Brain Advance Access originally published online on February 5, 2009
Brain 2009 132(3):810-819; doi:10.1093/brain/awn366
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Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis
1 Folkhälsan Institute of Genetics, Department of Medical Genetics and Neuroscience Center, University of Helsinki, Finland 2 Institute of Inherited Metabolic Disorders, Charles University, First Faculty of Medicine and University Hospital, Prague, Czech Republic 3 Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada 4 Department of Pediatrics, Hacettepe University Faculty of Medicine, Section of Child Neurology, Ankara, Turkey 5 Dr Sami Ulus Children's Hospital, Ankara, Turkey 6 Department of Pediatrics, Ege University Medical Faculty, Izmir, Turkey 7 MRC Laboratory for Molecular Cell Biology, General and Adolescent Paediatric Unit, UCL Institute of Child Health and Department of Genetics, Environment and Evolution, University College London, London, UK
Correspondence to: Anna-Elina Lehesjoki, Folkhälsan Institute of Genetics, Biomedicum Helsinki, P.O. Box 63 (Haartmaninkatu 8), 00014 University of Helsinki, Finland. E-mail: anna-elina.lehesjoki{at}helsinki.fi
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.
Key Words: CLN7; MFSD8; mutations; neuronal ceroid lipofuscinosis
Abbreviations: CL, curvilinear; ER, endoplasmic reticulum; NCLs, neuronal ceroid lipofuscinoses; vLINCL, variant late-infantile onset NCL
Received October 8, 2008. Revised November 28, 2008. Accepted December 5, 2008.