Descriptive report of the variant adult visceral form non-neuronopathic of Νiemann-Ρick type C disease in a Spanish series

Abstracts / Molecular Genetics and Metabolism 117 (2016) S14–S124

Given the persistent findings and lack of progression, it possibly reflects accumulation of abnormal metabolites, potentially with enlarged perivascular spaces. These findings may be secondary to Gaucher disease or another yet unknown metabolic disorder. Further evaluation is underway. doi:10.1016/j.ymgme.2015.12.342

185 Evaluation of suspicion index and plasma biomarkers as efficient tool in the diagnosis of Νiemann-Ρick disease type C Laura López de Frutosa,b, Pilar Alfonsoa,b,c, Jorge J. Cebollaa,b, Pilar Irúnb,d, Pilar Giraldoa,b,c, aFundación Española para el Estudio y la Terapéutica de la Enfermedad de Gaucher y otras Lisosomales (FEETEG), Zaragoza, Spain, bInstituto de Investigación Sanitaria Aragón (IIS Aragón), Zaragoza, Spain, cCentro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain, dCentro de Invetigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain Niemann-Pick disease type C (NPC) is a rare autosomal recessive and neurovisceral lipid storage disorder with a heterogeneous presentation. Because of it, in 2012 a Suspicion Index tool (NPC-SI) was developed. Other surrogated markers of the disease have been evaluated as the CCL18/PARC, Chitotriosidase (ChT) or 7Ketocholesterol (7-KC) determinations, whereas non has been demostrated as best criteria in NPC screening. The purpose of this study is to perform a retrospective analysis of the NPC suspected individuals to assess the efficiency of the NPC-SI and the other markers above mentioned depending on NPC1 and NPC2 genotyping results. From June’14 to September’15 we received 105 samples with clinical suspicion of NPC disease. The NPC-SI was calculated by the physicians. The determinations of biomarkers were carried out according to laboratory standard procedures. NPC1 and NPC2 sequencing were performed when at least one of biomarkers was higher than our cut-off values or the NPC-SI was equal or higher than 70 in adults. The biomarkers efficiencies were analyzed by the predictive values, specificity and sensibility. Only 74 samples were taking in account for this analysis due to NPC-SI missing data. According to genetic diagnosis, 4 subjects were affected, 3 were carriers of two or more unknown significance variants, 9 were carriers of one heterozygous variant, and 58 had no variants. All biomarker ranges of predicted positive values were between 0.02 - 0.5, and negative between 0.5 - 0.76. The best specificity (100%) and the best sensibility (100%) were shown by 7-KC. Any possible combination among markers improved the individual results. According to our results the most appropriate surrogated marker to the NPC disease screening was 7-KC. In our opinion, the NPC-SI shows that is not the best criteria to suggest the genetic diagnostic. doi:10.1016/j.ymgme.2015.12.343

186 Descriptive report of the variant adult visceral form nonneuronopathic of Νiemann-Ρick type C disease in a Spanish series Laura López de Frutosa,b, Pilar Alfonsoa,b,c, Pilar Irúnb,c, Jorge J. Cebollaa,b, Inmaculada Ballesterosd, Nilda Venegase, Abelardo Barezf, Jesús Villarrubiag, Enrique Calderónh, Juana Claveli, Susana Cantareroj, Pilar Leónk, Alberto Villarejol, Carlos Leivam, Carmen Loureiron, Manuel Gaonao, Emilio Ojedap, Pilar Giraldoa,b,c, aFundación Española para el Estudio y la Terapéutica de la Enfermedad de Gaucher y otras

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Lisosomales (FEETEG), Zaragoza, Spain, bInstituto de Investigación Sanitaria Aragón, Zaragoza, Spain, cCentro de Invetigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain, dHospital Unversitario Miguel Servet, Zaragoza, Spain, eParc Sanitari Sant Joan de Déu, St Boi de Llobregat, Spain, fHospital Nuestra Señora de Sonsoles, Ávila, Spain, gHospital Universitario Ramón y Cajal, Madrid, Spain, h Hospital Universitario Virgen del Rocio, Sevilla, Spain, iHospital General de Castellón, Castellón, Spain, jHospital Universitario de Móstoles, Móstoles, Spain, kHospital Universitario Dr Preset, Valencia, Spain, l Hospital Universitario 12 de Octubre, Madrid, Spain, mHospital General Universitario de Alicante, Alicante, Spain, nHospital do Meixoeiro, Vigo, Spain, oHospital Universitario de Burgos, Burgos, Spain, pHospital Puerta de Hierro, Madrid, Spain Niemann-Pick disease type C (NPC) is a rare autosomal recessive lipid storage disorder with a heterogeneous presentation. This disease is characterized by visceral, neurological and psychiatric manifestations. The majority of patients develop the symptomatology in early childhood but there are different variants that appear in adults. The variant adult visceral non-neuronopathic form is very rare and there are a few reports about this and it is possible that it has a different genetic and clinical entity. This study presents a descriptive report of adult patients with organomegaly and presence of foam cells in bone marrow or spleen aspiration. In the screening performed to search a lysosomal disorder we detect an increase specific plasma biomarkers and the sequencing of NPC1 or NPC2 identify several variants linked to NPC. In the last five years a total of 363 suspicious NPC studies had been performed in our laboratory, 50 of them had one or more variations described as pathogenic or unknown significance, and 14 of these only had visceromegaly as unique clinical manifestation. In the analysis of this 14 cases, the median age was 39 years (r:23-60) and the ratio male/female 10/4. The Chitotriosidase activity was 265 nmol/mL/hour (r:0-1493). The mean concentration for CCL18/PARC was 168 ng/mL (r:22-558) and for 7-Ketocholesterol, in five patients, was 155 ng/mL (r:b2-423). This genetic study showed the following variations (apart from polymorphisms): p.Cys177Gly, p.Asn222Ser, p.Thr375Ala, p.Gln775Pro, p.Leu846Pro, p.Asn916Ser, p.Pro1007Ala, p.Ala1151Thr, p.Glu1188Term, c.1947 + 8 g b c in NPC1. The NPC2 gene does not show variations. The follow up of this patients do no shown presence of neurological or psychiatric manifestations. It is necessary to perform complementary studies and analyzes more patients with these variants, to clarify the relation between the non-neurological disease and this variant. doi:10.1016/j.ymgme.2015.12.344

187 Acid ceramidase deficiency leads to multiple skin abnormalities in a mouse model of Farber disease Lucia Lopez-Vasqueza,b, Shaalee Dworskia,b, Roxane Pouliotc, Todd Galbraithc, Mustafa A. Kamanib, Dan Lacroixc, François A. Augerc,d, Jeffrey A. Medina,b, aUniversity of Toronto, Toronto, ON, Canada, b University Health Network, Toronto, ON, Canada, cCHU de Québec Research Centre, Quebec, QC, Canada, dUniversité Laval, Quebec, QC, Canada Ceramides are a class of diverse and complex sphingolipids that play an essential role in many biological functions. They are the major lipid constituent of lamellar sheets of the intercellular spaces of the stratum corneum, the outermost layer of the epidermis. Lamellar sheets are responsible for the barrier property of the epidermis and ceramides are implicated in the water permeability barrier function of the skin. We recently developed a mouse model of acid ceramidase (ACD) deficiency (P361R variation) that