Hereditary spastic paraplegia

Hereditary spastic paraplegias (HSP) are a rare group of inherited neurodegenerative diseases which mainly affect the longest axons of the corticospinal tract and the dorsal column (which supply the lower limbs). HSP is caused by defects in genes which code for proteins essential for fast axonal neurotransmission. HSP can affect any age group. Patients present with upper motor neuron palsy of bilateral lower limbs, gait abnormalities, and urinary urgency/urge incontinence. Dorsal column dysfunction is usually mild. Additional neurological features such as epilepsy, peripheral neuropathy, or cerebellar signs may be present (complicated HSP). Diagnosis is mainly clinical. MRI of the spinal cord may demonstrate spinal cord atrophy. Treatment is mainly supportive, with skeletal muscle relaxants, botulinum toxin, and physiotherapy for muscle spasticity. HSP may be nonprogressive (childhood-onset) or progressive (adult-onset). Patients with progressive HSP are often wheelchair-bound by the age of 70 years. Patients with HSP have a normal life-expectancy.

• Incidence: < 10 per 100,000 general population ^[1]
• Age of onset: variable (from early childhood till the 8^th decade of life)

Epidemiological data refers to the US, unless otherwise specified.

• Genetic defect
  • Autosomal dominant (most common)
  • Autosomal recessive
  • X-linked inheritance
  • Sporadic mutations

• Defect in genes required for normal (fast) neurotransmission in the axons → degeneration mainly of the long axons
• Primarily affects the longest axons of the corticospinal tract and the dorsal column → progressive upper motor neuron paralysis and dorsal column dysfunction symptoms in the lower limbs

References:^[2]

Pure HSP (Uncomplicated HSP)

Pure HSP is characterized by an insidious onset and slow progression of the following symptoms

• Upper motor neuron paralysis of bilateral lower limbs
  • Spasticity/hypertonicity → contractures
  • Decreased muscle strength
  • Gait abnormalities: delayed initiation of walking (childhood onset HSP); scissor gait (late onset HSP)
  • Brisk deep tendon reflexes; extensor plantar reflex (Babinski sign)
• Dorsal column dysfunction in bilateral lower limbs (usually mild; only detected on examination): decreased/loss of vibration sense, 2-point discrimination sense, and position sense
• Urinary urgency and urge incontinence

Complicated HSP

Patients with complicated HSP have all the features of pure HSP as well as additional neurological features, such as:

• Epilepsy, intellectual disability, dementia
• Cerebellar or extrapyramidal symptoms
• Peripheral neuropathy
• Loss of vision

References:^{[3][4][5][6][7]}

The diagnosis of HSP is based on a positive family history, characteristic clinical features, and the exclusion of other neurological conditions.

• MRI of the brain and spinal cord: mild atrophy of the cervical and thoracic spinal cord in pure HSP
• Nerve conduction studies and electromyography: may be normal or show mild motor neuropathy
• Motor evoked potentials: decreased or absent in bilateral lower limbs (based on severity of paralysis)
• Molecular genetic testing: to differentiate HSP from other inherited ataxias (spinocerebellar ataxia or Friedreich ataxia)
• Vitamin B12 levels should be checked; HIV and syphilis testing should also be performed to rule out these conditions.

Lumbar puncture and CSF analysis are usually normal.

References:^[4][8]

References:^[4][8]

The differential diagnoses listed here are not exhaustive.

• There is no known cure for HSP.
• Supportive therapy (for spasticity)
  • Skeletal muscle relaxants or botulinum toxin
  • Orthotic braces, canes, or crutches as required
  • Physiotherapy: passive stretching and exercises to avoid the development of contractures, maintain flexibility
• Anticholinergics (e.g., oxybutynin, hyoscyamine) for treatment of urinary urgency

References:^[5][9][10]

• Prognosis depends on the age of onset.
  • Early onset HSP (in childhood): may be nonprogressive; most patients remain ambulant
  • Late onset: progressive; most patients will require wheelchairs by age 70
• Life-expectancy: normal

References:^[3][4]