Research Article| Volume 249, ISSUE 1, P1-6, November 01, 2006

Download started.


Niemann–Pick C disease in Spain: Clinical spectrum and development of a disability scale



      To describe the clinical evolution of Niemann–Pick C disease to identify possible factors involved in the diagnosis and severity of the disease.


      A clinical database and a severity scale was created to evaluate 45 patients diagnosed with Niemann–Pick type C in the last 28 years in Spain.


      Complete clinical data were obtained from 30 patients, all were confirmed to have mutations in the NPC1 gene. Regarding clinical form, 3 were perinatal, 7 severe infantile, 6 late infantile, 11 juvenile and 3 adult. Biochemical phenotype was classic in 26. Splenomegaly was present in 28 patients (93%) with a wide range of age at detection. The first symptom of neurological disease was clumsiness, followed in 2–4 years by cerebellar signs. Ophthalmoplegia appeared 2–4 years later and became complete 1–2 years after onset. Dysarthria appeared by the time of complete ophthalmoplegia. Diagnosis was made before the onset of neurological signs in patients with the severe infantile form, at the time of onset of cerebellar signs in the late infantile form and complete ophthalmoplegia in late onset forms.


      In our series, splenomegaly is present in 96% of patients, even in late onset forms during the first years of life. Clumsiness in children with otherwise normal motor development precedes the onset of ataxia by 2–4 years in Niemann Pick type C. A disability scale could be useful for monitoring evolution, establishing possible phenotypic correlations and evaluating future therapies.


      NPC (Niemann–Pick disease type C), SI (severe infantile form), LI (late infantile form)


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of the Neurological Sciences
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Vanier MT, Suzuki K. Niemann–Pick diseases. In: Vinken PJ, Bruyn GW (Eds.) Handbook of clinical neurology. Vol 66/ revised ser vol 22:Moser HW (Ed) Neurodystrophies and Neurolipidoses. Elsevier Science, Amsterdam; 1996. p. 133–62.

