Skip to main content

A model of neuronopathic Gaucher disease

Journal of Inherited Metabolic Disease volume 26, pages 629–639 (2003)Cite this article

Abstract

Summary: Gaucher disease (GD) is a lysosomal disorder involving the accumulation of glucocerebroside in the liver, spleen, bones and brain. Some patients exhibit only systemic disease (type I), but others have additional neurological signs which may lead to rapid neurodegeneration in infancy (type II) or take a more intermediate course (type III). Types II and III are collectively known as neuronopathic Gaucher disease (NGD). Systemic disease can now be treated by enzyme replacement therapy (ERT), but its efficacy in NGD is limited. Two infants who presented with bulbar palsy and failure to thrive were enzymatically diagnosed at 8 months with NGD. They were started on high-dose ERT (120 IU/kg every 2 weeks). Both underwent serial oculomotor assessment and an audiological battery, including visual reinforcement audiometry, otoacoustic emissions, and the auditory brain stem response (ABR). Biochemical markers showed an incomplete systemic response to ERT, but neurological deterioration was relentless, leading to death at 16 and 25 months. Oculomotor testing revealed a complete absence of saccadic eye movements and progressive bilateral sixth nerve palsy in one. Audiological assessment revealed progressive deterioration of ABRs, but with normal peripheral hearing and otoacoustic emissions. Both infants showed neurological deterioration in spite of high-dose ERT. The audiological findings suggested a loss of inner hair cell pathway function with preserved outer hair function, similar to what is seen in auditory neuropathy. The unusual pattern of audiological and oculomotor abnormalities is consistent with an excitotoxic mechanism predisposing nerve cells to glucocerebroside toxicity. Such excitotoxic damage may be amenable to direct therapeutic intervention.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

REFERENCES

  • Altarescu G, Hill S, Wiggs E, et al (2001) The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease. J Pediatrics 138: 539-547.

    CAS  Article  Google Scholar 

  • Aoki M, Takahashi Y, Miwa Y, et al (2001) Improvement of neurological symptoms by enzyme replacement therapy for Gaucher disease type IIIb. Eur J Pediatr 160: 63–74.

    PubMed  CAS  Article  Google Scholar 

  • Barton NW, Furbish FS, Murray GJ, Garfield M, Brady RO (1990) Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci USA 87: 1913–1916.

    PubMed  CAS  Article  Google Scholar 

  • Beutler E, Grabowski GA (1995) Gaucher disease. In Scriver CR, Beaudet A, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2641–2670.

    Google Scholar 

  • Conradi N, Kyllerman M, Mansson JE, Percy AK, Svennerholm L (1991) Late-infantile Gaucher disease in a child with myoclonus and bulbar signs: neuropathological and neurochemical findings. Acta Neuropathologica 82: 152-157.

    PubMed  CAS  Article  Google Scholar 

  • Erikson A, Johansson K, Mansson JE, Svennerholm L (1993) Enzyme replacement therapy of infantile Gaucher disease. Neuropediatrics 24: 237–238.

    PubMed  CAS  Google Scholar 

  • Erikson A, Bembi B, Schiffman R (1997) Neuronopathic forms of Gaucher's disease. Baillere's Clinical Haematology 10: 711–723.

    CAS  Google Scholar 

  • Grafe M, Thomas C, Schneider J, Katz B, Wiley C (1988) Infantile Gaucher's disease: a case with neuronal storage. Ann Neurol 23: 300–303.

    PubMed  CAS  Article  Google Scholar 

  • Harris CM, Kriss A, Shawkat F, Taylor D (1992) The use of video in assessing and illustrating abnormal eye movements in young children. J Audiov Media Med 15: 113–116.

    PubMed  CAS  Google Scholar 

  • Harris CM, Taylor DS, Vellodi A (1999) Ocular motor abnormalities in Gaucher disease. Neuropediatrics 30: 289–293.

    PubMed  CAS  Article  Google Scholar 

  • Harrison RV (1998) An animal model of auditory neuropathy. Ear Hear 19: 355-361.

    PubMed  CAS  Google Scholar 

  • Hurley RM, Musiek FE (1994) Effectiveness of transient-evoked otoacoustic emissions (TEOAEs) in predicting hearing level. J Am Acad Audiol 5: 195-203.

    PubMed  CAS  Google Scholar 

  • ISO (1989) ISO 8253–1: Acoustics Audiometric Test Methods, I: Basic Pure Tone Air and Bone Conduction Threshold Audiometry. Geneva: International Organization for Standardization.

    Google Scholar 

  • Jacobs M, Harris CM, Shawkat F, Taylor D (1992) The objective assessment of abnormal eye movements in infants and young children. Austr NZ J Ophthalmol 20: 185-195.

    CAS  Google Scholar 

  • Jacobson GP, Jacobson JT, Ramadan N, Hyde M (1994) Auditory brainstem response measures in acoustic nerve and brainstem disease. In Jacobson JT, ed. Principles and Applications in Auditory Evoked Potentials, London: Allyn and Bacon, Chapter 16.

    Google Scholar 

  • Jerger J (1984) Classification of tympanogram types. In Northern JL, Downs MP, eds. Hearing in Children. 3rd edn. Baltimore, MD: Williams and Wilkins, 183 186.

    Google Scholar 

  • Kaga K, Ono M, Yakumaru K, Owada M, Mizutani T (1998) Brainstem pathology of infantile Gaucher's disease with only wave I and II of auditory brainstem response. J Laryngol Otol 112: 1069–1073.

    PubMed  CAS  Google Scholar 

  • Kaga M, Azuma C, Imamura T, Murakami T, Kaga K (1982) Auditory brainstem response (ABR) in infantile Gaucher's disease. Neuropediatrics 13: 207–210.

