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K30 Journal Club 22 September 2009

K30 Journal Club 22 September 2009. Agnes Chen, MD Assistant Professor of Pediatrics and Neurology Harbor-UCLA Medical Center David Geffen School of Medicine at UCLA. Krabbe disease. Infantile Krabbe disease. Autosomal recessive

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K30 Journal Club 22 September 2009

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  1. K30 Journal Club22 September 2009 Agnes Chen, MD Assistant Professor of Pediatrics and Neurology Harbor-UCLA Medical Center David Geffen School of Medicine at UCLA

  2. Krabbe disease

  3. Infantile Krabbe disease • Autosomal recessive • Defective lysosomal enzyme is in the brain and peripheral nerves: galactocerebrosidase • Normal labor, delivery, and early development • Median survival: 13 months after onset of symptoms due to rapid neurodegeneration • Failure to thrive, vegetative state, respiratory insufficiency and infections • Only one treatment available: hematopoetic stem cell transplantation

  4. Infantile Krabbe disease—Hagberg stages (1969) • Stage 1: irritability, inconsolable crying, hypersensitivity to light and touch • Stage 2: regression of motor milestones with increasing tone, flexor posturing of arms, extensor posturing of legs, severe arching of back, abnl eye mvmts, loss of visual fixation with optic atrophy, seizures • Stage 3: decerebrate, deaf, blind, unable to eat

  5. Treatment challenges • Hematopoietic stem cell transplantation only helps presymptomatic infants diagnosed at birth (known affected sibling or New York State newborn screening) • Intrathecal enzyme replacement is being developed • What are the outcome measures? • What is the natural history of this disease? • Is it ethical to do a clinical trial with a control arm?

  6. Longitudinal observation • All cases in Sweden in 14 years • Mean age of onset 4 months • Earliest age of onset 1 month • Mean age of death 1.2 years • Observations are prior to use of tube feeding

  7. Issues with the original Hagberg paper • How precise are the stages? • What is the current natural history in the era of modern supportive care?

  8. When is it too late to transplant? • How can we help general pediatricians diagnose these patients earlier? • Once the diagnosis is made, how can we help general pediatricians counsel families? • Looked at 42 Krabbe patients who were screened for transplant • A clinical staging system developed to categorize these patients • Then, examined relationship between posttransplant neurodevelopmental outcomes and pre-transplant stage • Major flaw in this study is the retrospective staging of patients

  9. Outcome measures for the brain • Neuropathology—brain biopsy • Imaging--MRI • Neurological exam—clinical parameters • Cognitive and behavioral testing • Biomarkers—CSF protein, enzyme level • Neurophysiological measures—nerve conduction velocity (NCV), brainstem auditory evoked response (BAER), visual evoked potentials (VEP), EEG

  10. How good are the outcome measures? • Linear correlations were calculated between stage of disease and baseline outcome measures • More of the patients in advanced stages had abnormal neurophysiological measures • However, lack of standardization and sensitivity make these poor outcome measures %Stage 1 %Stage 2 %Stage 3 %Stage 4 Trend P

  11. How was staging system created?

  12. Algorithm for staging system based on 27 patients

  13. Cognitive development STAGE 1 STAGE 2 STAGE 3

  14. Future directions • Staging system can be validated if patients staged prospectively prior to transplant • Planning our own natural history study • Natural history study will help determine what are good endpoints • Future treatment trial with intrathecal enzyme replacement will use results of natural history study as control data

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