What is hereditary spastic paraparesis (HSP)?

Hereditary Spastic Paraplegia (HSP)

Hereditary spastic paraplegia (HSP) is a group of rare genetic disorders characterized by progressive weakness and spasticity primarily affecting the lower extremities, caused by degeneration of corticospinal tract axons and resulting in a progressive gait disorder.

Clinical Features

Primary Symptoms

• Progressive spasticity and weakness of the lower limbs
• Increased muscle tone and hyperreflexia
• Positive Babinski sign
• Gait disturbance with difficulty walking

Classification

1. Pure HSP

   • Limited to lower limb spasticity, hyperreflexia, and motor deficits
   • May include mild sensory disturbances and urinary symptoms
   • Generally has a better prognosis

2. Complicated HSP

   • Lower limb spasticity plus additional neurological or non-neurological features
   • May include:
     • Cognitive impairment
     • Seizures
     • Visual/hearing impairment
     • Ataxia
     • Peripheral neuropathy
     • Thin corpus callosum
     • Extrapyramidal features

Epidemiology

• Prevalence ranges from 0.1 to 9.6 per 100,000 population 1
• Can affect individuals of all ethnic groups
• Age of onset varies widely:
  • Early-onset forms (childhood): may stabilize and not worsen significantly
  • Late-onset forms (adulthood): typically show slow, progressive deterioration 2

Genetics and Inheritance Patterns

• More than 80 genetic types identified to date 3, 2
• Inheritance patterns include:
  • Autosomal dominant (most common)
  • Autosomal recessive
  • X-linked
  • Mitochondrial inheritance 3

Pathophysiology

• Primary pathological finding: degeneration of corticospinal tract axons (maximal in thoracic spinal cord)
• Secondary degeneration of fasciculus gracilis fibers (maximal in cervico-medullary region)
• Predominantly affects the distal ends of long central nervous system axons 2

Molecular Mechanisms

HSP-related genes encode proteins involved in various cellular functions:

1. Axonal transport (e.g., KIF1A, KIF5A)
2. Endoplasmic reticulum morphology (e.g., Atlastin, Spastin)
3. Mitochondrial function (e.g., paraplegin)
4. Myelin formation (e.g., Proteolipid protein)
5. Protein folding and ER-stress response
6. Corticospinal tract development
7. Fatty acid and phospholipid metabolism
8. Endosome membrane trafficking 2

Diagnosis

• Clinical evaluation of spastic paraparesis
• Family history assessment
• Genetic testing:
  • Targeted gene panels
  • Whole exome sequencing
  • Whole genome sequencing
• Neuroimaging (MRI) to rule out other causes and identify complications:
  • May show thin corpus callosum in some forms
  • Regional volume loss patterns in specific types 4
• Electrophysiological studies:
  • EMG may show chronic neurogenic changes
  • Motor and sensory evoked potentials may be abnormal 3

Differential Diagnosis

• Multiple sclerosis
• Tropical spastic paraparesis (HTLV-1 associated myelopathy)
• Structural spinal cord lesions
• Vitamin B12 deficiency
• Copper deficiency
• Adrenomyeloneuropathy
• Primary lateral sclerosis
• Neurodegeneration with brain iron accumulation
• Dopa-responsive dystonia

Management

• Currently no disease-modifying treatments available 4
• Treatment is primarily symptomatic:

  1. Pharmacological management:

     • Antispasticity medications (baclofen, tizanidine, dantrolene)
     • Botulinum toxin injections for focal spasticity
     • Intrathecal baclofen for severe spasticity

  2. Physical therapy:

     • Regular stretching exercises
     • Gait training
     • Strengthening exercises
     • Range of motion exercises

  3. Assistive devices:

     • Ankle-foot orthoses
     • Walkers
     • Wheelchairs for advanced cases

  4. Surgical interventions:

     • Selective dorsal rhizotomy in selected cases
     • Tendon release procedures for contractures

Prognosis

• Highly variable depending on:
  • Genetic subtype
  • Age of onset
  • Pure vs. complicated form
• Pure forms typically have normal life expectancy
• Complicated forms may have reduced life expectancy depending on associated features
• Most patients with adult-onset HSP eventually require walking aids, but many remain ambulatory with assistance

Special Considerations

• Genetic counseling is essential for affected families
• Regular monitoring for complications (contractures, falls, urinary dysfunction)
• Psychological support for coping with progressive disability
• Multidisciplinary care involving neurologists, physical therapists, urologists, and geneticists is beneficial

Recent Advances

• Novel gene discoveries continue to expand our understanding of HSP
• Animal models (including zebrafish, Drosophila, and mice) are being used to explore disease mechanisms and potential treatments 2
• Emerging therapeutic approaches targeting specific molecular pathways are under investigation