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POSTER PRESENTATIONS

Friday, May 20, 1730-1830

  • P101 UPLC-MS/MS analysis of keratan sulfate related disaccharides as biomarkers for Morquio A Syndrome patients

  • P102 Culturally sensitive provision of rapid biochemical and molecular diagnosis at birth in children at risk for metabolic disorders

  • P103 Case report of two siblings with fumarase deficiency: diagnostic odyssey solved and counselling dilemma begins

  • P104 Canadian Fabry Disease Initiative Study (CFDI): 8 year outcomes of a randomized controlled trial of enzyme replacement therapy (ERT)

  • P105 Canadian Fabry Disease Initiative Study (CFDI): A prospective study of patient outcomes during switch of enzyme replacement therapy (ERT)

  • P106 Outcomes of infants with positive newborn screens for VLCAD deficiency in Southern Alberta

  • P107 Breastfeeding and breastfeeding sustainability in newborns with inborn errors of metabolism identified through expanded newborn screening

  • P108 Pre-analytical factors influencing blood ammonia measurement: an experimental update

  • P109 Clinical Validation of a Point-of-care (POC) Analyzer for Whole Blood Ammonia Measurement in Patients Affected with Urea Cycle Disorders (UCD)

  • P110 Acute and chronic management in atypical ethylmalonic encephalopathy: a case report

  • P112 Patient/caregiver online surveys on the natural history of very rare diseases: creatine deficiencies and MPS IV B/late-onset GM1 (LO-GM1) as examples

  • P114 Energy intake from modified low protein foods may support treatment goals for plasma phenylalanine concentrations in children with phenylalanine hydroxylase deficiency

  • P115 Sitosterolemia – a case report

  • P116 Screening for Fabry cardiomyopathy using cardiac magnetic resonance imaging

  • P117 Hypogonadotropic hypogonadism in males with glycogen storage disease type 1

  • P118 Short-term biological variance of PHE in patients with phenylketonuria

  • P119 Triheptanoin (UX007) treatment in patients with long-chain fatty acid oxidation disorders (LC-FAOD) and cardiomyopathy

  • P121 Proposed study of possible unmet clinical care needs of PKU adults diagnosed via newborn screening

  • P122 Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis

  • P123 Delineating the patient population with Medium chain acyl-CoA dehydrogenase deficiency (MCADD): British Columbia Children’s Hospital (BCCH) clinic experience

  • P124 Neuropsychological and quality of life outcomes in untreated adults with mild hyperphenylalaninemia with phenylalanine levels between 360 and 600 µmol/L

  • P125 Characterization of the biochemical, molecular and clinical phenotype of patients with a diagnosis of VLCADD, including those identified via NBS in the Maritime region of Canada, as well as British Columbia

  • P126 Cardiac Outcomes in Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency in the Maritimes: The Role of ECG and ECHO in Long Term Follow-Up

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    P101 UPLC-MS/MS analysis of keratan sulfate related disaccharides as biomarkers for Morquio A Syndrome patients

    Pamela Lavoie, M.Sc.a, Michel Boutin, Ph.D.a, Christiane Auray-Blais LL.M., Ph.D.a.

    aDivision of Medical Genetics, Department of Pediatrics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, CR-CHUS, Hospital Fleurimont, Sherbrooke, QC.

    Objectives: Mucopolysaccharidosis (MPS) type IVA (Morquio A syndrome), is an autosomal recessive lysosomal storage disorder due to a defect of the enzyme N-acetylgalactosamine-6-sulfatase, which is involved in the degradation of keratan sulfate (KS), a glycosaminoglycan (GAG). The objectives of this research project were to: 1) develop and validate an efficient and robust ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) KS method; 2) evaluate the sensitivity and specificity of this method in a cohort of untreated MPS patients; 3) determine normal reference values for KS disaccharides; 4) compare the UPLC-MS/MS method to the DMB-based spectrophotometry methodology for total GAG measurements.

    Design & Methods: Keratanase II was added to urine samples for a 3 hour-digestion at 40 °C. The detection of two main disaccharides (Galb1-4GlcNAc(6S), and Gal(6S)b1-4GlcNAc(6S)) was achieved using a Xevo TQ-S mass spectrometry system (Waters Corp.) following a HILIC chromatography using an Acquity I-Class UPLC equipped with a BEH amide column.

    Results: All Morquio A syndrome patients had abnormal values of KS disaccharides normalized to creatinine, while the DMB-based spectrophotometry methodology showed normal results for 4 out of 9 Morquio A patients. However, KS was also found to be slightly elevated in patients with other MPS types (I, II, and VI), where KS is not expected to be elevated considering the enzyme deficiencies involved.

    Conclusion: The quantitation of urinary KS disaccharides by mass spectrometry in patients with Morquio A syndrome is a useful tool for high-risk screening studies, and for the diagnosis and monitoring of patients under enzyme replacement therapy.

    Keywords: MPS IVA, Morquio A syndrome, keratan sulfate, mass spectrometry, biomarkers

    Funding Acknowledgement: BioMarin Pharmaceuticals Inc.

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    P102 Culturally sensitive provision of rapid biochemical and molecular diagnosis at birth in children at risk for metabolic disorders

    Chitra Prasada,b,d FRCPC FCCMG, Melanie Napiera,b MSc, Sharan Goobiea,b,d FRCPC FCCMG, Natalya Karpa,b,d FRCPC FCCMG, Victoria Mok Siua,b,d FRCPC FCCMG, Suzanne Ratkob RD, Pranesh Chakrabortye FRCPC FCCMG, C. Anthony Ruparb,c,d PhD FCCMG.

    aSection of Genetics and Metabolism.

    bDepartment of Paediatrics.

    cDepartments of Pathology & Laboratory Medicine and Biochemistry.

    dWestern University and London Health Sciences Centre, London, ON, Canada.

    eNewborn Screening Children’s Hospital of Eastern Ontario.

    Background: Prenatal diagnosis allows for identification of subsequent affected offspring in families who have already had a child with a severe metabolic disorder. Sometimes this is not an option, due to religious or other reasons. Children with severe metabolic disorders often present within 48 hours after birth, before newborn screening (NBS) results are available, and typically experience complicated and lengthy hospitalizations. Our centre has established rapid biochemical and DNA based testing for families who have chosen not to have prenatal diagnosis.

    Methods & Results: We have identified 11 sib-pairs affected with maple syrup urine disease (Mennonite) (p.Y438N homozygous), galactosemia (Amish) (p.Q188R homozygous) Gastric intrinsic factor (GIF) deficiency (Mennonite) (c.79+IG>A and C.973delG deletion compound heterozygous) and Transcobalamin (TC) deficiency (Albanian) (R399X homozygous). In each case, cord and /or peripheral blood specimens were collected at delivery of subsequent sibs. Out of a total of 11 sibs, 5 were affected. Screen-positive Ontario newborn screening results were received between day 6 and day 8 of life.

