Clinical report
New mutation in a young woman diagnosed with Niemann–Pick disease type C
Nueva mutación descrita en una mujer joven con esplenomegalia, diagnosticada de enfermedad de Niemann-Pick tipo C
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Coll, Pilar Alfonso" "autores" => array:6 [ 0 => array:4 [ "nombre" => "Ana" "apellidos" => "Lario" "email" => array:1 [ 0 => "ana.lario@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Carlos" "apellidos" => "de Miguel" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Emilio" "apellidos" => "Ojeda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "Santiago" "apellidos" => "Gil" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "María J." "apellidos" => "Coll" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 5 => array:3 [ "nombre" => "Pilar" "apellidos" => "Alfonso" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Servicio de Hematología y Hemoterapia, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Centro de Diagnóstico Biomédico, Hospital Clínic, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Departamento de Bioquímica y Biología Celular y Molecular, Universidad de Zaragoza, Zaragoza, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nueva mutación descrita en una mujer joven con esplenomegalia, diagnosticada de enfermedad de Niemann-Pick tipo C" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 783 "Ancho" => 1040 "Tamanyo" => 110749 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abdominal MRI showing absence of vascular disorders and splenomegaly.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Niemann–Pick disease is part of a group of metabolic diseases classified as lysosomal storage disorders with autosomal recessive inheritance. They comprise two distinct entities: the first includes types A and B, with a sphingomyelinase deficiency, and the second, Type C,<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">1</span></a> in which there is a LDL cholesterol processing and transport abnormality.</p><p id="par0010" class="elsevierStylePara elsevierViewall">Among the Niemann–Pick disease, the most common clinical form is Niemann–Pick Type B disease, which is not associated with neurological symptoms. However, the occurring of neurological symptoms is a frequent form of presentation in types A and C. The splenomegaly is a common finding in all variants of Niemann–Pick disease.</p><p id="par0015" class="elsevierStylePara elsevierViewall">The suspected diagnosis is based on clinical presentation and morphology of the bone marrow. In types A and B, the final diagnosis is established by enzymatic studies (sphingomyelinase deficiency), and in Type C, by documenting the accumulation of unesterified cholesterol at intracellular level (fibroblast culture or <span class="elsevierStyleItalic">filipin test</span>)<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">2</span></a> or by molecular biology techniques (<span class="elsevierStyleItalic">NPC1</span> and <span class="elsevierStyleItalic">NPC2</span> gene mutations).<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">3,4</span></a> The oxysterols test<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">5</span></a> can be a support in diagnosis.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The enzyme replacement therapy with recombinant acid sphingomyelinase is not yet an established procedure in Niemann–Pick Type B (phase 2 of the clinical trial has not started yet). Miglustat,<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">6–10</span></a> a glucosylceramide synthase inhibitor, has recently been approved in Europe – in 2009 – and in Japan in 2012 in specific cases of Niemann–Pick Type C to prevent the progression of neurological symptoms.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Patient and results</span><p id="par0025" class="elsevierStylePara elsevierViewall">We report the case of a 27-year-old female patient who had an asymptomatic splenomegaly discovered after an ultrasound was performed due to a recurrent urinary tract infection. She had no individual or familial medical history. All developmental milestones during childhood occurred normally and never had behavioural or school problems.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The patient had mild thrombocytopenia as the only blood test abnormality (platelets 127<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>10<span class="elsevierStyleSup">9</span>/L); the rest of the CBC results were normal. Biochemical determinations were normal except for a slight increase in total cholesterol (223<span class="elsevierStyleHsp" style=""></span>mg/dl), while HDL cholesterol was normal (53<span class="elsevierStyleHsp" style=""></span>mg/dl); moreover, the values of LDL cholesterol and triglycerides were 150<span class="elsevierStyleHsp" style=""></span>mg/dl and 101<span class="elsevierStyleHsp" style=""></span>mg/dl, respectively. Serological tests were normal. An abdominal MRI ruled out vascular disorders and confirmed splenomegaly (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Bone marrow aspirate and biopsy showed the presence of multiple large size histiocytic cells with abundant and foamy cytoplasm, along with sea blue histiocytes with a tendency to form small groups that were evenly spread in the aspirate (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The cytochemical behaviour of these cells were positive for acid phosphatase and TRAP, showing intracellular lipid deposits (Sudan Black and Oil Red).<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">11</span></a> In immunohistochemistry, these cells had an intense multifocal reactivity for histiocytic differentiation markers (CD68 and CD163).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">With high suspicion of a deposition disease, an enzyme study was performed, showing normal activity of acid glucocerebrosidase (6.4<span class="elsevierStyleHsp" style=""></span>nmol/mg prot/h, ruling out Gaucher disease), similar to acid sphingomyelinase (0.394<span class="elsevierStyleHsp" style=""></span>nmol/mg prot/h, ruling out the Niemann–Pick disease, types A and B). Chitotriosidase levels were elevated (653<span class="elsevierStyleHsp" style=""></span>nmol/ml<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>h [3–32<span class="elsevierStyleHsp" style=""></span>nmol/ml<span class="elsevierStyleHsp" style=""></span>×<span class="elsevierStyleHsp" style=""></span>h]), but not within 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 findings or neurological involvement data, except for the already known splenomegaly (19<span class="elsevierStyleHsp" style=""></span>cm long).</p><p id="par0040" class="elsevierStylePara elsevierViewall">She was evaluated by Neurology and Ophthalmology and the Neuro-ophthalmologic examination was described as: normal psychomotor/cognitive development and normal birth; without neurological symptoms (there were no crisis, dystonia, ataxia, cranial nerve involvement or psychiatric symptoms). The neurological examination was normal (strength, sensitivity, cranial nerves, cerebellum, march and variants, normal ocular fundus), with the exception of widespread underactivity of stretch reflexes.