title: Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB.
abstract: Mutations of the cystatin B gene (CSTB; OMIM 601145) are known to cause Unverricht-Lundborg disease or progressive myoclonic epilepsy-1A (EPM1A, MIM #254800). Most patients are homozygous for an expanded (>30) dodecamer repeat in the promoter region of CSTB, or are compound heterozygotes for the dodecamer repeat and a point mutation. We report two adolescent sisters born to consanguineous parents of Sri Lankan descent who presented with profound global developmental delay, microcephaly, cortical blindness and axial hypotonia with appendicular hypertonia. Neither sibling ever developed head control, independent sitting or ambulation, and never developed speech. The elder sister had a seizure disorder. Both sisters had profound microcephaly and distinct facial features. On serial brain imaging, they had progressive atrophy of the corpus callosum and supratentorial brain, and diffuse hypomyelination with progressive loss of myelin signal. Exome sequencing revealed both siblings to be homozygous for a c.218dupT (p.His75Serfs*2) mutation in exon 3 of CSTB. The neuroimaging features of our patients are consistent with those observed in Cstb-knockout mice, which supports the hypothesis that disease severity is inversely correlated with the amount of residual functional cystatin B protein.
authors.affiliation: Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Alan
authors.initials: A
authors.lastname: O'Brien
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Division of Paediatric Neuroradiology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Blaser
authors.affiliation: Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.|The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
authors.affiliation: Department of Paediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Paediatrics, Division of Neurology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
mesh_terms: D000293:Adolescent; D019575:Blindness, Cortical / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D003337:Corpus Callosum / Q000000981:diagnostic imaging / Q000473:pathology; D055313:Cystatin B / Q000235:genetics*; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D020279:Hereditary Central Nervous System Demyelinating Diseases / Q000175:diagnosis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D009186:Myelin Sheath / Q000473:pathology; D010375:Pedigree; D013577:Syndrome
chemical_list: C524994:CSTB protein, human; D055313:Cystatin B