    Discussion and Conclusions: Probands with each of the 4 autosomal recessive metabolic disorders required prolonged hospitalization for hemodialysis or sepsis at <1week or developed bone marrow failure by 2 months. Subsequent affected sibs were diagnosed and managed appropriately prior to availability of NBS results, thus completely avoiding hospitalization and complications. Access to rapid biochemical and molecular technology allows for culturally sensitive delivery of diagnosis and care based on positive family history. This has made a demonstrable difference in the prognosis and outcome of patients with severe metabolic conditions.

    Keywords: DNA based diagnosis, Newborn screening, maple syrup urine disease, galactosemia, transcobalamin deficiency and gastric intrinsic factor deficiency

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    P103 Case report of two siblings with fumarase deficiency: diagnostic odyssey solved and counselling dilemma begins

    Melanie Napiera, Charushree Prasadb, Tony Rupara, Chitra Prasadc.

    aLondon Health Sciences Centre.

    bIsaac Walton Killam Health Centre.

    cWestern University/LHSC London.

    Objectives: To appreciate the diagnostic odyssey of fumarase deficiency as well as the unique challenges associated with providing genetic counselling and clinical management for family members identified to carry a heterozygous FH mutation.

    Design & Methods: Two siblings, age 10 years and 3 years, with developmental delay, hypotonia, strabismus, thinning of the corpus callosum and failure to thrive were thoroughly investigated for possible genetic and metabolic etiologies. Following extensive testing, whole exome sequencing was ordered.

    Results: Both children were identified to be compound heterozygous in FH for a maternally inherited c.1431_1433dupAAA pathogenic variant and a novel, paternally inherited c.1390+1G>T variant (interpreted to be disease-causing). Previous investigations included urine organic acid analyses on two occasions for both sibs that did not demonstrate an elevation of fumaric acid. Neither parent demonstrates features of hereditary leiomyomatosis and renal cell cancer (HLRCC), an autosomal dominant tumour predisposition syndrome caused by heterozygous FH mutations. Further genetic testing of family members demonstrates low penetrance for an HLRCC phenotype in FH heterozygotes.

    Conclusions: Fumarase deficiency cannot always be diagnosed by concentration of urine fumaric acid and a high index of suspicion should be maintained in the context of normal biochemical results. There appears to be low penetrance of the HLRCC phenotype in family members carrying a heterozygous FH mutation which allows for great uncertainty in the provision of surveillance recommendations and quoting lifetime renal cancer risk. Further studies are required to delineate HLRCC risk for family members of individuals diagnosed with fumarase deficiency.

    Keywords: Fumarase deficiency, hereditary leiomyomatosis and renal cell cancer, fumarate hydratase, genetic counselling

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    P104 Canadian Fabry Disease Initiative Study (CFDI): 8 year outcomes of a randomized controlled trial of enzyme replacement therapy (ERT)

    Michael Westa, Daniel G. Bichetb, Robin Caseyc, Joe T.R. Clarked, Mark Iwanochkoe, Aneal Khanf, Sandra Sirrsg, Chantal Morelh, Christiane Auray-Blaisi, Steve Doucettej, Kaye LeMoinek.

    aDepartment of Medicine, Division of Nephrology, Dalhousie University.

    bDepartment of Medicine, Hôpital du Sacré-Coeur de Montréal and University of Montreal, Montreal, QC, Canada.

    cMedical Genetics, Department of Pediatrics (retired), University of Calgary.

    dHospital for SickKids.

    eDepartment of Medicine.

    fUniversity of Calgary/Alberta Children’s Hospital.

    gVancouver General Hospital.

    hMedical Genetics.

    iCR-CHUS-Hospital Fleurimont.

    jDepartment of Community Health and Epidemiology.

    kDepartment of Nursing.

    Objective: To determine the long-term clinical outcomes in Fabry disease during ERT.

    Methods: The CFDI is a prospective multicenter study of ERT in Fabry disease in Canada started in 2007. Patients who met national Fabry disease treatment guidelines received ERT. Cohort b were enzyme naïve patients randomized 1:1 to agalsidase beta 1.0 mg/kg or agalsidase alfa 0.2 mg/kg both EOW. Outcomes were defined as clinical events-renal, cardiac, neurologic and death. We report the clinical outcomes during ERT at year 8 of this trial.

    Results: By year 8 there are 409 enrolled, 130 M (31.8%), 242 F (59.2%), and 37 children (9%), with 117 in cohort 1b. Between May 2010 and 2012 patients in cohort 1b randomized to agalsidase beta received alfa due to shortage of agalsidase beta. Cohort 1b mean age 43.0 years had 69 (60%) patients on alfa and 46 (40%) on beta over 66.3±26.3 months. Baseline clinical parameters and concomitant drug use did not differ except for Mainz Severity Score Index 23.2±8.7 on alfa vs. 27.6±10.1 on beta (p=0.02). Outcomes of renal and cardiac parameters and Kaplan Meier analysis of time free of first clinical event (p=0.66) on different ERT do not differ. There were more clinical events on alfa (45) than beta (15), reflecting prevalence of ERT use.

    Conclusions: The CFDI study remains the longest-running and largest randomized prospective trial of ERT in Fabry disease. In adults with Fabry disease, there appears to be little or no difference in clinical outcomes after 8 years of standard dose ERT.

    Keywords: Fabry disease, enzyme replacement therapy, agalsidase, outcomes

    Funding: The provincial governments of Canada, Genzyme, a Sanofi company, Shire Inc.

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    P105 Canadian Fabry Disease Initiative Study (CFDI): A prospective study of patient outcomes during switch of enzyme replacement therapy (ERT)

    Michael Westa, Daniel G. Bichetb, Robin Caseyc, Joe T.R. Clarked, Mark Iwanochkoe, Aneal Khanf, Sandra Sirrsg, Chantal Morelh, Christiane Auray-Blaisi, Steve Doucettej, Kaye LeMoinek.

    aDepartment of Medicine, Division of Nephrology, Dalhousie University.

    bDepartment of Medicine, Hôpital du Sacré-Coeur de Montréal and University of Montreal, Montreal, QC, Canada.

    cMedical Genetics, Department of Pediatrics (retired), University of Calgary.

    dHospital for SickKids.

    eDepartment of Medicine.

    fUniversity of Calgary/Alberta Children’s Hospital.

    gVancouver General Hospital.

    hMedical Genetics.

    iCR-CHUS-Hospital Fleurimont.

    jDepartment of Community Health and Epidemiology.

    kDepartment of Nursing.

