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Neuropediatrics 2024; 55(05): 303-310
DOI: 10.1055/s-0044-1787706
Original Article

Phenotypic/Genotypic Profile of Children with Neuronal Ceroid Lipofuscinosis in Southern Brazil

Berkmis Viana Santos
1   Department of Neurology, Hospital Pequeno Príncipe, Curitiba, Paraná, Brazil
,
Josiane de Souza
2   Departament of Medical Genetic, Hospital Pequeno Príncipe, Curitiba, Paraná, Brazil
,
Michelle Silva Zeny
1   Department of Neurology, Hospital Pequeno Príncipe, Curitiba, Paraná, Brazil
,
Mara Lúcia Schmitz Ferreira Santos
1   Department of Neurology, Hospital Pequeno Príncipe, Curitiba, Paraná, Brazil
,
Daniel Almeida do Valle 
1   Department of Neurology, Hospital Pequeno Príncipe, Curitiba, Paraná, Brazil
› Author Affiliations Funding None.
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Abstract

Introduction Neuronal ceroid lipofuscinoses (CLNs) are a group of lysosomal storage disorders of genetic origin, characterized by progressive neurodegeneration and intracellular accumulation of autofluorescent lipopigment. Thirteen genes related to CLNs are currently described, showing genetic and allelic heterogeneity, most of them with an autosomal recessive pattern. Due to the few descriptions of cases related to CLNs in Brazil, it is necessary to describe the phenotypic and genotypic characteristics of these patients. This study aims to evaluate the genotypic profile and correlate it with the phenotypic characteristics of patients with CLN in a children's hospital.

Methods This study was performed as a descriptive cross-sectional study with analysis of medical records, imaging, and laboratory tests of patients who had a confirmed molecular diagnosis of CLN.

Results The sample consisted of 11 patients from nine families with different subtypes of CLNs (CLN2, 5, 6, 7, and 8), with CLN2 being the most prevalent in the study. A total of 16 mutation variants were identified in genes associated with the five CLNs described in this study, with typical and atypical clinical phenotypes depending on the subtype and its variants.

Conclusion Novel mutations identified in the patients in this study showed phenotypes of rapid and severe progression in the CLN2 patient and similar characteristics in CLN6 and CLN7 patients, as previously described in the literature.

