Lysosomal storage diseases

Abstract

Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive traits. These disorders are individually rare but collectively affect 1 in 5,000 live births. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most LSDs have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. LSD-associated genes encode different lysosomal proteins, including lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for macromolecule catabolism, recycling and signalling, and defects that impair any of these functions cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, ‘storage’) or impair the transport of molecules, which can result in cellular damage. Consequently, the cellular pathogenesis of these diseases is complex and is currently incompletely understood. Several LSDs can be treated with approved, disease-specific therapies that are mostly based on enzyme replacement. However, small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Organs affected in disorders of lysosomes and LROs.
Fig. 2: Complexity of lysosomal proteins and their functions.
Fig. 3: Selected examples of cellular pathogenesis in LSDs.
Fig. 4: LROs.
Fig. 5: Gene therapy methods in use for the treatment of LSDs.
Fig. 6: Gene editing.

Change history

  • 17 May 2019

    In the originally published version of Figure 3, APP was incorrectly linked to CMA. In addition, the label for NCP2 was omitted, and GlcSph was incorrectly labelled as GlcCer. This figure has now been corrected.

  • 18 October 2018

    In the version of the article originally published, in Figure 2 and the accompanying legend, LIMP 2 was incorrectly referred to as LIMP 1. The article has now been corrected.

References

  1. 1.

    Di Fruscio, G. et al. Lysoplex: an efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway. Autophagy 11, 928–938 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Palmieri, M. et al. Characterization of the CLEAR network reveals an integrated control of cellular clearance pathways. Hum. Mol. Genet. 20, 3852–3866 (2011).

    Article  CAS  Google Scholar 

  3. 3.

    Chapel, A. et al. An extended proteome map of the lysosomal membrane reveals novel potential transporters. Mol. Cell Proteom. 12, 1572–1588 (2013).

    Article  CAS  Google Scholar 

  4. 4.

    Schroder, B. et al. Integral and associated lysosomal membrane proteins. Traffic 8, 1676–1686 (2007).

    Article  CAS  Google Scholar 

  5. 5.

    Sleat, D. E. et al. Mass spectrometry-based protein profiling to determine the cause of lysosomal storage diseases of unknown etiology. Mol. Cell Proteom. 8, 1708–1718 (2009).

    Article  CAS  Google Scholar 

  6. 6.

    Szklarczyk, D. et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 43, D447–D452 (2015).

    Article  CAS  Google Scholar 

  7. 7.

    Parenti, G., Andria, G. & Ballabio, A. Lysosomal storage diseases: from pathophysiology to therapy. Annu. Rev. Med. 66, 471–486 (2015).

    Article  CAS  Google Scholar 

  8. 8.

    Meikle, P. J., Hopwood, J. J., Clague, A. E. & Carey, W. F. Prevalence of lysosomal storage disorders. JAMA. 281, 249–254 (1999).

    Article  CAS  Google Scholar 

  9. 9.

    US National Library of Medicine, Genetics Home Reference. NIH https://ghr.nlm.nih.gov/ (2018).

  10. 10.

    Nita, D. A., Mole, S. E. & Minassian, B. A. Neuronal ceroid lipofuscinoses. Epilept. Disord. 18, 73–88 (2016).

    Google Scholar 

  11. 11.

    Aronson, N. N. Jr Aspartylglycosaminuria: biochemistry and molecular biology. Biochim. Biophys. Acta 1455, 139–154 (1999).

    Article  CAS  Google Scholar 

  12. 12.

    Witkop, C. J. et al. Albinism and Hermansky-Pudlak syndrome in Puerto Rico. Bol. Asoc. Med. P R. 82, 333–339 (1990).

    CAS  PubMed  Google Scholar 

  13. 13.

    Witkop, C. J., Almadovar, C., Pineiro, B. & Nunez Babcock, M. Hermansky-Pudlak syndrome (HPS). An epidemiologic study. Ophthalm. Paediatr. Genet. 11, 245–250 (1990).

    Article  CAS  Google Scholar 

  14. 14.

    Kishnani, P. S. et al. A retrospective, multinational, multicenter study on the natural history of infantile-onset Pompe disease. J. Pediatr. 148, 671–676 (2006).

    Article  Google Scholar 

  15. 15.

    Kishnani, P. S. et al. Recombinant human acid α-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 68, 99–109 (2007).

    Article  CAS  Google Scholar 

  16. 16.

    van der Meijden, J. C. et al. Long-term follow-up of 17 patients with childhood Pompe disease treated with enzyme replacement therapy. J. Inherit Metab. Dis. https://doi.org/10.1007/s10545-018-0166-3 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Bley, A. E. et al. Natural history of infantile G(M2) gangliosidosis. Pediatrics 128, e1233–e1241 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Schulz, A. et al. Study of intraventricular cerliponase alfa for CLN2 disease. N. Engl. J. Med. 378, 1898–1907 (2018).

    Article  CAS  Google Scholar 

  19. 19.

    Jones, H. N. et al. Oropharyngeal dysphagia in infants and children with infantile Pompe disease. Dysphagia 25, 277–283 (2010).

    Article  Google Scholar 

  20. 20.

