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

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Highlights

  • Emphasize the association between some TPP1 mutations and a mild CLN phenotype

  • Expand the spectrum of CLN mild phenotype, with parkinsonian and dystonic features

  • Emphasize the need of measuring TPP1 activity in fibroblasts in controversial cases

  • Document that WES can be useful for clinically undiagnosed, complex phenotypes

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.

Introduction

Neuronal ceroid lipofuscinoses (NCLs) are progressive neurodegenerative diseases characterized by aberrant intracellular storage of lipopigments in either granular, curvilinear, or fingerprint patterns in various tissues [1]. Among Italian newborns, NCLs have been estimated to have an incidence of 0.98/100,000 live birth, and a prevalence of 1.2/1,000,000 [2]. These disorders are inherited as autosomal recessive traits, and are genetically heterogeneous and clinically variable. Traditionally, NCLs have been classified by age at onset [3], [4] (NCL Mutation Database, http://www.ucl.ac.uk/ncl/mutation), with three major conditions, including infantile (INCL or CLN1), late-infantile (LINCL or CLN2) and juvenile (JNCL or CLN3) forms. In addition, rare late-infantile (CLN5, CLN6, CLN7, and CLN8), congenital (CLN10), and adult (ANCL) variants have been described. Among these disorders, CLN2 is caused by biallelic mutations in TPP1, which encodes the lysosomal enzyme tripeptidyl peptidase 1 [5], and is characterized by early onset (2–4 years), seizures, myoclonic jerks, and early progressive cognitive impairment. Also visual impairment manifests early (4–6 years), with an aggressive course, rapidly leading to blindness. Disease progression generally rapidly evolves over 6–8 months, with loss of motor and cognitive performances by the age of five. Life expectancy is usually poor (6 years to adolescence). Motor hallmark is limb spasticity with hypotonic trunk and loss of head control. Gastrostomy can be necessary within the first decade. MRI findings are not specific, consisting mostly in cerebellar and (later) cerebral atrophy [3], [4]. Photopic electroretinogram (ERG) amplitude reduces early, before the onset of visual impairment. Electroencephalogram (EEG) shows spikes in the occipital region in response to photic stimulation at 1–2 Hz [2]. Accumulation of pure curvilinear bodies is the histological hallmark of the disease.

In this report, we describe three sibs with a complex juvenile neurodegenerative phenotype characterized by cognitive and motor impairment, the latter presenting with myoclonus, dystonia and bradykinesia, which gradually progressed to apraxia and ataxia of gait. Whole exome sequencing (WES) allowed to identify the occurrence of compound heterozygosity for a truncating and a hypomorphic TPP1 mutation in the three sibs as the molecular event underlying this atypical phenotype. This report further expands the phenotypic spectrum associated with TPP1 mutations.

Section snippets

Laboratory analyses

The following laboratory investigations have been performed on the three sibs: blood count and acanthocytes research, apolypoprotein A-1 and B; blood chemistry/ammonium, coagulation, urine copper test, iron metabolism assessment, serum lactic and pyruvic acid, haemogas, serum amino acids, urinary organic acids, very long chain fatty acids, α, ß-esosaminidase, arylsulfatase A, α-mannosidase, ß-galactosidase, hormonal assessment, abdominal ultrasound (AU), EEG, somatosensory evoked potentials

Clinical characterization

The three siblings were full-term born from healthy apparently non-consanguineous parents from a small town of central Italy (25,000 inhabitants). Pregnancies and deliveries were uncomplicated, and early psychomotor development was normal in all sibs. The proband (patient 1) exhibited learning difficulties and decline of school performances at the age of 6 years. At the age of nine, he developed dystonic stuttering and frequent backward falls. He developed dysarthria at 12 years, swallowing

Discussion

Here we report on the identification of compound heterozygosity for a missense (c.1340G>A, p.R447H) and a truncating (c.790C>T, p.Q264X) mutation affecting TPP1 in three siblings exhibiting a peculiar neurologic phenotype characterized by dystonia–parkinsonism, cognitive impairment, gait ataxia and apraxia, and pyramidal signs.

TPP1 gene mutations had previously been established to cause the late-infantile disease type of neuronal ceroid lipofuscinosis, CLN2. The three affected siblings showed a

Founding source of the study

This work was in part supported by funds from Istituto Superiore di Sanità Ricerca Corrente (GGP10020) 2012 (to M.T.).

Conflict of Interest and financial disclosures of all authors (for the preceding 12 months) linked to this work

DI GIACOPO R, CIANETTI L, CAPUTO V, LA TORRACA I, PIEMONTE F, CIOLFI A, PETRUCCI S, CARTA C, MARIOTTI P, LEUZZI V, VALENTE E.M., D'AMICO, A; BERTINI E, TARTAGLIA M, ZAMPINO G. stock ownership in medically-related fields: none; intellectual property rights: none; consultancies: none; expert testimony: none; advisory boards: none; employment: none; partnerships: none; contracts: none; honoraria: none; royalties: none; grants: none; others: none. BENTIVOGLIO AR. Stock ownership in

Acknowledgments

The authors gratefully acknowledge the patients and their parents for participating in this study. The authors gratefully acknowledge Luca Weber for video editing.

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    Authors declare that the manuscript has not been published, nor submitted elsewhere for print or electronic publication consideration. The study was conducted following the principles outlined in the “Helsinki Declaration” 2004 (http://www.wma.net.ethicsunit.helsinki.htm). The informed consent was obtained for the publication of the video. The publication has been approved by all co-authors, as well as by the responsible authorities at the institute where the work has been carried out. All authors declare that there are not competing financial interests in relation to the submitted work.

    1

    These authors contributed equally as the senior investigators for this work.

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