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The Neuronal Ceroid Lipofuscinosis (NCL) Disorders Genetic Aspects

The Neuronal Ceroid Lipofuscinosis (NCL) Disorders Genetic Aspects. Katherine Sims, MD MGH-CHGR Joint Program in the NCL Disorders Department of Neurology MGH Harvard Medical School Boston, MA USA 2012. Batten, F. E.

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The Neuronal Ceroid Lipofuscinosis (NCL) Disorders Genetic Aspects

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  1. The Neuronal Ceroid Lipofuscinosis (NCL) Disorders Genetic Aspects Katherine Sims, MD MGH-CHGR Joint Program in the NCL Disorders Department of Neurology MGH Harvard Medical School Boston, MA USA 2012

  2. Batten, F. E. Cerebral degeneration with symmetrical changes in the maculae in two members of a family Trans.Ophthal.Soc.U.K. 23:386-390, 1903

  3. as a group, the most common neurodegenerative disorder of childhood + age dependent phenotypic expression developmental failure or regression/dementia seizures, myoclonus movement disorder visual loss/blindness premature death Neuronal Ceroid Lipofuscinosis Disorders

  4. NCL Disorders Genetic inheritance: autosomal recessive (AR) Incidence: ~1:12,500 live births (northern Europe, US) Pathology: lipofuscin accumulation in cytosomes proteins, oxidized alcohol-insoluble lipids, dolichols, dolichol-linked oligosaccharides, metal ions subunit C saposin D

  5. Ultrastructure of Storage Material curvilinear profiles (CL) granular osmiophilic deposits (GRODs) 10,000X 20,000X rectilinear bodies (RL) fingerprint profiles (FP) 30,000X 15,000X Haltia M. Biochim et Biophys Acta. 2006; 1762: 850-856

  6. The NCL Disorders Categorization:age of onset predominant/sequential cardinal features pathologic inclusions enzymatic or molecular characterization Diagnostic approach: neurodevelopmental history & exam biopsy –wbc (buffy coat), skin +/or muscle for EM ancillary testing[VER, ERG, EEG, MRI] enzyme analysisdiagnosis in CLN1 & CLN2 DNA testing:diagnosis prognosis, management/Rx trials genetic counseling

  7. NCL Molecular Timeline CLN 12-ATP13A2 CLN 14–KCTD7 CLN 4-DNAJC5 CLN 13-in review CLN 7-MFSD8 CLN 10-CTSD CLN 8/EPMR CLN 11-GRN CLN 1-PPT1 CLN 2-TPP1 CLN 3 CLN 6 CLN 5 1995 1997 1998 1999 2002 2006 2007 2011 2012 • identification over last 2 decades – 13 genes & encoded proteins • elaboration of lysosomal autophagy (including mitophagy) • and intersecting cellular catabolic pathways (including UPS) • increased pathobiologic understanding of lysosomal disorders • storage (toxicity) plus deficiency disorders • across the age spectrum – congenital to adult-onset dementias KB Sims NDC 2012

  8. CLN10 • Cathepsin D (CTSD) – lysosomal aspartic protease • transported to lysosome by mannose-6-phosphate receptor • prosaposin as substrate • autosomal recessive • congenital onset • rapid onset developmental failure, blindness, seizures • Tyr255X; Ser100Phe • late-infantile – splice mutations • juvenile – missense mutations

  9. CLN1Molecular Genetics • Palmitoyl-Protein Thioesterase 1 (PPT1) • autosomal recessive • DNA Point mutations Finnish:homozygous Arg122Trp – classic early onset • USA: infantile, late-infantile, juvenile,adult phenotypes • exon 1: Met1Ile,Leu10X, His39Gln • exon 2: Thr75Pro [13%],Met57AsnfsX45 • exon 3:Arg79Gly, Cys96Thr,Tyr109Asp • exon 4: Arg122Trp,del398X • exon 5: Arg151X [40%],Arg164X,Gln177Glu • exon 6: Glu184Lys,Val181Met • exon 7:Tyr215SerfsX5 • exon 8: Tyr247His

  10. CLN 14KCTD7 autosomal recessive infantile onset seizures, motor & speech developmental failure visual failure FP > GROD inclusions defective protein processing involved in cross-talk: autophagy & UPS mutation spectrum being defined

  11. CLN2Molecular Genetics • Autosomal recessive • cLINCL “classic” • TPP1 common mutations[North America & Europe] • ~ 60% mutations of total 98 [pan-ethnic] • ~ 78% patients at least one common mutation • Intron 5: c.509-1G>C [splice acceptor site] • Exon 6: Arg208X • other mutations: missense, splice, small & large deletions, nonsense

  12. Variant late-infantile (vLINCL) CLN5[“Finnish variant”; 13q22]soluble lysosomalglycoprotein; ER retention Fin major = c.1175delAT, late-infantile other mutations throughout gene, unique, pan-ethnic majority late infantile; some juvenile & adult cases CLN6[15q21-23] ER transmembrane protein • rare, classic late-infantile phenotype • pan-ethnic, ethnic predominate mutations, mild phenotypic effect • some adult onset – progressive myoclonic epilepsy (PME) CLN7[MFSD8; 4q28] major facilitator superfamily [MFS] transporter protein, lysosomal membrane localization originally identified in Turkish but pan-ethnic • rare juvenile or adult onset, milder, protracted course • CLN8[EMPR/vLINCL; 8p23] ER-Golgi transmembrane • Finnish – EPMR, juvenile onset, without visual loss [mutation-specific phenotype] • vLINCL – pan-ethnic, late-infantile onset, myoclonus & visual loss early

