Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: Clinical, molecular and biochemical characterization in three sibs

Raffaella Di Giacopo, Luciano Cianetti, Viviana Caputo, Ilaria La Torraca, Fiorella Piemonte, Andrea Ciolfi, Simona Petrucci, Claudio Carta, Paolo Mariotti, Vincenzo Leuzzi, Enza Maria Valente, Adele D'Amico, Annarita Bentivoglio, Enrico Bertini, Marco Tartaglia, Giuseppe Zampino

Research output: Contribution to journalArticlepeer-review


Abstract Objective This work investigated the molecular cause responsible for a late-onset parkinsonism-dystonia phenotype in three Italian siblings, and clinically characterize this condition. Methods Extensive neurophysiological and neuroradiological exams were performed on the three sibs. Most frequent late-onset metabolic diseases were ruled out through laboratory and biochemical analyses. A whole exome sequencing (WES) approach was used to identify the molecular cause underlying this condition. Results and conclusions Peculiar neurologic phenotype was characterized by dystonia-parkinsonism, cognitive impairment, gait ataxia and apraxia, pyramidal signs. WES analysis allowed the identification of a compound heterozygosity for two nucleotide substitutions (c.1340G>A, p.R447H; c.790C>T, p.Q264X) affecting the TPP1 gene in the three affected siblings. Biochemical analyses demonstrated abrogated TPP1 catalytic activity in primary skin fibroblasts, but revealed residual activity in leukocytes. Our findings document that late infantile neuronal ceroid lipofuscinosis (CLN2), which is caused by TPP1 gene mutations, should be considered in the differential diagnosis of autosomal recessive dystonia-parkinsonism syndromes. The availability of enzyme replacement therapy and other therapeutic approaches for ceroid lipofuscinoses emphasizes the value of reaching an early diagnosis in patients with atypical and milder presentation of these disorders.

Original languageEnglish
Article number13806
Pages (from-to)65-71
Number of pages7
JournalJournal of the Neurological Sciences
Issue number1-2
Publication statusPublished - Sep 15 2015


  • Autosomal recessive Parkinson-dystonia
  • Differential diagnoses of late infantile parkinsonism
  • Late infantile ceroid lipofuscinoses
  • Protracted CLN2 disease
  • TPP1 gene mutations
  • Whole exome sequencing

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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