    PubMed  CAS  Article  Google Scholar 

  • Kaye EM, Ullman MD, Wilson ER, Barranger JA (1986) Type 2 and type 3 Gaucher disease: a morphological and biochemical study. Ann Neurol 20: 223–230.

    PubMed  CAS  Article  Google Scholar 

  • Kemp DT, Ryan S, Bray P (1990) A guide to the effective use of otoacoustic emissions. Ear Hear 11: 93–105.

    PubMed  CAS  Article  Google Scholar 

  • Korkotian E, Schwarz A, Pelled D, Schwarzmann G, Segal M, Futerman AH (1999) Elevation of intracellular glucosylceramide levels results in an increase in endoplasmic reticulum density and in functional calcium stores in cultured neurons. J Biol Chem 274: 21673–21678.

    PubMed  CAS  Article  Google Scholar 

  • Kraus N, Ozdamar O, Stein L, Reed N (1984) Absent auditory brainstem response: peripheral hearing loss or brainstem dysfunction? Laryngoscope 94: 400–406.

    PubMed  CAS  Google Scholar 

  • Lacey DJ, Terplan K (1984) Correlating auditory evoked and brainstem histologic abnormalities in infantile Gaucher's disease. Neurology 34: 539–541.

    PubMed  CAS  Google Scholar 

  • Leigh J, Zee DS (1999) The Neurology of Eye Movements, 3rd edn. Oxford: Oxford University Press.

    Google Scholar 

  • Masek BJ, Sims KB, Bove CM, et al (1999) Quality of life assessment in adults with type 1 Gaucher disease. Qual Life Res 8: 263–268.

    PubMed  CAS  Article  Google Scholar 

  • McConnel F, Ward PH (1984) Auditory behavior index for infants: stimulus and level of response. In Northern JL, Downs MP, eds. Hearing in Children, 3rd edn. Baltimore, MD: Williams and Wilkins, 135.

    Google Scholar 

  • Miller JD, McCluer R, Kanfer JN (1973) Gaucher's disease: neurologic disorder in adult siblings. Ann Intern Med 78: 883–887.

    PubMed  CAS  Google Scholar 

  • Orvisky E, Sidransky E, McKinney CE, et al (2000) Glucosylsphingosine accumulation in mice and patients with type 2 Gaucher disease begins early in gestation. Pediatr Res 48: 233–237.

    PubMed  CAS  Google Scholar 

  • Pastores GM (1997) Gaucher's disease. Pathological features. Bailliere's Clinical Haematology 10: 739–749.

    PubMed  CAS  Google Scholar 

  • Patterson MC, Horowitz M, Abel RB, et al (1993) Isolated horizontal supranuclear gaze palsy as a marker of severe systemic involvement in Gaucher's disease. Neurology 43: 1993–1997.

    PubMed  CAS  Google Scholar 

  • Pelled D, Shogomori H, Futerman AH (2000) The increased sensitivity of neurons with elevated glucocerebroside to neurotoxic agents can be reversed by imiglucerase. J Inherit Metab Dis 23: 175–184.

    PubMed  CAS  Article  Google Scholar 

  • Platt FM, Neises GR, Reinkensmeier G, et al (1997) Prevention of lysosomal storage in Tay Sachs mice treated with N-butyldeoxynojirimycin. Science 276: 428–431.

    PubMed  CAS  Article  Google Scholar 

  • Pujol R, Puel JL (1999) Excitotoxicity, synaptic repair, and functional recovery in the mammalian cochlea: a review of recent findings. Ann N Y Acad Sci 884: 249–254.

    PubMed  CAS  Article  Google Scholar 

  • Salvi RJ, Wang J, Ding D, Stecker N, Arnold S (1999) Auditory deprivation of the central auditory system resulting from selective inner hair cell loss: animal model of auditory neuropathy. Scand Audiol Suppl 51: 1–12.

    PubMed  CAS  Google Scholar 

  • Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI (1996) Auditory neuropathy. Brain 119: 741–753.

    PubMed  Google Scholar 

  • Takahashi T, Yoshida Y, Sato W, et al (1998) Enzyme therapy in Gaucher disease type 2: an autopsy case. Tohoku J Exp Med 186: 143–149.

    PubMed  CAS  Article  Google Scholar 

  • Takeno S, Wake M, Mount RJ, Harrison RV (1998) Degeneration of spiral ganglion cells in the chinchillas after inner hair cell loss induced by carboplatin. Audiol Neurootol 3: 281–290.

    PubMed  CAS  Article  Google Scholar 

  • Vivian AJ, Harris CM, Kriss A, Battin M, Neville BGR, Taylor DSI (1993) Oculomotor signs in infantile Gaucher disease. Neuroophthalmology 13: 151-155.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Audiological Medicine, Great Ormond Street Hospital for Children, London

    P. E. Campbell & T. Sirimanna

  2. Plymouth Institute of Neuroscience, Plymouth University, Plymouth, UK

    C. M. Harris

  3. Department of Metabolic Medicine Unit, Great Ormond Street Hospital for Children, London

    A. Vellodi

Authors
  1. P. E. Campbell
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. M. Harris
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. Sirimanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Vellodi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. E. Campbell.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Campbell, P.E., Harris, C.M., Sirimanna, T. et al. A model of neuronopathic Gaucher disease. J Inherit Metab Dis 26, 629–639 (2003). https://doi.org/10.1023/B:BOLI.0000005619.14180.5c

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:BOLI.0000005619.14180.5c

Keywords

  • Enzyme Replacement Therapy
  • Gauche Disease
  • Auditory Brainstem Response
  • Outer Hair Cell
  • Otoacoustic Emission