title: Novel SACS mutations associated with intellectual disability, epilepsy and widespread supratentorial abnormalities.
abstract: We describe eight subjects from two consanguineous families segregating with autosomal recessive childhood onset spastic ataxia, peripheral neuropathy and intellectual disability. The degree of intellectual disability varied from mild to severe and all four affected individuals in one family developed aggressive behavior and epilepsy. Using exome sequencing, we identified two novel truncating mutations (c.2656C>T (p.Gln886*)) and (c.4756_4760delAATCA (p.Asn1586Tyrfs*3)) in the SACS gene responsible for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). MRI revealed typical cerebellar and pontine changes associated with ARSACS as well as multiple supratentorial changes in both families as likely contributing factors to the cognitive symptoms. Intellectual disability and behavioral abnormalities have been reported in some cases of ARSACS but are not a part of the characteristic triad of symptoms that includes cerebellar ataxia, spasticity and peripheral neuropathy. Our combined findings bring further knowledge to the phenotypic spectrum, neurodegenerative changes and genetic variability associated with the SACS gene of clinical and diagnostic importance.
authors.affiliation: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan; Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 08 Uppsala, Sweden. Electronic address: zafar.ali@igp.uu.se.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Ali
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 08 Uppsala, Sweden. Electronic address: joakim.klar@igp.uu.se.
authors.forename: Joakim
authors.initials: J
authors.lastname: Klar
authors.affiliation: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan. Electronic address: jameel.biotech@gmail.com.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Jameel
authors.affiliation: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan. Electronic address: kamalkhan9200@gmail.com.
authors.forename: Kamal
authors.initials: K
authors.lastname: Khan
authors.affiliation: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan. Electronic address: ambrinfatimach@yahoo.com.
authors.forename: Ambrin
authors.initials: A
authors.lastname: Fatima
authors.affiliation: Department of Radiology, Uppsala University, 751 85 Uppsala, Sweden. Electronic address: raili.raininko@radiol.uu.se.
authors.forename: Raili
authors.initials: R
authors.lastname: Raininko
authors.affiliation: Human Molecular Genetics Laboratory, National Institute for Biotechnology and Genetic Engineering (NIBGE), PIEAS, 38000 Faisalabad, Pakistan. Electronic address: shahid_baig2002@yahoo.com.
authors.forename: Shahid
authors.initials: S
authors.lastname: Baig
authors.affiliation: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 751 08 Uppsala, Sweden. Electronic address: niklas.dahl@igp.uu.se.
authors.forename: Niklas
authors.initials: N
authors.lastname: Dahl
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging; D003241:Consanguinity; D004827:Epilepsy / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D009421:Nervous System Malformations / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D055815:Young Adult
chemical_list: D006360:Heat-Shock Proteins; C404403:SACS protein, human
keywords: Epilepsy; Intellectual disability; MRI; SACS gene; Supratentorial abnormalities