Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica’s experience
Tóm tắt
Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G > T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population. To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to characterize via molecular testing their causative mutations. DNA extracted from buccal swabs was used for CLN6 gene sequencing. Participants’ sociodemographic and clinical characteristics were also obtained from their medical records. Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens. This investigation supports that the previously characterized c.214G > T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.
Tài liệu tham khảo
Warrier V, Vieira M, Mole SE. Genetic basis and phenotypic correlations of the neuronal ceroid lipofusinoses. Biochim Biophys Acta Mol Basis Dis. 2013;1832(11):1827–30.
Nelvagal H, Lange J, Takahashi K, Tarczyluk-Wells M, Cooper J. Pathomechanisms in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta Mol Basis Dis. 2019;30:165570.
Johnson T, Cain J, White K, Ramirez-Montealegre D, Pearce D, Weimer J. Therapeutic landscape for Batten disease: current treatments and future prospects. Nat Rev Neurol. 2019;15(3):161–78.
Kousi M, Lehesjoki A, Mole S. Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2012;33(1):42–63.
Mole S. Neuronal ceroid lipofuscinoses (NCL). Eur J Paediatr Neurol. 2006;10(5–6):255–7.
Butz E, Chandrachud U, Mole S, Cotman S. Moving towards a new era of genomics in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta Mol Basis Dis. 2019;30:165571.
Bajaj L, Sharma J, di Ronza A, Zhang P, Eblimit A, Pal R, et al. A CLN6-CLN8 complex recruits lysosomal enzymes at the ER for Golgi transfer. J Clin Investig. 2020;130(8):4118–32.
Cárcel-Trullols J, Kovács AD, Pearce DA. Cell biology of the NCL proteins: what they do and don’t do. Biochim Biophys Acta Mol Basis Dis. 2015;1852(10):2242–55.
von Eisenhart-Rothe P, Grubman A, Greferath U, Fothergill L, Jobling A, Phipps J, et al. Failure of autophagy-lysosomal pathways in rod photoreceptors causes the early retinal degeneration phenotype observed in Cln6nclf mice. Investig Ophthalmol Vis Sci. 2018;59(12):5082–97.
Heine C, Koch B, Storch S, Kohlschütter A, Palmer D, Braulke T. Defective endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal degradation of endocytosed arylsulfatase A. J Biol Chem. 2004;279(21):22347–52.
Cain J, Likhite S, White K, Timm D, Davis S, Johnson T, et al. Gene therapy corrects brain and behavioral pathologies in CLN6-Batten disease. Mol Ther. 2019;27(10):1836–47.
Morgan J, Magee H, Wong A, Nelson T, Koch B, Cooper J, et al. A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease. PLoS ONE. 2013;8(11):e78694.
Mole SE, Cotman SL. Genetics of the neuronal ceroid lipofuscinoses (Batten disease). Biochim Biophys Acta Mol Basis Dis. 2015;1852(10):2237–41.
Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord. 2016;18(S2):73–88.
Cannelli N, Garavaglia B, Simonati A, Aiello C, Barzaghi C, Pezzini F, et al. Variant late infantile ceroid lipofuscinoses associated with novel mutations in CLN6. Biochem Biophys Res Commun. 2009;379(4):892–7.
Nafi O, Ramadan B, Riess O, Buchert R, Froukh T. Two cases of variant late infantile ceroid lipofuscinosis in Jordan. World J Clin cases. 2019;7(2):203–8.
Peña J, Montiel-Nava C, Delgado W, Hernández M, Cardozo J, Mora E, et al. Characterization of neuronal ceroid lipofuscinosis in Venezuelan children. Rev Neurol. 2004;38(1):42–8.
Petersen B, Handwerker M, Huppertz H. Neuroradiological findings in classical late infantile neuronal ceroid-lipofuscinosis. Pediatr Neurol. 1996;15(4):344–7.
Kohan R, Pesaola F, Guelbert N, Pons P, Oller-Ramírez A, Rautenberg G, et al. The neuronal ceroid lipofuscinoses program: A translational research experience in Argentina. Biochim Biophys Acta. 2015;1852(10 Pt B):2301–11.
