Autosomal Recessive Spinocerebellar Ataxia 7 (SCAR7) is Caused by Variants in TPP1, The Gene Involved in Classic Late-Infantile Neuronal Ceroid Lipofuscinosis 2 Disease (CLN2 Disease)


  • Additional Supporting Information may be found in the online version of this article.

  • Rowida Almomani's present address is Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

  • Communicated by Prof. Christine Van Broeckhoven

  • Contract grant sponsors: EC's 7th Framework Programme (223026, 223143, 200754); China Scholarship Council.

Correspondence to: Martijn H. Breuning, Center for Human and Clinical Genetics, Leiden University Medical Center, P.O. Box 9600, 2300RC, Leiden, The Netherlands. E-mail: or Anneke J.A. Maat-Kievit, Department of Clinical Genetics, Ee2091, ErasmusMC, Postbox 2040, 3000 CA Rotterdam, The Netherlands. E-mail:


Spinocerebellar ataxias are phenotypically, neuropathologically, and genetically heterogeneous. The locus of autosomal recessive spinocerebellar ataxia type 7 (SCAR7) was previously linked to chromosome band 11p15. We have identified TPP1 as the causative gene for SCAR7 by exome sequencing. A missense and a splice site variant in TPP1, cosegregating with the disease, were found in a previously described SCAR7 family and also in another patient with a SCAR7 phenotype. TPP1, encoding the tripeptidyl-peptidase 1 enzyme, is known as the causative gene for late infantile neuronal ceroid lipofuscinosis disease 2 (CLN2 disease). CLN2 disease is characterized by epilepsy, loss of vision, ataxia, and a rapidly progressive course, leading to early death. SCAR7 patients showed ataxia and low activity of tripeptidyl-peptidase 1, but no ophthalmologic abnormalities or epilepsy. Also, the slowly progressive evolution of the disease until old age and absence of ultra structural curvilinear profiles is different from the known CLN2 phenotypes. Our findings now expand the phenotypes related to TPP1-variants to SCAR7. In spite of the limited sample size and measurements, a putative genotype–phenotype correlation may be drawn: we hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7.