Abstract
The neuronal ceroid lipofuscinoses (NCLs) are autosomal recessively inherited disorders collectively considered to be one among the most common pediatric neurodegenerative lysosomal storage diseases. Four main clinical subtypes have been described based on the age at presentation: infantile, late infantile, juvenile and adult types. In addition, rare congenital cases of NCL have been reported in the literature. Previously, a homozygous mutation in the cathepsin D gene has been shown to cause congenital NCL in a patient of Pakistani origin. We report a case of a 39-week estimated gestational age female infant with severe microcephaly and hypertonia, whereas MRI showed generalized hypoplasia of the cerebral and cerebellar hemispheres. The infant died on day two after birth. Postmortem examination revealed a small, firm brain with extensive neuronal loss and gliosis. Remaining neurons, astrocytes and macrophages contained PAS-positive storage material with granular ultrastructure and immunoreactivity against sphingolipid activator protein D. A diagnosis of congenital NCL was rendered with a novel mutation, c.299C > T (p.Ser100Phe) in exon 3 of the cathepsin D gene. In the patient fibroblasts, cathepsin D activity was marginal, but the protein appeared stable and normally processed. This was confirmed in overexpression studies. Importantly, by identification of the mutation in the family, we were able to confirm the first prenatal diagnosis excluding cathepsin D deficiency in the younger sibling of the patient.
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Acknowledgments
We would like to thank Dr. Peter Lobel for his helpful discussions and Lauren Keswick M.S. Medical Illustration for her technical and artistic assistance. Portions of this data were presented as a poster at the XVI International Congress of Neuropathology in 2006 [Fritchie K, Thorne LB, Armao DM, Marino T, Tennison MB, Powell CM, Suzuki K Congenital Neuronal ceroid lipofuscinosis: a new disease and pursuit of molecular classification. Brain Pathology 16(Supp 1) (Sept 2006), p. S135, 2006]. This work was funded in part by the Folkhälsan Research Foundation and Academy of Finland (214343). Eija Siintola is a fellow of the Helsinki Biomedical Graduate School, University of Helsinki.
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Fritchie, K., Siintola, E., Armao, D. et al. Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). Acta Neuropathol 117, 201–208 (2009). https://doi.org/10.1007/s00401-008-0426-7
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DOI: https://doi.org/10.1007/s00401-008-0426-7