A case of progressive spastic paraparesis

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Slide 2: R.A • 47 year-old man, M + 3, “ farmer”, Moroccan descent • 2 ½ - 3 year history of progressive leg weakness AskTheNeurologist.Com

Slide 3: History I Jan 2001:- • Tripped and fell and hurt back • Suffered LBP radiating down R leg • First noticed leg weakness AskTheNeurologist.Com

Slide 4: History 2 Over following 2 years 9 months:- • Progressive leg stiffness • R leg affected predominantly • Gait difficulty • Frequency of urination…occasionally incontinent AskTheNeurologist.Com

Slide 5: History 3 July 2001:- • Hepatosplenomegaly found incidentally • Anaemia • Myelofibrosis diagnosed (bone marow bx) • Treatment commenced ( B12, Folate) AskTheNeurologist.Com

Slide 6: History 4 • Denies - Arm involvement - Speech / visual disturbance - Cognitive involvement AskTheNeurologist.Com

Slide 7: History 5 • In childhood normal acquisition of motor- milestones • No noticeable problems in walking, running or athletic ability in early life AskTheNeurologist.Com

Slide 8: Family History Father:- • Age 40 began to suffer gait difficulty • Over 20 years progressed until bed-ridden with loss of sphincter control • Died aged 70 from “ pressure sores” • Arms, speech vision, cognition all unaffected at death AskTheNeurologist.Com

Slide 9: Family History II Sister (aged 47):- • Suffered from LBP aged 39 “ discopathy” • 1 ½ years ago others noticed gait disturbance • 1 year ago RTA…from then on she noticed gait difficulty. • Recently urgency of micturition AskTheNeurologist.Com

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Slide 11: Examination • Cognitively intact • Cranial nerves intact • Tone normal in arms, increased in legs • Power preserved in arms • Right leg 4+/ 5 global • Left leg 5/5 • Reflexes increased Legs>>arms • Ankle and knee clonus bilaterally • Babinski bilaterally AskTheNeurologist.Com

Progressive Spastic Paraparesis PBL case study

Slide 12: Examination II • Decreased vibration sense in legs • Sensory level mid-lower thoracic • Romberg mildly positive • No cerebellar signs • Gait spastic AskTheNeurologist.Com

Slide 13: Investigations I • CBC - normal • Biochem - normal • B12 - 596 (normal) • LP : - TP 368 - PMN 1 , LYM 0, RBC 1 - OCB -ve AskTheNeurologist.Com

Slide 14: Investigations II • Immunology: – ANA – ANCA – Anti Ro / La – Anti-cardiolipin antibodies – Immune electrophoresis ALL NEGATIVE AskTheNeurologist.Com

Slide 15: Investigations III • Infective: – HIV -ve – HTLV-1 pending – VDRL pending AskTheNeurologist.Com

Slide 16: Investigations IV • Imaging – Previous MRI of cervical, thoracic and lumbar – sacral cord all normal – Repeat thoracic MRI normal AskTheNeurologist.ComProgressive Spastic ParaparesisSlide 17: DD • Infective : - HTLV – 1 - HIV - Syphilis • Inflammatory - MS ( primary progressive) • Compressive - spondylosis - neoplastic • Metabolic - B12 deficiency • Toxic - Lathyrism • Hereditary - Hereditary spastic paraparesis • Degenerative - Primary lateral sclerosis AskTheNeurologist.Com

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Slide 22: Progressive-Spastic-Paraparesis

Slide 23: Stained with Luxol fast blue – stains myelinated axons AskTheNeurologist.Com

Slide 24: A L A L AskTheNeurologist.Com

Slide 25: TYPE I TYPE II Onset before 35 years Onset after 35 years Slower course More rapidly evolving course Weakness, Sensory loss More prominent and urinary symptoms weakness, sensory loss less marked and urinary symptoms Usually ambulant until Usually lose ability to death from other cause walk by age 60-70 AskTheNeurologist.Com

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Slide 32: HSP caused by impaired development of the corticospinal tract AskTheNeurologist.Com

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Slide 34: PLP mutation • PLP ( proteolipid protein) is one of major protein components of CNS myelin • A mutation at same locus is responsible for disease “ Pelizaeus-Merbacher” disease ( severe disease due to hypomyelination of CNS) AskTheNeurologist.Com

Slide 35: Progressive Spastic Paraparesis PBL case study

Slide 36: Paraplegin • Codes for type of metalloprotease known as AAA metalloprotease. • Shown ( via immunofluorescence) to localise to within mitochondia. • Muscle biopsies of affected patients show evidence of mitochondrial dysfunction: - e.g. Ragged – red fibres, cytochrome – oxidase negative fibres AskTheNeurologist.Com

Slide 37: Paraplegin II • Severity of muscle findings correlates with severity of HSP! • Relevance of muscle changes unclear AskTheNeurologist.Com

Slide 38: Paraplegin III • AAA metalloproteases are invloved in “ chaperone-like” activity as well as other intracellular functions • Can participate in protein quality-control via binding to aberrantly-folded peptides and directing them towards proteolysis. AskTheNeurologist.Com

Slide 39: Paraplegin II • ? accumulation of aberrant peptides within the mitochondria results in mitochondrial dysfunction • Ultimately results in energy deficit for cell • Fits-in well with late age of onset • Ubiquitous expression of paraplegin… ..selective dysfunction may reflect high metabolic demand AskTheNeurologist.Com

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Progressive Spastic Paraparesis PBL case study

Slide 41: Treatment options • Antispasticity drugs ( e.g baclofen) • Regular physiotherapy • Botox injections • Minor surgical procedures AskTheNeurologist.Com

Slide 42: Follow-Up • A novel mutation in the SPG4 (spastin) gene was subsequently isolated in this family AskTheNeurologist.Com

Progressive-Spastic-Paraparesis PBL case study