Skip to main content
SpringerLink
Log in

Neurological findings in Hunter disease: Pathology and possible therapeutic effects reviewed

  • Review
  • Published:
Journal of Inherited Metabolic Disease

Summary

Hunter disease (mucopolysaccharidosis type II, MPS II) is an X-linked lysosomal storage disease caused by deficiency of iduronate-2-sulfatase. Accumulation of chondroitin sulfate B and heparan sulfate in various tissues is the biochemical consequence of MPS II. Children with Hunter disease are normal at birth, and symptoms occur between 2 and 10 years of age. Typical symptoms include coarse facies with enlarged tongue and prominent forehead as well as a short, stocky built stature with short neck. The cardiovascular, respiratory and gastrointestinal systems may be affected, and oral, dermatological and psychiatric as well as neurological complications are described. Life expectancy is markedly reduced and may be limited to 12 years for severely affected patients. The most common causes of death are airway obstruction and cardiac failure. The most severe symptoms may result from neurological symptoms or complications including hydrocephalus, spinal cord compression, cervical myelopathy, optic nerve compression, and hearing impairment. Patients may also develop carpal tunnel syndrome, sleep apnoea, seizures or mental retardation. This review describes characteristic neurological manifestations in MPS II and its underlying pathophysiology. In addition, an appraisal is given whether or not enzyme replacement therapy may be able to improve in particular the neurological symptoms of Hunter disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Abraham FA, Yatziv S, Russell A, Auerbach E (1974) Electrophysiological and psychophysical findings in Hunter syndrome. Arch Ophthalmol 91: 181–186.

    PubMed  CAS  Google Scholar 

  • Altarescu G, Chicco G, Whybra C, et al (2008) Correlation between interleukin-6 promoter and C-reactive protein (CRP) polymorphisms and CRP levels with the Mainz Severity Score Index for Fabry disease. J Inherit Metab Dis 31: 117–123.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Altarescu G, Zimran A, Michelakakis H, Elstein D (2005) TNF-alpha levels and TNF-alpha gene polymorphism in type I Gaucher disease. Cytokine 31: 149–152.

    Article  PubMed  CAS  Google Scholar 

  • Alves S, Mangas M, Prata MJ, et al (2006) Molecular characterization of Portuguese patients with mucopolysaccharidosis type II shows evidence that the IDS gene is prone to splicing mutations. J Inherit Metab Dis 29: 743–754.

    Article  PubMed  CAS  Google Scholar 

  • Ballenger CE, Swift TR, Leshner RT, El Gammal TA, McDonald TF (1980) Myelopathy in mucopolysaccharidosis type II (Hunter syndrome). Ann Neurol 7: 382–385.

    Article  PubMed  CAS  Google Scholar 

  • Banna M, Hollenberg R (1987) Compressive meningeal hypertrophy in mucopolysaccharidosis. AJNR Am J Neuroradiol 8: 385–386.

    PubMed  CAS  Google Scholar 

  • Beck M (1983) Papilloedema in association with Hunter’s syndrome. Br J Ophthalmol 67: 174–177.

    Article  PubMed  CAS  Google Scholar 

  • Capablo JL, Franco R, de Cabezon AS, Alfonso P, Pocovi M, Giraldo P (2007) Neurologic improvement in a type 3 Gaucher disease patient treated with imiglucerase/miglustat combination. Epilepsia 48: 1406–1408.

    Article  PubMed  CAS  Google Scholar 

  • Collins ML, Traboulsi EI, Maumenee IH (1990) Optic nerve head swelling and optic atrophy in the systemic mucopolysaccharidoses. Ophthalmology 97: 1445–1449.

    PubMed  CAS  Google Scholar 

  • Dekaban AS, Constantopoulos G (1977) Mucopolysaccharidosis type I, II, IIIA and V. Pathological and biochemical abnormalities in the neural and mesenchymal elements of the brain. Acta Neuropathol (Berl) 39: 1–7.

    Article  CAS  Google Scholar 

  • Dickson P, McEntee M, Vogler C, et al (2007) Intrathecal enzyme replacement therapy: successful treatment of brain disease via the cerebrospinal fluid. Mol Genet Metab 91: 61–68.

    Article  PubMed  CAS  Google Scholar 

  • Erikson A, Forsberg H, Nilsson M, Astrom M, Mansson JE (2006) Ten years’ experience of enzyme infusion therapy of Norrbottnian (type 3) Gaucher disease. Acta Paediatr 95: 312–317.

    Article  PubMed  Google Scholar 

  • Fisher RC, Horner RL, Wood VE (1974) The hand in mucopolysaccharide disorders. Clin Orthop Relat Res 191–199.

  • Fowler GW, Sukoff M, Hamilton A, Williams JP (1975) Communicating hydrocephalus in children with genetic inborn errors of metabolism. Childs Brain 1: 251–254.

