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DOI: 10.1055/s-0037-1613681
Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder
Publication History
17 October 2017
20 November 2017
Publication Date:
28 December 2017 (online)
Abstract
Neuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.
Keywords
congenital neuronal ceroid lipofuscinosis - CLN10 - CTSD - cathepsin D - targeted exome sequencing* Both authors contributed equally to the manuscript.
† Deceased author.
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References
- 1 Mole SE, Williams RE. Neuronal Ceroid-Lipofuscinoses. In: Adam MP, Ardinger HH, Pagon RA. , et al., eds. GeneReviews®. Seattle, WA: University of Washington; ; 1993–2017. https://www.ncbi.nlm.nih.gov/books/NBK1428/ . Accessed December 11, 2017
- 2 Nosková L, Stránecký V, Hartmannová H. , et al. Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal-dominant adult-onset neuronal ceroid lipofuscinosis. Am J Hum Genet 2011; 89 (02) 241-252
- 3 Nita DA, Mole SE, Minassian BA. Neuronal ceroid lipofuscinoses. Epileptic Disord 2016; 18 (S2): 73-88
- 4 Steinfeld R, Reinhardt K, Schreiber K. , et al. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet 2006; 78 (06) 988-998
- 5 Siintola E, Partanen S, Strömme P. , et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 2006; 129 (Pt 6): 1438-1445
- 6 Fritchie K, Siintola E, Armao D. , et al. Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). Acta Neuropathol 2009; 117 (02) 201-208
- 7 Doccini S, Sartori S, Maeser S. , et al. Early infantile neuronal ceroid lipofuscinosis (CLN10 disease) associated with a novel mutation in CTSD. J Neurol 2016; 263 (05) 1029-1032
- 8 Lek M, Karczewski KJ, Minikel EV. , et al; Exome Aggregation Consortium. Analysis of protein-coding genetic variation in 60,706 humans. Nature 2016; 536 (7616): 285-291
- 9 Baker EH, Levin SW, Zhang Z, Mukherjee AB. Evaluation of disease progression in INCL by MR spectroscopy. Ann Clin Transl Neurol 2015; 2 (08) 797-809
- 10 Baker EH, Levin SW, Zhang Z, Mukherjee AB. MRI brain volume measurements in infantile neuronal ceroid lipofuscinosis. AJNR Am J Neuroradiol 2017; 38 (02) 376-382
- 11 Zhang X, Ling J, Barcia G. , et al. Mutations in QARS, encoding glutaminyl-tRNA synthetase, cause progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. Am J Hum Genet 2014; 94 (04) 547-558
- 12 Boltshauser E, Scheer I, Huisman TA, Poretti A. Cerebellar cysts in children: a pattern recognition approach. Cerebellum 2015; 14 (03) 308-316