    Objectives: To determine the effect of switch from agalsidase beta 1.0 mg/kg EOW to agalsidase alfa 0.2mg/kg EOW in patients with Fabry disease.

    Methods: The CFDI is a prospective multicenter study of ERT in Fabry disease in Canada. Due to shortage worldwide of agalsidase beta, 37 Fabry patients switched ERT. We report the outcomes (clinical events-renal, cardiac, neurologic and death) of these patients during treatment with agalsidase beta and alfa. The first six months post switch were censored because of possible carry over effect from prior agalsidase beta treatment.

    Results: 37 Fabry adults (25 M, 12 F) mean age 47.8±12.6 years, Mainz Severity Score Index 32.6±11.5, ESRD 32.4%, hypertension 56.8%, pacemaker 46% and stroke/TIA 27% were included. There was no significant difference in clinical parameters pre (32.6±11.5 months) to post switch (42.5±7.8 months). There were 19 clinical events (prevalence 27%) on beta vs. 29 (prevalence 47.2%) on alfa. With censoring of the first 6 months on alfa, there were 14 events (prevalence 39%). Event free survival did not differ between beta and alfa by Kaplan Meyer analysis. Clinical event rates did not differ at 17.5 per 1000 patient months on beta or alfa after 6 months and 19.0/1000 months including the first 6 months on alfa. Cardiac events were the most common in all periods.

    Conclusions: The CFDI study is the only prospective study of Fabry patient outcomes during ERT switch. Switch from agalsidase beta to alfa was associated with a transient increase in clinical events for 6 months.

    Keywords: Fabry disease, enzyme replacement therapy, agalsidase, outcomes

    Funding: The provincial governments of Canada, Genzyme, a Sanofi company, Shire Inc.

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    P106 Outcomes of infants with positive newborn screens for VLCAD deficiency in Southern Alberta

    Marisa Charda,c, Karen Saboa, Aneal Khana,b,c, Rebecca Sparkesa,b,c.

    aAlberta Children’s Hospital, Calgary, Canada.

    bDept. of Pediatrics, University of Calgary, Canada.

    cDept. of Medical Genetics, University of Calgary, Canada.

    Objectives: Very long chain fatty acyl-CoA dehydrogenase (VLCAD) deficiency is a fatty acid oxidation disorder (FAOD) with a spectrum of severity ranging from a potentially fatal, neonatal cardiomyopathic form to mild late-onset variants with minimal or no symptoms. After a positive newborn screen it can be difficult to accurately predict the phenotype with the diagnostic testing available. The aim of this study was to determine the outcomes of infants with screen positive results for VLCAD deficiency.

    Methods: In this retrospective cohort study, the medical files of all patients who screened positive for VLCAD deficiency since expanded newborn screening began in Southern Alberta on April 1, 2007 were reviewed. We determined the false positive and true positive rates of screening, newborn screen results, diagnostic testing (acylcarnitines, fatty acid oxidation studies, ACADVL genotype), dietary and illness management, follow up tests, and clinical features.

    Results: Seventeen (17) patients screened positive for VLCAD deficiency. Of those, one was symptomatic with severe neonatal-onset disease. Another five patients likely had mild VLCAD deficiency, and only one of these patients has been symptomatic to date. The remaining 11 patients had indeterminate results, and of these five were likely false positive due to heterozygosity for one pathogenic ACADVL variant.

    Conclusions: Newborn screening for VLCAD can be lifesaving. However, the majority who screen positive will be heterozygous ACADVL mutation carriers, have mild or asymptomatic VLCAD deficiency or have an indeterminate diagnosis which may lead to family anxiety and possibly to over-medicalization of some children.

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    P107 Breastfeeding and breastfeeding sustainability in newborns with inborn errors of metabolism identified through expanded newborn screening

    Laura L. Nagya MSc RD, Penny Zhanga BSc, Heather Olivierib MSW RSW, Karen Tama ScM CGC, Jonathan Kronicka MD PhD FRCPC.

    aDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON.

    bDivison of Neurology, The Hospital for Sick Children, Toronto, ON.

    Background: Newborn screening (NBS) facilitates early diagnosis of potentially devastating inborn errors of metabolism (IEM). Treatment of some IEM involves dietary interventions (ex: special formula/medical food). Breastfeeding is deemed best for infants, although may not be permitted exclusively for infants with an IEM. Receiving an IEM diagnosis via NBS in the first weeks of life while breastfeeding is being established may disrupt breastfeeding continuation.

    Objectives: To determine the number of infants exclusively breastfed at the time of receiving a true-positive NBS result and the number of infants that receive breast milk (exclusively or not exclusively) after IEM diagnosis. Additionally, to determine factors impacting breastfeeding duration in this population.

    Methods: Patient charts of eligible true-positive NBS infants (N=142) were analyzed for age, feed type, wellness at NBS retrieval, diagnosis, and interventions. Two-sample T-tests and ANOVA were used for analysis.

    Results: 55% of infants were exclusively breastfed and 90% received some breast milk at NBS retrieval (mean age 9.5±4.0 days). Mean breastfeeding duration amongst all IEM diagnoses was 121±135 days. Infants receiving medical food had significantly shorter breastfeeding duration (71.5±104 days) than infants not receiving medical food (143±146 days; P=0.01). Infants unwell at retrieval breastfed less (48.0±102 days) than infants well at retrieval (132±139 days; P=0.03). 9% of mothers saw a lactation consultant/public health nurse.

    Conclusions: Breastfeeding rates in positive NBS infants at time of retrieval are comparative to the Canadian population but unwell infants and those put on medical food are most likely to have breastfeeding or breast milk provision stopped.

    Keywords: newborn screening, breastfeeding, nutrition, medical food

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    P108 Pre-analytical factors influencing blood ammonia measurement: an experimental update

    Fabienne Parentea MD PhD, Khalid Sumailya MD, Juliette Bréhatb, Carine Nyalendob,c PhD DEPD.

    aBiochemistry Division, McGill University Health Centre, Montreal, QC.

    bBiochemistry Department, CHU Sainte-Justine, Montreal, QC.

    cBiochemistry and Molecular Medicine Department, University of Montreal, Montreal, QC.

    Background: Blood ammonia (NH3) is the main marker for the diagnosis and follow-up of patients affected with Urea Cycle Disorders (UCD).

    Objectives: The aim of this study was to review and quantify the impact of pre-analytical factors such as phlebotomy technique, air exposure, temperature and time delay during specimen transportation and handling on ammonia concentration.

