A prospective natural history study of Krabbe disease in a patient cohort with onset between 6 months and 3 years of life

Abstract

Background: Krabbe disease is a rare neurodegenerative disorder caused by a deficiency in the lysosomal enzyme galactocerebrosidase. Patients with Krabbe disease present with a variable disease course depending on their age of onset. The purpose of this prospective cohort study was to characterize the natural progression of Krabbe disease in a large group of patients with disease onset between 6 and 36 months of life who were evaluated with a standardized protocol.

Methods: All patients with Krabbe disease who had onset between 6 and 36 months of age and were prospectively evaluated between 2000 to 2017 were included. Standardized neurodevelopmental, physical, and neurological examinations were performed. Other assessments included neuroradiologic and neurophysiologic tests, enzyme level, cerebrospinal fluid analysis, and GALC pathogenic variants when available. Descriptive statistics were used for analysis. Survival curve was estimated using the Kaplan-Meier method.

Results: Thirty-five patients (26 boys, 9 girls) with disease onset between 6 and 36 months of age were evaluated. Median age at symptom onset was 11.5 months, with a median delay of 3.5 months between onset of symptoms and diagnosis. Of the 32 symptomatic patients, 23 presented with initial signs or symptoms of disease between 6 and 12 months of life; nine presented after 12 months. The most common initial signs and symptoms were loss of acquired developmental milestones, irritability, abnormal gait, motor delay, and abnormal muscle tone. The most common magnetic resonance imaging abnormality was increased T2 signal in the periventricular white matter. Nerve conduction velocity results were abnormal for 21 of 24 patients. Patients with onset after 12 months had less peripheral nerve involvement and slower disease progression. Abnormal cerebrospinal fluid protein levels were obtained for 13 of 16 symptomatic children. Protein levels were normal in all asymptomatic children.

Conclusions: Based on our findings, we propose reclassifying the group of patients with onset ≤12 months as infantile and the > 12 month group as late-infantile. Patients with onset > 12 months are more likely to benefit from hematopoietic stem cell transplantation. The proposed change in classifications will allow physicians to improve their ability to recognize and diagnose patients and more precisely assess potential treatment effects after transplantation.

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

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. Symptoms that were used in creating the severity index are designated with asterisks

Fig. 2

Height, weight, and head circumference of boys and girls with Krabbe disease. The x axis shows the patient's age in years and the y axis shows the height in centimeters. 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. The blue shaded area represents the 95% confidence interval. The overall median survival was 6.7 years. The x axis shows age in years and below the number of patients at risk for an event. The y axis probablity of survival

Fig. 4

Developmental progression of children with Krabbe disease from birth to 8 years of age. Age-equivalent scores (i.e., developmental age) are graphed against actual age for (a) cognitive development, (b) adaptive behavior, (c) receptive language, (d) expressive language, (e) gross motor function, and (f) fine motor function to allow comparisons across tests and monitor development over time. The lines and diamonds represent individual patients, with red indicating patients with disease onset ≤12 months and blue indicating patients with onset > 12 months. The shaded gray area represents typical development with the lines representing the mean and approximate 95% interval for typically developing children

Fig. 5

Close up of developmental progression of children with Krabbe disease, from birth to 3 years of age. Age-equivalent scores (i.e., developmental age) are graphed against actual age for (a) cognitive development, (b) adaptive behavior, (c) receptive language, (d) expressive language, (e) gross motor function, and (f) fine motor function to allow comparisons across tests and monitor development over time. The lines and diamonds represent individual patients, with red indicating patients with disease onset ≤12 months and blue indicating patients with onset > 12 months. The shaded gray area represents typical development with the lines representing the mean and approximate 95% interval for typically developing children

Fig. 6

Classifying early onset Krabbe patients. This is a conceptual diagram of a proposed patient classification system for children with onset between 0 and 36 months of age. By using this classification system, physicians will be better able to predict patient phenotype. The text in the blue arrows represents age of onset. The text in the blue circles represent a patient’s score on the severity index. Patients can be classified as either “late-infantile” or “infantile.” Infantile patients are further subdivided into “severe infantile” and “less severe infantile” based on their age of onset and severity score