Original ArticlePatterns of Magnetic Resonance Imaging Abnormalities in Symptomatic Patients With Krabbe Disease Correspond to Phenotype
Introduction
Krabbe disease is a rare, autosomal recessive neurodegenerative disease that involves both the central and peripheral nervous system. It results from a deficiency of the enzyme galactocerebrosidase that, under normal circumstances, is responsible for myelin turnover by breaking down galactocerebroside. Galactocerebrosidase is also responsible for the breakdown of galactosylsphingosine (psychosine), a substance that is highly toxic to oligodendroglia and myelin. Interest in Krabbe disease has increased in the past 7 years because of the advent of universal newborn screening for Krabbe disease in New York. It had been anticipated that the incidence of Krabbe disease would have been 1/100,000, with 90% of children having the early infantile phenotype.1 After 7 years and >1.8 million babies tested, however, only five infants have been identified as having early infantile Krabbe disease, whereas the majority of children with positive newborn screens, confirmatory low galactocerebrosidase activity, and two mutations have so far remained clinically normal.
These findings are of more than academic interest because the only treatment for Krabbe disease is hematopoietic cell transplantation, a procedure associated with significant morbidity and a 10% to 15% mortality rate. Moreover, to be effective in children with the early infantile phenotype, transplantation must be performed before symptom onset. To further complicate the situation, there are five different phenotypes of Krabbe disease, including early infantile (onset 0-6 months), late infantile (onset 7-12 months), later onset (onset 13 months-10 years), adolescent (onset 11-20 years), and adult (onset 21 years or greater).2, 3, 4 Unfortunately, neither low galactocerebrosidase activity nor most mutations reliably predict phenotype. Therefore an infant identified by the newborn screening program with low galactocerebrosidase activity and two mutations may have early infantile Krabbe disease, necessitating emergent hematopoietic cell transplantation, may have a later onset phenotype that may not become clinically manifest for decades, or may remain unaffected.
In response to the perceived need to identify predictors of phenotype in this rare disease, the World-Wide Krabbe Registry was opened in 2008. The registry has previously provided data on the results of neurodiagnostic studies in early and later onset phenotypes of Krabbe disease as well as the role of galactocerebrosidase in predicting phenotype.2, 3, 5 In our previous reports, the descriptions of initial magnetic resonance imaging (MRI) were based on the interpretations done in each patient's local medical center. We now describe the results of a central review of initial MRI in this symptomatic population to determine whether the pattern of MRI abnormality corresponds with phenotype.
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Methods and Materials
This retrospective nonblinded study was approved by the Children and Youth Institutional Review Board of the University at Buffalo School of Medicine. Informed consents were obtained from the patients' parents or from the patients themselves if they were adolescent and adult-onset patients. All patients were enrolled in the World-Wide Krabbe Registry. Initial MRI scans and official reports were requested from the hospitals at which the scans were performed. Scans had been obtained before
Early infantile Krabbe disease
MRI scans were available on 39 children whose symptom onset was 0-6 months. The ages at symptom onset, initial MRI, and diagnosis are provided in Table. Sixty-four percent (25/39) of children received their initial MRI between 3 and 6 months of age. The time between symptom onset and MRI was 3 months or less in 27/39 (69%). The first MRI was not obtained until at least 6 months after symptom onset in three children.
The initial MRI was abnormal in 38/39 children (Fig 1). The most common
Discussion
Loes developed a point-based system in the evaluation of MRI scans in Krabbe disease that was to be used in the assessment of novel therapies, much as he had done earlier with adrenoleukodystrophy and metachromatic leukodystrophy.6, 7, 8 There are several difficulties with this approach, however. First, the patients were divided into two categories—those <2 years and >2 years of age—which combines patients with early infantile, late infantile, and some later onset phenotypes into the “early
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