    Nicolino, M. et al. Clinical outcomes after long-term treatment with alglucosidase alfa in infants and children with advanced Pompe disease. Genet. Med. 11, 210–219 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Chakrapani, A., Vellodi, A., Robinson, P., Jones, S. & Wraith, J. E. Treatment of infantile Pompe disease with alglucosidase alpha: the UK experience. J. Inherit Metab. Dis. 33, 747–750 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Settembre, C., Fraldi, A., Medina, D. L. & Ballabio, A. Signals from the lysosome: a control centre for cellular clearance and energy metabolism. Nat. Rev. Mol. Cell Biol. 14, 283–296 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Medina, D. L. & Ballabio, A. Lysosomal calcium regulates autophagy. Autophagy 11, 970–971 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Todkar, K., Ilamathi, H. S. & Germain, M. Mitochondria and lysosomes: discovering bonds. Front. Cell Dev. Biol. 5, 106 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Kilpatrick, B. S. et al. An endosomal NAADP-sensitive two-pore Ca(2+) channel regulates ER-endosome membrane contact sites to control growth factor signaling. Cell Rep. 18, 1636–1645 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Annunziata, I., Sano, R. & d’Azzo, A. Mitochondria-associated ER membranes (MAMs) and lysosomal storage diseases. Cell Death Dis. 9, 328 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Wong, Y. C., Ysselstein, D. & Krainc, D. Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554, 382–386 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Grabowski, G. A. Overview of inflammation in neurometabolic diseases. Semin. Pediatr. Neurol. 24, 207–213 (2017).

    Article  Google Scholar 

  29. 29.

    Rigante, D., Cipolla, C., Basile, U., Gulli, F. & Savastano, M. C. Overview of immune abnormalities in lysosomal storage disorders. Immunol. Lett. 188, 79–85 (2017).

    Article  CAS  Google Scholar 

  30. 30.

    Vitner, E. B., Platt, F. M. & Futerman, A. H. Common and uncommon pathogenic cascades in lysosomal storage diseases. J. Biol. Chem. 285, 20423–20427 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Vitner, E. B. et al. RIPK3 as a potential therapeutic target for Gaucher’s disease. Nat. Med. 20, 204–208 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Wada, R., Tifft, C. J. & Proia, R. L. Microglial activation precedes acute neurodegeneration in Sandhoff disease and is supressed by bone marrow transplantation. Proc. Natl Acad. Sci. USA 97, 10954–10959 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Jeyakumar, M. et al. Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126, 974–987 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Jeyakumar, M. et al. NSAIDs increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin. Ann. Neurol. 56, 642–649 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Bosch, M. E. & Kielian, T. Neuroinflammatory paradigms in lysosomal storage diseases. Front. Neurosci. 9, 417 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Smith, D., Wallom, K. L., Williams, I. M., Jeyakumar, M. & Platt, F. M. Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1. Neurobiol. Dis. 36, 242–251 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Yamaguchi, A. et al. Possible role of autoantibodies in the pathophysiology of GM2 gangliosidoses. J. Clin. Invest. 113, 200–208 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Ballabio, A. & Gieselmann, V. Lysosomal disorders: from storage to cellular damage. Biochim. Biophys. Acta 1793, 684–696 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Saftig, P. in Fabry Disease: Perspectives from 5 Years of FOS (eds Mehta, A., Beck, M. & Sunder-Plassmann, G.) 21–31 (2006).

  40. 40.

    Sidransky, E. & Lopez, G. The link between the GBA gene and parkinsonism. Lancet Neurol. 11, 986–998 (2012). This review summarizes the link between mutations in a rare disease-causing gene, GBA , and a common neurological disorder, PD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Annunziata, I. et al. Lysosomal NEU1 deficiency affects amyloid precursor protein levels and amyloid-beta secretion via deregulated lysosomal exocytosis. Nat. Commun. 4, 2734 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zanoteli, E. et al. Muscle degeneration in neuraminidase 1-deficient mice results from infiltration of the muscle fibers by expanded connective tissue. Biochim. Biophys. Acta 1802, 659–672 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Machado, E. et al. Regulated lysosomal exocytosis mediates cancer progression. Sci. Adv. 1, e1500603 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Bellettato, C. M. & Scarpa, M. Pathophysiology of neuropathic lysosomal storage disorders. J. Inherit. Metab. Dis. 33, 347–362 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Sidransky, E. et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N. Engl. J. Med. 361, 1651–1661 (2009). This study proves a strong genetic relationship between GBA mutations and risk of PD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Borger, D. K., Aflaki, E. & Sidransky, E. Applications of iPSC-derived models of Gaucher disease. Ann. Transl Med. 3, 295 (2015).

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    De Filippis, L., Zalfa, C. & Ferrari, D. Neural stem cells and human induced pluripotent stem cells to model rare CNS diseases. CNS Neurol Disord Drug Targets. https://doi.org/10.2174/1871527316666170615121753 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Lojewski, X. et al. Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway. Hum. Mol. Genet. 23, 2005–2022 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Panicker, L. M. et al. Induced pluripotent stem cell model recapitulates pathologic hallmarks of Gaucher disease. Proc. Natl Acad. Sci. USA 109, 18054–18059 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Aflaki, E. et al. A new glucocerebrosidase chaperone reduces alpha-synuclein and glycolipid levels in iPSC-derived dopaminergic neurons from patients with Gaucher disease and parkinsonism. J. Neurosci. 36, 7441–7452 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Mistry, P. K. et al. Gaucher disease: progress and ongoing challenges. Mol. Genet. Metab. 120, 8–21 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Beutler, E. Gaucher’s disease. N. Engl. J. Med. 325, 1354–1360 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Borger, D. K., Sidransky, E. & Aflaki, E. New macrophage models of Gaucher disease offer new tools for drug development. Macrophage (Houst) 2, e712 (2015).

    Google Scholar 

  54. 54.

