title: Diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2 disease): Expert recommendations for early detection and laboratory diagnosis.
abstract: Neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of lysosomal storage disorders. NCLs include the rare autosomal recessive neurodegenerative disorder neuronal ceroid lipofuscinosis type 2 (CLN2) disease, caused by mutations in the tripeptidyl peptidase 1 (TPP1)/CLN2 gene and the resulting TPP1 enzyme deficiency. CLN2 disease most commonly presents with seizures and/or ataxia in the late-infantile period (ages 2-4), often in combination with a history of language delay, followed by progressive childhood dementia, motor and visual deterioration, and early death. Atypical phenotypes are characterized by later onset and, in some instances, longer life expectancies. Early diagnosis is important to optimize clinical care and improve outcomes; however, currently, delays in diagnosis are common due to low disease awareness, nonspecific clinical presentation, and limited access to diagnostic testing in some regions. In May 2015, international experts met to recommend best laboratory practices for early diagnosis of CLN2 disease. When clinical signs suggest an NCL, TPP1 enzyme activity should be among the first tests performed (together with the palmitoyl-protein thioesterase enzyme activity assay to rule out CLN1 disease). However, reaching an initial suspicion of an NCL or CLN2 disease can be challenging; thus, use of an epilepsy gene panel for investigation of unexplained seizures in the late-infantile/childhood ages is encouraged. To confirm clinical suspicion of CLN2 disease, the recommended gold standard for laboratory diagnosis is demonstration of deficient TPP1 enzyme activity (in leukocytes, fibroblasts, or dried blood spots) and the identification of causative mutations in each allele of the TPP1/CLN2 gene. When it is not possible to perform both analyses, either demonstration of a) deficient TPP1 enzyme activity in leukocytes or fibroblasts, or b) detection of two pathogenic mutations in trans is diagnostic for CLN2 disease.
authors.affiliation: Department of Diagnostic Genomics, PathWest Laboratory Medicine WA, Nedlands, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Fietz
authors.affiliation: Department of Medical Genetics, Alfaisal University, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Moeenaldeen
authors.initials: M
authors.lastname: AlSayed
authors.affiliation: Chemical Pathology, Camelia Botnar Laboratories, Great Ormond Street Hospital, London, UK.
authors.forename: Derek
authors.initials: D
authors.lastname: Burke
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Cohen-Pfeffer
authors.affiliation: Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvořáková
authors.affiliation: Medical Genetics Service, HCPA, Department of Genetics, UFRGS, INAGEMP, Porto Alegre, Brazil.
authors.forename: Roberto
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Izzo
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Jahnová
authors.affiliation: Newborn Screening and Metabolic Diagnostics Unit, Hamburg University Medical Center, Hamburg, Germany.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Lukacs
authors.affiliation: MRC Laboratory for Molecular Cell Biology, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mole
authors.affiliation: Facultad de Ciencias Médicas, Universidad Nacional de Córdoba and National Research Council-CONICET, Córdoba, Argentina.
authors.forename: Ines
authors.initials: I
authors.lastname: Noher de Halac
authors.affiliation: Sanford Children's Health Research Center, Sioux Falls, SD, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
authors.affiliation: Institute of Inherited Metabolic Disorders, First Faculty of Medicine, Charles University in Prague, General University Hospital in Prague, Prague, Czech Republic.
authors.forename: Helena
authors.initials: H
authors.lastname: Poupetova
authors.affiliation: Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Specchio
authors.affiliation: Neurogenetics DNA Diagnostic Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Winnie
authors.initials: W
authors.lastname: Xin
authors.affiliation: BioMarin Pharmaceutical Inc., Novato, CA, USA. Electronic address: NMiller@bmrn.com.
authors.forename: Nicole
authors.initials: N
authors.lastname: Miller
mesh_terms: D000626:Aminopeptidases / Q000097:blood* / Q000235:genetics; D001921:Brain / Q000503:physiopathology; D002675:Child, Preschool; D003704:Dementia / Q000150:complications / Q000503:physiopathology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000097:blood* / Q000235:genetics; D059788:Dried Blood Spot Testing; D042241:Early Diagnosis; D056947:Enzyme Replacement Therapy; D005260:Female; D006801:Humans; D007805:Language Development Disorders / Q000150:complications / Q000503:physiopathology; D007962:Leukocytes / Q000201:enzymology; D008297:Male; D009154:Mutation; D009472:Neuronal Ceroid-Lipofuscinoses / Q000097:blood* / Q000150:complications / Q000235:genetics / Q000503:physiopathology; D010641:Phenotype; D057057:Serine Proteases / Q000097:blood* / Q000235:genetics; D000091346:Tripeptidyl-Peptidase 1
chemical_list: D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human
keywords: Expert recommendations; Genetic cause of epilepsy; Laboratory diagnosis; Lysosomal storage disorder; Neurodegeneration; Neuronal ceroid lipofuscinosis