title: Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: Clinical, molecular and biochemical characterization in three sibs.
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.
  
  
  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.
authors.affiliation: Center for Neurocognitive Rehabilitation (CERiN), Mind/Brain Sciences (CIMEC), University of Trento, Azienda Provinciale per i Servizi Sanitari (APSS), Trento, Italy; Centro per i Disturbi del Movimento, Università Cattolica del sacro Cuore, Rome, Italy. Electronic address: raffaella.digiacopo@unitn.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Di Giacopo
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Luciano
authors.initials: L
authors.lastname: Cianetti
authors.affiliation: Dipartimento di Medicina Sperimentale, Università La Sapienza, Rome, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Caputo
authors.affiliation: Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: La Torraca
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Piemonte
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ciolfi
authors.affiliation: Dipartimento di Medicina Sperimentale, Università La Sapienza, Rome, Italy; Laboratorio Mendel, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Petrucci
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Carta
authors.affiliation: Istituto di Neuropsichiatria Infantile, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Mariotti
authors.affiliation: Dipartimento di Pediatria e Neuropsichiatria Infantile, Università La Sapienza, Rome, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Leuzzi
authors.affiliation: Laboratorio Mendel, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Dipartimento di Medicina e Chirurgia, Università di Salerno, Italy.
authors.forename: Enza Maria
authors.initials: EM
authors.lastname: Valente
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: D'Amico
authors.affiliation: Centro per i Disturbi del Movimento, Università Cattolica del sacro Cuore, Rome, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Bentivoglio
authors.affiliation: Unit of Neuromuscular and Neurodegenerative Diseases, Bambino Gesu' Children's Research Hospital, Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.affiliation: Dipartimento di Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Tartaglia
authors.affiliation: Istituto di Clinica Pediatrica, Università Cattolica del Sacro Cuore, Rome, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zampino
mesh_terms: D000626:Aminopeptidases / Q000235:genetics*; D019295:Computational Biology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D004569:Electroencephalography; D005071:Evoked Potentials / Q000502:physiology; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D009154:Mutation / Q000235:genetics*; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D057057:Serine Proteases / Q000235:genetics*; D035781:Siblings; D012867:Skin / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D000091346:Tripeptidyl-Peptidase 1; D055815:Young Adult
chemical_list: D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human
keywords: Autosomal recessive Parkinson–dystonia; Differential diagnoses of late infantile parkinsonism; Late infantile ceroid lipofuscinoses; Protracted CLN2 disease; TPP1 gene mutations; Whole exome sequencing