Letter to the Editor
New variant associated with Niemann-Pick disease type C: neurological manifestations and biochemical, molecular, and cellular characterisation
Nueva variante asociada a enfermedad de Niemann-Pick tipo C: manifestaciones neurológicas y caracterización bioquímica, molecular y celular
a Instituto de Investigación Sanitaria Aragón (IIS Aragón), Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain
b Servicio de Neurología, Hospital Comarcal de Melilla, Melilla, Spain
c Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Centro de Investigaciones en Bioquímica y Biología Molecular-Nanomedicina, Institut de Recerca Hospital Vall d’Hebrón, Barcelona, Spain
d Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain
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Figuras representativas de la tinción del colesterol mediante Filipin III en fibroblastos de nuestro paciente (A) y de un control (B). Las células se cultivas en cubreobjetos y se mantienen durante 72<span class="elsevierStyleHsp" style=""></span>h en un medio libre de lipoproteínas antes de cambiarlas a un medio rico en lipoproteínas de baja densidad durante 24<span class="elsevierStyleHsp" style=""></span>h. Posteriormente se fijan y tiñen con el colorante Filipin III. Ampliación a ×200</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "L. López de Frutos, J. Romero-Imbroda, V. Rodríguez-Sureda, P. Giraldo" "autores" => array:4 [ 0 => array:2 [ "nombre" => "L." "apellidos" => "López de Frutos" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Romero-Imbroda" ] 2 => array:2 [ "nombre" => "V." "apellidos" => "Rodríguez-Sureda" ] 3 => array:2 [ "nombre" => "P." 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Occlusion is observed in the proximal right internal carotid artery (a) and proximal middle cerebral artery (b). Control angiography scans obtained after the first (c) and second (d) passes with the stent retriever.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "M. Serra Martínez, C. Avellaneda-Gómez, N. Cayuela Caudevilla, A. Rodríguez Campello" "autores" => array:4 [ 0 => array:2 [ "nombre" => "M." "apellidos" => "Serra Martínez" ] 1 => array:2 [ "nombre" => "C." "apellidos" => "Avellaneda-Gómez" ] 2 => array:2 [ "nombre" => "N." "apellidos" => "Cayuela Caudevilla" ] 3 => array:2 [ "nombre" => "A." 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López de Frutos, J. Romero-Imbroda, V. Rodríguez-Sureda, P. Giraldo" "autores" => array:4 [ 0 => array:4 [ "nombre" => "L." "apellidos" => "López de Frutos" "email" => array:1 [ 0 => "llopezdefrutos.uit@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" => "J." "apellidos" => "Romero-Imbroda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "V." "apellidos" => "Rodríguez-Sureda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 3 => array:3 [ "nombre" => "P." "apellidos" => "Giraldo" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Instituto de Investigación Sanitaria Aragón (IIS Aragón), Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Neurología, Hospital Comarcal de Melilla, Melilla, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Centro de Investigaciones en Bioquímica y Biología Molecular-Nanomedicina, Institut de Recerca Hospital Vall d’Hebrón, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nueva variante asociada a enfermedad de Niemann-Pick tipo C: manifestaciones neurológicas y caracterización bioquímica, molecular y celular" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1427 "Ancho" => 3199 "Tamanyo" => 377571 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Structural alterations in the NPC1 protein. Interactions between the Ser1048, Tyr1091, and Val856 (A) or Ala856 (B) amino acids. Images generated using the 3JD8 sequence (PDB) on the Swiss-PdbViewer software.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Niemann-Pick disease type C (NPC; MIM #257220 and MIM #607625) is caused by an inborn error of metabolism and follows an autosomal recessive inheritance pattern. The disease is characterised by an alteration to intracellular cholesterol transport, causing lysosomal and/or late endosomal accumulation of several metabolites.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">1,2</span></a> The causal genes are <span class="elsevierStyleItalic">NPC1</span> (MIM *607623) and <span class="elsevierStyleItalic">NPC2</span> (MIM *607625). <span class="elsevierStyleItalic">NPC1</span> accounts for 95% of published cases, with <span class="elsevierStyleItalic">NPC2</span> covering 4%.