Med Clin (Barc). 2016;146(11):494–496

w ww.e l sev ier .es /medic inac l in ica

Clinical report

New mutation in a young woman diagnosed with Niemann–Pickdisease type C�

Ana Larioa,∗, Carlos de Miguela, Emilio Ojedaa, Santiago Gila, María J. Collb, Pilar Alfonsoc

a Servicio de Hematología y Hemoterapia, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spainb Centro de Diagnóstico Biomédico, Hospital Clínic, Barcelona, Spainc Departamento de Bioquímica y Biología Celular y Molecular, Universidad de Zaragoza, Zaragoza, Spain

a r t i c l e i n f o

Article history:Received 2 September 2015Accepted 28 January 2016Available online 30 July 2016

Keywords:Lipid disordersGeneticsHaematology (including blood transfusion)Molecular geneticsNeuroophtalmology

a b s t r a c t

Background and objective: To describe a new molecular variant of Niemann–Pick disease type C (NPC) ina 27 year-old patient with splenomegaly and abolition of osteotendinous reflexes.Material and methods: NPC1 is the main gene with described mutation in NPC disease. Here we report acase with a new mutation, p.N916S, not described before in a patient diagnosed with NPC.Results: p.N916S was described as a cause of NPC disease by predictive programmes Mutation Master,PolyPhen2 and SIFT.Conclusions: p.N916S is a new mutation detected as a cause of NPC disease in a patient without severeneurological symptoms.

© 2016 Elsevier Espana, S.L.U. All rights reserved.

Nueva mutación descrita en una mujer joven con esplenomegalia,diagnosticada de enfermedad de Niemann-Pick tipo C

Palabras clave:Trastornos de lípidosGenéticaHematología (incluida transfusiónsanguínea)Genética molecularNeurooftalmología

r e s u m e n

Fundamento y objetivo: Describir una nueva variante molecular del Niemann-Pick tipo C (NPC) en unapaciente de 27 anos con esplenomegalia y abolición de reflejos osteotendinosos.Material y métodos: NPC1 es el principal gen mutado en el NPC. Presentamos un caso con una nuevamutación, p.N916S, no descrita previamente en pacientes con NPC.Resultados: p.N916S fue descrita como causa de la enfermedad de NPC por los programas predictivosMutation Master, PolyPhen2 y SIFT.Conclusiones: p.N916S es una nueva mutación detectada como causa de NPC en una paciente sin síntomasneurológicos graves.

© 2016 Elsevier Espana, S.L.U. Todos los derechos reservados.

Introduction

Niemann–Pick disease is part of a group of metabolic diseasesclassified as lysosomal storage disorders with autosomal recessiveinheritance. They comprise two distinct entities: the first includes

� Please cite this article as: Lario A, de Miguel C, Ojeda E, Gil S, Coll MJ, Alfonso P.Nueva mutación descrita en una mujer joven con esplenomegalia, diagnosticada deenfermedad de Niemann-Pick tipo C. Med Clin (Barc). 2016;146:494–496.

∗ Corresponding author.E-mail address: ana.lario@gmail.com (A. Lario).

types A and B, with a sphingomyelinase deficiency, and the sec-ond, Type C,1 in which there is a LDL cholesterol processing andtransport abnormality.

Among the Niemann–Pick disease, the most common clinicalform is Niemann–Pick Type B disease, which is not associated withneurological symptoms. However, the occurring of neurologicalsymptoms is a frequent form of presentation in types A and C. Thesplenomegaly is a common finding in all variants of Niemann–Pickdisease.

The suspected diagnosis is based on clinical presentation andmorphology of the bone marrow. In types A and B, the finaldiagnosis is established by enzymatic studies (sphingomyelinase

2387-0206/© 2016 Elsevier Espana, S.L.U. All rights reserved.

A. Lario et al. / Med Clin (Barc). 2016;146(11):494–496 495

Fig. 1. Abdominal MRI showing absence of vascular disorders and splenomegaly.

deficiency), and in Type C, by documenting the accumulation ofunesterified cholesterol at intracellular level (fibroblast culture orfilipin test)2 or by molecular biology techniques (NPC1 and NPC2gene mutations).3,4 The oxysterols test5 can be a support in diag-nosis.

The enzyme replacement therapy with recombinant acid sphin-gomyelinase is not yet an established procedure in Niemann–PickType B (phase 2 of the clinical trial has not started yet).Miglustat,6–10 a glucosylceramide synthase inhibitor, has recentlybeen approved in Europe – in 2009 – and in Japan in 2012 in spe-cific cases of Niemann–Pick Type C to prevent the progression ofneurological symptoms.

Patient and results

We report the case of a 27-year-old female patient who hadan asymptomatic splenomegaly discovered after an ultrasoundwas performed due to a recurrent urinary tract infection. Shehad no individual or familial medical history. All developmen-tal milestones during childhood occurred normally and never hadbehavioural or school problems.

The patient had mild thrombocytopenia as the only bloodtest abnormality (platelets 127 × 109/L); the rest of the CBCresults were normal. Biochemical determinations were normalexcept for a slight increase in total cholesterol (223 mg/dl), whileHDL cholesterol was normal (53 mg/dl); moreover, the values ofLDL cholesterol and triglycerides were 150 mg/dl and 101 mg/dl,respectively. Serological tests were normal. An abdominal MRIruled out vascular disorders and confirmed splenomegaly (Fig. 1).Bone marrow aspirate and biopsy showed the presence of multi-ple large size histiocytic cells with abundant and foamy cytoplasm,along with sea blue histiocytes with a tendency to form smallgroups that were evenly spread in the aspirate (Fig. 2). Thecytochemical behaviour of these cells were positive for acid phos-phatase and TRAP, showing intracellular lipid deposits (Sudan Blackand Oil Red).11 In immunohistochemistry, these cells had an intensemultifocal reactivity for histiocytic differentiation markers (CD68and CD163).

With high suspicion of a deposition disease, an enzyme studywas performed, showing normal activity of acid glucocerebrosi-dase (6.4 nmol/mg prot/h, ruling out Gaucher disease), similarto acid sphingomyelinase (0.394 nmol/mg prot/h, ruling out theNiemann–Pick disease, types A and B). Chitotriosidase levels wereelevated (653 nmol/ml × h [3–32 nmol/ml × h]), but not within

Fig. 2. Bone marrow aspirate-biopsy. (A) Bone marrow aspirate with presence offoamy histiocytes. (B) Accumulation of sea blue histiocytes. (C) Bone marrow biopsywith foamy histiocytes and sea blue histiocytes.

Gaucher disease range (considering the range and determination),indicating that we were facing a probable deposition disease.A whole body MRI was also performed without relevant findingsor neurological involvement data, except for the already knownsplenomegaly (19 cm long).

She was evaluated by Neurology and Ophthalmology and theNeuro-ophthalmologic examination was described as: normalpsychomotor/cognitive development and normal birth; withoutneurological symptoms (there were no crisis, dystonia, ataxia,cranial nerve involvement or psychiatric symptoms). The neurolog-ical examination was normal (strength, sensitivity, cranial nerves,

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