    Study Design & Methods: Capillary and venous samples were collected on standard lithium heparin gel tubes from normal subjects and patients hospitalized in the intensive care unit (ICU). The samples were kept at room temperature or stored at 4 °C up to 4h before and after centrifugation, with or without air exposure.

    Results: As previously described, ammonia concentration increases in capillary samples (average of 10 micromol/L compared to venous samples) and correlates with hemolytic index. No statistical and clinically significant difference in ammonia values between specimens stored at room temperature and at 4 °C up to 1 hour after blood collection (n=20, p < 0 ,147) were observed. In contrast, a statistically significant increase in ammonia concentration was seen when specimens were kept at room temperature 2 hours after centrifugation (n=20, p < 0 ,001). The same findings were also noted in specimens emanating from ICU patients. Air exposure had no impact on ammonia results in our laboratory.

    Conclusions: The impact of the metabolism of blood nitrogen on ammonia concentration is minimal when samples are kept at room temperature during transportation to the laboratory. Even if gel separator tubes are used, specimens must be analyzed rapidly after centrifugation unless they are stored at 4 °C.

    Keywords: ammonia, pre-analytical

    Acknowledgements: the authors thank Medunik Canada for supporting laboratory technologist teaching sessions on clinical use and pre-analytical factors of blood ammonia measurement.

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    P109 Clinical Validation of a Point-of-care (POC) Analyzer for Whole Blood Ammonia Measurement in Patients Affected with Urea Cycle Disorders (UCD)

    Khalid Sumailya MD, Carine Nyalendob,c PhD DEPD and Fabienne Parentea MD PhD FCCMG.

    aBiochemistry Division, McGill University Health Centre, Montreal, QC.

    bBiochemistry Department , CHU Sainte-Justine, Montreal, QC.

    cBiochemistry and Molecular Medicine Department , University of Montreal, Montreal, QC.

    Background: Blood ammonia (NH3) is the main marker for the diagnosis and follow-up of patients affected with Urea Cycle Disorders (UCD). Repetitive venous sampling is often difficult in patients less than 1 year of age. Many pre-analytical factors can cause a spurious increase in ammonia levels when samples are sent to the central laboratory for analysis.

    Objectives: The aim of this study was to clinically validate a bedside testing device for whole blood ammonia measurement (PocketChem BM TA BA-4140, Arkay Inc.) by assessing precision, linearity, repeatability, and accuracy.

    Design & Methods: Coefficients of variation (CV) were determined by repeated measurements of two control solutions. Accuracy was investigated by performing recovery experiments with ammonium sulfate. Clinical samples and ammonium sulfate spiked samples were used to do comparison studies with the enzymatic reference method on plasma (Beckman AU) and validate the linearity and limit of detection of the device. Capillary blood analysis was done on UCD patients and normal subjects.

    Results: Between day CV is comparable to within day CV (5% and 8 % for concentrations of 180 micromol/Land 80 micromol/L respectively). The analytical range is comprised between 10 and 280 micromol/L. The average recovery is 100 %. There is a good correlation and concordance with the reference method. The analysis of capillary samples from finger or heel prick is subject to significant inter-users variation.

    Conclusions: The PocketChem BA has acceptable precision, accuracy and satisfactory agreement with a reference method. The POC analyzer may be suitable for clinical use by well-trained staffs.

    Keywords: blood ammonia, POCT

    Acknowledgements: The authors thank Medunik Canada for supporting the validation of the PocketChem BM TA BA in patients affected with Urea Cycle Disorders.

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    P110 Acute and chronic management in atypical ethylmalonic encephalopathy: a case report

    Thomas M. Kitzlera, Indra R. Guptab, Bradley Ostermanc, Chantal Poulind, Yannis Trakadisa, Daniela Buhasa.

    aDepartment of Medical Genetics, McGill University Health Centre, Montreal, QC.

    bDeparment of Pediatrics, Division of Nephrology, McGill University Health Centre, Montreal, QC.

    cDepartment of Pediatric Neurology, Centre Hospitalier de l’Université Laval (CHUL), Quebec City, QC.

    dDepartment of Pediatrics, Division of Neurology, McGill University Health Centre, Montreal, QC.

    Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (H2S). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of H22S levels. Accumulation of H2S is thought to cause the characteristic metabolic derangement found in EE. Recently introduced treatment strategies in EE, such as combined use of metronidazole (MNZ) and N-acetylcysteine (NAC), are aimed at lowering chronic H2S load. Experience with treatment strategies directed against acute episodes of metabolic decompensation (e.g., hemodialysis) is limited. Here we present an unusually mild, molecularly confirmed, case of EE in a 17 year old male on chronic treatment with MNZ and NAC. During a severe episode of metabolic decompensation, we employed continuous renal replacement therapy (CRRT) to regain metabolic control. On continuous treatment with NAC and MNZ during the months preceding the acute event, plasma thiosulfate levels ranged from 1.6 to 4 microg/mL (reference range 2 microg/mL) and had a mean value of 2.5 microg/mL. During the acute decompensation, thiosulfate levels were 6.7 microg/mL together with hyperlactatemia, ethylmalonic aciduria, and increased C4- and C5-acylcarnitines. CRRT decreased thiosulfate within 24 hours to 1.4 microg/mL. Following discontinuation of CRRT, mean thiosulfate levels were 3.2 microg/mL (range: 2.4 – 3.7 microg/mL) accompanied by metabolic normalization on blood gas, acylcarnitine profile, and urine organic acids. In conclusion, CRRT may help to regain metabolic control in patients with EE who have an acute metabolic decompensation on chronic treatment with NAC and MNZ.

    Keywords: Ethylmalonic encephalopathy, neurometabolic disorder

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    P112 Patient/caregiver online surveys on the natural history of very rare diseases: creatine deficiencies and MPS IV B/late-onset GM1 (LO-GM1) as examples

    Maria B. Bleiera, Nataliya Yuskiva MD MPH, Maria Bolduta MPH RN, Tina Priestb, Sylvia Stockler-Ipsiroglua MD PhD.

    aDivision of Biochemical Diseases, BC Children’s Hospital, Vancouver, BC. Department of Pediatrics, University of British Columbia, Vancouver, BC.

    bThe Priest Family Fund for Morquio B, Vancouver, BC.

    Objectives: This study is being conducted in response to the inquiries of multiple rare disease patients who are not registered to medical or research centers. Online surveys for patient/caregivers have been created instead of physician surveys to investigate the natural history of two very rare diseases: creatine deficiencies and MPS IV B/LO-GM1.

