hereditary spastic paraplegia

Hereditary Spastic

Paraplegia By Mohammad

Zubair

Hereditary Spastic Paraplegia (HSP)

Definition:  is a group of inherited diseases whose main feature is progressive stiffness and contraction (spasticity) in the lower limbs , as a result of damage to or dysfunction of the nerves.

1-10 in 100,000 people worldwide have HSP

Can affect people of all ages , but average age at onset is 24

Many different names

1

•Hereditary spastic paresis

2

•Familial spastic paraplegia

3

•Strumpell-Lorrain disease: first described 1883-1888

4

•French Settlement

Classification

Based on symptoms

Based on mode of inheritance

Based on patient's age at onset

Based on associated gene

Based on symptoms

Pure

HSPComplicated

HSP

Affects the legs only More common Bladder symptoms may occur eg “urgency”

Spastic paraplegia with a variety of other problems Other neurological problems eg ataxia (poor balance) Intellectual disability , dementia, extrapyramidal signs,Seizures

Complicated HSP

Pure HSP

Based on mode of

inheritance

Autosomal dominant

Autosomal recessive

X-linked recessive 

manner

Based on patient's age at

onset

Type I

<35 years

Type II

>35 years

Spasticity>>weakness muscle weaknessurinary symptomssensory loss 

spasticity

Based on associated gene (Genetics)

Neuronal degeneration mutations at specific genes

Genetic mapping has identified at least 52 different HSP loci, designated SPG 1 through 52 

 Different genetic types of HSP usually cannot be distinguished by clinical and neuroimaging parameters alone

SPG1 (Spastic Paraplegia 1)

Masa syndrome Gareis-Mason syndrome Crash syndrome

Mutation in Gene >>>>> L1 or L1CAM protein Transmembrane protein >>>>  neurite outgrowth

guidance, neuronal cell migration and survival Locus = Xq28 X-Linked

SPG2

Mutation in Gene >>>>> Proteolipid protein 1(PLP1)

Transmembrane protein >>>> leukodystrophy and dysmyelination, resulting in axonal degeneration

Locus = Xq22 X-Linked

SPG4

Mutation in Gene SPAST >>>>> Spastin protein  Microtubule-severing protein >>>  membrane

trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis   

Locus = 2p22–p21 Autosomal dominant

SPG15

Kjellin syndrome Mutation in Gene >>>>> ZFYVE26 progressive stiffness and increased reflexes

in the leg muscles as well as retinal degeneration

Locus =14q24.1 Autosomal recessive

SPG17

Silver syndrome Mutation in Gene  BSCL2 >>>>> Seipin protein Phenotype overlapping with distal spinal

muscular atrophy type VA Locus = 11q13 Autosomal dominant

SPG18

Mutation in Gene >>>>> Erlin-2 Characterised by joint contractures

and intellectual disability Locus = 8p11.23 Autosomalrecessive

Neuropathology

.HSP

defects in the mechanisms that transport proteins and other substances through the cell

HSP

1- Impaired cellular membrane trafficking(spastin,atlastin-1 proteins>> shape ER membrane)

Neuropathology cont….

Long nerves

they have to transport cellular material

through long distances

HSP

2- Mitochondrial dysfunctionParaplegin protein>>m-AAA protease>> ATP dependent proteolytic complex>>control protein quality and ribosome assembly

In Neuron Level

terminal

portions of

the longe

st descending and ascending tracts

• corticospinal tracts to the legs

• fasciculus gracilis

Spinocortical Tracts

• Lesser Extent

no evidence of primary  demyelination

AxonalDegeneration

Clinical Features

Symptoms depend on the type of HSP inherited Main feature >>> progressive spasticity in the

lower limbs, due to pyramidal tract dysfunction In the lower extremities, spasticity is increased at

the hamstrings, quadriceps and ankles  Weakness is most notable at the iliopsoas , tibialis

anterior, hamstring musclesdifficulty in walking, decreased vibratory sense at

the ankles, and paresthesia In lower extremities hyperreflexia, brisk reflexes,

extensor plantar reflexes

Abnormal reflex during Gait/walkingNormal reflex during walking

additional symptoms in complicated form include: peripheral neuropathy, amyotrophy, ataxia, mentalretardation, ichthyosis, epilepsy,optic neuropathy, dementia, deafness, or problems with speech, swallowing or breathing

Diagnosis

HistoryComplainseg .walking difficulty

Family history any relatives affected?

Examinationleg muscles feel stiffbrisk reflexes

Instrumental TestsBrain and spine MRIRule out other causes

Genetic testing

Genetic testing

• Diagnostic - Person is affected with symptoms - Wants to know the cause

• Predictive - Person not affected with symptoms - Has a relative eg parent with HSP

Differential Diagnosis

Childhood onset• Diplegic cerebral palsy• Structural (Chiari malformation,

atlanto-axial subluxation)• Leucodystrophy (eg, Krabbe’s)• Metabolic (arginase defi ciency,

abetalipoproteinaemia)• Levodopa-responsive dystonia• Infection (myelitis)• Multiple sclerosis

Adult onset• Cervical spine degenerative

disease• Multiple sclerosis• Motor neuron disease• Neoplasm (primary/secondary

spinal tumour, parasagittal meningioma)

• Infection (myelitis)• Dural arteriovenous malformation• Chiari malformation• Adrenoleucodystrophy• Hereditary spastic paraplegia• Spinocerebellar ataxias• Vitamin defi ciency (B12 and E)• Lathyrism• Levodopa-responsive dystonia• Infection (syphilis, human T-cell

leukaemia virus 1, HIV)• Copper deficiency

Treatment

No specific treatment is known that would prevent, slow, or reverse HSP

Available therapies mainly consist of  symptomatic medical management and promoting physical and emotional well-being

Managemeny Strategy

Prevention of provocative Factors

Team Decision making

Treatment Options

Physical Treatment Medical Treatment

Gen.Spasticity

Foc.Spasticity

Reg.Spasticity

Oral Agents

Botulinum Toxins.Phenol Blockade

Intra-Thecal Baclofen

•  Baclofen– a voluntary muscle relaxant to relax muscles and reduce tone

• Tizanidine – to treat nocturnal or intermittent spasms• Diazepam and Clonazepam – to decrease intensity of spasms• Oxybutynin chloride– an involuntary muscle relaxant and

spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems

• Tolterodine tartate – an involuntary muscle relaxant and spasmolytic agent, used to reduce spasticity of the bladder in patients with bladder control problems

• Botulinu toxin – to reduce muscle overactivity• Antidepressants (such as selective serotonin re-uptake

inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors) – for patients experiencing clinical depression

Physical Therapy

To restore and maintain the ability to move To reduce muscle tone To maintain or improve range of motion and

mobility To increase strength and coordination To prevent complications, such as frozen

joints, contractures, or bedsores.