Haifa, Israel, bPfizer Inc., New York, NY, USA, cUniversity of MichiganMedical School, An Arbor, MI, USA

Gaucher disease (GD) is a rare, lysosomal disorder caused byfunctional defects in the enzyme acid β-glucosidase. Along withhematologic and visceral symptoms of GD, patients can experiencechronic fatigue resulting in functional disability and reduced quality oflife. Although patients with GD consider fatigue a core symptom, fewclinical studies have systematically assessed it. The absence of practiceguidelines regarding the measurement of fatigue in GD may discouragehealth care providers frommeasuring this domain. This significant gap isreflected in the scientific literature; a MEDLINE search of “Gaucherdisease” AND “fatigue” generated minimal results (MeSH terms, n = 4;text terms, n = 14). Of these studies, one showed that patients with GDconsidered fatigue one of themost debilitating symptoms of the disease,negatively impacting the ability to perform school, work, and socialactivities. The Functional Assessment of Chronic Illness Therapy-Fatigue(FACIT-F) is a short, 13-item, tool that measures a patient’s level offatigue during daily activities over the past week. FACIT-F hasdemonstrated equivalence in interview vs self-report formats, can beused in clinical settings, and has been translated in N45 languages. Themodified Fatigue Severity Scale (mFSS) is a 9-item, self-report question-naire that rates fatigue severity on a scale of 0 to 10, and has been highlycorrelated with the FACIT-F. Finally, the National Institutes of HealthPatient Reported Outcomes Measurement Information System(PROMIS) Fatigue Short Form is a 7-item, patient self-assessment offatigue severity on a scale of 1 (not at all) to 5 (very much). Thesesymptom-specific scales have been used to assess fatigue severity innumerous chronic illnesses (eg, depression, cancer, rheumatoid arthritis,stroke), but generally not in GD. Evidence of FACIT-F sensitivity totreatment effects in GD comes from a recent study reporting significantimprovements in fatigue following weekly acupuncture sessions. Theeffects of approved enzyme replacement therapies (ERT), imiglucerase,velaglucerase alfa, or taliglucerase alfa, on GD-related fatigue has yet tobe determined. A limited number of early studies reported improve-ments in fatigue symptoms following ERT, although no fatigue-specificscaleswere used.Weplan to drawupon the literature discussed above toinform the development of a culturally sensitive measure of fatigue thatis not linked to literacy. The goals of this presentation are to: 1) establishthe need for reliable, validated, and highly specific tools for assessingfatigue in clinical trials and the clinical treatment of GD; 2) set forth anapproach to develop such a measure; and 3) propose an expertconsensus project to establish the criteria for clinically significant fatiguein GD. Editorial and medical writing support was provided by PelotonAdvantage, LLC, and was funded by Pfizer.

doi:10.1016/j.ymgme.2013.12.055

44Hematopoietic stem cell gene therapy for cystinosis: a new hopefor a multi-systemic degenerative disorder

Stephanie Cherqui, University of California, San Diego, La Jolla, CA, USA

Cystinosis is an autosomal metabolic disease belonging to the familyof lysosomal disorders. Mutations in the CTNS gene, encoding alysosomal cystine transporter, lead to cystine accumulation and multi-organ failure such as blindness, myopathy, diabetes and central nervoussystem defects. Affected individuals also develop proximal tubulopathyand eventually progress to end stage renal failure. Treatment is availablewith the drug cysteamine to reduce intracellular cystine content.However, cysteamine only delays the progression of the disease. In April2012, thefirst clinical trial using stemcells for cystinosiswas approved as

an allogeneic hematopoietic stemand progenitor cell (HSPC) transplantto be conducted at University of California, Los Angeles. This trial wasbased on the preclinical studies we performed in the mouse model ofcystinosis, the Ctns-/- mice, which showed that transplantation ofHSPCs expressing a functional Ctns gene led to the abundant tissueintegration of bone marrow-derived cells, a significant decrease ofcystine accumulation and kidney preservation. However, allogeneictransplants are associated with high risks of mortality and morbidity.Thus, our long-term goal is to develop an autologous transplantationstrategy of HSPCs genetically modified ex vivo to express a functionalCTNS gene as a treatment for cystinosis. Preclinical studies using a SIN-lentivirus vector containing CTNS to transduce Ctns-/- HSPCs andtransplanted in Ctns-/- mice were promising. Transduced cells werecapable of reducing cystine in all tissues and of improving kidneyfunction. We submitted a pre-IND in March 2013 and had theteleconference with the FDA in April 2013. CBER/FDA committeeapproved our plan for the pharmacology/toxicology studies to test thesafety of our lentiviral vector construct in vitro and in vivo. These studiesshould lead to an IND for a phase I clinical trial for autologous, lentiviralvector-modified, CD34+ HSPC transplantation for cystinosis. We arenow conducting the toxicology studies using a batch of pCCL-CTNSlentiviral vector preparation produced under comparable GoodManufacturing Practice. In parallel, we are investigating the mechanismby which HSPC are able to lead to tissue repair in the context of a non-hematopoietic multi-systemic lysosomal disorder, especially when theprotein involved is a lysosomal transmembrane protein such ascystinosin. Our preliminary data showed that HSPC differentiate intotissue resident phagocytic cells that are a key player for tissue repair andthat cross-correction occurs even if the protein involved is a lysosomaltransmembrane protein.

