{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:38:28Z","timestamp":1760236708924,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T00:00:00Z","timestamp":1640044800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004281","name":"National Science Center","doi-asserted-by":"publisher","award":["2011\/01\/B\/NZ4\/03455"],"award-info":[{"award-number":["2011\/01\/B\/NZ4\/03455"]}],"id":[{"id":"10.13039\/501100004281","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>We report on a 36-year-old man with cerebellar-extrapyramidal syndrome and severe heart failure because of dilated cardiomyopathy of unknown origin. Dysarthria and cardiac arrhythmia began at early childhood (4 years of age). Brain MRI (28 years of age) demonstrated severe cerebellar atrophy. At the age 32, he presented with dysarthria, ataxia, dystonia, and tremor of the right hand, bilateral slowed neural conduction in the visual pathways, and decreased mental acuity. At the age of 33 years, the patient underwent cardiac transplantation because of severe dilated cardiomyopathy. In the TPP1 gene, biallelic variants were identified: previously reported p.(Leu13Pro) and novel p.(Tyr508Cys) variant. Additionally, hemizygous novel missense variant in the ABCD1 gene was inherited from the mother p.(Arg17His). Normal very-long-chain fatty acids (VLCFA) levels both in patient and his mother excluded ABCD1 mutation as the pathogenic one. Tripeptidyl peptidase 1 (TPP1) activity was reduced (8,8 U\/mg protein\/h; reference range: 47.4 \u00b1 10.7). In light microscopy the biopsy specimens obtained from explanted heart showed severe myocyte hypertrophy with perinuclear vacuolization with inclusions. Electron microscopy revealed absence of lipofuscin accumulation, no ultrastructural curvilinear profiles, fingerprint bodies, or granular osmiophilic deposits (GRODs) in lysosomes. As described here, the patient presents clinical symptoms observed in benign forms of ceroid lipofuscinosis type 2 (CLN2) and simultaneously some features of autosomal recessive spinocerebellar ataxia type 7 (SCAR7), which is also caused by mutations in the TPP1 gene.<\/jats:p>","DOI":"10.3390\/life12010003","type":"journal-article","created":{"date-parts":[[2021,12,21]],"date-time":"2021-12-21T09:50:43Z","timestamp":1640080243000},"page":"3","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Tripeptidyl Peptidase 1 (TPP1) Deficiency in a 36-Year-Old Patient with Cerebellar-Extrapyramidal Syndrome and Dilated Cardiomyopathy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2848-6407","authenticated-orcid":false,"given":"Agnieszka","family":"\u0141ugowska","sequence":"first","affiliation":[{"name":"Department of Genetics, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joanna K.","family":"Purzycka-Olewiecka","sequence":"additional","affiliation":[{"name":"Department of Genetics, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6286-5526","authenticated-orcid":false,"given":"Rafa\u0142","family":"P\u0142oski","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Medical University of Warsaw, ul. A. Pawi\u0144skiego 3c, 02-106 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gra\u017cyna","family":"Truszkowska","sequence":"additional","affiliation":[{"name":"Molecular Biology Laboratory, Department of Medical Biology, National Institute of Cardiology, ul. Alpejska 42, 04-628 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maciej","family":"Pronicki","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Children\u2019s Memorial Health Institute, al. Dzieci Polskich 20, 04-730 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Felczak","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2393-4194","authenticated-orcid":false,"given":"Mateusz","family":"\u015apiewak","sequence":"additional","affiliation":[{"name":"Magnetic Resonance Unit, Department of Radiology, National Institute of Cardiology, ul. Alpejska 42, 04-628 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aleksandra","family":"Podlecka-Pi\u0119towska","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Warsaw, ul. Banacha 1a, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martyna","family":"Sitek","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical University of Warsaw, ul. Banacha 1a, 02-097 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1451-2069","authenticated-orcid":false,"given":"Zofia T.","family":"Bili\u0144ska","sequence":"additional","affiliation":[{"name":"Unit for Screening Studies in Inherited Cardiovascular Diseases, National Institute of Cardiology, ul. Alpejska 42, 04-628 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Przemys\u0142aw","family":"Leszek","sequence":"additional","affiliation":[{"name":"Department of Heart Failure and Transplantology, National Institute of Cardiology, ul. Alpejska 42, 04-628 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0142gorzata","family":"Bednarska-Makaruk","sequence":"additional","affiliation":[{"name":"Department of Genetics, Institute of Psychiatry and Neurology, Al. Sobieskiego 9, 02-957 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,21]]},"reference":[{"key":"ref_1","first-page":"347","article-title":"Beretning om et maerkeligt Sygdomstilfaelde hos fire Soedskende i Naerheden af Roeraas","volume":"1","author":"Stengel","year":"1826","journal-title":"Eyr Et Med. Tidskr."