  13. CLN3JNCL (Batten) • autosomal recessive • lysosomal transmembrane protein • 1 kb deletion seen in ~ 73% disease alleles [>90% cases] • founder mutation • loss exons 7 & 8 • point mutations, rare but > 40 different identified [private] • small insertions/deletions • missense, nonsense, splice site • large deletions

  14. Early Adult-onset NCLs (KUFS) Phenotypic Classification adult-onset [30-40 yrs age] ø visual failure/retinal degeneration sporadic; AR >>AD lysosomal inclusions: FP, GROD, [RL] extracerebral biopsy failure often autopsy diagnosis Type A early: seizures, myoclonus, neuropsychiatric symptoms late: dementia, ataxia, dysarthria Type B early: mobility loss [extrapyramidal/cerebellar], dementia uncommon: seizures

  15. CLN4DNAJC5 ADKufs(Parry type) onset: teenage to 30-40yrs dementia, seizures, myoclonus preserved vision • gene identification: 2011 mutation spectrum being defined Cysteine-String Protein-a (CSPa) neuronal specific expression [synaptic vesicle surface complex] ? role in synaptic vessel degradation or synapse function ? interacts with PPT 1 (CLN1)

  16. CLN 11Progranulin (GRN) • link between rare lysosomal disorder & common neurodegenerative disease • highlight pleotropic effects of heterozygous/homozygous mutations • Single family report (Smith KR et al, AJHG June 2012) • autosomal recessive • GRN homozygous c.813_816del (p.Thr272Serfs*10) • rectilinear and fingerprint inclusions • mouse model (homozygous Grn deletion) --> microglial activation, increased ubiquination, excess lipopigment deposition • GRN heterozygous mutations in FTLD-TDP (VanDeerlin et al Nat Genet 2010) • autosomal dominant, TDP43 inclusions • 10-20% of FTLD are GRN-associated [FTLD-GRN] • TMEM106B variant SNPs increase genetic risk for FTLD-TDP but decreases penetrance of FTLD-GRN [co-localizes with progranulin in late endo-lysosomes]

  17. CLN12 ATP13A2 ATP13A2 - P-type ATPase, lysosomal protein transports inorganic cations & other substrates across cell membranes ? maintenance of lysosomal pH parkinsonism: linked to lysosomal autophagy pathway as well as alpha-synuclein ******** • Kufor-Rakeb syndrome; PARK9 autosomal recessive juvenile parkinsonism (rigidity, bradykinesia) pyramidal degeneraltion: spasticity, supranuclearupgaze paresis, dementia mutation spectrum: deletion, duplication, insertion, splice [truncating mutations]  ER retention pathology:impaired lysosomal degradation (Usenovic et al J Neurosci 2012)  accumulation alpha-synuclein and toxicity • CLN12 autosomal recessive, juvenile onset (2nd decade) seizures, cognitive & motor regression, +/- visual failure pathology:autofluorescent bodies, FP; retinal lipofuscin

  18. The NCL Disorders KB Sims NDC 2012

  19. Pathogenesis Model Settembre C et al. Hum. Mol. Genet. 2008;17:119-129

  20. NCL protein localization KCTD7(CLN 14) Ubiquitin-Proteosome DNAJC5 (CLN 4) CLN 6 CLN 8 CLN 3 CLN 5 TPP1 (CLN 2) GRN (CLN 11) PPT1 (CLN 1) CTSD (CLN 10) MFSD8 (CLN 7) mutant ATP13A2 (CLN 12) a-synuclein aggregation endosomal- and lysosomal autophagy pathway convergence

  21. NCL Diagnosis • Clinical phenotype • Electrophysiology • Neuroradiology • Pathologic inclusions • Enzyme testing for CLN1 [PPT1], CLN2 [TPP1] • Molecular screening

  22. Genetic Testing • Individual genes – Sanger sequencing • Next-generation sequencing (ngs) • NCL panel, including candidate genes • whole exome (WES) • whole genome (WGS) • Newborn screening Ware J S et al. Heart doi:10.1136/heartjnl-2011-300742

  23. MGH Neurogenetics DNA Diagnostic Lab ~ 2500 cases for NCL molecular testing [Sanger sequencing] molecularly undefined cases (7%) single mutation cases (3%) ~1000 probands and carriers with ≥1 pathogenic mutation CLN1 (2%) CLN2 (15%) CLN3 (43%) CLN5 (12%) CLN6 (15%) CLN7 (2%) CLN8 (1%) ~ 125 lymphoblastoid and ~50 fibroblast lines Biorepository iPS lines from NCL patients brain autopsy material from 12 NCL cases

  24. ngs NCL panels MGH Neurogenetics DNA Diagnostic Lab www.dnalab.org CLIA # 22DO883928

  25. Genetic Counselinga tool for families

  26. Susan Cotman, PhD, Marcy MacDonald, PhD John Staropoli MD, PhD Kathie Sims, MD Amel Karaa, MD Danielle Metterville, MS MGH-CHGR Joint Program in the NCL Disorders MGH Neurogenetics DNA Diagnostic Laboratory Kathie Sims, MD Winnie Xin, PhD Rosemary Kiely Xin Cao PhD Kendrick Goss PhD Other MGH and HMS Collaborators Mark Daly PhD – bioinformatics Vamsi Mootha MD-systems biology Michael Chu PhD – molecular geneticist Joe Thakuria MD – clinical geneticist Harvard iPS Core

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