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Diagnosis is challenging due to the great clinical heterogeneity of the condition and the difficulty of laboratory testing. Symptoms are generally classified into 3 broad groups: visceral, neurological, and psychiatric. The most frequent symptoms are splenomegaly, vertical gaze palsy, and cataplexy.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">3</span></a> A screening tool based on clinical manifestations (the NPC Suspicion Index) has been created to guide diagnosis; the tool assigns a score reflecting the risk of NPC and the suitability of additional studies to clarify the diagnosis.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">4,5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">We present the case of a 26-year-old woman of Berber origin; she had history of intellectual disability and psychotic disorder, for which she was receiving olanzapine 5<span class="elsevierStyleHsp" style=""></span>mg. She was referred to our centre due to abnormal movement and gait alterations of less than one year's progression. The neurological examination revealed dysarthria, hypomimia, vertical gaze palsy, global bradykinesia with isolated distal myoclonus, and mild ataxic gait without arm swing. Brain MRI and DaTSCAN® revealed no relevant abnormalities. The ophthalmic examination revealed cherry-red spots on both maculae. Abdominal ultrasound detected splenomegaly (13.8<span class="elsevierStyleHsp" style=""></span>cm). The patient scored 104 on the NPC suspicion index (64th percentile).</p><p id="par0020" class="elsevierStylePara elsevierViewall">To confirm the diagnosis, we tested plasma chitotriosidase activity<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">6</span></a> and concentrations of the chemokine CCL18 (PARC)<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">7</span></a> and 7-ketocholesterol (7-CC)<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">8–10</span></a> using methods described elsewhere. All 3 biomarkers were above the intra-laboratory reference limit.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Sequencing of <span class="elsevierStyleItalic">NPC1</span> and <span class="elsevierStyleItalic">NPC2</span> was performed according to the Sanger method with small modifications to the protocol published by Zech's study group, identifying 2 variants in <span class="elsevierStyleItalic">NPC1</span>: p.Ile1061Thr (previously described by Yamamoto et al.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">11</span></a>) and p.Val856Ala (not previously described).</p><p id="par0030" class="elsevierStylePara elsevierViewall">Cholesterol accumulation in fibroblasts was analysed with cytochemical staining using Filipin III (Sigma-Aldrich; Spain)<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">12</span></a>; 70% of fibroblasts were positive for cholesterol accumulation (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">To rule out other lysosomal conditions of the same metabolic pathway, we studied lysosomal acid lipase<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a> and sphingomyelinase<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">14</span></a> activity in lysate from leukocytes; results were within the intra-laboratory reference limits.</p><p id="par0040" class="elsevierStylePara elsevierViewall">As the p.Val856Ala variant had not previously been described, and given its location in a cysteine-rich loop that accounts for approximately one-third of the described pathogenic variants,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> we performed an in silico analysis of the mutation. Clustal Omega was used to run a sequence conservation analysis, with comparison against 30 species, revealing that the region is highly conserved. Simultaneously, we used the NPC1 structure published on Protein Data Bank by Gong and colleagues in 2016 (Cryo-EM structure of the full-length human NPC1 at 4.4 angstrom; PDB access number: 3JD8) and modelled the pathogenic variant with the free software application Swiss-PdbViewer, revealing reduced electrostatic interactions in the variant form (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>). The DUET stability predictor detected reduced stability in the protein containing the p.Val856Ala variant (ΔΔG: −1.457 vs ΔΔG: 0<span class="elsevierStyleHsp" style=""></span>kcal/mol). According to the guidelines of the American College of Medical Genetics,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> this variant would be catalogued as “likely pathogenic.”