},{"key":"ref_2","first-page":"165","article-title":"Sur un cas jusqu\u2019a pr\u00e9sente non d\u00e9crit de I\u00b4idiotie amaurotique famili\u00e0le compliqu\u00e9e par une hypoplasie du cervelet","volume":"13","author":"Jansky","year":"1908","journal-title":"Sborna L\u00e9k"},{"key":"ref_3","first-page":"7","article-title":"Ueber sp\u00e4tinfantile amaurotische Idiotie mit Kleinhirnsymptomen","volume":"50","author":"Bielschowsky","year":"1913","journal-title":"Dtsch. Z. Nervenheilkd."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"165570","DOI":"10.1016\/j.bbadis.2019.165570","article-title":"Pathomechanisms in the neuronal ceroid lipofuscinoses","volume":"1866","author":"Nelvagal","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7550","DOI":"10.1074\/jbc.M412047200","article-title":"Glycosaminoglycans modulate activation, activity, and stability of tripeptidyl-peptidase I in vitro and in vivo","volume":"280","author":"Golabek","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.gene.2016.08.031","article-title":"Analysis of large-scale whole exome sequencing data to determine the prevalence of genetically-distinct forms of neuronal ceroid lipofuscinosis","volume":"593","author":"Sleat","year":"2016","journal-title":"Gene"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S1474-4422(18)30368-5","article-title":"Clinical challenges and future therapeutic approaches for neuronal ceroid lipofuscinosis","volume":"18","author":"Mole","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1016\/S2352-4642(18)30179-2","article-title":"Disease characteristics and progression in patients with late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease: An observational cohort study","volume":"2","author":"Nickel","year":"2018","journal-title":"Lancet Child. Adolesc Health"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1002\/ajmg.10660","article-title":"Late infantile neuronal ceroid lipofuscinosis: Quantitative description of the clinical course in patients with CLN2 mutations","volume":"112","author":"Steinfeld","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.seizure.2018.08.027","article-title":"Homozygous missense TPP1 mutation associated with mild late infantile neuronal ceroid lipofuscinosis and the genotype-phenotype correlation","volume":"69","author":"Chen","year":"2019","journal-title":"Seizure"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1016\/j.oret.2020.01.011","article-title":"Symmetric Age Association of Retinal Degeneration in Patients with CLN2-Associated Batten Disease","volume":"4","author":"Kovacs","year":"2020","journal-title":"Ophthalmol. Retin."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1111\/cts.12292","article-title":"Precision Genomic Medicine in Cystic Fibrosis","volume":"8","author":"Chang","year":"2015","journal-title":"Clin. Trans. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1007\/s00401-008-0349-3","article-title":"Atypical CLN2 with later onset and prolonged course: A neuropathologic study showing different sensitivity of neuronal subpopulations to TPP1 deficiency","volume":"116","author":"Elleder","year":"2008","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jns.2015.05.021","article-title":"Protracted late infantile ceroid lipofuscinosis due to TPP1 mutations: Clinical, molecular and biochemical characterization in three sibs","volume":"356","author":"Cianetti","year":"2015","journal-title":"J. Neurol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1111\/jpc.15250","article-title":"Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world","volume":"57","author":"Pessoa","year":"2021","journal-title":"J. Paediatr. Child. Health"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1212\/WNL.0000000000001876","article-title":"TPP1 deficiency: Rare cause of isolated childhood-onset progressive ataxia","volume":"85","author":"Dy","year":"2015","journal-title":"Neurology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1002\/humu.22292","article-title":"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)","volume":"34","author":"Sun","year":"2013","journal-title":"Hum. Mutat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"858","DOI":"10.1136\/jmg.2004.019232","article-title":"A new locus for a childhood onset, slowly progressive autosomal recessive spinocerebellar ataxia maps to chromosome 11p15","volume":"41","author":"Breedveld","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_19","unstructured":"(2021, September 03). Available online: https:\/\/panelapp.genomicsengland.co.uk."