title: Neuronal ceroid lipofuscinosis (NCL) is caused by the entire deletion of CLN8 in the Alpenländische Dachsbracke dog.
abstract: Neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage diseases that have been described in a variety of dog breeds, where they are caused by different mutations in different genes. However, the causative gene defect in the breed Alpenländische Dachsbracke remained unknown so far. Here we present two confirmed cases of NCL in Alpenländische Dachsbracke dogs from different litters of the same sire with a different dam harboring the same underlying novel mutation in the CLN8 gene. Case 1, a 2-year-old male Alpenländische Dachsbracke was presented with neurological signs including disorientation, character changes including anxiety states and aggressiveness, sudden blindness and reduction of food intake. Magnetic resonance imaging (MRI) scans showed cerebral atrophy with dilation of all cerebral ventricles, thinning of the intermediate mass of the thalamus and widening of the cerebral sulci. Postmortem examination of the central nervous system (CNS) showed neuronal loss in the cerebral cortex, cerebellum and spinal cord with massive intracellular deposits of ceroid pigment. Additional ceroid-lipofuscin deposits were observed in the enteric nervous system and in macrophages within spleen, lymph nodes and lung. Ultrastructural analyses confirmed NCL with the presence of osmiophilic membrane bounded lamellar-like structures. Case 2, a 1,5-year old female Alpenländische Dachsbracke was presented with progressive generalized forebrain disease including mental changes such as fearful reactions to various kinds of external stimuli and disorientation. The dog also displayed seizures, absence of menace reactions and negative cotton-ball test with normal pupillary light reactions. The clinical and post mortem examination yielded similar results in the brain as in Case 1. Whole genome sequencing of Case 1 and PCR results of both cases revealed a homozygous deletion encompassing the entire CLN8 gene as the most likely causative mutation for the NCL form observed in both cases. The deletion follows recessive inheritance since the dam and a healthy male littermate of Case 1 were tested as heterozygous carriers. This is the first detailed description of CLN8 gene associated NCL in Alpenländische Dachsbracke dogs and thus provides a novel canine CLN8 model for this lysosomal storage disease. The presence of ceroid lipofuscin in extracerebral tissues may help to confirm the diagnosis of NCL in vivo, especially in new dog breeds where the underlying mutation is not known.
authors.affiliation: Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany. Electronic address: Manuela.Hirz@vetmed.uni-giessen.de.
authors.forename: M
authors.initials: M
authors.lastname: Hirz
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Drögemüller
authors.affiliation: Institute of Neuropathology, Justus-Liebig-University Giessen, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Schänzer
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland.
authors.forename: V
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Dietschi
authors.affiliation: Institute of Neuropathology Charité, University Berlin, Germany.
authors.forename: H H
authors.initials: HH
authors.lastname: Goebel
authors.affiliation: Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Hecht
authors.affiliation: Clinic for Small Animals - Surgery, Justus-Liebig-University Giessen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Laubner
authors.affiliation: Clinic for Small Animals - Surgery, Justus-Liebig-University Giessen, Germany.
authors.forename: M J
authors.initials: MJ
authors.lastname: Schmidt
authors.affiliation: Clinic for Small Animals - Neurology, Vetsuisse Faculty, University of Zurich, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Steffen
authors.affiliation: Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Hilbe
authors.affiliation: Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Köhler
authors.affiliation: Institute of Genetics, Vetsuisse Faculty, University of Bern, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Institute of Veterinary Pathology, Justus-Liebig-University Giessen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Herden
mesh_terms: D000818:Animals; D001344:Autopsy; D004283:Dog Diseases / Q000000981:diagnostic imaging* / Q000235:genetics* / Q000473:pathology; D004285:Dogs; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000662:veterinary; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology / Q000662:veterinary*; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D008565:Membrane Proteins
keywords: Alpenländische Dachsbracke; Deletion of CLN8; Dog; Lysosomal storage disease; Neuronal ceroid lipofuscinosis (NCL); Whole genome sequencing