    Aflaki, E. et al. Lysosomal storage and impaired autophagy lead to inflammasome activation in Gaucher macrophages. Aging Cell 15, 77–88 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Aflaki, E., Westbroek, W. & Sidransky, E. The complicated relationship between Gaucher disease and parkinsonism: insights from a rare disease. Neuron 93, 737–746 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Wong, K. et al. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol. Genet. Metab. 82, 192–207 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Vitner, E. B. & Futerman, A. H. in Sphingolipids in Disease. Handbook of Experimental Pharmacology, vol 216 (eds Gulbins E. & Petrache I.) 405–419 (Springer, Vienna 2013).

  58. 58.

    Vitner, E. B., Farfel-Becker, T., Eilam, R., Biton, I. & Futerman, A. H. Contribution of brain inflammation to neuronal cell death in neuronopathic forms of Gaucher’s disease. Brain 135, 1724–1735 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Vitner, E. B. et al. Induction of the type I interferon response in neurological forms of Gaucher disease. J. Neuroinflamm. 13, 104 (2016).

    Article  CAS  Google Scholar 

  60. 60.

    Allen, M. J., Myer, B. J., Khokher, A. M., Rushton, N. & Cox, T. M. Pro-inflammatory cytokines and the pathogenesis of Gaucher’s disease: increased release of interleukin-6 and interleukin-10. Q. J. Med. 90, 19–25 (1997).

    Article  CAS  Google Scholar 

  61. 61.

    Cox, T. M. Gaucher disease: understanding the molecular pathogenesis of sphingolipidoses. J. Inherit. Metab. Dis. 24, 106–121 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Pandey, M. K. et al. Complement drives glucosylceramide accumulation and tissue inflammation in Gaucher disease. Nature 543, 108–112 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Aker, M., Zimran, A., Abrahamov, A., Horowitz, M. & Matzner, Y. Abnormal neutrophil chemotaxis in Gaucher disease. Br. J. Haematol. 83, 187–191 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Deganuto, M. et al. Altered intracellular redox status in Gaucher disease fibroblasts and impairment of adaptive response against oxidative stress. J. Cell. Physiol. 212, 223–235 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Thomas, A. S., Mehta, A. & Hughes, D. A. Gaucher disease: haematological presentations and complications. Br. J. Haematol. 165, 427–440 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Enquist, I. B. et al. Murine models of acute neuronopathic Gaucher disease. Proc. Natl Acad. Sci. USA 104, 17483–17488 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Farfel-Becker, T., Vitner, E. B. & Futerman, A. H. Animal models for Gaucher disease research. Dis. Model. Mech. 4, 746–752 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Tayebi, N. et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol. Genet. Metab. 73, 313–321 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Aflaki, E. et al. Efferocytosis is impaired in Gaucher macrophages. Haematologica 102, 656–665 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Pringsheim, T., Jette, N., Frolkis, A. & Steeves, T. D. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 29, 1583–1590 (2014).

    Article  Google Scholar 

  71. 71.

    Mazzulli, J. R. et al. Gaucher disease glucocerebrosidase and alpha-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell 146, 37–52 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Cullen, V. et al. Acid beta-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter alpha-synuclein processing. Ann. Neurol. 69, 940–953 (2011).

    Article  CAS  Google Scholar 

  73. 73.

    Zunke, F. et al. Reversible conformational conversion of alpha-synuclein into toxic assemblies by glucosylceramide. Neuron 97, 92–107 (2018).

    Article  CAS  Google Scholar 

  74. 74.

    Robak, L. A. et al. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease. Brain 140, 3191–3203 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Suzuki, Y., Oshima, A. & Nanba, E. in The Metabolic and Molecular Bases of Inherited Disease Vol. 3 (eds Scriver, C. R., Beadet, A. L., Valle, D. & Sly, W. S.) 3775–3809 (McGraw Hill, 2001).

  76. 76.

    d’Azzo, A., Tessitore, A. & Sano, R. Gangliosides as apoptotic signals in ER stress response. Cell Death Differ. 13, 404–414 (2006).

    Article  CAS  Google Scholar 

  77. 77.

    Ledeen, R. W. & Wu, G. GM1 ganglioside: another nuclear lipid that modulates nuclear calcium. GM1 potentiates the nuclear sodium-calcium exchanger. Can. J. Physiol. Pharmacol. 84, 393–402 (2006).

    Article  CAS  Google Scholar 

  78. 78.

    Ledeen, R. W. & Wu, G. The multi-tasked life of GM1 ganglioside, a true factotum of nature. Trends Biochem. Sci. 40, 407–418 (2015).

    Article  CAS  Google Scholar 

  79. 79.

    Hahn, C. N. et al. Generalized CNS disease and massive GM1-ganglioside accumulation in mice defective in lysosomal acid beta-galactosidase. Hum. Mol. Genet. 6, 205–211 (1997).

    Article  CAS  Google Scholar 

  80. 80.

    Tessitore, A. et al. A GM1-ganglioside-mediated activation of the unfolded protein response causes neuronal death in a neurodegenerative gangliosidosis. Mol. Cell. 15, 753–766 (2004).

    Article  CAS  Google Scholar 

  81. 81.

    Sano, R. et al. GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis. Mol. Cell 36, 500–511 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Yanagisawa, K., Odaka, A., Suzuki, N. & Ihara, Y. GM1 ganglioside-bound amyloid beta-protein (A beta): a possible form of preamyloid in Alzheimer’s disease. Nat. Med. 1, 1062–1066 (1995).

    Article  CAS  Google Scholar 

  83. 83.

    Yanagisawa, K. GM1 ganglioside and Alzheimer’s disease. Glycoconj. J. 32, 87–91 (2015).