Sharp J, Wheeler R, Parker K, Gardiner R, Williams R, Mole S. Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis. Hum Mutat. 2003;22(1):35–42.
Markham A. Cerliponase Alfa: first global approval. Drugs. 2017;77(11):1247–9.
Wheeler R, Sharp J, Schultz R, Joslin J, Williams R, Mole S. The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am J Hum Genet. 2002;70(2):537–42.
Matsumoto A, Nagashima M, Iwama K, Mizuguchi T, Makino S, Ikeda T, et al. Rapid progression of a walking disability in a 5-year-old boy with a CLN6 mutation. Brain Dev. 2019;41(8):726–30.
Gao H, Boustany R-MN, Espinola JA, Cotman SL, Srinidhi L, Antonellis KA, et al. Mutations in a Novel CLN6-Encoded Transmembrane Protein Cause Variant Neuronal Ceroid Lipofuscinosis in Man and Mouse. Am J Hum Genet. 2002;70(2):324–35.
Auger KJ, Ajene A, Lerner T. Progress toward the Cloning of CLN6, the gene underlying a variant LINCL. Mol Genet Metab. 1999;66(4):332–6.
Haines JL, Boustany RM, Alroy J, Auger KJ, Shook KS, Terwedow H, et al. Chromosomal localization of two genes underlying late-infantile neuronal ceroid lipofuscinosis. Neurogenetics. 1998;1(3):217–22.
Boustany R-M. Neurodystrophies and lipodosis. In: Moser H, editor. Handbook of clinical neurology, vol. 22. Amsterdam: Elsevier; 1997. p. 671–700.
Mole S. UCL NCL Mutation and, Patient Database [Internet]. 2019 [cited 2019 Nov 15]. Available from: https://www.ucl.ac.uk/ncl-disease/mutation-and-patient-database.
Cialone J, Adams H, Augustine E, Marshall F, Kwon J, Newhouse N, et al. Females experience a more severe disease course in Batten disease. J Inherit Metab Dis. 2012;35(3):549–55.
Ostergaard J. Juvenile neuronal ceroid lipofuscinosis (Batten disease): current insights. Degener Neurol Neuromuscul Dis. 2016;6:73–83.
Carvajal-Carmona L, Ophoff R, Service S, Hartiala J, Molina J, Leon P, et al. Genetic demography of Antioquia (Colombia) and the Central Valley of Costa Rica. Hum Genet. 2003;112(5–6):534–41.
Herra SA, Hevia FJ, Vargas M, Schosinsky K. Fulminant Wilson’s disease in Costa Rica. Clinico-pathological study of 7 cases. G E N. 1990;44(1):9–14.
Loudianos G, Dessi V, Lovicu M, Angius A, Figus A, Lilliu F, et al. Molecular characterization of Wilson disease in the Sardinian population—evidence of a founder effect. Hum Mutat. 1999;14(4):294–303.
Verma R, Raut T, Tiwari N, Malhotra K, Hussain N, Malhotra H. Late infantile neuronal ceroid lipofuscinosis: a case report with review of literature. Ann Indian Acad Neurol. 2013;16(2):282–5.
Simonati A, Williams R, Nardocci N, Laine M, Battini R, Schulz A, et al. Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5. Dev Med Child Neurol. 2017;59(8):815–21.
Steinfeld R, Heim P, von Gregory H, Meyer K, Ullrich K, Goebel HH, et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients withCLN2 mutations. Am J Med Genet. 2002;112(4):347–54.
Mole S, Haltia M. The Neuronal Ceroid-Lipofuscinoses (Batten Disease). In: Roger N, Rosenberg R, JM P, editors. Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease. San Diego, California; 2015. p. 793–808.
Al-Muhaizea M, Al-Hassnan Z, Chedrawi A. Variant late infantile neuronal ceroid lipofuscinosis (CLN6 gene) in Saudi Arabia. Pediatr Neurol. 2009;41(1):74–6.