    Design & Methods: This study utilizes two REDCap based online surveys to collect cross-sectional, qualitative data from patients and their families. Patient advocates helped to evaluate the survey for its quality. A total of 67 questions for creatine deficiencies and 72 questions for Morquio B/LO-GM1 were made pertaining to patients’ demographics, their health, treatments, quality of life, access to healthcare, diagnostic history, lifestyle, and participation in clinical trials. The study links are hosted on parent support group websites such as morquiob.com, the Association for Creatine Deficiencies (creatineinfo.org), and the National Organization for Rare Diseases (rarediseases.org).

    Results: There has been positive feedback to the survey postings on various support groups on Facebook. As a result there have been 9 hits for the creatine survey and 5 hits for Morquio B/LO-GM1 after a week of posting, with numbers continuing to increase. Data collection will occur over a one year period.

    Conclusions: Online surveys are easily accessible tools that allow for greater sampling of populations with rare diseases. The natural history data collected will contribute to the establishment of clinically meaningful outcomes for future trials, and will also help to counsel newly diagnosed patients about their health expectations.

    Keywords: natural history, patient/caregiver surveys, creatine deficiency disorders, MPS IV B, late-onset GM1 gangliosidosis

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    P114 Energy intake from modified low protein foods may support treatment goals for plasma phenylalanine concentrations in children with phenylalanine hydroxylase deficiency

    Beth Haliburtona BSc, RD, Glenda Courtney-Martina PhD, RD, Annette Feigenbaumb MD, Valerie Austina BSc, RD.

    aDepartment of Clinical Dietetics, Hospital for Sick Children, Toronto, ON.

    bDivision of Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, ON.

    Introduction: Phenylalanine hydroxylase (PAH) deficiency is treated with a phenylalanine (phe)- restricted diet, to achieve recommendations for plasma phe concentrations. The diet comprises natural low protein foods (NLPF), modified low protein foods (MLPF) and medical food (MF). Research demonstrates that MF (phe-free protein supplement) is essential to the efficacy of the diet.

    Objective: This study aims to show that MLPF (low in phe, high in energy) is also important to the efficacy of the diet.

    Design & Methods: In a prospective observational study, plasma phe concentrations were measured and 3-day diet records analyzed for 48 children (10.7±4.6 years) with PAH deficiency. Age and intakes of protein and energy were examined in relation to plasma phe concentrations, expressed as a percentage of the upper acceptable values for age.

    Results: Daily protein intake was 172±51% of dietary reference intakes and energy intake was 99±21% of estimated energy requirements (for low activity). MLPF contributed 18±12% to daily energy intake. In univariate analysis, plasma phe concentrations were positively associated with age (p < 0 .001), but negatively associated with total protein intake (p < 0 .01), total energy intake (p < 0 .05) and energy intake from MLPF (p < 0 .05). In multiple regression analysis, only age was independently significant (p < 0 .001).

    Conclusion: In this group of children with PAH deficiency, age appeared to be the only determinant of plasma phe concentrations, but dietary energy and protein contributed to the overall significance of the statistical models. These models suggest that energy intake from MLPF may be necessary in order to achieve recommended plasma phe concentrations.

    Keywords: Phenylalanine hydroxylase deficiency, phenylalanine-restricted diet

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    P115 Sitosterolemia – a case report

    Lesley Turnera, Sara Fernandezb, Sean Connorsb, Sergei Likhodib, Vikram Chadurkarb, Gena Shepherdb.

    aMemorial University/Janeway Children’s Health Centre.

    bEastern Health.

    Sitosterolemia is a rare autosomal disease. It is caused by homozygous or compound heterozygous mutations in ABCG8 or ABCG5. Mutations in these genes cause excessive absorption of plant sterols and decreased hepatic excretion into bile which leads to elevated concentrations of plasma phytosterols. Clinical features of the condition include xanthomas, premature atherosclerosis, hemolytic anemia and macrothrombocytopenia.

    We report a 42 year old man with a recent diagnosis of Sitosterolemia. At the age of fourteen he was diagnosed with Neiman Pick C. This was based on a history of splenomegaly requiring splenectomy, thrombocytopenia, abnormal liver biopsy with lipid abnormalities and abnormal cholesterol ester formation in cultured fibroblasts. The patient was reassessed in the metabolic clinic at the age of 36 years. He had developed additional medical concerns. He had a mitral valve replacement, dilated cardiomyopathy and he had an ICD implanted. He had no neurologic abnormalities and the diagnosis of Neiman Pick C was questioned. Molecular and biochemical investigations for Neiman Pick C were requested and were normal, refuting this diagnosis, however, an alternative diagnosis was not made. The patient was reassessed at age 41. Whole exome sequencing was requested and a pathogenic homozygous mutation was identified in ABCG8. Several variants of unknown significance in different genes were also identified that may be playing a role in the patient’s clinical features including three variants in TTN and one variant in DMD. We report our patient to highlight the rare condition Sitosterolemia and describe the clinical features associated with this condition.

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    P116 Screening for Fabry cardiomyopathy using cardiac magnetic resonance imaging

    Hassan Hazaria BSc, James Whiteb MD, Israel Belenkieb MD, Floyd Snyderc PhD, Jillian Parboosinghc PhD, Ryan Lamontc PhD, Stuart Hutchisonb MD, Steven C. Greenwayb,d MS, MD, Aneal Khanc,d MSc, MD.

    aMedical Sciences, University of Calgary, Calgary, AB.

    bDepartment of Cardiac Sciences, University of Calgary, Calgary, AB.

    cDepartment of Medical Genetics, University of Calgary, Calgary, AB.

    dDepartment of Pediatrics, University of Calgary, Calgary, AB.

    Objective: Fabry disease (FD) may be present in 1 to 3 percent of patients with hypertrophic cardiomyopathy (HCM). Special applications of cardiac MRI (CMR), such as late gadolinium enhancement (LGE) and non-contrast T1 mapping, show potential for identifying features of FD. The aim of this study is to evaluate the utility of CMR in identifying causes of HCM such as Fabry disease, using a genetic screening panel.

    Design & Methods: This is the first prospective, case-control study to evaluate LGE and T1 mapping using a 3-Tesla CMR in patients with undifferentiated HCM. Patients with HCM at the time of CMR were enrolled for genetic testing. Patients with secondary causes of HCM (e.g. hypertension) were excluded. DNA sequencing was performed on an Illumina MiSeq™ platform using a panel of 55 genes. We anticipate enrolment of 200 subjects.

    Results: So far 13 patients were recruited and 9 have undergone sequencing. CMR identified no cases of FD in agreement with DNA analysis. Five of the subjects had a putative sarcomeric protein mutation, 1 case had mitochondrial disease, and 3 were variants of uncertain significance.

