Maria L. Beltran-Quintero, Nicholas A. Bascou, Michele D. Poe, David A. Wenger, Carlos A. Saavedra-Matiz, Matthew J. Nichols and Maria L. Escolar Orphanet Journal of Rare Diseases 2019 14:46 Click here to view publication
Background
Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzymeA protein needed by the body to break down certain substances by causing a biochemical reaction within the cells. In Krabbe disease, galactocerebrosidase is the deficient enzyme. Words that end in , β-galactocerebrosidase, resulting in demyelinationA process whereby the body breaks down the protective coating surrounding nerves. 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.
Methods
Patients 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.
Results
We 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 spasticityA term that describes muscles that are continually contracted and often described by patients as stiff and tight muscles. This stiffness and tightness can interfere with many activities of daily livin, and developmental delay. Other prevalent symptoms included axial hypotoniaSynonymous with muscle weakness., 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 galactocerebrosidaseA specific enzyme that receives its instructions from the GALC gene. When the GALC gene isn’t working properly, the enzyme, galactocerebrosidase, is unable to break down certain fats called galactol More enzyme activity was 0.05 nmol/h/mg protein. The median survival was 2 years.
Conclusions
This 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.