Keywords

ceroid lipofuscinosis - neuronal - genetic association studies - children


Publication History

Received: 23 March 2024

Accepted: 12 May 2024

Article published online:
10 June 2024

© 2024. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Jadav RH, Sinha S, Yasha TC. et al. Clinical, electrophysiological, imaging, and ultrastructural description in 68 patients with neuronal ceroid lipofuscinoses and its subtypes. Pediatr Neurol 2014; 50 (01) 85-95
    CrossrefPubMedGoogle Scholar
  • 2 Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology 2012; 79 (02) 183-191
    CrossrefPubMedGoogle Scholar
  • 3 Lourenço CM, Pessoa A, Mendes CC. et al. Revealing the clinical phenotype of atypical neuronal ceroid lipofuscinosis type 2 disease: Insights from the largest cohort in the world. J Paediatr Child Health 2021; 57 (04) 519-525
    CrossrefPubMedGoogle Scholar
  • 4 Cárcel-Trullols J, Kovács AD, Pearce DA. Cell biology of the NCL proteins: what they do and don't do. Biochim Biophys Acta 2015; 1852 (10 Pt B): 2242-2255
    CrossrefPubMedGoogle Scholar
  • 5 Naseri N, Sharma M, Velinov M. Autosomal dominant neuronal ceroid lipofuscinosis: clinical features and molecular basis. Clin Genet 2021; 99 (01) 111-118
    CrossrefPubMedGoogle Scholar
  • 6 Nelvagal HR, Lange J, Takahashi K, Tarczyluk-Wells MA, Cooper JD. Pathomechanisms in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta Mol Basis Dis 2020; 1866 (09) 165570
    CrossrefPubMedGoogle Scholar
  • 7 Puga ACS, Jardim LB, Chimelli L, De Souza CF, Clivati M. Neuronal ceroid lipofuscinoses: a clinical and morphological study of 17 patients from Southern Brazil. Arq Neuropsiquiatr 2000; 58: 597-606
    CrossrefPubMedGoogle Scholar
  • 8 Santorelli FM, Garavaglia B, Cardona F. et al. Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy. Orphanet J Rare Dis 2013; 8: 19
    CrossrefPubMedGoogle Scholar
  • 9 Wyrwich KW, Schulz A, Nickel M. et al. An adapted clinical measurement tool for the key symptoms of CLN2 disease. J Inborn Errors Metab Screen 2018; 6: 1-7
    CrossrefPubMedGoogle Scholar
  • 10 Richards S, Aziz N, Bale S. et al. ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17 (05) 405-424
    CrossrefPubMedGoogle Scholar
  • 11 Kohan R, Pesaola F, Guelbert N. et al. The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina. Biochim Biophys Acta 2015; 1852 (10 Pt B): 2301-2311
    CrossrefPubMedGoogle Scholar
  • 12 Pesaola F, Guelbert G, Venier AC. et al. “Atypical” phenotypes of neuronal ceroid lipofuscinosis: The Argentine Experience in the Genomic Era. J Inborn Errors Metab Screen 2021; 9: e20210009
    CrossrefPubMedGoogle Scholar
  • 13 Rahim AA, Russell C, Mole SE. Special edition: The NCLs/Batten disease. Biochim Biophys Acta Mol Basis Dis 2020; 1866: 165824
    CrossrefPubMedGoogle Scholar
  • 14 Gardner E, Mole SE. The Genetic basis of phenotypic heterogeneity in the neuronal ceroid lipofuscinoses. Front Neurol 2021; 12: 754045
    CrossrefPubMedGoogle Scholar
  • 15 Mole SE, Cotman SL. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta 2015; 1852 (10 Pt B): 2237-2241
    CrossrefPubMedGoogle Scholar
  • 16 Novoa MC, Burnham TF. Desafios para a universalização da genética clínica: o caso brasileiro. Rev Panam Salud Publica 2011; 29 (01) 61-68
    CrossrefPubMedGoogle Scholar
  • 17 Schulz A, Specchio N, de Los Reyes E. et al. Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study. Lancet Neurol 2024; 23 (01) 60-70
    CrossrefPubMedGoogle Scholar
  • 18 Kohan R, Carabelos MN, Xin W. et al. Neuronal ceroid lipofuscinosis type CLN2: a new rationale for the construction of phenotypic subgroups based on a survey of 25 cases in South America. Gene 2013; 516 (01) 114-121
    CrossrefPubMedGoogle Scholar
  • 19 Walus M, Kida E, Wisniewski KE, Golabek AA. Ser475, Glu272, Asp276, Asp327, and Asp360 are involved in catalytic activity of human tripeptidyl-peptidase I. FEBS Lett 2005; 579 (06) 1383-1388
    CrossrefPubMedGoogle Scholar
  • 20 Guhaniyogi J, Sohar I, Das K, Stock AM, Lobel P. Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis. J Biol Chem 2009; 284 (06) 3985-3997
    CrossrefPubMedGoogle Scholar
  • 21 Pal A, Kraetzner R, Gruene T. et al. Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. J Biol Chem 2009; 284 (06) 3976-3984
    CrossrefPubMedGoogle Scholar
  • 22 Bessa C, Teixeira CA, Dias A. et al. CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype. Mol Genet Metab 2008; 93 (01) 66-73
    CrossrefPubMedGoogle Scholar
  • 23 Xin W, Mullen TE, Kiely R. et al. CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL. Neurology 2010; 74 (07) 565-571
    CrossrefPubMedGoogle Scholar
  • 24 Teixeira CA, Espinola J, Huo L. et al. Novel mutations in the CLN6 gene causing a variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat 2003; 21 (05) 502-508
    CrossrefPubMedGoogle Scholar
  • 25 Rus C-M, Weissensteiner T, Pereira C. et al. Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center. Orphanet J Rare Dis 2022; 17 (01) 179
    CrossrefPubMedGoogle Scholar
  • 26 Badilla-Porras R, Echeverri-McCandless A, Weimer JM. et al. Neuronal ceroid lipofuscinosis type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica's experience. Orphanet J Rare Dis 2022; 17 (01) 13
    CrossrefPubMedGoogle Scholar
  • 27 Cannelli N, Garavaglia B, Simonati A. et al. Variant late infantile ceroid lipofuscinoses associated with novel mutations in CLN6. Biochem Biophys Res Commun 2009; 379 (04) 892-897
    CrossrefPubMedGoogle Scholar
  • 28 Chin JJ, Behnam B, Davids M. et al. Novel mutations in CLN6 cause late-infantile neuronal ceroid lipofuscinosis without visual impairment in two unrelated patients. Mol Genet Metab 2019; 126 (02) 188-195
    CrossrefPubMedGoogle Scholar
  • 29 Nicolaou P, Tanteles GA, Votsi C. et al. A novel CLN6 variant associated with juvenile neuronal ceroid lipofuscinosis in patients with absence of visual loss as a presenting feature. Front Genet 2021; 12: 746101
    CrossrefPubMedGoogle Scholar
  • 30 Sun G, Yao F, Tian Z, Ma T, Yang Z. A first CLN6 variant case of late infantile neuronal ceroid lipofuscinosis caused by a homozygous mutation in a boy from China: a case report. BMC Med Genet 2018; 19 (01) 177
    CrossrefPubMedGoogle Scholar
  • 31 Khan KN, El-Asrag ME, Ku CA. et al. for NIHR BioResource-Rare Diseases and UK Inherited Retinal Disease Consortium. Specific alleles of CLN7/MFSD8, a protein that localizes to photoreceptor synaptic terminals, cause a spectrum of nonsyndromic retinal dystrophy. Invest Ophthalmol Vis Sci 2017; 58 (07) 2906-2914
    CrossrefPubMedGoogle Scholar
  • 32 Pesaola F, Kohan R, Cismondi IA. et al. Enfermedad CLN8 congenita de lipofuscinosis neuronal ceroidea: un nuevo fenotipo. Rev Neurol 2019; 68 (04) 155-159
    PubMedGoogle Scholar
  • 33 Cannelli N, Cassandrini D, Bertini E. et al. Novel mutations in CLN8 in Italian variant late infantile neuronal ceroid lipofuscinosis: another genetic hit in the Mediterranean. Neurogenetics 2006; 7 (02) 111-117
    CrossrefPubMedGoogle Scholar
  • 34 Yıldırım M, Köse E, Keçeli AM, Balasar Ö, Şimşek N. Status dystonicus associated with CLN8 disease. Brain Dev 2021; 43 (04) 571-575
    CrossrefPubMedGoogle Scholar