Main Article Content
Niemann–Pick disease, Type C; lysosomal storage disorder; phenotypic heterogeneity; heterozygous missense mutation; early infantile onset; supranuclear gaze palsy; early diagnosis; miglustat.
Background: Niemann-Pick disease type C (NPC) is a lysosomal storage disease caused by mutations in NPC1 or NPC2 genes.
Case presentation: We present two brothers with the same compound heterozygous variants in exon 13 of the NPC1 gene (18q11.2), the first one (c.1955C> G, p. Ser652Trp), inherited from the mother, the second (c.2107T>A p.Phe703Ile) inherited from the father, associated to the classical biochemical phenotype of NPC.
The two brothers presented unspecific neurologic symptoms with difference in age of onset: one presented dyspraxia and motor clumsiness at age 7 years, the other showed a systemic presentation with hepatosplenomegaly noted at the age of two months and neurological symptoms onset at age 4 with speech disturbance. Clinical evolution and neuroimaging data led to the final diagnosis. Systemic signs did not correlate with the onset of neurological symptoms. Miglustat therapy was started in both patients.
We highlight the extreme phenotypic heterogeneity of NP-C in the presence of the same genetic variant and the unspecificity of neurologic signs at onset as previously reported. We report some positive effects of miglustat on disease progression assessed also with neuropsychological follow-up, with an age-dependent response.
 Evans W, Hendriksz C. Niemann–Pick type C disease–the tip of the iceberg? A review of neuropsychiatric presentation, diagnosis and treatment. BJPsych Bull. 2017; 41(2):109-114.
 Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F. Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update. Mol Genet Metab. 2012; 106:330–44.
 Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010; 5:16.
 M. Pineda, M. Walterfang, M. Patterson Miglustat in Niemann-Pick disease type C patients: a review. Orphanet Journal of Rare Diseases 2018; 13:140.
 Wijburg FA, Sedel F, Pineda M, Hendriksz CJ, Fahey M, Walterfang M, et al. Development of a Suspicion Index to aid diagnosis of Niemann-Pick disease type C. Neurology. 2012; 78:1560–7.
 Garver WS, Jelinek D, Meaney FJ, Flynn J, Pettit KM, Shepherd G, et al. The National Niemann-Pick Type C1 Disease Database: correlation of lipid profiles, mutations, and biochemical phenotypes. J Lipid Res. 2010;51:406–15.
 Tozza S, Dubbioso R., Iodice R., Topa A, Esposito M, Ruggiero L, Spina E, De Rosa E, Sacca’ F, Santoro L, Manganelli F Long-term therapy with miglustat and cognitive decline in the adult form of Niemann-Pick disease type C: a case report.
 Benussi A, Alberici A, Premi E, Bertasi V, Cotelli MS, Turla M Phenotypic heterogeneity of Niemann-Pick disease type C in monozygotic twins. J Neurol . 2015;262:642–647.
 Fu R, Yanjanin NM, Elrick MJ, Ware C, Lieberman AP, Porter FD. Apolipoprotein E genotype and neurological disease onset in Niemann-Pick disease, type C1. Am J Med Genet A. Nov 2012;158A(11):2775-80.
 New Niemann-Pick type C1 gene mutation associated with very severe disease course and marked early cerebellar vermis atrophy. Fusco C, Russo A, Galla D, Hladnik U, Frattini D, Giustina ED. J Child Neurol 2013 Dec;28(12):1694-7