hereditary spastic paraplegia

HEREDITARY SPASTIC PARAPLEGIA

Dr.Y.Sasikumar

Hereditary spastic paraplegia (HSP) is a large group of inherited neurologic disorders, in which the prominent feature is a progressive spastic paraparesis.

Dr. Str ü mpell first described hereditary forms of spastic paraplegia in 1883.

HSP is group of genetic disorders , the modes of inheritance: autosomal dominant, autosomal recessive, Mitochondrial inheritance and x-linked recessive.

Hereditary spastic paraplegia (HSP) is also called familial spastic paraparesis .

In Europe, the frequency of HSP is estimated to be 1-9 cases per 100,000 population..

HSP may occur at any age, from infancy through late adulthood (eg, 85 y).

Most patients experience the onset of symptoms between the second and fourth decades of life.

Degeneration of the ends of the corticospinal tracts within the spinal cord.

The ends of the longest fibers, which supply the lower extremities, are affected to a much greater extent than are the fibers to the upper body.

Most people with HSP do not have symptoms in the hands or arms.

PATHOPHYSIOLOGY

Impaired cellular membrane trafficking

o More particularly axonal transport of macromolecules and organelles.

o Mutation of proteins, spastin and atlastin-1 causes impaired cellular membrane trafficking.

Mitochondrial dysfunction

o Paraplegin , an ATP-dependent proteolytic complex located at the mitochondrial inner membrane, which controls protein quality and regulates ribosome assembly.

o Mutation causes mitochondrial dysfunction.

Mutation of myelin protein gene

Patients with this form of HSP generally show evidence of myelin abnormalities, which are known to affect axon function.

Hereditary Spastic Paraplegias are classified 1. Based on the symptoms (pure form

versus complicated form);

2. Based on their mode of inheritance (autosomal dominant, autosomal recessive or x-linked)

3. Based on the patient’s age at onset.

CLASSIFICATION

Based on symptoms

Spasticity in the lower limbs alone is described as pure HSP.

Complicated HSP, additional symptoms may

include peripheral neuropathy, epilepsy, ataxia, optic neuropathy, retinopathy, dementia, ichthyosis, mental retardation, deafness, and problems with speech, swallowing.

Complicated HSP is rare.

Based on patient's age at onset

Type I is characterized by age onset below 35 years.

 Spasticity of the lower limbs is more marked than weakness.

Type II is characterized by onset over 35 years.

Muscle weakness, urinary symptoms and sensory loss are more marked

Based on mode of inheritance

There are four different modes of inheritance:

 autosomal dominant 

autosomal recessive

Mitochondrial inheritance 

 x-linked recessive.

Autosomal dominant represents the most common mode of inheritance

o To date, the locations of several genes have been identified by Genetic mapping .

o 18 types of dominantly inherited pure or complicated HSP are known.

o 17 types of recessively inherited HSP.

o 3 types of X-linked HSP.

Type Gene Locus Description

Autosomal dominant

SPG4 (spastinprotein)

2p22-p21 Disturbances in axonal cytoskeleton

Autosomal dominant

SPG3A(atlastin protein)

14q11-q21 Abnormal synaptic structure and impaired neurotransmission, Also known as Strumpell disease.

Autosomal dominant

SPG10 (KIF5Aprotein)

12q13 associated with distal muscle atrophy.

Autosomal recessive HSP

SPG7 16q24.3 mitochondrial malfunction in neurons, leading to axonal degeneration

Autosomal recessive HSP

SPG20 13q12.3 cause distal muscle wasting.[28

X-linked SPG1, Neuronal Cell Adhesion Molecule L1 

Xq28  interfere with neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts.

TypeGene Locus Description

Autosomal recessive HSP

SPG20 13q12.3 Distal muscle wasting

X-Linked SPG2 xq22 Mutations in the proteolipid protein cause progressive leukodystrophy and dysmyelination, resulting in axonal degeneration.[29

X-Linked SPG1 11q13  interfere with neuronal cell migration and neuronal cell survival, causing reduced corticospinal tracts.

Symptoms

o The classic symptom of HSP is progressive difficulty in walking.

o Patients usually have difficulty lifting their toes; as a result, they drag their toes when walking.

o In later stages, patients experience

difficulty flexing the thigh muscle when walking.

o Experience increased muscle tone.

o Some patients complain of reduced sensation in the distal regions of the legs.

o Some people also experience urinary problems (eg, incontinence)

o Some patients eventually may require the use of a wheelchair.

Abnormal gait

o Increasing stiffness in the legs is associated with frequent tripping.

o Uncontrollable shaking of the legs may be noted when the patient ambulates.

o Dragging of the feet, scissoring of the legs during ambulation.

