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Progressive Spastic Paraparesis AskTheNeurologist.Com Author Anon
R.A <ul><li>47 year-old man, M + 3, “ farmer”, Moroccan descent </li></ul><ul><li>2 ½ - 3 year history of progressive leg ...
History I <ul><li>Jan 2001:- </li></ul><ul><li>Tripped and fell and hurt back </li></ul><ul><li>Suffered LBP radiating dow...
History 2 <ul><li>Over following 2 years 9 months:- </li></ul><ul><li>Progressive leg stiffness </li></ul><ul><li>R leg af...
History 3 <ul><li>July 2001:- </li></ul><ul><li>Hepatosplenomegaly found incidentally </li></ul><ul><li>Anaemia </li></ul>...
History 4 <ul><li>Denies </li></ul><ul><ul><li>Arm involvement </li></ul></ul><ul><ul><li>Speech / visual disturbance </li...
History 5 <ul><li>In childhood normal acquisition of motor-milestones </li></ul><ul><li>No noticeable problems in walking,...
Family History <ul><li>Father:- </li></ul><ul><li>Age 40 began to suffer gait difficulty </li></ul><ul><li>Over 20 years p...
Family History II <ul><li>Sister (aged 47):- </li></ul><ul><li>Suffered from LBP aged 39 “ discopathy” </li></ul><ul><li>1...
 
Examination <ul><li>Cognitively intact </li></ul><ul><li>Cranial nerves intact </li></ul><ul><li>Tone normal in arms, incr...
<ul><li>Decreased vibration sense in legs </li></ul><ul><li>Sensory level mid-lower thoracic </li></ul><ul><li>Romberg mil...
Investigations I <ul><li>CBC - normal </li></ul><ul><li>Biochem - normal </li></ul><ul><li>B12 - 596 (normal) </li></ul><u...
<ul><li>Immunology: </li></ul><ul><ul><li>ANA </li></ul></ul><ul><ul><li>ANCA </li></ul></ul><ul><ul><li>Anti Ro / La </li...
<ul><li>Infective: </li></ul><ul><ul><li>HIV -ve </li></ul></ul><ul><ul><li>HTLV-1 pending </li></ul></ul><ul><ul><li>VDRL...
<ul><li>Imaging </li></ul><ul><ul><li>Previous MRI of cervical, thoracic and  lumbar – sacral cord all normal </li></ul></...
DD <ul><li>Infective : - HTLV – 1 </li></ul><ul><li>- HIV </li></ul><ul><li>- Syphilis </li></ul><ul><li>Inflammatory - MS...
 
 
 
 
 
Stained with Luxol fast blue – stains myelinated axons
A  L A  L
Usually lose ability to walk by age 60-70 Usually ambulant until death from other cause More prominent weakness, sensory l...
 
 
 
 
 
 
HSP caused by impaired development of the   corticospinal tract
 
PLP mutation <ul><li>PLP ( proteolipid protein) is one of major protein components of CNS myelin </li></ul><ul><li>A mutat...
 
Paraplegin <ul><li>Codes for type of metalloprotease known as AAA metalloprotease. </li></ul><ul><li>Shown  ( via immunofl...
<ul><li>Severity of muscle findings correlates with severity of HSP! </li></ul><ul><li>Relevance of muscle changes unclear...
<ul><li>AAA metalloproteases are invloved in  “ chaperone-like” activity as well as other intracellular functions </li></u...
<ul><li>? accumulation of aberrant peptides within the mitochondria results in mitochondrial dysfunction </li></ul><ul><li...
 
Treatment options <ul><li>Antispasticity drugs ( e.g baclofen) </li></ul><ul><li>Regular physiotherapy </li></ul><ul><li>B...
Follow-Up <ul><li>A novel mutation in the SPG4 (spastin) gene was subsequently isolated in this family </li></ul>
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Progressive Spastic Paraparesis

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The case of a man who developed progressive gait disturbance and lower limb spasticity

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  • My dear Mr Derkar,
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Transcript of "Progressive Spastic Paraparesis"

