SPG8, SPG20, SPG46, SPG58.9 In addition, most SPG subtypes, particularly X-linked SPG2, are linked with thinning of the spinal cord.1

Clinical Presentation and Complications

Due to the diverse genetic markers that lead to HSP, many clinical manifestations exist.1 Age of onset of HSP varies significantly, from as young as a couple of months up to 70 years of age.4 Patients predominantly present with gait impairment resulting from lower extremity weakness and spasticity,10 a feature which may only be evident while walking.9

According to a meta-analysis, gait disturbance was the patients’ most common initial presentation.9 Other presenting features include hyperreflexia and extensor plantar responses.2 In most of the time, spasticity is more apparent than weakness.11 Another critical presenting symptom is urinary urgency.10 In a cross-sectional report survey, HSP patients reported polyuria and nocturia more often than controls. 12 Not to mention, HSP patients commonly complained of constipation, or alternating constipation and diahrrea.12Many individuals experience rapid progression of symptoms, such as worsening of gait impairment, in a uniform or nonuniform manner.10 Moreover, early signs of HSP include mild stiffness, which may be accompanied by loss of muscle tone in the lower extremities.1

Workup and Diagnosis

Diagnosis largely depends on an extensive history and physical exam, considering the absence of family history should not rule out HSP.2 Usually, HSP is diagnosed by exclusion, specifically in the absence of family history.2

Diagnostic differentials include multiple sclerosis and cerebral palsy. Following a comprehensive history, MRI findings may aid in diagnosis. A study reported significant cortical and subcortical atrophy in an Antero-caudal pattern in patients diagnosed with HSP.13 Along the lines of another study, MRIs in known cases of autosomal dominant HSP indicate evident spinal cord atrophy.14

Management and prognosis

No studies have claimed an exact cure or prevention for HSP, and most management is directed toward improving quality of life. Management of HSP focuses mainly on symptoms such as stiffness and spasms,1 for which oral anti-spastic medications, such as baclofen, can be used.2 A study exploring possible HSP management showed that using botulinum toxin injections type A (Btx-A) effectively treats lower limb spasticity.15 Similarly, a different study reported that Btx-A led to variable degrees of improvement in spasticity and gait velocity.15 Not to mention the improvement of non-motor manifestations such as fatigue.15

Patients may also turn to physical therapy comprising exercise regimes and electrical stimulation.1 It has been shown that a combination of both physiotherapy and medications provides a good outcome for patients1 although no clear indications exist on the type and timing for optimal results.16 Physiotherapy also shows extreme benefits towards healthy cardiovascular conditioning.10

Figure 1- Overview of HSP management and treatment 1

Surgical intervention may be opted for as a final resort. However, not many studies have been conducted to prove its efficacy. A case report outlined decreased spasticity and improved gait following intrathecal baclofen delivery.17 Other studies indicated that selective dorsal rhizotomy (SDR), a procedure widely used to relieve spasticity related to cerebral palsy, has led to a significant decrease in spasms and spasticity.16

Patients’ outcomes are highly variable and dependent on the associated genotype.2 Generally, patients with pure-type HSP have an average life expectancy and don’t suffer many complications.10 Hence, the prognosis is variable and dependent on the patients themselves.

Recent updates6

Drugs have been tested on zebrafish; animal models of HSP, including dorsomorphin and miglustat. These drugs showed significant preservation of the motor phenotype. However, no clinical trials have been conducted yet.


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