doi:10.1016/j.ymgme.2013.12.056

45Survival and developmental milestones among Pompe registrypatients with classic infantile-onset Pompe disease withdifferent timing of initiation of treatment with enzymereplacement therapy (ERT)

Yin-Hsiu Chiena, Ans vander Ploegb, SimonA. Jonesc, Barry Byrned, AshokVellodie, Nancy Leslief, Eugen Mengelg, Suma Shankarh, PranootTanpaibooni, David W. Stocktonj, Julia B. Hennermannk, ZsuzsannaDevecseril, Judy Kempfl, Joan Keutzerl, Priya S. Kishnanim, aNationalTaiwan University Hospital, Taipei, Taiwan, bErasmus MC UniversityMedical Center, Rotterdam, Netherlands, cUniversity of Manchester,Manchester, UK, dUniversity of Florida, Gainesville, FL, USA, eGreat OrmondStreet Hospital for Children NHS Foundation Trust, London, UK, fCincinnatiChildren’s Hospital Medical Center, Cincinnati, OH, USA, gUniversity ofMainz, Mainz, Germany, hEmory University School of Medicine, Atlanta, GA,USA, iChildren’s National Medical Center, Washington, DC, USA, jWayneState University School of Medicine, Detroit, MI, USA, kChariteUniversitaetsmedizin Berlin, Berlin, Germany, lGenzyme, a Sanofi company,Cambridge, MA, USA, mDuke University Medical Center, Durham, NC, USA

Pompe disease presents as a clinical spectrumwith variable severity,progression, and muscle involvement. Early clinical diagnosis andinitiation of enzyme replacement therapy (ERT), before the developmentof serious, irreversible symptoms, is important, especially in classicinfantile-onset Pompe disease (IOPD). Untreated classic IOPD, charac-terized by symptom onset at ≤12 months of age with progressivecardiomyopathy and generalized muscle weakness causing severelydelayedmotor development and compromised respiratory function, hasreported 12-month survival rates ranging from 8% to 25.7% overall, and

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16.9% ventilator-free (van denHout et al. Pediatrics 2003; Kishnani et al. JPediatr 2006). We assessed survival, ventilator-free survival, and motordevelopmentalmilestones in classic IOPD patients enrolled in the PompeRegistry (sponsored by Genzyme, a Sanofi company). All classic IOPDpatients (symptom onset at ≤12 months of age with cardiomyopathy)with a record of receiving ERT in the Registry were eligible for analysis.Patients were divided into those with a recorded first ERT infusion atb3 months and at ≥3 months of age for comparison. Events weredefined as death and use of invasive ventilation therapy or death, anddevelopmental milestones, including motor milestones. The time to theevent was derived as the time from birth. A total of 140 classic IOPDpatients were eligible for analysis. Patients in the b3 month ERTinitiation group (n= 36) were diagnosed earlier than those treated at≥3 months of age (n= 104): at 1 month vs 4.8 months of age,respectively. Patients who started ERT at b3 months of age had bettersurvival rates at 36months than patients who started ERT at≥3 monthsof age (81% vs 61%, respectively). The same patterns were seen forinvasive ventilator-free survival rates at 36months (76% vs 56%). After 3years of therapy, when compared to infants who started ERT at≥3 months of age, more infants who started ERT at b3 months showedgreatermuscle strength in arms (pulls self to stand: 72% vs 47%) and legs(bears weight on legs: 79% vs 66%). Results were similar when patientsfrom Taiwan, who may have been identified by newborn screening andnot clinical diagnosis, were excluded. Earlier initiation of ERT in classicIOPD patients appears to improve the chances of survival and lead tobetter retention of muscle strength and improvement of symptoms inthese young patients affected most severely by Pompe disease.

doi:10.1016/j.ymgme.2013.12.057

46Abnormal filipin staining and phenotypic overlap between acidsphingomyelinase deficiency and Niemann-Pick C disease

Heather J. Churcha, Christine Egertona, Karen L. Tyleea, Kate Riddicka,Simon A. Jonesa, Uma Ramaswamib, aManchester Centre for GenomicMedicine, Manchester, UK, bRoyal Free Hospital, London, UK