    Article  CAS  Google Scholar 

  84. 84.

    Hirano-Sakamaki, W. et al. Alzheimer’s disease is associated with disordered localization of ganglioside GM1 molecular species in the human dentate gyrus. FEBS Lett. 589, 3611–3616 (2015).

    Article  CAS  Google Scholar 

  85. 85.

    Calamai, M. et al. Single molecule experiments emphasize GM1 as a key player of the different cytotoxicity of structurally distinct Aβ1-42 oligomers. Biochim. Biophys. Acta 1858, 386–392 (2016).

    Article  CAS  Google Scholar 

  86. 86.

    Calamai, M. & Pavone, F. S. Partitioning and confinement of GM1 ganglioside induced by amyloid aggregates. FEBS Lett. 587, 1385–1391 (2013).

    Article  CAS  Google Scholar 

  87. 87.

    d’Azzo, A., Machado, E. & Annunziata, I. Pathogenesis, emerging therapeutic targets and treatment in sialidosis. Expert Opin. Orphan Drugs 3, 491–504 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Bonten, E. J., Annunziata, I. & d’Azzo, A. Lysosomal multienzyme complex: pros and cons of working together. Cell. Mol. Life Sci. 71, 2017–2032 (2014).

    Article  CAS  Google Scholar 

  89. 89.

    de Geest, N. et al. Systemic and neurologic abnormalities distinguish the lysosomal disorders sialidosis and galactosialidosis in mice. Hum. Mol. Genet. 11, 1455–1464 (2002).

    Article  Google Scholar 

  90. 90.

    Yogalingam, G. et al. Neuraminidase 1 is a negative regulator of lysosomal exocytosis. Dev. Cell 15, 74–86 (2008). This study is the first demonstration that excessive lysosomal exocytosis downstream of NEU1 deficiency is responsible for the pathogenesis of sialidosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    Wu, X. et al. Vacuolization and alterations of lysosomal membrane proteins in cochlear marginal cells contribute to hearing loss in neuraminidase 1-deficient mice. Biochim. Biophys. Acta 1802, 259–268 (2010).

    Article  CAS  Google Scholar 

  92. 92.

    Reddy, A., Caler, E. V. & Andrews, N. W. Plasma membrane repair is mediated by Ca(2+)-regulated exocytosis of lysosomes. Cell 106, 157–169 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Vanier, M. T. Niemann-Pick disease type C. Orphanet J. Rare Dis. 5, 16 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Lloyd-Evans, E. et al. Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat. Med. 14, 1247–1255 (2008).

    Article  CAS  Google Scholar 

  95. 95.

    Lee, H. et al. Bone marrow-derived mesenchymal stem cells prevent the loss of Niemann-Pick type C mouse Purkinje neurons by correcting sphingolipid metabolism and increasing sphingosine-1-phosphate. Stem Cells 28, 821–831 (2010).

    Article  CAS  Google Scholar 

  96. 96.

    Visentin, S. et al. The stimulation of adenosine A2A receptors ameliorates the pathological phenotype of fibroblasts from Niemann-Pick type C patients. J. Neurosci. 33, 15388–15393 (2013).

    Article  CAS  Google Scholar 

  97. 97.

    Xu, M. et al. δ-Tocopherol reduces lipid accumulation in Niemann-Pick type C1 and Wolman cholesterol storage disorders. J. Biol. Chem. 287, 39349–39360 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Liscum, L. Niemann-Pick type C mutations cause lipid traffic jam. Traffic 1, 218–225 (2000).

    Article  CAS  Google Scholar 

  99. 99.

    Ioannou, Y. A. Multidrug permeases and subcellular cholesterol transport. Nat. Rev. Mol. Cell Biol. 2, 657–668 (2001).

    Article  CAS  Google Scholar 

  100. 100.

    Davies, J. P., Chen, F. W. & Ioannou, Y. A. Transmembrane molecular pump activity of Niemann-Pick C1 protein. Science 290, 2295–2298 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Goldman, S. D. & Krise, J. P. Niemann-Pick C1 functions independently of Niemann-Pick C2 in the initial stage of retrograde transport of membrane-impermeable lysosomal cargo. J. Biol. Chem. 285, 4983–4994 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. 102.

    Auer, I. A. et al. Paired helical filament tau (PHFtau) in Niemann-Pick type C disease is similar to PHFtau in Alzheimer’s disease. Acta Neuropathol. 90, 547–551 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Huizing, M., Helip-Wooley, A., Westbroek, W., Gunay-Aygun, M. & Gahl, W. A. Disorders of lysosome-related organelle biogenesis: clinical and molecular genetics. Annu. Rev. Genom. Hum. Genet. 9, 359–386 (2008).

    Article  CAS  Google Scholar 

  104. 104.

    Raposo, G., Fevrier, B., Stoorvogel, W. & Marks, M. S. Lysosome-related organelles: a view from immunity and pigmentation. Cell Struct. Funct. 27, 443–456 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Neudorfer, O. et al. Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet. Med. 7, 119–123 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Veys, K. R., Elmonem, M. A., Arcolino, F. O., van den Heuvel, L. & Levtchenko, E. Nephropathic cystinosis: an update. Curr. Opin. Pediatr. 29, 168–178 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  107. 107.

    Patterson, M. C. et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol. Genet. Metab. 106, 330–344 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108.

    Evans, W. R. & Hendriksz, C. J. Niemann-Pick type C disease - the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment. BJPsych Bull. 41, 109–114 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Cooper, J. D., Tarczyluk, M. A. & Nelvagal, H. R. Towards a new understanding of NCL pathogenesis. Biochim. Biophys. Acta 1852, 2256–2261 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 110.

