Nicholas Bascou, Anthony DeRenzo, Michele D. Poe and Maria L. Escolar
Bascou et al. Orphanet Journal of Rare Diseases (2018) 13:126
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Natural history studies are an essential part to understanding rare genetic disorders and they play a very important role in evaluating the efficacy of newly developed treatments such as gene therapy and enzyme replacement therapy. This is the largest and most comprehensive prospective study describing the natural history of patients with Krabbe disease with onset between 6 and 36 months of age.
This article summarizes the natural history of Krabbe disease and based on the findings, the authors propose shifting the current classification of Krabbe disease and classifying patients with onset between birth and 12 months as infantile and patients with onset between 13 and 36 months as late-infantile. Furthermore, by using this new proposed classification system, doctors will be better able to predict patient expression of the disease (phenotype).
- The prospective study evaluated 35 patients (26 boys, 9 girls) between 2000 to 2017. Patients were followed at one center using a standardized protocol.
- The average age at diagnosis was 17.8 months (median = 16, range = 0–39).
- The average delay between appearance of initial symptoms and diagnosis of Krabbe disease was approximately 4.6 months (median = 3.5, range = 0–21).
- Initial signs and symptoms of disease were defined as a change that caused parental and/or physician concern. For the 32 symptomatic patients, the most common initial signs and symptoms were:
- Loss of developmental milestones ( 41%),
- Irritability (38%),
- Abnormal gait ( 22%),
- Motor delay (16%),
- Abnormal muscle tone (13%), and
- Slurred speech (9%).
- Less common initial signs and symptoms were poor feeding (6%), loss of vision (6%), large head size (3%), and decreased arm movements (3%).
- Patients with onset > 12 months are more likely to benefit from hematopoietic stem cell transplantation.
- Currently, the early-infantile phenotype is used to describe patients with age of onset between 0 and 5 months, and the definition for the late-infantile phenotype typically describes patients with onset between 6 months and 36 months.
- Results of the current study bring these conventions into question and suggest that patients with onset between 6 and 12 months are more similar to patients with onset between 0 and 5 months than they are patients with onset after 12 months of age in respect to their symptoms and rate and severity of progression.
- In consideration of these findings, the authors propose shifting the paradigm and classifying patients with onset between birth and 12 months as infantile, and patients with onset between 13 and 36 months as late-infantile.
- Ultimately, a better understanding of the presenting symptoms of infantile and late-infantile Krabbe disease will increase awareness among pediatricians and result in earlier diagnostic referrals and recruitment for future clinical trials.