Decreased sense of balance

o A common symptom of HSP is a decreased sense of balance.

o For many people, this is the first symptom.

o Epilepsy, ataxia, optic neuropathy, retinopathy, dementia, ichthyosis, mental retardation, deafness, and problems with speech, swallowing.

Physical Signs

o Upper extremity muscle tone and strength are normal.

o In the lower extremities, muscle tone is increased at the hamstrings, quadriceps, and ankles.

o Weakness is most notable at the iliopsoas muscles, the tibialis anterior muscles, and, to a lesser extent, the hamstring muscles.

o Muscle wasting may occur in patients with pure HSP.

o It is mild and is limited to atrophy of the shins in elderly & wheelchair-dependent patients.

o Peripheral nerves are normal in patients with pure HSP.

o Vibratory sensation is often mildly diminished in the distal lower extremities.

o Deep tendon reflexes are pathologically increased (3+ to 4+) in the lower extremities.

o The patient's gait demonstrates circumduction owing to a difficulty with hip flexion and ankle dorsiflexion.

o Ankle clonus, and extensor plantar responses are uniformly present.

o Hoffman sign may be observed.

o High-arched feet (pes cavus) are generally present and are usually prominent in older patients.

Genetic Testing

Imaging StudiesMRI scans may demonstrate atrophy of the spinal cord.

Cortical evoked potentials –(used to measure neurotransmission in corticospinal tracts)

show reduced conduction velocity and reduced amplitude of the evoked potential in the corticospinal tract .

Lower extremity somatosensory evoked potentials -show a conduction delay in dorsal column fibers.

workup

Cortical evoked potentials of the arms are usually normal.

CSF -Usually normal,some may show

increased protein level.

Autopsy studies of autosomal dominant HSP have demonstrated axonal degeneration of the long descending tracts(ventral and lateral corticospinal tracts).

Degeneration was maximal in the distal axons of these fibers.

HISTOLOGIC FINDINGS

Spinocerebellar fibers are involved to a lesser extent.

Neuronal cell bodies of degenerating fibers

are preserved.

Loss of anterior horn cells is observed in some cases.

Currently, no specific treatment exists to prevent, retard, or reverse progressive disability in patients with HSP.

Rehabilitation programme

o Regular physical therapy (PT) is important for maintaining and improving range of motion (ROM) and muscle strength.

o PT does not reduce the degenerative process within the spinal cord.

TREATMENT

The exercise programs include strengthening, stretching, and aerobic exercises.

Strengthening exercises - These help to strengthen muscles & decreasing the rate of functional impairment.

o Exercise may also help to slow the development of disuse atrophy.

o Back-strengthening exercises may help to reduce or eliminate back pain (due poor gait, poor posture, use of a mobility device).

Stretching exercises – These help to maintain or increase ROM and

to reduce muscle cramps.

Aerobic exercises –

o These improve cardiovascular fitness, reduce fatigue, and increase endurance and general fitness.

o Walking, bicycle riding, water aerobics, and swimming

Exercise also has a positive psychological effect, helping to reduce stress and produce feelings of well-being.

Medication The goals of pharmacotherapy are to reduce

morbidity and prevent complications.

Antispasmotic drugs

Eg-Oxybutynin 

o Inhibits the action of acetylcholine on smooth muscle

o Causes an increase in bladder capacity and a decrease in uninhibited contractions.

SKELETAL MUSCLE RELAXANT

Baclofen 

o Induce the hyperpolarization of afferent terminals and inhibit monosynaptic and polysynaptic reflexes at the spinal level.

Tizanidine

o Centrally acting muscle relaxant.

Dantroline sodium 

o Stimulates muscle relaxation by modulating skeletal muscle contractions at the site beyond the myoneural junction.

Botilinum toxino Binds to receptor sites on motor nerve

terminals and inhibits the release of acetylcholine, which in turn inhibits the transmission of impulses in neuromuscular tissue.

o This agent is most useful for treating spasticity in the gastrocnemius and soleus muscles.

Benzodiazepines

Diazepam (Valium) 

o Depresses all levels of CNS, possibly by increasing the activity of GABA.

Gastrocnemius-soleus contracture: o This condition is more common when

symptoms begin in childhood rather than in adulthood.

Cold feet:

o Many people with HSP complain of cold feet.

o Cold feet may be related to abnormal thermoregulation of cutaneous vessels; however, circulation is usually preserved.

COMPLICATIONS

Fatigue:

o The extra effort required for walking, because of muscle weakness in the legs.

o Various medications prescribed for HSP cause drowsiness & fatigue.

o Many patients with HSP may not get their required amount sleep, because of leg cramps or spasms or as a result of the frequent need to urinate during the night.

Stress and depression

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