    Preising, M. N., Abura, M., Jager, M., Wassill, K. H. & Lorenz, B. Ocular morphology and function in juvenile neuronal ceroid lipofuscinosis (CLN3) in the first decade of life. Ophthalm. Genet. 38, 252–259 (2017).

    Article  CAS  Google Scholar 

  111. 111.

    Williams, R. E. et al. Management strategies for CLN2 disease. Pediatr. Neurol. 69, 102–112 (2017).

    Article  Google Scholar 

  112. 112.

    Introne, W. J. et al. Neurologic involvement in patients with atypical Chediak-Higashi disease. Neurology 88, e57–e65 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  113. 113.

    Suzuki, K. Enzymic diagnosis of sphingolipidoses. Methods Enzymol. 50, 456–488 (1978).

    Article  CAS  Google Scholar 

  114. 114.

    Kaback, M. et al. Tay-Sachs disease—carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA. 270, 2307–2315 (1993). This seminal paper discusses the high-risk population screening that reduced the incidence of a uniformly fatal disease by 90% within 10 years.

    Article  CAS  Google Scholar 

  115. 115.

    Regier, D. S., Proia, R. L., D’Azzo, A. & Tifft, C. J. The GM1 and GM2 Gangliosidoses: natural history and progress toward therapy. Pediatr. Endocrinol. Rev. 13, 663–673 (2016).

    PubMed  Google Scholar 

  116. 116.

    van der Tol, L. et al. A systematic review on screening for Fabry disease: prevalence of individuals with genetic variants of unknown significance. J. Med. Genet. 51, 1–9 (2014).

    Article  CAS  Google Scholar 

  117. 117.

    Hoffman, J. D. et al. Next-generation DNA sequencing of HEXA: a step in the right direction for carrier screening. Mol. Genet. Genom. Med. 1, 260–268 (2013).

    Article  CAS  Google Scholar 

  118. 118.

    [No authors listed]. Committee Opinion Number 691. American College of Obstetricians and Gynecologists https://www.acog.org/Clinical-Guidance-and-Publications/Committee-Opinions/Committee-on-Genetics/Carrier-Screening-for-Genetic-Conditions (2017).

  119. 119.

    Schielen, P., Kemper, E. A. & Gelb, M. H. Newborn screening for lysosomal storage diseases: a concise review of the literature on screening methods, therapeutic possibilities and regional programs. Int. J. Neonatal Screen. https://doi.org/10.3390/ijns3020006 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Cox, T. M. Innovative treatments for lysosomal diseases. Best Pract. Res. Clin. Endocrinol. Metab. 29, 275–311 (2015).

    Article  CAS  Google Scholar 

  121. 121.

    Hobbs, J. R. et al. Reversal of clinical features of Hurler’s disease and biochemical improvement after treatment by bone-marrow transplantation. Lancet 2, 709–712 (1981). This study is the first demonstration that Hurler syndrome is a treatable disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 122.

    Aldenhoven, M. & Kurtzberg, J. Cord blood is the optimal graft source for the treatment of pediatric patients with lysosomal storage diseases: clinical outcomes and future directions. Cytotherapy 17, 765–774 (2015).

    Article  CAS  Google Scholar 

  123. 123.

    Boelens, J. J. et al. Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning. Blood 121, 3981–3987 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. 124.

    Poe, M. D., Chagnon, S. L. & Escolar, M. L. Early treatment is associated with improved cognition in Hurler syndrome. Ann. Neurol. 76, 747–753 (2014).

    Article  Google Scholar 

  125. 125.

    Sly, W. S., Kaplan, A., Achord, D. T., Brot, F. E. & Bell, C. E. Receptor-mediated uptake of lysosomal enzymes. Prog. Clin. Biol. Res. 23, 547–551 (1978). This paper reviews the evidence for recognition of lysosomal enzymes by receptors for mannose and for mannose 6-phosphate.

    CAS  PubMed  Google Scholar 

  126. 126.

    Kan, S. H. et al. Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB. Proc. Natl Acad. Sci. USA 111, 14870–14875 (2014).

    Article  CAS  Google Scholar 

  127. 127.

    Grabowski, G. A. Gaucher disease and other storage disorders. Hematol. Am. Soc. Hematol. Educ. Program 2012, 13–18 (2012).

    Google Scholar 

  128. 128.

    Zimran, A. How I treat Gaucher disease. Blood 118, 1463–1471 (2011).

    Article  CAS  Google Scholar 

  129. 129.

    Boado, R. J., Lu, J. Z., Hui, E. K., Lin, H. & Pardridge, W. M. Insulin receptor Antibody-alpha-N-Acetylglucosaminidase fusion protein penetrates the primate blood-brain barrier and reduces glycosoaminoglycans in Sanfilippo Type B fibroblasts. Mol. Pharm. 13, 1385–1392 (2016).

    Article  CAS  Google Scholar 

  130. 130.

    Markham, A. Cerliponase Alfa: first global approval. Drugs 77, 1247–1249 (2017).

    Article  CAS  Google Scholar 

  131. 131.

    Broomfield, A., Jones, S. A., Hughes, S. M. & Bigger, B. W. The impact of the immune system on the safety and efficiency of enzyme replacement therapy in lysosomal storage disorders. J. Inherit Metab. Dis. 39, 499–512 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. 132.

    Afroze, B. & Brown, N. Ethical issues in managing Lysosomal storage disorders in children in low and middle income countries. Pak. J. Med. Sci. 33, 1036–1041 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  133. 133.

