Krabbe disease: Clinical, biochemical and molecular information on six new patients and successful retrospective diagnosis using stored newborn screening cards

• Published in: Molecular genetics and metabolism Vol. 105; no. 1; pp. 126 - 131
• Main Authors: Puckett, R.L., Orsini, J.J., Pastores, G.M., Wang, R.Y., Chang, R., Saavedra-Matiz, C.A., Torres, P.A., Zeng, B., Caggana, M., Lorey, F., Abdenur, J.E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2012
• Subjects: Adolescent; Bone marrow transplant; Brain - pathology; Child; Child, Preschool; DNA Mutational Analysis; Dried Blood Spot Testing; Fatal Outcome; Female; Galactocerebrosidase; Galactosylceramidase - metabolism; HSCT; Humans; Infant; Infant, Newborn; Krabbe disease; Leukodystrophy, Globoid Cell - blood; Leukodystrophy, Globoid Cell - diagnosis; Leukodystrophy, Globoid Cell - enzymology; Leukodystrophy, Globoid Cell - pathology; Lysosomal storage diseases; Magnetic Resonance Imaging; Male; Neonatal Screening; Newborn screening; Retrospective Studies; Newborn screening; Lysosomal storage diseases; Bone marrow transplant; Galactocerebrosidase; HSCT; Krabbe disease
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2011.10.010

To present clinical, biochemical and molecular information on six new clinically diagnosed Krabbe disease patients and assess the sensitivity of retrospective galactocerebrosidase measurement in their newborn screening samples.
Medical records were reviewed. Galactocerebrosidase activity was measured in leukocytes and, retrospectively, in the patients' newborn screening cards (stored for 1.4 to 13.5years). GALC gene mutation analysis was performed.
Five patients with Krabbe disease, one of whom also had hydrocephalus, became symptomatic during infancy. A sixth patient presented with seizures and developmental regression at age two and had a protracted disease course. Galactocerebrosidase activity in leukocytes ranged from 0.00 to 0.20nmol/h/mg protein. Low galactocerebrosidase activity (range: 3.2% to 11.1% of the daily mean), consistent with Krabbe disease, was detected in each of the newborn screening samples. GALC molecular analysis identified six previously unreported mutations and two novel sequence variants.
Our cases highlight the clinical variability of Krabbe disease. Galactocerebrosidase activity in newborn dried blood spots is a highly sensitive test, even when samples have been stored for many years. The high frequency of private mutations in the GALC gene may limit the use of genetic information for making treatment decisions in the newborn period.
► Clinical, biochemical, molecular information on six patients with Krabbe disease. ► One patient presented with hydrocephalus. ► Retrospective galactocerebrosidase analysis in NBS samples stored up to 13years. ► NBS test demonstrated 100% sensitivity and specificity. ► Five previously unreported mutations and 2 novel variants identified in GALC gene.