    Article  PubMed  CAS  Google Scholar 

  • Froissart R, Blond JL, Maire I, et al (1993) Hunter syndrome: gene deletions and rearrangements. Hum Mutat 2: 138–140.

    Article  PubMed  CAS  Google Scholar 

  • Gills JP, Hobson R, Hanley WB, McKusick VA (1965) Electroretinography and fundus oculi findings in Hurler’s disease and allied mucopolysaccharidoses. Arch Ophthalmol 74: 596–603.

    PubMed  CAS  Google Scholar 

  • Goldberg MF, Duke JR (1967) Ocular histopathology in Hunter’s syndrome. Systemic mucopolysaccharidosis type II. Arch Ophthalmol 77: 503–512.

    PubMed  CAS  Google Scholar 

  • Grubb JH, Vogler C, Levy B, Galvin N, Tan Y, Sly WS (2008) Chemically modified beta-glucuronidase crosses blood-brain barrier and clears neuronal storage in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A 105: 2616–2621.

    Article  PubMed  CAS  Google Scholar 

  • Hayes E, Babin R, Platz C (1980) The otologic manifestations of mucopolysaccharidoses. Am J Otol 2: 65–69.

    PubMed  CAS  Google Scholar 

  • Hill CM, Hogan AM, Onugha N, et al (2006) Increased cerebral blood flow velocity in children with mild sleep-disordered breathing: a possible association with abnormal neuropsychological function. Pediatrics 118: e1100–e1108.

    Article  PubMed  Google Scholar 

  • Hoffmann B, Schwahn B, Knobbe CB, et al (2006) Acute neuronopathic Gaucher disease complicated by fatal gastrointestinal bleeding. Neuropediatrics 37: 163–165.

    Article  PubMed  CAS  Google Scholar 

  • Hunter C (1917) A rare disease in two brothers. R Soc Med 10, 104–116.

    Google Scholar 

  • Jones MZ, Alroy J, Rutledge JC, et al (1997) Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics. J Neuropathol Exp Neurol 56: 1158–1167.

    Article  PubMed  CAS  Google Scholar 

  • Kakkis E, McEntee M, Vogler C, et al (2004) Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I. Mol Genet Metab 83: 163–174.

    Article  PubMed  CAS  Google Scholar 

  • Karpati G, Carpenter S, Eisen AA, Wolfe LS, Feindel W (1974) Multiple peripheral nerve entrapments. An unusual phenotypical variant of the Hunter syndrome (mucopolysaccharidosis II) in a family. Arch Neurol 31: 418–422.

    PubMed  CAS  Google Scholar 

  • Kato T, Kato Z, Kuratsubo I, et al (2007) Evaluation of ADL in patients with Hunter disease using FIM score. Brain Dev 29: 298–305.

    Article  PubMed  Google Scholar 

  • Kenyon KR (1976) Ocular manifestations and pathology of systemic mucopolysaccharidoses. Birth Defects Orig Artic Ser 12: 133–153.

    PubMed  CAS  Google Scholar 

  • Kurihara M, Kumagai K, Goto K, Imai M, Yagishita S (1992) Severe type Hunter's syndrome. Polysomnographic and neuropathological study. Neuropediatrics 23: 248–256.

    PubMed  CAS  Google Scholar 

  • Lee C, Dineen TE, Brack M, Kirsch JE, Runge VM (1993) The mucopolysaccharidoses: characterization by cranial MR imaging. AJNR Am J Neuroradiol 14: 1285–1292.

    PubMed  CAS  Google Scholar 

  • MacDougal B, Weeks PM, Wray RC Jr (1977) Median nerve compression and trigger finger in the mucopolysaccharidoses and related diseases. Plast Reconstr Surg 59: 260–263.

    PubMed  CAS  Google Scholar 

  • Matheus MG, Castillo M, Smith JK, Armao D, Towle D, Muenzer J (2004) Brain MRI findings in patients with mucopolysaccharidosis types I and II and mild clinical presentation. Neuroradiology 46: 666–672.

    Article  PubMed  Google Scholar 

  • Muenzer J, Wraith JE, Beck M, et al (2006) A phase II/III clinical study of enzyme replacement therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med 8: 465–473.

    Article  PubMed  CAS  Google Scholar 

  • Narita AS, Russell-Eggitt I (1996) Bilateral epiretinal membranes: a new finding in Hunter syndrome. Ophthalm Genet 17: 75–78.

    Article  CAS  Google Scholar 

  • Neely J, Carpenter J, Hsu W, Jordan L, Restrepo L (2006) Cerebral infarction in Hunter syndrome. J Clin Neurosci 13: 1054–1057.

