title: Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene.
abstract: Neuronal ceroid lipofuscinosis (NCL) refers to a growing heterogeneous group of neurodegenerative disorders characterized by lysosomal accumulation of abnormal autofluorescent material. NCLs are traditionally classified clinically according to their age of onset. Variable late infantile NCL (vLINCL) is the most genetically heterogeneous subtype as it has been shown to be caused by mutations in at least six genes. We report on 5 patients of a consanguineous family who presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration. Disease course was severe; all patients were in a vegetative state by the second decade of life, and eventually die prematurely (except in one case). Ultrastructural studies of brain and rectal mucosa disclosed accumulation of storage material in various patterns including fingerprint, curvilinear, and granular osmiophilic deposits consistent with the diagnosis of NCL. Brain pathologic features from a living patient are first reported here and shed light on disease progression and pathogenesis. Using a combination of whole genome autozygosity mapping and candidate gene direct sequencing, we identified a mutation in MFSD8, c.472G>A (p.Gly158Ser), which was found to segregate with the disease phenotype in the family. This study underscores the importance of a combined clinic-molecular workup in NCLs and other neurodegenerative conditions.
authors.affiliation: Metabolic Unit, Rambam Medical Center, Israel; Rappaport School of Medicine, Technion Haifa, Israel.
authors.forename: Hanna
authors.initials: H
authors.lastname: Mandel
authors.affiliation: Department of Pharmacology, University of California, San Diego, CA, USA.
authors.forename: Ksenya
authors.initials: K
authors.lastname: Cohen Katsanelson
authors.affiliation: Rappaport School of Medicine, Technion Haifa, Israel; Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: Morad
authors.initials: M
authors.lastname: Khayat
authors.affiliation: Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: Ilana
authors.initials: I
authors.lastname: Chervinsky
authors.affiliation: Department of Pathology, Rambam Medical Center, Israel.
authors.forename: Eugene
authors.initials: E
authors.lastname: Vladovski
authors.affiliation: Milman-David Biomedical Research Unit, Haifa, Israel.
authors.forename: Theodor C
authors.initials: TC
authors.lastname: Iancu
authors.affiliation: Rappaport School of Medicine, Technion Haifa, Israel; Department of Dermatology, Rambam Medical Center, Israel.
authors.forename: Margarita
authors.initials: M
authors.lastname: Indelman
authors.affiliation: Rappaport School of Medicine, Technion Haifa, Israel; Pediatric Department A', Emek Medical Center, Afula, Israel.
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Horovitz
authors.affiliation: Department of Dermatology, Tel Aviv Sourasky Medical Center, Israel; Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Eli
authors.initials: E
authors.lastname: Sprecher
authors.affiliation: Rappaport School of Medicine, Technion Haifa, Israel; Genetic Institute, Emek Medical Center, Afula, Israel.
authors.forename: Stavit A
authors.initials: SA
authors.lastname: Shalev
authors.affiliation: Rappaport School of Medicine, Technion Haifa, Israel; Genetic Institute, Emek Medical Center, Afula, Israel; Pediatric Department A', Emek Medical Center, Afula, Israel. Electronic address: spiegelr@zahav.net.il.
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
mesh_terms: D000293:Adolescent; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D020125:Mutation, Missense; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D055815:Young Adult
chemical_list: C522398:MFSD8 protein, human; D026901:Membrane Transport Proteins
keywords: Autosomal recessive; Lysosomal storage; Neuronal ceroid lipofuscinosis; Retinal degeneration