    McGill, J. J. et al. Enzyme replacement therapy for mucopolysaccharidosis VI from 8 weeks of age — a sibling control study. Clin. Genet. 77, 492–498 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. 134.

    Aerts, J. M., Hollak, C. E., Boot, R. G., Groener, J. E. & Maas, M. Substrate reduction therapy of glycosphingolipid storage disorders. J. Inherit Metab. Dis. 29, 449–456 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Lachmann, R. H. & Platt, F. M. Substrate reduction therapy for glycosphingolipid storage disorders. Expert Opin. Investig. Drugs 10, 455–466 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. 136.

    Cox, T. et al. Novel oral treatment of Gaucher’s disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355, 1481–1485 (2000). This study provides the first clinical evidence of the efficacy of SRT using the first approved SRT drug, miglustat, in Gaucher disease type I.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Hollak, C. E., Hughes, D., van Schaik, I. N., Schwierin, B. & Bembi, B. Miglustat (Zavesca) in type 1 Gaucher disease: 5-year results of a post-authorisation safety surveillance programme. Pharmacoepidemiol. Drug Safety 18, 770–777 (2009).

    Article  CAS  Google Scholar 

  138. 138.

    Poole, R. M. Eliglustat: first global approval. Drugs 74, 1829–1836 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Belmatoug, N. et al. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur. J. Intern. Med. 37, 25–32 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  140. 140.

    Patterson, M. C. et al. Oral miglustat in Niemann-Pick type C (NPC) disease. Rev. Neurol. (Separata) 43, 8 (2006).

    Google Scholar 

  141. 141.

    Patterson, M. C., Vecchio, D., Prady, H., Abel, L. & Wraith, J. E. Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol. 6, 765–772 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Shayman, J. A. ELIGLUSTAT TARTRATE: glucosylceramide synthase inhibitor treatment of type 1 Gaucher disease. Drugs Future 35, 613–620 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. 143.

    Platt, F. M., Neises, G. R., Dwek, R. A. & Butters, T. D. N-Butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J. Biol. Chem. 269, 8362–8365 (1994).

    CAS  PubMed  Google Scholar 

  144. 144.

    Walterfang, M. et al. Dysphagia as a risk factor for mortality in Niemann-Pick disease type C: systematic literature review and evidence from studies with miglustat. Orphanet J. Rare Dis. 7, 76 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Lyseng-Williamson, K. A. Miglustat: a review of its use in niemann-pick disease type C. Drugs 74, 61–74 (2014).

    Article  CAS  Google Scholar 

  146. 146.

    Cox, T. M. Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the potential treatment of Gaucher disease and other lysosomal storage diseases. Curr. Opin. Investig. Drugs 11, 1169–1181 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Cox, T. M. & Mistry, P. K. Therapeutic position of eliglustat. Blood Cells Mol. Dis. 69, 117–118 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  148. 148.

    Lachmann, R. H. Miglustat. Oxford GlycoSciences/Actelion. Curr. Opin. Investig. Drugs 4, 472–479 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. 149.

    Belmatoug, N. et al. Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe. Eur. J. Intern. Med. 37, 25–32 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. 150.

    Clayton, N. P. et al. Antisense oligonucleotide-mediated suppression of muscle glycogen synthase 1 synthesis as an approach for substrate reduction therapy of Pompe disease. Mol. Ther. Nucleic Acids 3, e206 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 151.

    Parenti, G., Andria, G. & Valenzano, K. J. Pharmacological chaperone therapy: preclinical development, clinical translation, and prospects for the treatment of lysosomal storage disorders. Mol. Ther. 23, 1138–1148 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. 152.

    Markham, A. Migalastat: first global approval. Drugs 76, 1147–1152 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 153.

    Hughes, D. A. et al. Oral pharmacological chaperone migalastat compared with enzyme replacement therapy in Fabry disease: 18-month results from the randomised phase III ATTRACT study. J. Med. Genet. 54, 288–296 (2017). This clinical study compares the first-in-class approved small-molecule chaperone drug migalastat with standard-of-care ERT, showing its potential as an alternative to ERT in patients with Fabry disease with chaperonable mutations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. 154.

    Germain, D. P. et al. Treatment of Fabry’s disease with the pharmacologic chaperone migalastat. N. Engl. J. Med. 375, 545–555 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. 155.

    Schiffmann, R. et al. Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial. Orphanet J. Rare Dis. 13, 68 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  156. 156.

    Citro, V. et al. Identification of an allosteric binding site on human lysosomal alpha-galactosidase opens the way to new pharmacological chaperones for Fabry disease. PLOS One 11, e0165463 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. 157.

    Huang, I. C. et al. Quality of life information and trust in physicians among families of children with life-limiting conditions. Patient Relat. Outcome Meas. 2010, 141–148 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  158. 158.

    Somanadhan, S. & Larkin, P. J. Parents’ experiences of living with, and caring for children, adolescents and young adults with Mucopolysaccharidosis (MPS). Orphanet J. Rare Dis. 11, 138 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 159.

    Pelentsov, L. J., Laws, T. A. & Esterman, A. J. The supportive care needs of parents caring for a child with a rare disease: a scoping review. Disabil Health J. 8, 475–491 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  160. 160.

    Besier, T. et al. Anxiety, depression, and life satisfaction in parents caring for children with cystic fibrosis. Pediatr. Pulmonol 46, 672–682 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  161. 161.

    McConkie-Rosell, A. et al. Psychosocial profiles of parents of children with undiagnosed diseases: managing well or just managing? J. Genet. Couns. 27, 935–946 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  162. 162.

