Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months

Abstract

Background: Krabbe 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.

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 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.

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.

Keywords: Early-infantile; Globoid cell leukodystrophy; Infantile; Krabbe disease; Natural history; Newborn screening.

Conflict of interest statement

Ethics approval and consent to participate

All research was conducted with the approval of the institutional review boards (IRB) from the University of North Carolina (IRB-08-0237) and the University of Pittsburgh (IRB-PRO11050036).

Consent for publication

Approval was granted by the institutional review boards (IRB) from the University of North Carolina (IRB-08-0237) and the University of Pittsburgh (IRB-PRO11050036).

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Ages at which common symptoms appear in children with Krabbe disease. The red diamond represents the median age at which the symptom began. The lines show the minimum and maximum ages that the symptom began

Fig. 2

Height, weight, and head circumference of boys (blue) and girls (red) with Krabbe disease. Each circle depicts an individual measurement; lines connecting circles show multiple measurements for an individual child. The gray lines represent standard growth curves (gray lines = 3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th, and 97th percentiles)

Fig. 3

Kaplan–Meier curve of overall survival with a median survival of 2 years. The red shaded area represents the 95% confidence interval. The median survival was 2 years. The x-axis shows age in years and the table below the axis shows the number of patients at risk for an event. The y-axis indicates the cumulative survival to specific age. Each drop in the curve represents a death. The vertical lines along the curve indicate that a child was censored while still living (either because they received UCBT or that they were still living at the cutoff date of 11/01/2018). The cumulative probability is calculated as the product of the interval probabilities up to the age of the event. The denominator for the calculation of the interval probability is the number of children at risk at the time of the event. Children who are censored while living do not contribute to the denominator for the next event

Fig. 4

CSF protein levels. CSF protein levels were plotted against patient age. The red diamonds represent the CSF protein level at a single point in time. Levels from the same individual, but at different points in time, are connected by red lines. The blue shaded area represents 95% variability of CSF protein level of the normal population by age

Fig. 5

Cognitive development in children with Krabbe disease. Age-equivalent scores (i.e., developmental age) are graphed against actual age for cognitive development. Evaluations performed on the same individuals, longitudinally, are connected by blue lines. The gray lines from left to right represent the approximate 97.5th, 50th and 2.5th percentiles of development for normal age-matched controls

Fig. 6

Language development in children with Krabbe disease. Age-equivalent scores (i.e., developmental age) are graphed against actual age for (a) receptive and (b) expressive language. Evaluations performed on the same individuals, longitudinally, are connected by blue lines. The gray lines from left to right represent the approximate 97.5th, 50th and 2.5th percentiles of development for normal age-matched controls. Because of limitations in the Mullen Scales of Early Learning, the lowest AE a patient could score is 1 month

Fig. 7

Motor development in children with Krabbe disease. Age-equivalent scores (i.e., developmental age) are graphed against actual age for (a) gross and (b) fine motor. Evaluations performed on the same individuals, longitudinally, are connected by blue lines. The gray lines from left to right represent the approximate 97.5th, 50th and 2.5th percentiles of development for normal age-matched controls