Neuronal Ceroid Lipofuscinosis: Clinical and Laboratory Profile in Children from Tertiary Care Centre in South India

Abstract

Neuronal ceroid Lipofuscinosis (NCL), inherited disorders of lysosomal storage disorders, constitute the most common progressive encephalopathies with an incidence of 1.3 to 7 in 100,000 live births. We reported clinical, electrophysiological, radiological, ultrastructural, and molecular genetic features of NCL. This is a retrospective review, in a tertiary care center from January 2016 to December 2019. All children with clinical features of NCL and confirmed by pathogenic mutation and/or enzyme assay were included. A total of 60 children (male:female = 3:1) were studied. The commonest type was CLN 2 (41.7%). Neuroregression, seizures, and ataxia were present in all cases. Retinal arterial attenuation was seen in 38.33% cases. Magnetic resonance imaging (MRI) brain was abnormal in all patients, thalamic and caudate nucleus atrophy common in CLN1 (62%). Electroencephalography was abnormal in all children, but photoparoxysmal response at low intermittent photic stimulation frequencies was seen in four children of CLN2. Electron microscopy done in 43 children revealed abnormal inclusions in 20 (46.52%) children. Enzyme study showed low levels in 36 (78%) out of 46 cases. Of these, 21 had low tripeptidyl peptidase and 15 had low palmitoyl protein thioesterase levels. Molecular testing done in 26 cases showed pathogenic variant in 23 (88%) cases. Infantile onset with thalamic atrophy on MRI is common in CLN1 and refractory epilepsy, visual impairment and specific EEG changes are common in CLN2. These features are helpful in selecting enzyme assay for CLN1 versus CLN2. Electron microscopy helped in the diagnosis and genetic testing in subtyping. Thus, a multimode approach played a role in the diagnosis of NCL.

Keywords

cerebellar atrophy - CLN genetic loci - involuntary movements - myoclonic epilepsy - neuronal ceroid lipofuscinoses - neuroregression

Authors' Contributions

V.K.G. dedicated in supervision, guidance, and reviewing the manuscript. H.V. and K.S. were involved in the management of the child and the preparation of the manuscript. V.M.S. supported in the collection of data and the preparation of the manuscript. G.N. and R.S. were involved in diagnosis and final manuscript preparation. M.B., S.B., and M.R.N. provided valuable inputs in the diagnosis and final manuscript preparation.

Publication History

Received: 12 May 2020

Accepted: 08 July 2020

Article published online:
04 August 2020

• References

• 1 Glykys J, Sims KB. The neuronal ceroid lipofuscinosis disorders. In: Kenneth FSwaiman. ed. Swaiman Pediatric Neurology. 6th edition. Edinburgh: Elsevier saunders; 2018: 390-404
• 2 Zeman W, Donanne S, Dyken P, Green J. The NCL (Batten-Vogt syndrome). In: Vinken PJ, Bruyn GW. eds. Handbook of Neurology, Vol. 10. Amsterdam: NorthHolland Publishers; 1970: 588-679
• 3 Mole SE, Williams RE, Goebel HH. Correlations between genotype, ultrastructural morphology and clinical phenotype in the neuronal ceroid lipofuscinoses. Neurogenetics 2005; 6 (03) 107-126
• 4 Kousi M, Lehesjoki A-E, Mole SE. 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 (01) 42-63
• 5 Lewis G, Morrill AM, Conway-Allen SL, Kim B. Review of cerliponase alfa: recombinant human enzyme replacement therapy for late-infantile neuronal ceroid lipofuscinosis type 2. J Child Neurol 2020; 35 (05) 348-353
• 6 McLaren W, Pritchard B, Rios D, Chen Y, Flicek P, Cunningham F. Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 2010; 26 (16) 2069-2070
• 7 Zerbino DR, Achuthan P, Akanni W. et al. Ensembl 2018. Nucleic Acids Res 2018; 46 (D1): D754-D761
• 8 Landrum MJ, Lee JM, Benson M. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res 2016; 44 (D1): D862-D868
• 9 McKusick VA. Mendelian inheritance in man and its online version, OMIM. Am J Hum Genet 2007; 80 (04) 588-604
• 10 Welter D, MacArthur J, Morales J. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res 2014; 42 (Database issue): D1001-D1006
• 11 Stenson PD, Mort M, Ball EV. et al. The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 2017; 136 (06) 665-677
• 12 Mottaz A, David FP, Veuthey AL, Yip YL. Easy retrieval of single amino-acid polymorphisms and phenotype information using SwissVar. Bioinformatics 2010; 26 (06) 851-852
• 13 Auton A, Brooks LD, Durbin RM. et al; 1000 Genomes Project Consortium. A global reference for human genetic variation. Nature 2015; 526 (7571): 68-74
• 14 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
• 15 Nagasaki M, Yasuda J, Katsuoka F. et al; ToMMo Japanese Reference Panel Project. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat Commun 2015; 6: 8018
• 16 Sherry ST, Ward MH, Kholodov M. et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res 2001; 29 (01) 308-311
• 17 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
• 18 Kamate M, Prashanth GP, Hattiholi V. Clinico-investigative profile of infantile and late-infantile neuronal ceroid lipofuscinoses. Neurol India 2012; 60 (03) 316-320
• 19 Sinha S, Satishchandra P, Santosh V, Gayatri N, Shankar SK. Neuronal ceroid lipofuscinosis: a clinicopathological study. Seizure 2004; 13 (04) 235-240
• 20 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 (3A): 597-606
• 21 Kamate M, Hattiholi V. Novel neuroimaging finding in PPT1-Related neuronal ceroid lipofuscinosis. Pediatr Neurol 2012; 46: 325-328
• 22 Jadav RH, Sinha S, Yasha TC. et al. Magnetic resonance imaging in neuronal ceroid lipofuscinosis and its subtypes. Neuroradiol J 2012; 25 (06) 755-761
• 23 Autti T, Joensuu R, Aberg L. Decreased T2 signal in the thalami may be a sign of lysosomal storage disease. Neuroradiology 2007; 49 (07) 571-578
• 24 Specchio N, Bellusci M, Pietrafusa N, Trivisano M, de Palma L, Vigevano F. Photosensitivity is an early marker of neuronal ceroid lipofuscinosis type 2 disease. Epilepsia 2017; 58 (08) 1380-1388
• 25 Pérez-Poyato MS, Marfa MP, Abizanda IF. et al. Late infantile neuronal ceroid lipofuscinosis: mutations in the CLN2 gene and clinical course in Spanish patients. J Child Neurol 2013; 28 (04) 470-478
• 26 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
• 27 Acharya JN, Satishchandra P, Shankar SK. PME and related disorders, a clinical and pathological appraisal. Neurol India 1992; 40: 145-153
• 28 Sheth J, Mistri M, Bhavsar R. et al. Batten disease: biochemical and molecular characterization revealing novel PPT1 and TPP1 gene mutations in Indian patients. BMC Neurol 2018; 18 (01) 203