    Article  PubMed  Google Scholar 

  • Neufeld EF, Liebaers I, Epstein CJ, Yatziv S, Milunsky A, Migeon BR (1977) The Hunter syndrome in females: is there an autosomal recessive form of iduronate sulfatase deficiency? Am J Hum Genet 29: 455–461.

    PubMed  CAS  Google Scholar 

  • Neufeld E and Muenzer J (2001) The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3421–3454

    Google Scholar 

  • Ohmi K, Greenberg DS, Rajavel KS, Ryazantsev S, Li HH, Neufeld EF (2003) Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc Natl Acad Sci U S A 100: 1902–1907.

    Article  PubMed  CAS  Google Scholar 

  • Okumiya T, Kroos MA, Vliet LV, Takeuchi H, Van der Ploeg AT, Reuser AJ (2007) Chemical chaperones improve transport and enhance stability of mutant alpha-glucosidases in glycogen storage disease type II. Mol Genet Metab 90: 49–57.

    Article  PubMed  CAS  Google Scholar 

  • Papsin BC, Vellodi A, Bailey CM, Ratcliffe PC, Leighton SE (1998) Otologic and laryngologic manifestations of mucopolysaccharidoses after bone marrow transplantation. Otolaryngol Head Neck Surg 118: 30–36.

    Article  PubMed  CAS  Google Scholar 

  • Parsons VJ, Hughes DG, Wraith JE (1996) Magnetic resonance imaging of the brain, neck and cervical spine in mild Hunter’s syndrome (mucopolysaccharidoses type II). Clin Radiol 51: 719–723.

    Article  PubMed  CAS  Google Scholar 

  • Patil SP, Schneider H, Schwartz AR, Smith PL (2007) Adult obstructive sleep apnea: pathophysiology and diagnosis. Chest 132: 325–337.

    Article  PubMed  Google Scholar 

  • Pitz S, Ogun O, Bajbouj M, Arash L, Schulze-Frenking G, Beck M (2007) Ocular changes in patients with mucopolysaccharidosis I receiving enzyme replacement therapy: a 4-year experience. Arch Ophthalmol 125: 1353–1356.

    Article  PubMed  CAS  Google Scholar 

  • Sakakihara Y, Imabayashi T, Suzuki Y, Kamoshita S (1994) Elevated levels of dolichol in the brains of mucopolysaccharidosis and related disorders. Mol Chem Neuropathol 22: 97–103.

    PubMed  CAS  Google Scholar 

  • Sawkar AR, Cheng WC, Beutler E, Wong CH, Balch WE, Kelly JW (2002) Chemical chaperones increase the cellular activity of N370S beta-glucosidase: a therapeutic strategy for Gaucher disease. Proc Natl Acad Sci U S A 99: 15428–15433.

    Article  PubMed  CAS  Google Scholar 

  • Schwartz IV, Ribeiro MG, Mota JG, et al (2007) A clinical study of 77 patients with mucopolysaccharidosis type II. Acta Paediatr Suppl 96: 63–70.

    PubMed  Google Scholar 

  • Shapiro J, Strome M, Crocker AC (1985) Airway obstruction and sleep apnea in Hurler and Hunter syndromes. Ann Otol Rhinol Laryngol 94: 458–461.

    PubMed  CAS  Google Scholar 

  • Takahashi Y, Sukegawa K, Aoki M, et al (2001) Evaluation of accumulated mucopolysaccharides in the brain of patients with mucopolysaccharidoses by (1)H-magnetic resonance spectroscopy before and after bone marrow transplantation. Pediatr Res 49: 349–355.

    Article  PubMed  CAS  Google Scholar 

  • Tokic V, Barisic I, Huzjak N, Petkovic G, Fumic K, Paschke E (2007) Enzyme replacement therapy in two patients with an advanced severe (Hurler) phenotype of mucopolysaccharidosis I. Eur J Pediatr 166: 727–732.

    Article  PubMed  Google Scholar 

  • Topping TM, Kenyon KR, Goldberg MF, Maumenee AE (1971) Ultrastructural ocular pathology of Hunter's syndrome. Systemic mucopolysaccharidosis type II. Arch Ophthalmol 86: 164–177.

    PubMed  CAS  Google Scholar 

  • Tropak MB, Reid SP, Guiral M, Withers SG, Mahuran D (2004) Pharmacological enhancement of beta-hexosaminidase activity in fibroblasts from adult Tay-Sachs and Sandhoff Patients. J Biol Chem 279: 13478–13487.

    Article  PubMed  CAS  Google Scholar 

  • Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA (2005) Mucopolysaccharidosis type II in females: case report and review of literature. Pediatr Neurol 32: 270–272.

    Article  PubMed  Google Scholar 

  • Urayama A, Grubb JH, Banks WA, Sly WS (2007) Epinephrine enhances lysosomal enzyme delivery across the blood brain barrier by up-regulation of the mannose 6-phosphate receptor. Proc Natl Acad Sci U S A 104: 12873–12878.