</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical, biochemical, molecular, and cellular findings from our patient suggest that she has NPC due to compound heterozygosis of the p.Ile1061Thr variant and the previously undescribed p.Val856Ala variant.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: López de Frutos L, Romero-Imbroda J, Rodríguez-Sureda V, Giraldo P. Nueva variante asociada a enfermedad de Niemann-Pick tipo C: manifestaciones neurológicas y caracterización bioquímica, molecular y celular. Neurología. 2020;35:50–52.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1325 "Ancho" => 3199 "Tamanyo" => 421548 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Representative images from Filipin III cholesterol staining of fibroblasts from our patient (A) and a control (B). Cells were cultured for 72<span class="elsevierStyleHsp" style=""></span>hours on a coverslip in lipoprotein-free medium and then for 24<span class="elsevierStyleHsp" style=""></span>hours in a medium rich in low-density lipoproteins. They were subsequently fixed and stained with Filipin III. 200× magnification.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1427 "Ancho" => 3199 "Tamanyo" => 377571 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Structural alterations in the NPC1 protein. Interactions between the Ser1048, Tyr1091, and Val856 (A) or Ala856 (B) amino acids. 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Cebolla, Pilar Irún, and Carmen Domínguez for their invaluable contribution in laboratory testing.</p>" "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/21735808/0000003500000001/v1_202004040635/S2173580819300641/v1_202004040635/en/main.assets" "Apartado" => array:4 [ "identificador" => "9409" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Letters to the editor" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/21735808/0000003500000001/v1_202004040635/S2173580819300641/v1_202004040635/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173580819300641?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
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| 2024 November | 3 | 0 | 3 |
| 2024 October | 26 | 1 | 27 |
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| 2024 August | 25 | 3 | 28 |
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| 2024 May | 13 | 11 | 24 |
| 2024 April | 20 | 2 | 22 |
| 2024 March | 40 | 8 | 48 |
| 2024 February | 44 | 6 | 50 |
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| 2023 December | 64 | 9 | 73 |
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| 2023 September | 39 | 1 | 40 |
| 2023 August | 46 | 4 | 50 |
| 2023 July | 60 | 7 | 67 |
| 2023 June | 56 | 2 | 58 |
| 2023 May | 88 | 5 | 93 |
| 2023 April | 46 | 2 | 48 |
| 2023 March | 53 | 2 | 55 |
| 2023 February | 50 | 9 | 59 |
| 2023 January | 49 | 16 | 65 |
| 2022 December | 42 | 6 | 48 |
| 2022 November | 42 | 8 | 50 |
| 2022 October | 28 | 19 | 47 |
| 2022 September | 45 | 8 | 53 |
| 2022 August | 43 | 6 | 49 |
| 2022 July | 20 | 9 | 29 |
| 2022 June | 28 | 9 | 37 |
| 2022 May | 20 | 18 | 38 |
| 2022 April | 28 | 19 | 47 |
| 2022 March | 40 | 19 | 59 |
| 2022 February | 23 | 7 | 30 |
| 2022 January | 28 | 6 | 34 |
| 2021 December | 9 | 8 | 17 |
| 2021 November | 20 | 7 | 27 |
| 2021 October | 50 | 14 | 64 |
| 2021 September | 47 | 11 | 58 |
| 2021 August | 68 | 7 | 75 |
| 2021 July | 23 | 8 | 31 |
| 2021 June | 16 | 5 | 21 |
| 2021 May | 36 | 9 | 45 |
| 2021 April | 86 | 15 | 101 |
| 2021 March | 62 | 9 | 71 |
| 2021 February | 57 | 11 | 68 |
| 2021 January | 56 | 15 | 71 |
| 2020 December | 41 | 5 | 46 |
| 2020 November | 25 | 9 | 34 |
| 2020 October | 20 | 7 | 27 |
| 2020 September | 29 | 8 | 37 |
| 2020 August | 17 | 12 | 29 |
| 2020 July | 14 | 10 | 24 |
| 2020 June | 7 | 6 | 13 |
| 2020 May | 15 | 9 | 24 |
| 2020 April | 28 | 7 | 35 |
| 2020 March | 0 | 2 | 2 |
| 2020 February | 0 | 3 | 3 |
| 2020 January | 0 | 6 | 6 |
| 2019 December | 0 | 4 | 4 |
| 2019 November | 0 | 7 | 7 |
| 2019 October | 0 | 4 | 4 |
| 2019 September | 0 | 2 | 2 |
| 2019 July | 0 | 5 | 5 |
| 2019 June | 0 | 10 | 10 |
| 2019 May | 0 | 3 | 3 |
| 2019 April | 0 | 8 | 8 |
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