        • Patterson M.C.
        • Vanier M.T.
        • Suzuki K.
        • Morris J.A.
        • Karstea E.
        • Neufeld E.B.
        • et al.
        Niemann–Pick disease types C: a lipid trafficking disorder.
        in: Scriver C.R. Beaudet A.L. Sly W.S. Valle D. Childs B. Kinzler K.W. Vogelstein B. The metabolic and molecular bases of inherited disease. 8th ed. Mc Graw-Hill, New York2001: 3611-3634
        • Vanier M.T.
        • Rodriguez-Lafrasse C.
        • Rousson R.
        • Mandon G.
        • Boue J.
        • Choiset A.
        • et al.
        Type C Niemann–Pick disease: spectrum and phenotypic variation in disruption of intracellular LDL-derived cholesterol processing.
        Biochim Biophys Acta. 1991; 1096: 328-337
        • Steinberg S.J.
        • Ward C.P.
        • Fensom A.H.
        Complementation studies in Niemann–Pick disease type C indicate the existence of a second group.
        J Med Genet. 1994; 31: 317-320
        • Vanier M.T.
        • Duthel S.
        • Rodriguez-Lafrasse C.
        • Pentchev P.
        • Carstea E.D.
        Genetic heterogeneity in Niemann–Pick C disease: a study using somatic cell hybridization and linkage analysis.
        Am J Hum Genet. 1996; 58: 118-125
        • Davies J.P.
        • Chen F.W.
        • Ioannou Y.A.
        Transmembrane molecular pump activity of Niemann–Pick C1 protein.
        Science. 2000; 290: 2295-2298
        • Friedland N.
        • Liou H.L.
        • Lobel P.
        • Stock A.M.
        Structure of a cholesterol-binding protein deficient in Niemann–Pick type C2 disease.
        Proc Acad Sci U S A. 2003; 100: 2512-2517
        • Naureckiene S.
        • Sleat D.E.
        • Lackland H.
        • Fensom A.
        • Vanier M.T.
        • Wattiaux R.
        • et al.
        Identification of HE1 as the second gene of Niemann–Pick disease.
        Science. 2000; 290: 2298-2301
        • Millat G.
        • Chikh K.
        • Naureckiene S.
        • Sleat D.E.
        • Fensom A.H.
        • Higaki K.
        • et al.
        Niemann–Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group.
        Am J Hum Genet. 2001; 69: 1013-1021
        • Kruth H.S.
        • Comy M.E.
        • Butler J.D.
        • Vanier M.T.
        • Fink J.K.
        • Wenger D.A.
        • et al.
        Type C Niemann–Pick disease. Abnormal metabolism of low density lipoprotein in homozygous and heterozygous fibroblasts.
        J Biol Chem. 1986; 261: 16769-16774
        • Millat G.
        • Marçais C.
        • Tomasetto C.
        • Chikh K.
        • Fensom A.H.
        • Harzer K.
        • et al.
        Niemann–Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop.
        Am J Hum Genet. 2001; 68: 1373-1385
        • Fernandez-Valero E.M.
        • Ballart A.
        • Iturriaga C.
        • Lluch M.
        • Macias J.
        • Vanier M.T.
        • et al.
        Identification of 25 new mutations in 40 unrelated Spanish Niemann–Pick type C patients: genotype–phenotype correlations.
        Clin Genet. 2005 (Sep.); 68: 245-254
        • Ribeiro I.
        • Marcao A.
        • Amaral O.
        • Sa Miranda M.C.
        • Vanier M.T.
        • Millat G.
        Niemann–Pick type C disease: NPC1 mutations associated with severe and mild cellular cholesterol transport alterations.
        Hum Genet. 2001; 109: 24-32
        • Yerushalmi B.
        • Sokol R.J.
        • Narkewicz M.R.
        • Smith D.
        • Ashmead J.W.
        • Wenger D.A.
        Niemann–Pick disease type C in neonatal cholestasis at a North American Center.
        J Pediatr Gastroenterol Nutr. 2002; 35: 44-50
        • Imrie J.
        • Wraith J.E.
        Isolated splenomegaly as the presenting feature of Niemann–Pick disease type C.
        Arch Dis Child. 2001; 84: 427-429
        • Shulman L.M.
        • David N.J.
        • Weiner W.J.
        Psychosis as the initial manifestation of adult onset Niemann–Pick disease type C.
        Neurology. 1995; 45: 1739-1743
        • Lossos A.
        • Schlesinger I.
        • Okon E.
        • Abramsky O.
        • Vargal R.
        • Vanier M.T.
        • et al.
        Adult onset Niemann–Pick disease type C. Clinical, biochemical and genetic study.
        Arch Neurol. 1997; 54: 1536-1541
        • Denoix C.
        • Rodriguez-Lafrasse C.
        • Vanier M.T.
        • Navelet I.
        • Landrieu P.
        Cataplexy revealing an atypical form of Niemann–Pick disease type C.
        Arch Fr Pediatr. 1991; 48: 31-34
        • Zimran A.
        • Sorge J.
        • Kubitz M.
        • West C.
        • Beutler E.
        Prediction of severity of Gaucher's disease by identification of mutations at DNA level.
        Lancet. 1989 (Aug. 12); 2: 349-352
        • Loes D.J.
        • Moser H.
        • Stillman A.E.
        • Lockman L.
        • Latchaw R.E.
        • Krivit W.
        Adrenoleukodystrophy: a scoring method for brain MR observations.
        Am J Neuroradiol. 1994; 15: 1761-1766
        • Loes D.J.
        • Fatemi A.
        • Melhem E.R.
        • Gupte N.
        • Bezman L.
        • Moser H.W.
        • et al.
        Analysis of MRI patterns aids prediction of progression in X-linked adrenoleukodystrophy.
        Neurology. 2003; 61: 369-374