    Conclusions: This study utilized genetic testing to validate imaging results. Preliminary results show that CMR did not falsely identify any cases as FD. We found 55.6% of the cases had a sarcomeric protein mutation, similar to the literature. The study is currently open to recruitment and we hope to understand the role of CMR in the diagnosis of FD with further data.

    Keywords: Fabry disease, Hypertrophic cardiomyopathy, screening, cardiac MRI

    Funding Acknowledgement: Shire Human Genetic Therapies Center for Extramural Clinical Research and Education 10001391

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    P117 Hypogonadotropic hypogonadism in males with glycogen storage disease type 1

    Evelyn Wonga, Sandra Sirrsb Anna Lehmanc, Jane Gillisd, Daniel Metzgerd, Phillip Acotte.

    aUniversity of British Columbia.

    bVancouver General Hospital.

    cProvincial Medical Genetics Program and Adult Metabolic Diseases Clinic, Vancouver.

    dBC Children’s Hospital.

    eDalhousie University.

    We describe 4 patients with glycogen storage disease type 1a and 1b with hypogonadotropic hypogonadism resulting in testosterone deficiency. A possible mechanism may be recurrent elevations in cortisol in response to hypoglycemia leading to suppression of gonadotropin-releasing hormone (GnRH) release. Incorporating clinical and / or biochemical screening of the hypothalamic-pituitary-gonadal axis may be important in the management of this disease.

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    P118 Short-term biological variance of PHE in patients with phenylketonuria

    Murray Pottera, Michael T. Geraghtyb, Amy Penderc, Erica Langleyb.

    aMcMaster Children’s Hospital.

    bChildren’s Hospital of Eastern Ontario, Ottawa, ON.

    cMcMaster University.

    Control of blood phenylalanine (PHE) levels is the primary goal in managing phenylketonuria (PKU). Both the overall exposure to PHE (“area under the curve”) and the variation in PHE (“standard deviation of PHE levels”) are thought to contribute to long-term neurocognitive outcome.
    The objective of this study was to measure the diurnal variation of PHE in patients ≥4 years of age. Four groups were studied: Patients treated with diet alone who were in poor control or good control (>1/3 or ≤1/3, respectively, of monitoring PHE levels outside the target treatment range in the 6 months preceding enrolment, n=8 “Wide PHE” and n=10 “Target PHE”, respectively), patients treated with diet plus Kuvan (n=9 “Kuvan”), and patients with benign / mild hyperphenylalaninemia (not requiring diet, n=5 “Control”). Study subjects were admitted to the short-stay unit in the morning after an overnight fast and then pre-prandial and 1 and 2 hour post-prandial samples were collected for each meal over the next 24 hours. Whole blood dried blood spots (DBS) were analyzed for amino acids. The maximum, mean and standard deviation of PHE levels were calculated. Significance was calculated by two-way single factor ANOVA with post-hoc Man-Whitney U test. The mean PHE levels were 790, 288, 323, 300 uM for the Wide PHE, Target PHE, Kuvan and Control groups, respectively (p=0.0003, Wide PHE significantly higher than the other 3 groups). The maximum PHE levels showed the same pattern (p=0.0005). The standard deviation of PHE was not significantly different between the groups (68, 38, 53, 53 uM, respectively). In conclusion, PHE levels were higher in patients who historically had poor control of PHE levels, while patients who tended to be in good control on diet or who were on diet plus Kuvan had lower levels that were similar to controls.

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    P119 Triheptanoin (UX007) treatment in patients with long-chain fatty acid oxidation disorders (LC-FAOD) and cardiomyopathy

    Jerry Vockleya MD, Joel Charrowb MD, Jaya Ganeshbc MD, Marthand Eswarad MD, George M. Diaze MD, PhD, Elizabeth McCrackena MS, Robert Conwayf MD, Gregory M Ennsg MD, Raymond Y. Wangh MD, Deborah L. Marsdeni MD.

    aUniversity of Pittsburgh, School of Medicine, Pittsburgh, PA, USA.

    bDepartment of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, IL, USA.

    cDepartment of Genetics, Cooper University, Camden, NJ, USA.

    dDepartment of Medical Genetics, Sutter Medical Center, Sacramento, CA, USA.

    eDepartment of Genetics and Genomic Science, Icahn School of Medicine at Mt Sinai, New York, NY, USA.

    fDepartment of Genetics, Children’s Hospital of Michigan, Detroit, MI, USA.

    gDepartment of Medical Genetics, Lucile Packard Children’s Hospital, Stanford, CA, USA.

    hDepartment of Genetics, Children’s Hospital-Orange County, Orange, CA, USA.

    iUltragenyx Pharmaceutical Inc., Novato, CA, USA.

    Objectives: The most severe LC-FAOD phenotype may present in infancy, when energy demands are increased. Symptoms include cardiomyopathy, arrhythmia, hypoglycemia, and hepatic dysfunction. Morbidity and mortality are high despite detection by newborn screening (NBS) and early intervention with standard treatment, including supplementation with even medium chain triglycerides (MCT). Triheptanoin (UX007) is an investigational 7-carbon odd medium chain triglyceride, shown in animal studies to be both ketogenic and gluconeogenic, by providing anaplerotic substrate for the depleted TCA cycle.

    Design & Methods: Triheptanoin was provided through expanded access programs for 8 infants and 2 older patients with cardiomyopathy. All were previously treated with MCT. We reviewed data provided by the treating physicians.

    Results: Ten patients with LC-FAODs presented with cardiomyopathy in infancy or childhood, despite treatment with MCT. Eight were detected by NBS. Seven were treated with triheptanoin (4g/kg) on emergency treatment protocols and 3 in existing Early Access programs. Improvement occurred within 48 hours in 2 patients near death. Seven were successfully weaned from support and remain stable; a moderately severe patient with declining ventricular function did not require acute support. Two patients died: 1 developed pericardial effusion, bradycardia and cardiac arrest after treatment for almost 4 weeks; 1 died of sepsis, with normal heart function. Most common adverse events were GI related; 1 withdrew from treatment due to GI distress.

    Conclusions: These data demonstrate potential therapeutic benefit of triheptanoin treatment in patients with LC-FAOD cardiomyopathy. Further studies are warranted to confirm these initial promising findings.

    Funding Acknowledgment: Ultragenyx provided UX007 for emergency treatment protocols.

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    P121 Proposed study of possible unmet clinical care needs of PKU adults diagnosed via newborn screening

    John Adamsa,b BA, Nicole Pallonea BA, William B. Hanleya,c MD.

    aCanadian PKU and Allied Disorders, Toronto, ON.

    bCanadian Organization for Rare Disorders, Toronto, ON.

    cHospital for Sick Children Research Institute, Toronto, ON.

