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Hereditary spastic paraplegia
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Transcript of 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.