Niemann-Pick disease type C (NPC) resulting from mutations in theNPC1 or NPC2 gene and acid sphingomyelinase deficiency (ASMD,Niemann-Pick A/B) resulting from mutations in the SMPD1 gene, areautosomal recessive lysosomal lipid storage disorders with heteroge-neous neuro-visceral manifestations. Typically, a biochemical diagnosisof NPC is made by positive cholesterol staining with cultured skinfibroblasts (filipin staining) and confirmed by the analysis of geneticmutations in NPC1 or NPC2 gene. We present the second child born tonon-consanguineous Caucasian parents, who initially presented withhepatosplenomegaly, growth failure and developmental delay atanother hospital. Cholesterol esterification studies had showed a smallincrease in free cholesterol suggesting a diagnosis of NPC. Mutationanalysis results were not available. Having emigrated, at the age of10 years he presented to our unit with extreme faltering growth (weight13.3 kg and height 100.4 cm, both well below the 0.4th centile), noreported dysphagia,mild ataxia, severely delayed speechwith nonverbalcommunication, normal eye movement and dysmorphic facial features.In light of the above clinical presentation, further investigations wereperformed. Molecular analysis of the NPC1 and NPC2 genes did notdetect any known pathogenic variation from the published sequence.A full lysosomal enzyme screen identified a deficiency of acidsphingomyelinase in leucocytes (0.06 nmol/mg/hr, normal referencerange 1-10). This deficiency was confirmed in cultured fibroblasts(0.43 nmol/mg/hr, in assay controls 23.7 and 24.8), consistent with adiagnosis of ASMD (Niemann-Pick type A/B). Cholesterol traffickingassessed by filipin staining showed a reduced but clearly abnormal

staining pattern, similar to that see in fibroblast controls from knownASMD patients. Molecular analysis of the SMPD1 gene identified twomutations; fsA599 (thought to be novel) and p.Q292K (previously seenin NP-B) confirming the diagnosis of ASMD. This case highlights theheterogeneity in clinical presentations in children with ASMD and NPC,and the phenotypic overlap. We have identified a novel frame shiftmutation, resulting in a severe NP-A/B variant. The filipin stainingpattern observed in our patient could be interpreted as consistent withNPC if considered in isolation, but is also consistent with the diagnosis ofNP-A/B. Abnormal filipin staining in LAL deficiency has also beenreported. Our patient demonstrates the importance of excluding relevantlysosomal enzymedeficiencies as part of the diagnostic pathway forNPC.

doi:10.1016/j.ymgme.2013.12.058

47The impact on children and parents of participation in clinicalresearch trials for Morquio syndrome type A and Sanfilipposyndrome type A

Tara Clancy, Maria Farag, Deborah Holliday, Catherine Breen, SimonJones, Manchester Centre for Genomic Medicine, Manchester, UK

Clinical research trials of enzyme replacement therapy (ERT) forMorquio syndrome type A and Sanfilippo syndrome type A areunderway. Both involvemultiple study visits of 1-7 days, several invasiveprocedures and the use of a number of questionnaires and examinationsto assess the child’s development. This study explored the impact ofparticipation in the trial on children with Morquio syndrome type A andtheir parents (5/9 eligible families) and parents of children withSanfilippo syndrome type A (4/6 eligible families). Face-to-face semi-structured interviews were carried out with 7 children (age 6-12) withMorquio syndrome and 5 parents, and with 4 parents of children withSanfilippo type A syndrome. The main questions explored were:motivations for taking part, impact on life, and views on the informationreceived prior to the trial. The interviews were transcribed and keythemes identified through interpretative phenomenological analysis. Thechildren described the key role their parents played in providing themwith information and supporting them through medical procedures.They talked about what was “good” (e.g. making new friends and timewith the play specialist) and “bad” (e.g. fear of needles andmissing familyand friends) about taking part. Several factors influenced parents’decision-making, in particular a positive risk benefit assessment. Manyfelt there was no real choice because the current management optionsare limited. In fact, some saw the trial drug as treatment rather thanpotential treatment. Most of them felt that too much complexinformation was given during the consent process, but discussions withthe clinical trial team facilitated their understanding and positivelyinfluenced the decision for their child to participate. The clinical trial teamand other health care professionals provided practical and emotionalsupport, and moderated the parents’ expectations of the trial outcomes.The parents also talked about the significant impact the trial had onday-to-day life and the challenges of adapting to accommodate this. Theydescribed negative impacts on, for example, employment and family life.They also reported benefits including seeing an improvement in theirchild’s condition, meeting other families on the trial, and having a moreoptimistic outlook for the future. Overall, the children and parents had apositive attitude towards participation. They felt that the advantagesoutweighed the disadvantages, and that they would recommend takingpart in a similar trial to other children/families. There are no publicationson the views and experiences of children and/or their parents of takingpart in trials of ERT for the mucopolysaccharidoses. These findingsprovide an insight into the impact that this has on the lives of children,

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