Abstract
BackgroundKrabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, β-galactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. If left without treatment, Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients.MethodsPatients with early onset Krabbe disease were prospectively evaluated between 1999 and 2018. Data sources included diagnostic testing, parent questionnaires, standardized multidisciplinary neurodevelopmental assessments, and neuroradiological and neurophysiological tests.ResultsWe evaluated 88 children with onset between 0 and 5 months. Median age of symptom onset was 4 months; median time to diagnosis after onset was 3 months. The most common initial symptoms were irritability, feeding difficulties, appendicular spasticity, and developmental delay. Other prevalent symptoms included axial hypotonia, abnormal deep tendon reflexes, constipation, abnormal pupillary response, scoliosis, loss of head control, and dysautonomia. Results of nerve conduction studies showed that 100% of patients developed peripheral neuropathy by 6 months of age. Median galactocerebrosidase enzyme activity was 0.05 nmol/h/mg protein. The median survival was 2 years.ConclusionsThis is the largest prospective natural history study of Krabbe disease. It provides a comprehensive description of the disease during the first 2 years of life. With recent inclusion of state mandated newborn screening programs and promising therapeutic interventions, enhancing our understanding of disease progression in early onset Krabbe disease will be critical for developing treatments, designing clinical trials, and evaluating outcomes.
Highlights
Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, βgalactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems
Patients with Krabbe disease have been divided into subtypes based on their age of onset: early-infantile (0–5 months), late-infantile (6–36 months), juvenile (3– 16 years), and adult (> 16 years) [13,14,15]
hemopoietic stem cell transplantation (HSCT) works by introducing donor derived cells that migrate to the CNS, providing compensatory function for defective GALC
Summary
Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, βgalactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients. Patients with Krabbe disease have been divided into subtypes based on their age of onset: early-infantile (0–5 months), late-infantile (6–36 months), juvenile (3– 16 years), and adult (> 16 years) [13,14,15] Despite these long-established conventions in nomenclature, few standardized natural history studies of Krabbe disease have been conducted to define the phenotypes and the viability of these arbitrary subtypes remains to be tested by a rigorous, prospectively designed protocol. Outcomes in patients who are already symptomatic have been comparatively worse [16,17,18,19,20]
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