    Bolsover, F. E., Murphy, E., Cipolotti, L., Werring, D. J. & Lachmann, R. H. Cognitive dysfunction and depression in Fabry disease: a systematic review. J. Inherit Metab. Dis. 37, 177–187 (2014).

    Article  Google Scholar 

  163. 163.

    Arends, M., Hollak, C. E. & Biegstraaten, M. Quality of life in patients with Fabry disease: a systematic review of the literature. Orphanet J. Rare Dis. 10, 77 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  164. 164.

    Kloesel, B. & Holzman, R. S. Anesthetic management of patients with inborn errors of metabolism. Anesth Analg. 125, 822–836 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. 165.

    Goldstein, R. (ed.) Cameron’s Arc: Creating a Full Life (American Academy of Paediatrics, 2007).

  166. 166.

    Petersen, N. H. & Kirkegaard, T. HSP70 and lysosomal storage disorders: novel therapeutic opportunities. Biochem. Soc. Trans. 38, 1479–1483 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. 167.

    Kirkegaard, T. et al. Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci. Transl. Med. 8, 355ra118 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. 168.

    Keeling, K. M., Xue, X., Gunn, G. & Bedwell, D. M. Therapeutics based on stop codon readthrough. Annu. Rev. Genom. Hum. Genet. 15, 371–394 (2014).

    Article  CAS  Google Scholar 

  169. 169.

    Keeling, K. M. Nonsense suppression as an approach to treat lysosomal storage diseases. Diseases 4, 32 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. 170.

    Hein, L. K. et al. alpha-L-iduronidase premature stop codons and potential read-through in mucopolysaccharidosis type I patients. J. Mol. Biol. 338, 453–462 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. 171.

    Ory, D. S. et al. Intrathecal 2-hydroxypropyl-beta-cyclodextrin decreases neurological disease progression in Niemann-Pick disease, type C1: a non-randomised, open-label, phase 1–2 trial. Lancet 390, 1758–1768 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. 172.

    Chen, F. W., Li, C. & Ioannou, Y. A. Cyclodextrin induces calcium-dependent lysosomal exocytosis. PLOS One 5, e15054 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. 173.

    Dai, S. et al. Methyl-β-cyclodextrin restores impaired autophagy flux in Niemann-Pick C1-deficient cells through activation of AMPK. Autophagy 13, 1435–1451 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. 174.

    Davidson, C. D. et al. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLOS One 4, e6951 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Sands, M. S. & Davidson, B. L. Gene therapy for lysosomal storage diseases. Mol. Ther. 13, 839–849 (2006).

    Article  CAS  Google Scholar 

  176. 176.

    Aronovich, E. L. et al. Prolonged expression of secreted enzymes in dogs after liver-directed delivery of sleeping beauty transposons: implications for non-viral gene therapy of systemic disease. Hum. Gene Ther. 28, 551–564 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. 177.

    Sandrin, V., Russell, S. J. & Cosset, F. L. Targeting retroviral and lentiviral vectors. Curr. Top. Microbiol. Immunol. 281, 137–178 (2003).

    CAS  PubMed  Google Scholar 

  178. 178.

    Davidson, B. L. et al. Recombinant adeno-associated virus type 2, 4, and 5 vectors: transduction of variant cell types and regions in the mammalian central nervous system. Proc. Natl Acad. Sci. USA 97, 3428–3432 (2000).

    Article  CAS  Google Scholar 

  179. 179.

    Gilkes, J. A., Bloom, M. D. & Heldermon, C. D. Preferred transduction with AAV8 and AAV9 via thalamic administration in the MPS IIIB model: a comparison of four rAAV serotypes. Mol. Genet. Metab. Rep. 6, 48–54 (2016).

    Article  CAS  Google Scholar 

  180. 180.

    Foust, K. D. et al. Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat. Biotechnol. 27, 59–65 (2009).

    Article  CAS  Google Scholar 

  181. 181.

    Bevan, A. K. et al. Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. Mol. Ther. 19, 1971–1980 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. 183.

    Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377, 1713–1722 (2017).

    Article  CAS  Google Scholar 

  184. 184.

    Biffi, A. et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 341, 1233158 (2013).

    Article  CAS  Google Scholar 

  185. 185.

    Goina, E., Peruzzo, P., Bembi, B., Dardis, A. & Buratti, E. Glycogen reduction in myotubes of late-onset pompe disease patients using antisense technology. Mol. Ther. 25, 2117–2128 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. 186.

    van der Wal, E., Bergsma, A. J., Pijnenburg, J. M., van der Ploeg, A. T. & Pijnappel, W. Antisense oligonucleotides promote exon inclusion and correct the common c.-32-13T>G GAA splicing variant in pompe disease. Mol. Ther. Nucleic Acids 7, 90–100 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. 187.

    Siva, K., Covello, G. & Denti, M. A. Exon-skipping antisense oligonucleotides to correct missplicing in neurogenetic diseases. Nucleic Acid. Ther. 24, 69–86 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Corey, D. R. Nusinersen, an antisense oligonucleotide drug for spinal muscular atrophy. Nat. Neurosci. 20, 497–499 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. 189.

    Khvorova, A. & Watts, J. K. The chemical evolution of oligonucleotide therapies of clinical utility. Nat. Biotechnol. 35, 238–248 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. 190.

    Schneller, J. L., Lee, C. M., Bao, G. & Venditti, C. P. Genome editing for inborn errors of metabolism: advancing towards the clinic. BMC Med. 15, 43 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Sharma, R. et al. In vivo genome editing of the albumin locus as a platform for protein replacement therapy. Blood 126, 1777–1784 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. 192.

