Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis

Maria Kousi, Eija Siintola, Lenka Dvorakova, Hana Vlaskova, Julie Turnbull, Meral Topcu, Deniz Yuksel, Sarenur Gokben, Berge A. Minassian, Milan Elleder, Sara E. Mole, Anna Elina Lehesjoki

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)810-819
Number of pages10
JournalBrain
Volume132
Issue number3
DOIs
StatePublished - Mar 1 2009

Fingerprint

Neuronal Ceroid-Lipofuscinoses
Mutation
Roma
Genes
Founder Effect
Czechoslovakia
Ceroid Lipofuscinosis, Neuronal, 6
Causes
Amino Acid Substitution
Turkey
Neurodegenerative Diseases
Population
Onset
Phenotype
Neurons
Gene
Defects

Keywords

  • CLN7
  • MFSD8
  • Mutations
  • Neuronal ceroid lipofuscinosis

ASJC Scopus subject areas

  • Medicine(all)
  • Arts and Humanities (miscellaneous)
  • Clinical Neurology

Cite this

Kousi, M., Siintola, E., Dvorakova, L., Vlaskova, H., Turnbull, J., Topcu, M., ... Lehesjoki, A. E. (2009). Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain, 132(3), 810-819. https://doi.org/10.1093/brain/awn366

Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. / Kousi, Maria; Siintola, Eija; Dvorakova, Lenka; Vlaskova, Hana; Turnbull, Julie; Topcu, Meral; Yuksel, Deniz; Gokben, Sarenur; Minassian, Berge A.; Elleder, Milan; Mole, Sara E.; Lehesjoki, Anna Elina.

In: Brain, Vol. 132, No. 3, 01.03.2009, p. 810-819.

Research output: Contribution to journalArticle

Kousi, M, Siintola, E, Dvorakova, L, Vlaskova, H, Turnbull, J, Topcu, M, Yuksel, D, Gokben, S, Minassian, BA, Elleder, M, Mole, SE & Lehesjoki, AE 2009, 'Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis', Brain, vol. 132, no. 3, pp. 810-819. https://doi.org/10.1093/brain/awn366
Kousi M, Siintola E, Dvorakova L, Vlaskova H, Turnbull J, Topcu M et al. Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. Brain. 2009 Mar 1;132(3):810-819. https://doi.org/10.1093/brain/awn366
Kousi, Maria ; Siintola, Eija ; Dvorakova, Lenka ; Vlaskova, Hana ; Turnbull, Julie ; Topcu, Meral ; Yuksel, Deniz ; Gokben, Sarenur ; Minassian, Berge A. ; Elleder, Milan ; Mole, Sara E. ; Lehesjoki, Anna Elina. / Mutations in CLN7/MFSD8 are a common cause of variant late-infantile neuronal ceroid lipofuscinosis. In: Brain. 2009 ; Vol. 132, No. 3. pp. 810-819.
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abstract = "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.",
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