</p><p id="par0045" class="elsevierStylePara elsevierViewall">A molecular study by the sequencing of exons and exon-intron boundaries of the <span class="elsevierStyleItalic">NPC1</span> and <span class="elsevierStyleItalic">NPC2</span> genes in peripheral blood leukocytes found two mutations in the <span class="elsevierStyleItalic">NPC1 gene</span>, both in heterozygosity; one of them, the p.C177Y (c.530G>A), described previously<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">4</span></a> and the other, p.N916S (c.2747A</p><p id="par0050" class="elsevierStylePara elsevierViewall">This p.N916S mutation we describe as new has not previously appeared in the <span class="elsevierStyleItalic">Human Gene Mutation Database</span>. Although no studies have been developed regarding the expression of this variant, our predictive programme studies on mutation severity show that residue 916 is relevant to the NPC1 protein. On the other hand, the minor allele of this variant was not found in any allele analysed within the 1000 Genomes Project, for normal population.</p><p id="par0055" class="elsevierStylePara elsevierViewall">An oxysterols test was performed as a complementary diagnostic study. Plasma levels of cholestane-3b, 5a, 6b-triol (41.7<span class="elsevierStyleHsp" style=""></span>ng/ml) and 7-ketocholesterol (105.2<span class="elsevierStyleHsp" style=""></span>ng/ml) measured by <span class="elsevierStyleItalic">HPLC-ESI-MS</span>/<span class="elsevierStyleItalic">MS</span><a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">12</span></a> were high compared with the control range, a typical finding in Niemann–Pick Type C disease.</p><p id="par0060" class="elsevierStylePara elsevierViewall">Currently, the patient is working as a nurse. She has no neurological symptoms, and has begun treatment with atorvastatin 20<span class="elsevierStyleHsp" style=""></span>mg/day, with normalisation of total cholesterol levels (167<span class="elsevierStyleHsp" style=""></span>mg/dl) and a good performance for the rest of lipid profile parameters after 2 months of statin administration, which is presently maintained.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Discussion</span><p id="par0065" class="elsevierStylePara elsevierViewall">According to the medical literature, Niemann–Pick Type C disease is an extremely rare disease. This is obviously true, but perhaps it is also an underdiagnosed disease, since there have been reports of isolated splenomegaly as a way of presentation for the said disease.<a class="elsevierStyleCrossRefs" href="#bib0155"><span class="elsevierStyleSup">13–16</span></a> This should make us think about deposition diseases as part of the differential diagnosis in patients with splenomegaly, whether they have concomitant symptomatology or not. Many patients with Niemann–Pick Type C disease have no neurological symptoms until they are a lot older than 27 years of age,<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">17,18</span></a> being increasingly frequent the diagnoses during adulthood. In addition, the fact that more and more patients remain asymptomatic at the time of diagnosis indicates that the neuropsychological monitoring of these patients should be a priority and should be performed at least once a year from the date of diagnosis.</p><p id="par0070" class="elsevierStylePara elsevierViewall">In our view, there are two factors that differentiate our patient from the usual patient who is diagnosed with Niemann–Pick Type C disease. One of them is the absence of symptoms at the time of diagnosis, and the other, clearly differential, the presence of a mutation, p.N916S (c.2747A</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Conflicts of interest</span><p id="par0075" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interest.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:9 [ 0 => array:3 [ "identificador" => "xres733935" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec737686" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres733936" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec737687" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Patient and results" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Conflicts of interest" ] 8 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-09-02" "fechaAceptado" => "2016-01-28" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec737686" "palabras" => array:5 [ 0 => "Lipid disorders" 1 => "Genetics" 2 => "Haematology (including blood transfusion)" 3 => "Molecular genetics" 4 => "Neuroophtalmology" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec737687" "palabras" => array:5 [ 0 => "Trastornos de lípidos" 1 => "Genética" 2 => "Hematología (incluida transfusión sanguínea)" 3 => "Genética molecular" 4 => "Neurooftalmología" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">To describe a new molecular variant of Niemann–Pick disease type C (NPC) in a 27 year-old patient with splenomegaly and abolition of osteotendinous reflexes.</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Material and methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">NPC1</span> is the main gene with described mutation in NPC disease. Here we report a case with a new mutation, p.N916S, not described before in a patient diagnosed with NPC.</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">p.N916S was described as a cause of NPC disease by predictive programmes Mutation Master, PolyPhen2 and SIFT.</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">p.N916S is a new mutation detected as a cause of NPC disease in a patient without severe neurological symptoms.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Material and methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Fundamento y objetivo</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Describir una nueva variante molecular del Niemann-Pick tipo C (NPC) en una paciente de 27 años con esplenomegalia y abolición de reflejos osteotendinosos.</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Material y métodos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleItalic">NPC1</span> es el principal gen mutado en el NPC. Presentamos un caso con una nueva mutación, p.N916S, no descrita previamente en pacientes con NPC.</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">p.N916S fue descrita como causa de la enfermedad de NPC por los programas predictivos Mutation Master, PolyPhen2 y SIFT.</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">p.N916S es una nueva mutación detectada como causa de NPC en una paciente sin síntomas neurológicos graves.</p></span>" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Fundamento y objetivo" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Material y métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">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 de enfermedad de Niemann-Pick tipo C. Med Clin (Barc). 2016;146:494–496.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 783 "Ancho" => 1040 "Tamanyo" => 110749 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Abdominal MRI showing absence of vascular disorders and splenomegaly.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 2178 "Ancho" => 978 "Tamanyo" => 442824 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Bone marrow aspirate-biopsy. (A) Bone marrow aspirate with presence of foamy histiocytes. 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