TY - JOUR
T1 - Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis
AU - Kousi, Maria
AU - Siintola, Eija
AU - Dvorakova, Lenka
AU - Vlaskova, Hana
AU - Turnbull, Julie
AU - Topcu, Meral
AU - Yuksel, Deniz
AU - Gokben, Sarenur
AU - Minassian, Berge A.
AU - Elleder, Milan
AU - Mole, Sara E.
AU - Lehesjoki, Anna Elina
N1 - Funding Information:
We thank the families that participated in this study, as well as Marianne Rohrbach, Stacey Hewson, Eva Kostalova, Gul Serdaroglu, Larisa Stolnaja, Claudia Kitzmüller, Ahmed Mohamed and Teija-Tuulia Toivonen for their contribution. This study was supported by the Center of Excellence in Complex Disease Genetics of the Academy of Finland, the Folkhälsan Research Foundation, the Institute of Inherited Metabolic Disorders support (project MSM 0021620806), the Ministry of Health of the Czech Republic grant (NR/8351-3), the Wellcome Trust (054606) and the Batten Disease Support and Research Association. M.K. is fellow of the Helsinki Biomedical Graduate School. B.A.M. holds a Canada Research Chair in Pediatric Neurogenetics.
PY - 2009/3
Y1 - 2009/3
N2 - The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative disorders of childhood, are characterized by the accumulation of autofluorescent storage material mainly in neurons. Although clinically rather uniform, variant late-infantile onset NCL (vLINCL) is genetically heterogeneous with four major underlying genes identified so far. We evaluated the genetic background underlying vLINCL in 119 patients, and specifically analysed the recently reported CLN7/MFSD8 gene for mutations in 80 patients. Clinical data were collected from the CLN7/MFSD8 mutation positive patients. Eight novel CLN7/MFSD8 mutations and seven novel mutations in the CLN1/PPT1, CLN2/TPP1, CLN5, CLN6 and CLN8 genes were identified in patients of various ethnic origins. A significant group of Roma patients originating from the former Czechoslovakia was shown to bear the c.881C>A (p.Thr294Lys) mutation in CLN7/MFSD8, possibly due to a founder effect. With one exception, the CLN7/MFSD8 mutation positive patients present a phenotype indistinguishable from the other vLINCL forms. In one patient with an in-frame amino acid substitution mutation in CLN7/MFSD8, the disease onset was later and the disease course less aggressive than in variant late-infantile NCL. Our findings raise the total number of CLN7/MFSD8 mutations to 14 with the majority of families having private mutations. Our study confirms that CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. CLN7/MFSD8 should be considered a diagnostic alternative not only in variant late-infantile but also later onset NCL forms with a more protracted disease course. A significant number of NCL patients in Turkey exist, in which the underlying genetic defect remains to be determined.
AB - The neuronal ceroid lipofuscinoses (NCLs), the most common neurodegenerative disorders of childhood, are characterized by the accumulation of autofluorescent storage material mainly in neurons. Although clinically rather uniform, variant late-infantile onset NCL (vLINCL) is genetically heterogeneous with four major underlying genes identified so far. We evaluated the genetic background underlying vLINCL in 119 patients, and specifically analysed the recently reported CLN7/MFSD8 gene for mutations in 80 patients. Clinical data were collected from the CLN7/MFSD8 mutation positive patients. Eight novel CLN7/MFSD8 mutations and seven novel mutations in the CLN1/PPT1, CLN2/TPP1, CLN5, CLN6 and CLN8 genes were identified in patients of various ethnic origins. A significant group of Roma patients originating from the former Czechoslovakia was shown to bear the c.881C>A (p.Thr294Lys) mutation in CLN7/MFSD8, possibly due to a founder effect. With one exception, the CLN7/MFSD8 mutation positive patients present a phenotype indistinguishable from the other vLINCL forms. In one patient with an in-frame amino acid substitution mutation in CLN7/MFSD8, the disease onset was later and the disease course less aggressive than in variant late-infantile NCL. Our findings raise the total number of CLN7/MFSD8 mutations to 14 with the majority of families having private mutations. Our study confirms that CLN7/MFSD8 defects are not restricted to the Turkish population, as initially anticipated, but are a relatively common cause of NCL in different populations. CLN7/MFSD8 should be considered a diagnostic alternative not only in variant late-infantile but also later onset NCL forms with a more protracted disease course. A significant number of NCL patients in Turkey exist, in which the underlying genetic defect remains to be determined.
KW - CLN7
KW - MFSD8
KW - Mutations
KW - Neuronal ceroid lipofuscinosis
UR - http://www.scopus.com/inward/record.url?scp=64849091209&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=64849091209&partnerID=8YFLogxK
U2 - 10.1093/brain/awn366
DO - 10.1093/brain/awn366
M3 - Article
C2 - 19201763
AN - SCOPUS:64849091209
SN - 0006-8950
VL - 132
SP - 810
EP - 819
JO - Brain
JF - Brain
IS - 3
ER -