    Article  PubMed  CAS  Google Scholar 

  • Van Aerde J, Campbell A (1983) Hydrocephalus and shunt placement. Am J Dis Child 137: 187–188.

    PubMed  Google Scholar 

  • Van Aerde J, Plets C, Van der Hauwaert L (1981) Hydrocephalus in Hunter syndrome. Acta Paediatr Belg 34: 93–96.

    PubMed  Google Scholar 

  • Vedolin L, Schwartz IV, Komlos M, et al (2007a) Brain MRI in mucopolysaccharidosis: effect of aging and correlation with biochemical findings. Neurology 69: 917–924.

    Article  PubMed  CAS  Google Scholar 

  • Vedolin L, Schwartz IV, Komlos M, et al (2007b) Correlation of MR imaging and MR spectroscopy findings with cognitive impairment in mucopolysaccharidosis II. AJNR Am J Neuroradiol 28: 1029–1033.

    Article  PubMed  CAS  Google Scholar 

  • Vellodi A, Young E, Cooper A, Lidchi V, Winchester B, Wraith JE (1999) Long-term follow-up following bone marrow transplantation for Hunter disease. J Inherit Metab Dis 22: 638–648.

    Article  PubMed  CAS  Google Scholar 

  • Villani GR, Gargiulo N, Faraonio R, Castaldo S, Gonzalez YR, Di Natale P (2007) Cytokines, neurotrophins, and oxidative stress in brain disease from mucopolysaccharidosis IIIB. J Neurosci Res 85: 612–622.

    Article  PubMed  CAS  Google Scholar 

  • Vogler C, Levy B, Grubb JH, et al (2005) Overcoming the blood–brain barrier with high-dose enzyme replacement therapy in murine mucopolysaccharidosis VII. Proc Natl Acad Sci U S A 102: 14777–14782.

    Article  PubMed  CAS  Google Scholar 

  • Wolf D (1942) Microscopic study of temporal bones in dysostosis multiplex (gargoylism). Laryngoscope 52: 218–223.

    Google Scholar 

  • Wraith JE, Beck M, Lane R, et al (2007) Enzyme replacement therapy in patients who have mucopolysaccharidosis I and are younger than 5 years: results of a multinational study of recombinant human alpha-l-iduronidase (laronidase). Pediatrics 120: e37–e46 [Epub 2007 Jun 4].

    Article  PubMed  Google Scholar 

  • Wraith JE, Cooper A, Thornley M, et al (1991) The clinical phenotype of two patients with a complete deletion of the iduronate-2-sulphatase gene (mucopolysaccharidosis II–Hunter syndrome). Hum Genet 87: 205–206.

    Article  PubMed  CAS  Google Scholar 

  • Yatziv S, Epstein CJ (1977) Hunter syndrome presenting as macrocephaly and hydrocephalus. J Med Genet 14: 445–447.

    PubMed  CAS  Google Scholar 

  • Young ID, Harper PS (1982) Mild form of Hunter’s syndrome: clinical delineation based on 31 cases. Arch Dis Child 57: 828–836.

    Article  PubMed  CAS  Google Scholar 

  • Young ID, Harper PS (1983) The natural history of the severe form of Hunter’s syndrome: a study based on 52 cases. Dev Med Child Neurol 25: 481–489.

    PubMed  CAS  Google Scholar 

  • Yuen A, Dowling G, Johnstone B, Kornberg A, Coombs C (2007) Carpal tunnel syndrome in children with mucopolysaccaridoses. J Child Neurol 22: 260–263.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Pediatrics, University Children’s Hospital, Heinrich-Heine-University, Moorenstr. 5, D-40225, Düsseldorf 20, Germany

    S. Al Sawaf, E. Mayatepek & B. Hoffmann

Authors
  1. S. Al Sawaf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Mayatepek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Hoffmann.

Additional information

Communicating editor: Olaf Bodamer

Competing interests: B. Hoffmann received an unrestricted research grant from Shire Deutschland GmbH. The sponsor had no role in developing, finalizing or submitting this manuscript. The author(s) confirm independence from the sponsor and the content of this article has not been influenced by Shire Deutschland GmbH.

References to electronic databases: Mucopolysaccharidosis type II: OMIM 309900. Iduronate-2-sulfatase: EC 3.1.6.13; HUGO-approved gene symbol: IDS.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Al Sawaf, S., Mayatepek, E. & Hoffmann, B. Neurological findings in Hunter disease: Pathology and possible therapeutic effects reviewed. J Inherit Metab Dis 31, 473–480 (2008). https://doi.org/10.1007/s10545-008-0878-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-008-0878-x

Keywords

Search

Navigation