    Objectives: To inform clinicians of proposed study of potential unmet needs for clinical care of PKU adults early diagnosed through newborn screening (NBS) programs. The objectives of this study are to document: (a) history of confirmed diagnoses of PKU via NBS programs in each jurisdiction, (b) the status of long-term follow-up of NBS confirmed diagnosed cases and (c) possible unmet needs for clinical care of this population.

    Design & Methods: The hypothesis of this study is that likely the majority of PKU adults diagnosed via NBS programs in Canada are not in active clinical case notwithstanding the recommendation in 2000 of the international scientific consensus conference that PKU requires treatment for life.1 This hypothesis is based on the observations and estimates of a similar study in the United States published in 2013 that an estimated 71 percent of early-diagnosed PKU adults were not in active clinical care.2

    This study will start by ascertaining the numbers of cases of confirmed diagnoses of PKU by each provincial and territorial NBS program annually since the start of each program. This work will likely involve extensive archival research for some programs. This work will provide the denominator. The study will continue with a survey of treating clinics across Canada to ascertain the number of PKU adults who are in active clinical care currently. This survey will provide the numerator. The study will include follow-up with clinics to refine the available data.

    The CIMDRN study project cannot address this hypothesis as it is focused on pediatric patients.

    Results: Data will be analyzed to confirm or otherwise the hypothesis. Results will be shared with treating clinics and governments to help address the extent of unmet needs for clinical care focused on PKU adults.

    Conclusions: To be determined.

    References:

    1Phenylketonuria: Screening and Management. NIH Consensus Statement online 2000 October 16-18: 17(3): 1-27

    2Newborn screening 50 years later: access issues faced by adults with PKU. Genetics in Medicine (2013) 15, 591-599

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    P122 Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis

    Saikat Santraa,* MD, Jessie M. Cameronb PhD, Casper Shyrd MSc, Linhua Zhangd,e PhD, Britt Drögemöllerc PhD, Colin J. Rossc,d,e PhD, Wyeth W. Wassermanac,d PhD, Ron A. Weversf PhD, Richard J. Rodenburgg PhD, Girish Guptea MD, Mary Anne Preecea PhD, Clara D. van Karnebeekd,e,* MD PhD.

    aBirmingham Children’s Hospital, Birmingham, UK.

    bGenetics and Genome Biology Program, Peter Gilgan Centre for Research and Learning, Toronto, Canada.

    cDepartment of Medical Genetics, University of British Columbia, Vancouver, Canada.

    dCentre for Molecular Medicine, Child & Family Research Institute, Vancouver, Canada.

    eDepartment of Pediatrics, University of British Columbia, Canada .

    fDepartment of Laboratory Medicine – Translational Metabolic Laboratory, Radboudumc, Nijmegen, Netherlands.

    gNijmegen Center for Mitochondrial Disorders, Departments of Pediatrics, Translational Metabolic Laboratory, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

    Background: We report a patient from a consanguineous family who presented with transient acute liver failure and biochemical patterns suggestive of disturbed urea cycle and mitochondrial function, for whom conventional genetic/metabolic investigations for acute liver failure failed to yield a diagnosis.

    Methods: Trio whole exome sequencing was performed (42X) with bio-informatics analysis via our TIDEX customized pipeline, and subsequent Sanger sequencing of candidates. PEPCK activity was measured in transfected mutant vs wildtype COS-1 cells in the direction of oxaloacetate formation (published methods).

    Results: Of the 14 genes harbouring recessive / hemizgous (n=9) and de novo (n=5) mutations, the homozygous 12-bp deletion (p.GVPLV123V) in PCK1 encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK) was the most compelling based on function and (likely) pathogenic nature of the variants. Compared to wildtype transfected COS-1cells, mutant PEPCK activity was significantly reduced, similar to the empty vector, confirming the deleterious nature of the homozygous PCK1 mutant.

    Discussion: We propose that PEPCK deficiency should be considered in the young child with unexplained liver failure, especially with TCA cycle metabolite accumulation on urine organic acid/amino acid profiles with hyperammonemia suggestive of a proximal urea cycle defect during the acute episode. If suspected, intravenous administration of dextrose should be initiated. Long-term management comprising avoidance of fasting with the provision of a glucose polymer emergency regimen for illness management may be sufficient to prevent future episodes of liver failure.

    Conclusion: This case report provides further insights into the (patho-)physiology of energy metabolism, confirming the power of genomic analysis of unexplained biochemical phenotypes.

    Keywords: PEPCK, hyperammonemia, hepatopathy, lactic acidosis, treatment

    Funding Acknowledgment: BC Children’s Hospital Foundation, Genome BC (SOF-195), Michael Smith Foundation for Health Research (Scholar Award for CvK), Canadian Institutes for Health Research (#301221 grant).

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    P123 Delineating the patient population with Medium chain acyl-CoA dehydrogenase deficiency (MCADD): British Columbia Children’s Hospital (BCCH) clinic experience

    Kathleen Duddy RN, MSN, CPNP (P), Ramona Salvarinova MD, FRCPC, FCCMG, Graham Sinclair PhD FCCMG, Sylvia Stockler MD, PhD, MBA, FRCPC.

    Division of Biochemical Diseases, British Columbia Children’s Hospital; Department of Pediatrics University of British Columbia; British Columbia Newborn Screen Laboratory; Department of Pathology & Laboratory Medicine, Faculty of Medicine, University of British Columbia.

    Background: Medium chain acyl-CoA dehydrogenase deficiency (MCADD) is a rare genetic disorder, and the most common fatty acid oxidation disorder occurring 1 in 12000 births in British Columbia (BC). MCADD has been part of the new born screening (NBS) program in BC since 2002. Following confirmation of the newborn screening for MCADD, targeted genetic testing for the common two mutations in the ACADM gene is performed. Full gene sequencing is undertaken for patients where one or no common mutation is detected. We currently follow 50 patients with MCADD, age 4 weeks to 14 years. While initially all MCADD patients were started on L-Carnitine at birth, the practice was changed in 2013 supplementing only patients with below the normal free carnitine levels.

    Methods: Chart review was performed and information on several parameters was obtained: molecular results, patients started on L-carnitine at birth, carnitine supplementation including dosage and free carnitine levels.

    Results: The clinic follows 50 patients; 28 are homozygous for the common c.985A>G variant, and 4 patients are compound heterozygous for the c.985A>G and c.199T>G variant. Currently 37 patients are supplemented with L-Carnitine; dose ranging from 13 to 105 milligram/kilogram/day (mean of 43 milligram/kilogram/day). 7 patients were not started on L-carnitine at birth and maintained normal free carnitine level on follow up. With the change in practice 18 patients stopped L-carnitine, 11 of which required restarting supplementation.

