Acta Neuropathologica

, 117:201

Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10)

  • Karen Fritchie
  • Eija Siintola
  • Diane Armao
  • Anna-Elina Lehesjoki
  • Thomas Marino
  • Cynthia Powell
  • Michael Tennison
  • Jessica M. Booker
  • Sabine Koch
  • Sanna Partanen
  • Kinuko Suzuki
  • Jaana Tyynelä
  • Leigh B. Thorne
Case Report

DOI: 10.1007/s00401-008-0426-7

Cite this article as:
Fritchie, K., Siintola, E., Armao, D. et al. Acta Neuropathol (2009) 117: 201. doi:10.1007/s00401-008-0426-7

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.

Keywords

Cathepsin DLysosomal storage diseaseMolecular biologyNeuronal ceroid lipofuscinosis

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Karen Fritchie
    • 1
  • Eija Siintola
    • 2
  • Diane Armao
    • 1
  • Anna-Elina Lehesjoki
    • 2
  • Thomas Marino
    • 3
  • Cynthia Powell
    • 4
  • Michael Tennison
    • 5
  • Jessica M. Booker
    • 1
  • Sabine Koch
    • 6
  • Sanna Partanen
    • 6
  • Kinuko Suzuki
    • 1
  • Jaana Tyynelä
    • 6
  • Leigh B. Thorne
    • 1
    • 7
  1. 1.Department of Pathology and Laboratory MedicineUNC-Chapel HillChapel HillUSA
  2. 2.Department of Medical Genetics, Neuroscience Center, Folkhälsan Institute of GeneticsUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of RadiologyUNC-Chapel HillChapel HillUSA
  4. 4.Division of Genetics and Metabolism, Department of PediatricsUNC-Chapel HillChapel HillUSA
  5. 5.Department of NeurologyUNC-Chapel HillChapel HillUSA
  6. 6.Institute of Biomedicine/BiochemistryUniversity of HelsinkiHelsinkiFinland
  7. 7.Department of PathologyUNCChapel HillUSA