    Yin, H., Kauffman, K. J. & Anderson, D. G. Delivery technologies for genome editing. Nat. Rev. Drug Discov. 16, 387–399 (2017).

    Article  CAS  Google Scholar 

  193. 193.

    Pu, J., Guardia, C. M., Keren-Kaplan, T. & Bonifacino, J. S. Mechanisms and functions of lysosome positioning. J. Cell Sci. 129, 4329–4339 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. 194.

    Carette, J. E. et al. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature 477, 340–343 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. 195.

    Hulseberg, C. E., Feneant, L., Szymanska, K. M. & White, J. M. Lamp1 increases the efficiency of lassa virus infection by promoting fusion in less acidic endosomal compartments. MBio. https://doi.org/10.1128/mBio.01818-17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  196. 196.

    Fineran, P. et al. Pathogenic mycobacteria achieve cellular persistence by inhibiting the Niemann-Pick Type C disease cellular pathway. Wellcome Open Res. 1, 18 (2016).

    Article  Google Scholar 

  197. 197.

    Adam, M. P. et al. (eds) GeneReviews®. NCBI https://www.ncbi.nlm.nih.gov/books/NBK1116/ (2018).

  198. 198.

    Sinigerska, I. et al. Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population. Mol. Genet. Metab. 88, 93–95 (2006).

  199. 199.

    Holve, S., Hu, D. & McCandless, S. E. Metachromatic leukodystrophy in the Navajo: fallout of the American-Indian wars of the nineteenth century. Am. J. Med. Genet. 101, 203–208 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. 200.

    Ausems, M. G. et al. Frequency of glycogen storage disease type II in The Netherlands: implications for diagnosis and genetic counselling. Eur. J. Hum. Genet. 7, 713–716 (1999).

  201. 201.

    Kalatzis V. et al. Characterization of a putative founder mutation that accounts for the high incidence of cystinosis in Brittany. J. Am. Soc. Nephrol. 12, 2170–2174 (2001).

  202. 202.

    Aula, N. et al. The spectrum of SLC17A5-gene mutations resulting in free sialic acid storage diseases indicates some genotype-phenotype correlation. Am. J. Hum. Genet. 67, 832–840 (2000).

  203. 203.

    Greer, W. L. et al. The Nova Scotia (Type D) form of Niemann-Pick disease is caused by a G3097 to T transversion in NPC1. Am. J. Hum. Genet. 63, 52–54 (1998).

Download references

Acknowledgements

F.M.P. is a Royal Society Wolfson Merit award holder and a Wellcome Trust Investigator in Science. A.d.A. is supported by NIH grants DK095169 and GM104981, the Assisi Foundation of Memphis, Ultragenyx Pharmaceutical and the American Lebanese Syrian Associated Charities (ALSAC) and holds the Jewellers for Children Endowed Chair in Genetics and Gene Therapy. A.d.A. thanks B. Stelter (St. Jude Biomedical Communication) for help with the graphic design of Fig. 3 and I. Annunziata for her assistance with literature screening and building the End Note library for the Mechanisms/pathophysiology section. B.L.D. is supported by the Children’s Hospital of Philadelphia Research Institute and the NIH (NS76631, NS090390 and NS94355) and holds the Arthur V. Meigs Chair in Pediatrics. C.J.T. is supported by the Division of Intramural Research of the National Human Genome Research Institute of the NIH, US Department of Health and Human Services. C.J.T. thanks M. Huizing for design of Fig. 4 and organization of the section on disorders of LROs.

Reviewer information

Nature Reviews Disease Primers thanks M. Beck, J. Cooper, R. Giugliani, C. Hollak, G. Pastores and other anonymous referee(s) for their contribution to the peer review of this work.

Author information

Affiliations

Authors

Contributions

Introduction (all); Epidemiology (C.J.T.); Mechanisms/pathophysiology (A.d.A. and F.M.P.); Diagnosis, screening and prevention (C.J.T.); Management (E.F.N., B.L.D. and F.M.P.); Quality of life (C.J.T.); Outlook (all); Overview of Primer (F.M.P.).

Corresponding author

Correspondence to Frances M. Platt.

Ethics declarations

Competing interests

F.M.P. is a trustee of Gordon Research Conferences, Chair of the Scientific Advisory Board of the National Tay-Sachs & Allied Diseases Association (NTSAD), a cofounder of and consultant to IntraBio and a consultant to Actelion and Orphazyme. A.d.A. has received research support from Ultragenyx Pharmaceutical. B.L.D. founded Talee Bio, Inc. and Spark Therapeutics and is on the Scientific Advisory Board of Homology Medicines, Intellia Therapeutics, Prevail Therapeutics, Inc and Sarepta Therapeutics. E.F.N. has previously received funding from BioMarin and is a member of the Scientific Advisory Board of the National MPS Society. C.J.T. is supported by the Division of Intramural Research of the National Human Genome Research Institute of the NIH, US Department of Health and Human Services and is a member of the Scientific Advisory Board of NTSAD.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

ClinicalTrials.gov: https://clinicaltrials.gov/

Genetics Home Reference: https://ghr.nlm.nih.gov/

Human Fertilization and Embryology Authority: https://www.hfea.gov.uk/pgd-conditions/

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Platt, F.M., d’Azzo, A., Davidson, B.L. et al. Lysosomal storage diseases. Nat Rev Dis Primers 4, 27 (2018). https://doi.org/10.1038/s41572-018-0025-4

Download citation

Further reading

Search

Quick links

Sign up for the Nature Briefing newsletter for a daily update on COVID-19 science.
Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing