148Assessing health beliefs among women diagnosed andat-risk for Fabry disease: part 2

Katie A. Longa, Katherine C. Geroeb, David N. Finegoldb, aUniversityof Pittsburgh/Children's Hospital of Pittsburgh, Pittsburgh, PA, USA,bUniversity of Pittsburgh, Pittsburgh, PA, USA

Previous published literature examining the impact of Fabry diseasefor female heterozygotes has alluded to the idea that women with thisdisease have aunique clinical relationshipwith the healthcare systemandengage in Fabry disease medical management in amanner different fromtheir male counterparts. The past history of labeling these women ascarriers for the disease and asymptomatic has been proposed as onebarrier to females’ participation in evaluation and monitoring for Fabrydisease (Gibas 2008). However, the health beliefs unique to females withFabry disease have not been thoroughly addressed in the literature. Weattempt to examine this issue in more detail utilizing the Health BeliefModel, a mechanism to assess perceived susceptibility to and seriousnessof a disease, perceived benefit of engaging in a health behavior, andperceived barriers to performing this behavior. Part one of this studyexplored health beliefs among ten females through qualitative interviewsand is summarized in another abstract. For part two, fifty adult femalesdiagnosed and at-risk for Fabry disease from across the United Stateswere asked to participate in a concurrent demographic survey andwritten, multiple choice and open-ended health beliefs questionnaire.Themes emerging from analysis of part one of this study informed thedesign of the open-ended health beliefs questionnaire assessing per-ceived susceptibility to and seriousness of disease manifestations andperceived barriers and benefits to clinical evaluation, monitoring, andtreatment for Fabry disease. Preliminary findings demonstrate subjectsperceive the seriousness of Fabry disease to be similar for bothmales andfemales with the disease. Subjects also perceive females in general to besusceptible to a range of the manifestations of Fabry disease; however, incomparison, when asked to respond regarding personal susceptibility,there was inconsistency and a decreased response toward susceptibilityto disease manifestations. Interestingly, the majority of females do notbelieve “carrier” is an appropriate term to describe their status due to thepossibility a female could demonstrate symptoms of the disease. Of thepotential barriers to engaging in clinical evaluation, monitoring, andtreatment, the most commonly reported included feeling overwhelmedand anxiety. Analysis of this data is ongoing.

doi:10.1016/j.ymgme.2013.12.160

149GM2 synthase deficiency: a novel complex glycosphingolipiddisorder with neurological involvement

Charles M. Lourencoa, Giovanni Stevaninb, Stephan Zuchnerc, WilsonMarques Jr.a, aUniversity of Sao Paulo, Ribeirao Preto, Brazil, bCentre deRecherche de l’Institut du Cerveau et de la Moelle epiniere, GroupeHospitalier Pitie-Salpêtriere, Paris, France, cJohn P. Hussman Institute forHuman Genomics, University of Miami Miller School of Medicine, Miami,FL, USA

Introduction: The glycosyltransferases responsible for the synthesis ofglycoprotein and glycosphingolipid (GSL) sugar chains are residentmembrane proteins of the endoplasmic reticulum (ER) and Golgi step iscritical for the synthesis of all complex gangliosides enriched in thenervous system of vertebrates.

Objective: To report a new glycosphingolipid disorder in aBrazilian family caused by enzyme deficiency of beta-1,4-N-acetyl-

galactosaminyltransferase 1 (B4GALNT1) and its role in the synthesisof complex gangliosides.

Methodology: Biochemical and Molecular investigations were under-took in patients from a Brazilian kindred suffering with a progressiveneurological disease, presenting mainly as a Hereditary Spastic Paraple-gia (HSP). After molecular analysis of SPG11 and SPG15 genes andexcluding other inborn errors ofmetabolism (IEMs) associatedwithHSP,whole exome sequencing (WES) was performed. Results: Mutations inthe B4GALNT1 gene (in the SPG26 locus) were identified in all affectedpatients in the family; parents were heterozygous carriers of themutation. Patients affected by this disease have early onset spasticparesis, mild intellectual disability, cerebellar ataxia, strabismus andsome can develop psychiatric disturbance. Male hypogonadismwas alsonoticed. Brain MRI showed non specif white matter changes in olderpatients. Mutant mice with similar enzyme deficiency showed reducednerve conductivity with nerve degeneration in the sciatic nerve, dorsalroot ganglion, and spinal cord;wallerian degeneration andmotor neurondisorders could also be noticed.

Conclusions: Complex gangliosides synthesized via the action of GM2/GD2 synthase are enriched in the nervous system of vertebrates.Curiously, carbohydrate structures on gangliosides vary depending onthe spatiotemporal conditions, suggesting an important role in regula-tion of development and differentiation of the nervous system. Beta1,4-N-acetylgalactosaminyltransferase (GM2/GD2 synthase) is a key en-zymewhich catalyzes the conversion of GM3, GD3 and lactosylceramide(LacCer) to GM2, GD2 and asialo-GM2 (GA2), respectively. Althoughthere are many lysosomal disorders involved in ganglioside catabolismpresenting as neurodegenerative disorders, this enzyme deficiency is thesecond human disorder identified in the pathway of gangliosidebiosynthesis, suggesting that other human diseases can be caused bymetabolic errors in this biochemical pathway, highlightening the criticalroles of complex gangliosides in themaintenance of the architecture andfunctions of nerve tissues.

doi:10.1016/j.ymgme.2013.12.161

150Neurological phenotypes in Niemann-Pick disease type C (NPC):clinical, biochemical and neuroradiological retrospective reviewof 48 Brazilian patients

Charles M. Lourencoa, Vanessa Van Der Lindenb, Mara L.S.F. Santosc,Erlane M. Ribeirod, Denize Bonfime, Maria Luiza M. Saraiva Pereiraf,Fernanda Timmf, Roberto Giuglianif, Wilson M. Marques Jr.a, aUniversityof Sao Paulo, Ribeirao Preto, Brazil, bBarao de Lucena Hospital, Recife, Brazil,cPequeno Principe Hospital, Curitiba, Brazil, dAlbert Sabin Hospital,Fortaleza, Brazil, eHospital Regional Da Asa Sul, Brasilia, Brazil, fFederalUniversity of Rio Grande Do Sul, Porto Alegre, Brazil

Introduction: Niemann-Pick type C disease (NPC) is a rare inbornerror of metabolism caused by defective intracellular transport ofcholesterol. It can present with a wide range of neurologic findings,some of them quite non-specific.

Objective: This study discusses the wide neurological spectrum ofNP‐C.

Design: Retrospective cohort study.Results: 48 patients were included in the study. 30 out of 48 patients

were confirmed to have NPC by filipin staining (18 patients requiredmolecular analysis). Regarding clinical form, 5 were perinatal, 15infantile, 17 juvenile and 11 were adults. Prolonged neonatal jaundicewas a common feature and two of themwere diagnosed with “neonatalhepatitis”. Patients with perinatal form usually had hypotonia as themain feature, followed by later spasticity. Infantile patients usuallyhad “symptom-free” period, followed by relentless neurodegeneration:

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cerebellar ataxia, dystonia, learning disabilities and behavior changeswere commonly seen in this group. Juvenile patients, on the other hand,presented mostly with progressive psychiatric changes and extrapyra-midal features. Adult patients showed peculiar combination ofdystonia (especially oromandibular dystonia), eyelid apraxia (“blepha-rospasm-like”) and cognitive decline/dementia. Ocular abnormalitieswere seen in 36 patients (mostly, vertical supranuclear gaze paralysis).Leukoencephalopathy and progressive cerebral/cerebellar atrophy werethe main MRI features. Gelastic cataplexy, although present only in asubset of the infantile/juvenile patients, is a relatively specific findingfor NPC.

Conclusions: Neurological manifestations in NPC patients areextremely variable, even in the same sibship. Better understandingof the natural history of the disease is crucial for evaluation ofpotential therapeutic approaches in such a devastating disorder.

doi:10.1016/j.ymgme.2013.12.162

151Progression of feeding skills in infantile Pompe disease - theGOSH experience

Sonia Lozano, Ashok Vellodi, Alexander Broomfield, Great Ormond StreetHospital for Children NHS Foundation Trust, London, UK

Infantile Pompe disease is an autosomal recessive progressiveneuromuscular disorder. Dysphagia is often present prior to the startof enzyme replacement therapy (ERT)1 and is normally due to acombination of cardiac failure and neuromuscular weakness. Howev-er, long term feeding difficulties are reported even after prolongedtreatment with ERT2. Children presenting with infantile Pompedisease at Great Ormond Street Hospital receive routine baseline andfollow up swallow assessments. This study describes the feedingprogression of children on long term ERT, examining their overallswallow picture, and charts their method of feeding from diagnosis tocurrent status. This is a retrospective case note review of all childrenreferred to speech and language therapy for swallow assessment overa 5 year period. Method of feeding, weight centile, and ventilatorrequirements will be collated from 3 time points, initiation of ERT,6 months post initiation, and at the most recent assessment.Videofluoroscopy swallow study (VFSS) findings will be severitygraded on a validated severity scale. Nineteen patients are includedwith initial presentation including cardiomyopathy between the agesof 14 days to 2 years 4 months. Twelve are alive at the time of thestudy (age range 6 months - 9 years), four of whom are fully feedingtube dependent. Further data on swallow severity score and feedingmethodwill be presented across the 3 time points, with comparison ofchange in severity score and feeding method. Comparison will bemade between change in swallow skills with non-invasive ventilationrequirements. This study will provide information on the longer termfeeding presentation of children receiving ERT for infantile Pompedisease. Understanding the progression of swallowing skills isimportant for effective monitoring of patients, and appropriatecounselling at initial diagnosis. 1 Jones H, Muller C, Lin M, BanugariaS, Case L, Li J, O’Grady G, Heller J, Kishnani P (2009), Oropharyngealdysphagia in infants and children with infantile Pompe disease.dysphagia 25(4):277-83 2 Prater, Banugaria S, De Armey PA-C, BothaE, Stege E, Case L, Jones H, Phornphutkul C, Wang R, Young S, KishnaniP (2012), The emerging phenotype of long-term survivors withinfantile Pompe disease. Genetics in Medicine 14: 800-810.

doi:10.1016/j.ymgme.2013.12.163

152Difficulties in confirming the diagnosis of mucolipidosis II/III:case reports

Fernanda S. Ludwiga,b, Gabriela K. Curya, Renata V. Velhoc, TacianeAlegrac, Chong A. Kimd, Eline van Meele, Stuart Kornfeldf, Ida V.D.Schwartza, aHospital de Clinicas de Porto Alegre, Porto Alegre, Brazil,bPrograma de Pós Graduação em Medicina: Ciências Médicas UFRGS,Porto Alegre, Brazil, cPrograma de Pós-Graduação em Genética eBiologia Molecular UFRGS, Porto Alegre, Brazil, dInstituto da Criançada Faculdade de Medicina da USP, São Paulo, Brazil, eUniversity MedicalCenter Utrecht, Utrecht, Netherlands, fWashington University School ofMedicine, St Louis, WA, USA

Mucolipidoses II and III (ML II and III) are autosomal recessivelysosomal disorders (LSD) in which the essential mannose 6-phosphate recognition marker system is deficient. They are describedas being caused only by mutations in GNPTAB or GNPTG genes,which encodes for the N-acetylglucosamine-1-phosphotransferase(phosphotransferase), although there are other genes involved inthis system (such as the NAGPA gene). To describe 4 patients (A, B, C,D), with clinical and biochemical diagnosis of ML II/III, who presentinconclusive molecular diagnosis. All patients have been previouslyinvestigated through enzyme assays for lysosomal hydrolases inplasma (high activity all patients); the assays have been alsoperformed in fibroblasts for patients B and D (low activity oflysosomal hydrolases). Other LSD have been excluded as recom-mended. Patients were biochemically assessed for the presence ofphosphorylated residues of mannose-6-phosphate in CI-MPR affinitycolumn. Genetic analysis was performed by DNA sequencing of genesGNPTAB, GNPTG and NAGPA. ACGH analysis for the regions whichincludes GNPTAB or GNPTG genes was performed in order to detectlarge deletions or insertions (only for patient B). Phosphorylation oflysosomal acid hydrolases was severely impaired in all patients.Regarding the GNPTAB gene, patients C and D have been found to beheterozygous for a pathogenic mutation, but no mutations have beenfound in patients A and B. No mutations were found in both GNPTGand NAGPA genes, and no change was observed in the aCGH. Sinceit's possible that these patients have mutations that affect theactivity of the phosphotransferase and nothing conclusive was ob-served in DNA analysis, mutations may be occurring in a regulatoryregion as a promoter or enhancer. This report demonstrates thedifficulties of the DNA diagnosis of ML II/III, since mutations inGNPTAB and GNPTG are frequently identified, but some cases remaininconclusive and are usually not described in the literature. Support:FIPE/HCPA, FAPERGS, CNPq.

doi:10.1016/j.ymgme.2013.12.164

153Target-population screening for lysosomal disorders - a highlyefficient tool for the diagnosis of patients

Zoltan Lukacs, Rene Santer, Paulina Nieves, Cobos Hamburg UniversityMedical Center, Hamburg, Germany

Background: Lysosomal storage diseases present with highlyvariable symptoms and usually with different severity, dependingon the individual age of onset. Diagnosis is sometimes furtherdelayed because of the relative rarity of the diseases which does notmake them prime candidates in diagnostic algorithms. Recently,dried blood specimens have been introduced for enzyme activitymeasurement of a number of lysosomal enzymes and thereby, helpto facilitate testing.

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