Agnes Chen, MD Assistant Professor of Pediatrics and

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
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
What are the outcome measures?
What is the natural history of this disease?
Is it ethical to do a clinical trial with a control
•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
•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
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
More of the patients in advanced stages had
abnormal neurophysiological measures
However, lack of standardization and
sensitivity make these poor outcome
%Stage 1
%Stage 2
%Stage 3
%Stage 4
Trend P
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