  1. 1. Progressive Spastic Paraparesis AskTheNeurologist.Com Author Anon
  2. 2. R.A <ul><li>47 year-old man, M + 3, “ farmer”, Moroccan descent </li></ul><ul><li>2 ½ - 3 year history of progressive leg weakness </li></ul>
  3. 3. History I <ul><li>Jan 2001:- </li></ul><ul><li>Tripped and fell and hurt back </li></ul><ul><li>Suffered LBP radiating down R leg </li></ul><ul><li>First noticed leg weakness </li></ul>
  4. 4. History 2 <ul><li>Over following 2 years 9 months:- </li></ul><ul><li>Progressive leg stiffness </li></ul><ul><li>R leg affected predominantly </li></ul><ul><li>Gait difficulty </li></ul><ul><li>Frequency of urination…occasionally incontinent </li></ul>
  5. 5. History 3 <ul><li>July 2001:- </li></ul><ul><li>Hepatosplenomegaly found incidentally </li></ul><ul><li>Anaemia </li></ul><ul><li>Myelofibrosis diagnosed (bone marow bx) </li></ul><ul><li>Treatment commenced ( B12, Folate) </li></ul>
  6. 6. History 4 <ul><li>Denies </li></ul><ul><ul><li>Arm involvement </li></ul></ul><ul><ul><li>Speech / visual disturbance </li></ul></ul><ul><ul><li>Cognitive involvement </li></ul></ul>
  7. 7. History 5 <ul><li>In childhood normal acquisition of motor-milestones </li></ul><ul><li>No noticeable problems in walking, running or athletic ability in early life </li></ul>
  8. 8. Family History <ul><li>Father:- </li></ul><ul><li>Age 40 began to suffer gait difficulty </li></ul><ul><li>Over 20 years progressed until bed-ridden with loss of sphincter control </li></ul><ul><li>Died aged 70 from “ pressure sores” </li></ul><ul><li>Arms, speech vision, cognition all unaffected at death </li></ul>
  9. 9. Family History II <ul><li>Sister (aged 47):- </li></ul><ul><li>Suffered from LBP aged 39 “ discopathy” </li></ul><ul><li>1 ½ years ago others noticed gait disturbance </li></ul><ul><li>1 year ago RTA…from then on she noticed gait difficulty. </li></ul><ul><li>Recently urgency of micturition </li></ul>
  10. 11. Examination <ul><li>Cognitively intact </li></ul><ul><li>Cranial nerves intact </li></ul><ul><li>Tone normal in arms, increased in legs </li></ul><ul><li>Power preserved in arms </li></ul><ul><li>Right leg 4+/ 5 global </li></ul><ul><li>Left leg 5/5 </li></ul><ul><li>Reflexes increased Legs>>arms </li></ul><ul><li>Ankle and knee clonus bilaterally </li></ul><ul><li>Babinski bilaterally </li></ul>
  11. 12. <ul><li>Decreased vibration sense in legs </li></ul><ul><li>Sensory level mid-lower thoracic </li></ul><ul><li>Romberg mildly positive </li></ul><ul><li>No cerebellar signs </li></ul><ul><li>Gait spastic </li></ul>Examination II
  12. 13. Investigations I <ul><li>CBC - normal </li></ul><ul><li>Biochem - normal </li></ul><ul><li>B12 - 596 (normal) </li></ul><ul><li>LP : - TP 368 </li></ul><ul><li>- PMN 1 , LYM 0, RBC 1 </li></ul><ul><li> - OCB -ve </li></ul>
  13. 14. <ul><li>Immunology: </li></ul><ul><ul><li>ANA </li></ul></ul><ul><ul><li>ANCA </li></ul></ul><ul><ul><li>Anti Ro / La </li></ul></ul><ul><ul><li>Anti-cardiolipin antibodies </li></ul></ul><ul><ul><li>Immune electrophoresis </li></ul></ul><ul><ul><li>ALL NEGATIVE </li></ul></ul>Investigations II
  14. 15. <ul><li>Infective: </li></ul><ul><ul><li>HIV -ve </li></ul></ul><ul><ul><li>HTLV-1 pending </li></ul></ul><ul><ul><li>VDRL pending </li></ul></ul>Investigations III
  15. 16. <ul><li>Imaging </li></ul><ul><ul><li>Previous MRI of cervical, thoracic and lumbar – sacral cord all normal </li></ul></ul><ul><ul><li>Repeat thoracic MRI normal </li></ul></ul>Investigations IV
  16. 17. DD <ul><li>Infective : - HTLV – 1 </li></ul><ul><li>- HIV </li></ul><ul><li>- Syphilis </li></ul><ul><li>Inflammatory - MS ( primary progressive) </li></ul><ul><li>Compressive - spondylosis </li></ul><ul><li>- neoplastic </li></ul><ul><li>Metabolic - B12 deficiency </li></ul><ul><li>Toxic - Lathyrism </li></ul><ul><li>Hereditary - Hereditary spastic paraparesis </li></ul><ul><li>Degenerative - Primary lateral sclerosis </li></ul>
  17. 23. Stained with Luxol fast blue – stains myelinated axons
  18. 24. A L A L
  19. 25. Usually lose ability to walk by age 60-70 Usually ambulant until death from other cause More prominent weakness, sensory loss and urinary symptoms Weakness, Sensory loss and urinary symptoms less marked More rapidly evolving course Slower course Onset after 35 years Onset before 35 years TYPE II TYPE I
  20. 32. HSP caused by impaired development of the corticospinal tract
  21. 34. PLP mutation <ul><li>PLP ( proteolipid protein) is one of major protein components of CNS myelin </li></ul><ul><li>A mutation at same locus is responsible for disease “ Pelizaeus-Merbacher” disease ( severe disease due to hypomyelination of CNS) </li></ul>
  22. 36. Paraplegin <ul><li>Codes for type of metalloprotease known as AAA metalloprotease. </li></ul><ul><li>Shown ( via immunofluorescence) to localise to within mitochondia. </li></ul><ul><li>Muscle biopsies of affected patients show evidence of mitochondrial dysfunction: </li></ul><ul><li>- e.g. Ragged – red fibres, cytochrome – oxidase negative fibres </li></ul>
  23. 37. <ul><li>Severity of muscle findings correlates with severity of HSP! </li></ul><ul><li>Relevance of muscle changes unclear </li></ul>Paraplegin II
  24. 38. <ul><li>AAA metalloproteases are invloved in “ chaperone-like” activity as well as other intracellular functions </li></ul><ul><li>Can participate in protein quality-control via binding to aberrantly-folded peptides and directing them towards proteolysis. </li></ul>Paraplegin III
  25. 39. <ul><li>? accumulation of aberrant peptides within the mitochondria results in mitochondrial dysfunction </li></ul><ul><li>Ultimately results in energy deficit for cell </li></ul><ul><li>Fits-in well with late age of onset </li></ul><ul><li>Ubiquitous expression of paraplegin…..selective dysfunction may reflect high metabolic demand </li></ul>Paraplegin II
  26. 41. Treatment options <ul><li>Antispasticity drugs ( e.g baclofen) </li></ul><ul><li>Regular physiotherapy </li></ul><ul><li>Botox injections </li></ul><ul><li>Minor surgical procedures </li></ul>
  27. 42. Follow-Up <ul><li>A novel mutation in the SPG4 (spastin) gene was subsequently isolated in this family </li></ul>

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