Brain Advance Access originally published online on May 2, 2006
Brain 2006 129(6):1438-1445; doi:10.1093/brain/awl107
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Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis
1 Folkhälsan Institute of Genetics, Department of Medical Genetics and Neuroscience Center, University of Helsinki Helsinki, Finland 2 Institute of Biomedicine/Biochemistry and Neuroscience Research Program, Biomedicum Helsinki, University of Helsinki Helsinki, Finland 3 Department of Pathology, Haartman Institute, University of Helsinki Helsinki, Finland 4 Department of Pediatrics, Ullevål University Hospital Oslo, Norway 5 Department of Pathology, Ullevål University Hospital Oslo, Norway
Correspondence to: Dr Jaana Tyynelä, Institute of Biomedicine/Biochemistry, Haartmaninkatu 8, 00014 University of Helsinki, Helsinki, Finland E-mail: jaana.tyynela{at}helsinki.fi
Congenital neuronal ceroid-lipofuscinosis (NCL) is a devastating inherited neurodegenerative disorder of unknown metabolic basis. Eight patients with this rare disorder, all with similar clinical and neuropathological findings, have been reported, and here we describe two further patients. Previously, we showed that a mutation in the cathepsin D gene causes congenital NCL in sheep. On the basis of the neuropathological and ultrastructural similarities between the sheep and patients affected with congenital NCL, we screened the cathepsin D gene for mutations in a patient of Pakistani origin. We identified a nucleotide duplication, c.764dupA, in the cathepsin D gene in homozygous form in the patient, and in heterozygous form in his father. This duplication is likely to be disease-causing, as it creates a premature stop codon, predicting a truncation of the protein. When transiently expressed in cell cultures, the mutant protein was enzymatically inactive, but stable. In paraffin-embedded brain tissue samples of two affected siblings of the Pakistani patient, cathepsin D was absent, suggesting rapid degradation of the c.764dupA mutant cathepsin D at mRNA or protein level in vivo. Further, we were able to confirm lack of cathepsin D in the brain tissue of yet another, unrelated, patient of English origin with congenital NCL. On the basis of the present data, and the nearly identical clinical and/or pathological phenotype of the other reported cases of congenital NCL, it is reasonable to suggest that cathepsin D deficiency caused by mutations in the corresponding gene may underlie all cases of congenital NCL. The present observations also suggest that cathepsin D deficiency should be considered as a possible diagnosis in microcephalic neonates, who present with seizures at or before birth.
Key Words: lysosomal storage disorder; molecular biology; mutation; neuronal degeneration; newborn infant
Abbreviations: BHK, baby hamster kidney; CTSD, cathepsin D; GFAP, glial fibrillary acidic protein; NCL, neuronal ceroid-lipofuscinosis
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Received . Revised March 29, 2006. Accepted March 30, 2006.
*These authors contributed equally to this work.
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