    Summary: The MCADD patients differ in their need for carnitine supplementation. Further delineation of factors influencing this, including genotype correlation will be performed.

    Keywords: Medium chain acyl-CoA dehydrogenase deficiency, l-carnitine, free carnitine, new born screening, variants

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    P124 Neuropsychological and quality of life outcomes in untreated adults with mild hyperphenylalaninemia with phenylalanine levels between 360 and 600 µmol/L

    Ashley Wilsona, Laura Nagya, Annette Feigenbauma,b, Elizabeth Kerra, Enas Nasr, Komudi Siriwardenac.

    aDivision of Clinical and Metabolic Genetics, The Hospital for Sick Children and University of Toronto, Toronto, ON.

    bMetabolic & Mitochondrial Medicine, Rady Children’s Hospital, UCSD, San Diego, CA.

    cDepartment of Medical Genetics, Stollery Children’s Hospital, Edmonton, AB.

    Background: Thresholds to treat hyperphenylalaninemia have been historically discrepant, with the majority of clinics treating phenylalanine (PHE) levels >360 µmol/L. There is no consensus about the neuropsychological function and quality of life of untreated patients with mild hyperphenylalaninemia (MHP), with PHE levels 360-600 µmol/L. Further well designed studies of functioning in untreated individuals with MHP are needed to clarify findings of the limited studies that show variable outcomes in this population.

    Objectives: To determine whether neurocognitive, psychological, and quality of life outcomes for adults with MHP, as defined by untreated PHE levels between 360-600 µmol/L, are within the normal population values.

    Methods: Eligible subjects were administered a comprehensive neuropsychological battery measuring IQ, executive function, and quality of life. Statistical analysis was performed using z-tests and interclass correlation coefficients.

    Results: 10 subjects were studied. No difference was found in full-scale IQ scores using the Wechsler Adult Intelligence Scale when compared to Canadian normative data. On the Beck Depression and Anxiety Inventories, 10% of patients reported moderate depression, and 40% reported mild-moderate anxiety. CANTAB cognitive testing showed deficits in executive functioning, working memory, and reaction time when compared to age and gender normative data.

    Conclusion: The sample size was limited but these results warrant further research into the potential adverse effects of untreated MHP with PHE levels >360 µmol/L on executive function and emotional regulation. Improved treatment options, including better nutritional products to aid with diet adherence and pharmaceutical options, may make management of patients with MHP more feasible.

    Keywords:

    Funding Disclosure: Investigator initiated study funded by BioMarin Pharmaceuticals Inc.

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    P125 Characterization of the biochemical, molecular and clinical phenotype of patients with a diagnosis of VLCADD, including those identified via NBS in the Maritime region of Canada, as well as British Columbia

    Alana Newman, Kathleen Duddy, Meighan H. M. Kelly, Sarah Dyack, Ramona Salvarinova, Gabriella Horvath, Graham Sinclair, L. Jane Gillis.

    Objective: Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a rare genetic disorder of fatty acid metabolism. Accurate diagnosis and early detection are crucial for favourable clinical outcomes for these patients and for this reason VLCADD is now part of most expanded newborn screening (NBS) programs including the Canadian Maritime provinces of Nova Scotia, New Brunswick and Prince Edward Island, as well as British Columbia. Little is known about the clinical course of this heterogeneous condition and, while there are consensus protocols based on case studies and expert opinion, there are currently no evidence-based guidelines for diagnosis and treatment. Our aim was to review and summarize patient NBS and clinical data with our primary objective to characterize the biochemical, molecular and clinical phenotype of patients with a diagnosis of VLCADD, including those identified via NBS in the Maritime region of Canada, as well as British Columbia.

    Design & Methods: Data was collected using a chart review and included genotypes, clinical phenotype, and VLCAD residual enzyme activity (REA).

    Results: In the Maritime provinces, we have identified 18 patients ranging in age from birth to 25 years of age. We have identified previously reported mutations as well as a novel splice-site variant in patients of Acadian ancestry in those ascertained via NBS, as well as in those born prior to the availability of NBS for VLCADD. Ten of these patients are asymptomatic, while the remainder show a wide range of clinical phenotypes. Four patients have been identified via NBS in British Columbia, with different genotypes than those on the east coast, including four novel mutations. Three of these patients have been asymptomatic, while the fourth has presented with elevated creatine kinase with mild illnesses, and left ventricular hypertrophy.

    Conclusions: Review of clinical data showed that ≤10% REA correlates with development of symptoms in the Maritime patients including significant hypoglycemia, myopathy, cardiomyopathy and death. Moreover our data also suggest that individuals with REA within 10-15% are also at risk to develop symptoms. Genotype and REA are closely correlated, and even in cases where REA is unknown, the genotype can provide valuable prognostic information.

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    P126 Cardiac Outcomes in Very-Long-Chain Acyl-CoA Dehydrogenase Deficiency in the Maritimes: The Role of ECG and ECHO in Long Term Follow-Up

    Meighan Kellya, Kenny Wonga, L. Jane Gillisb, Alana Newmanc.

    aDalhousie University.

    bMaritime Medical Genetics Service, IWK Health Centre.

    cMemorial University of Newfoundland.

    Background and Aims: Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) is a rare disorder of fatty acid metabolism associated with multi-organ failure, cardiomyopathy and metabolic decompensation. With early diagnosis now achieved through newborn screening (NBS), treatment can be initiated before the onset of symptoms to prevent or reverse clinical deterioration. We sought to characterize cardiomyopathy and arrhythmias in patients with VLCADD in the Maritime Provinces and any association with residual enzyme activity.

    Methods: All patients in the Maritime Provinces diagnosed with VLCADD were included (N=18). Mutation type and residual enzyme activity was identified using functional enzyme assay. Previous echocardiogram (ECHO; N=42), electrocardiogram (ECG; N=43) and clinic reports were analyzed to document the presence or absence of cardiomyopathy and any documented arrhythmias or symptomatic events.

    Results: Residual enzyme activity ranged from 0-19%. Seventeen of 18 patients had an ECHO and ECG soon after diagnosis, with no significant findings. Five patients experienced transient symptoms (hypoglycemia and/or myopathy) with no cardiac sequelae. One patient (with 0% enzyme activity) was diagnosed with VLCADD and cardiomyopathy on autopsy before VLCADD screening was added to NBS.

    Conclusions: With early diagnosis by NBS and necessary treatment, patients with VLCADD in the Maritime provinces did not develop cardiomyopathy or symptomatic arrhythmias. Patients with residual enzyme activity as low as 4% experienced no cardiac involvement identified through repeat ECHO and ECG studies.


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