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1924","DOI":"10.1002\/humu.23860","article-title":"Mutation update: Review of TPP1 gene variants associated with neuronal ceroid lipofuscinosis CLN2 disease","volume":"40","author":"Gardner","year":"2019","journal-title":"Hum. Mutat."},{"key":"ref_21","unstructured":"(2021, September 03). NCL Resource\u2014A Gateway for Batten Disease. Available online: https:\/\/www.ucl.ac.uk\/ncl-disease."},{"key":"ref_22","unstructured":"(2021, September 03). Leiden Open Variation Database LOVD 3. Available online: https:\/\/databases.lovd.nl\/shared\/genes\/TPP1."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"165681","DOI":"10.1016\/j.bbadis.2020.165681","article-title":"Future perspectives: What lies ahead for Neuronal Ceroid Lipofuscinosis research?","volume":"1866","author":"Cooper","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1542\/peds.2006-0163","article-title":"Factors associated with establishing a causal diagnosis for children with cardiomyopathy","volume":"118","author":"Cox","year":"2006","journal-title":"Pediatrics"},{"key":"ref_25","first-page":"237","article-title":"Variable clinical presentation of glycogen storage disease type IV: From severe hepatosplenomegaly to cardiac insufficiency. Some discrepancies in genetic and biochemical abnormalities","volume":"14","author":"Truszkowska","year":"2018","journal-title":"Arch. Med. Sci."},{"key":"ref_26","first-page":"73","article-title":"Juvenile neuronal ceroid lipofuscinosis (Batten disease): Current insights","volume":"6","author":"Ostergaard","year":"2016","journal-title":"Degener. Neurol. Neuromuscul. Dis."},{"key":"ref_27","first-page":"1158","article-title":"A family with adult type ceroid lipofuscinosis (Kufs\u2019 disease) and heart muscle disease: Report of two autopsy cases","volume":"34","author":"Sakajiri","year":"1995","journal-title":"Intern. Med. (Tokyo Jpn.)"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"165643","DOI":"10.1016\/j.bbadis.2019.165643","article-title":"Cardiac pathology in neuronal ceroid lipofuscinoses (NCL): More than a mere co-morbidity","volume":"1866","author":"Rietdorf","year":"2020","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1111\/j.1469-8749.2011.04170.x","article-title":"Progressive conduction defects and cardiac death in late infantile neuronal ceroid lipofuscinosis","volume":"54","author":"Fukumura","year":"2012","journal-title":"Dev. Med. Child. Neurol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/gt.2017.4","article-title":"Extraneuronal pathology in a canine model of CLN2 neuronal ceroid lipofuscinosis after intracerebroventricular gene therapy that delays neurological disease progression","volume":"24","author":"Katz","year":"2017","journal-title":"Gene Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e20200012","DOI":"10.1590\/2326-4594-jiems-2020-0012","article-title":"Position of Experts Regarding Follow-Up of Patients with Neuronal Ceroid Lipofuscinosis-2 Disease in Latin America","volume":"8","author":"Guelbert","year":"2020","journal-title":"J. Inborn Errors Metab. Screen."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.carpath.2007.09.004","article-title":"Neuronal ceroid lipofuscinosis in a 31-years old woman presenting a bi-ventricular heart failure with restrictive features","volume":"18","author":"Fealey","year":"2009","journal-title":"Cardiovasc. Pathol."},{"key":"ref_33","first-page":"357","article-title":"Cardiac involvement in juvenile amaurotic idiocy--A specific heart muscle disorder. Histological findings in 13 autopsied patients","volume":"89","author":"Baandrup","year":"1981","journal-title":"Acta Pathol. Microbiol. Scand. A"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1053\/ejpn.2000.0465","article-title":"Cardiac pathology in neuronal ceroid lipofuscinoses\u2014A clinicopathologic correlation in three patients","volume":"5","author":"Hofman","year":"2001","journal-title":"Eur. J. Paediatr. Neurol."},{"key":"ref_35","first-page":"350","article-title":"An autopsy case of juvenile neuronal ceroid-lipofuscinosis with dilated cardiomyopathy","volume":"40","author":"Tomiyasu","year":"2000","journal-title":"Rinsho Shinkeigaku"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1161\/01.CIR.83.2.504","article-title":"Impairment of the myocardial ultrastructure and changes of the cytoskeleton in dilated cardiomyopathy","volume":"83","author":"Schaper","year":"1991","journal-title":"Circulation"}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/1\/3\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:50:17Z","timestamp":1760169017000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/12\/1\/3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,21]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["life12010003"],"URL":"https:\/\/doi.org\/10.3390\/life12010003","relation":{},"ISSN":["2075-1729"],"issn-type":[{"type":"electronic","value":"2075-1729"}],"subject":[],"published":{"date-parts":[[2021,12,21]]}}}