The Neuronal Ceroid Lipofuscinoses: A Case-Based Overview

Abstract

The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of inherited, progressive neurodegenerative diseases. Manifestations may begin between the neonatal period and young adulthood, depending on the various subtypes. The different phenotypes are similar and include visual loss, seizures, loss of motor and cognitive function, and early death. At autopsy, there is massive neuronal loss with characteristic storage in the remaining neurons. Neurons appear to die because of increased rates of apoptosis and altered autophagy as occurs in lysosomal storage diseases. A total of 13 neuronal ceroid lipofuscinoses (CLN) genetic forms have been identified so far (CLN type 1–14). In the present review, we propose a classification scheme of the major forms and report the case of a familial recurrence of NCL type 10, with a mutation in the CLN10 gene coding for the cathepsin D protein.

Keywords

neuronal ceroid lipofuscinosis - neurodegenerative diseases - CLN10

• References

• 1 Mole SE, Williams RE, Goebel HH. The Neuronal Ceroid Lipofuscinoses (Batten Disease). 2nd ed. Oxford, United Kingdom: Oxford University Press; 2011
• 2 Simonati A, Rizzuto N. Neuronal ceroid lipofuscinoses: pathological features of bioptic specimens from 28 patients. Neurol Sci 2000; 21 (3, Suppl): S63-S70
• 3 Bennett MJ, Rakheja D. The neuronal ceroid-lipofuscinoses. Dev Disabil Res Rev 2013; 17 (3) 254-259
• 4 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 (2) 241-252
• 5 Kohlschütter A, Williams RE, Goebel HH , et al. NCL diagnosis and algorithms. In: Mole SE, Williams RE, Goebel HH, eds. The Neuronal Ceroid Lipofuscinoses (Batten Disease). 2nd ed. Oxford, United Kingdom: Oxford University Press; 2011: 24-34
• 6 Williams RE, Mole SE. New nomenclature and classification scheme for the neuronal ceroid lipofuscinoses. Neurology 2012; 79 (2) 183-191
• 7 University College London. NCL mutation and patient database. Available at: www.ucl.ac.uk/ncl/mutation.shtml . Accessed Dec 3, 2015
• 8 Haltia M, Goebel HH. The neuronal ceroid-lipofuscinoses: a historical introduction. Biochim Biophys Acta 2013; 1832 (11) 1795-1800
• 9 Elleder M. Primary extracellular ceroid type lipopigment. A histochemical and ultrastructural study. Histochem J 1991; 23 (6) 247-258
• 10 Santorelli FM, Garavaglia B, Cardona F , et al. Molecular epidemiology of childhood neuronal ceroid-lipofuscinosis in Italy. Orphanet J Rare Dis 2013; 8: 19
• 11 Mitchison HM, Hofmann SL, Becerra CHR , et al. Mutations in the palmitoyl-protein thioesterase gene (PPT; CLN1) causing juvenile neuronal ceroid lipofuscinosis with granular osmiophilic deposits. Hum Mol Genet 1998; 7 (2) 291-297
• 12 Santavuori P, Vanhanen SL, Sainio K , et al. Infantile neuronal ceroid-lipofuscinosis (INCL): diagnostic criteria. J Inherit Metab Dis 1993; 16 (2) 227-229 Review
• 13 Steinfeld R, Heim P, von Gregory H , et al. Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet 2002; 112 (4) 347-354
• 14 Arsov T, Smith KR, Damiano J , et al. Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in CLN6. Am J Hum Genet 2011; 88 (5) 566-573
• 15 Smith KR, Damiano J, Franceschetti S , et al. Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage. Am J Hum Genet 2012; 90 (6) 1102-1107
• 16 Smith KR, Dahl HH, Canafoglia L , et al. Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis. Hum Mol Genet 2013; 22 (7) 1417-1423
• 17 Schulz A, Dhar S, Rylova S , et al. Impaired cell adhesion and apoptosis in a novel CLN9 Batten disease variant. Ann Neurol 2004; 56 (3) 342-350
• 18 Siintola E, Partanen S, Strömme P , et al. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 2006; 129 (Pt 6) 1438-1445
• 19 Hersheson J, Burke D, Clayton R , et al. Cathepsin D deficiency causes juvenile-onset ataxia and distinctive muscle pathology. Neurology 2014; 83 (20) 1873-1875
• 20 Bras J, Verloes A, Schneider SA, Mole SE, Guerreiro RJ. Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. Hum Mol Genet 2012; 21 (12) 2646-2650
• 21 Ramirez A, Heimbach A, Gründemann J , et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat Genet 2006; 38 (10) 1184-1191
• 22 Staropoli JF, Karaa A, Lim ET , et al. A homozygous mutation in KCTD7 links neuronal ceroid lipofuscinosis to the ubiquitin-proteasome system. Am J Hum Genet 2012; 91 (1) 202-208
• 23 Mole SE, Williams RE, Neuronal ceroid-lipofuscinoses. In: Pagon RA, Adam MP, Ardinger HH. , et al., eds. Seattle (WA): University of Washington, Seattle; 1993. –2015
• 24 Tomanin R, Zanetti A, D'Avanzo F , et al. Clinical efficacy of enzyme replacement therapy in paediatric Hunter patients, an independent study of 3.5 years. Orphanet J Rare Dis 2014; 9: 129
• 25 Parini R, Rigoldi M, Santus F , et al. Enzyme replacement therapy with agalsidase alfa in a cohort of Italian patients with Anderson-Fabry disease: testing the effects with the Mainz Severity Score Index. Clin Genet 2008; 74 (3) 260-266
• 26 Sechi A, Deroma L, Dardis A , et al. Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients. Mol Genet Metab 2014; 113 (3) 213-218
• 27 Lu JY, Nelvagal HR, Wang L, Birnbaum SG, Cooper JD, Hofmann SL. Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis. Mol Genet Metab 2015; 116 (1–2) 98-105
• 28 Neverman NJ, Best HL, Hofmann SL, Hughes SM. Experimental therapies in the neuronal ceroid lipofuscinoses. Biochim Biophys Acta 2015; 1852 (10 Pt B): 2292-2300