Agnes Chen, MD Assistant Professor of Pediatrics and Neurology Harbor-UCLA Medical Center David Geffen School of Medicine at UCLA       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    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      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? •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   How precise are the stages? What is the current natural history in the era of modern supportive care? •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       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    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 STAGE 1 STAGE 2 STAGE 3     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