Molecular genetics and metabolism.
`v. 105. no. 3 (Mar. 2012)
`General Collection
`W1 81621 R
`2012-04-10 06:30:15
`
`ISSN I 096-7192
`Volume I 05, Issue 3, March 2012
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`Volume 105 (3) 2012
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`ELSEVIER
`
`Amsterdam • Boston • London • New York • Oxford • Paris • Philadelphia • San Diego • St. Louis
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`Molecular Genetics and Metabolism
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`Volume 105, Issue 3, March 2012
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`Contents lists available at SciVerse ScienceDirect
`
`Molecular Genetics and Metabolism
`
`ELSEVIER
`
`journal homepage: www .. elsevier.com/locate/ymg me
`
`' :
`: I
`
`Volume 105, Issues 3, March 2012
`
`Special Issue: SIMD Abstracts for 2012
`
`CONTENTS
`
`Abstract/indexed in: BIOSIS, Chemical Abstracts, Current Contents/Life Sciences, EMBASE, EMBiology
`MEDLINE®, and Science Citation Index. Also covered in the abstract and citation database SciVerse Scopus®:
`Full text available on SciVerse ScienceDirect®
`
`SPECIALSEmON: PROGRAM AND ABSIRACTS FOR THE ANNUAL MEETING OF1HE SOCIEIY FOR INHERITED METABOUC DISORDERS
`
`273 Program for SIMD annual meeting: March 31-April 3, 2012, The Westin Charlotte, Charlotte, NC
`
`EDITORIAL FROM THE SIMD BOARD OF DIRECTORS
`
`367
`
`SIMD statement on investigational new drugs for rare disease therapies
`Nicola Longo
`
`MINI REVIEW
`
`368 Treatable inborn errors of metabolism causing intellectual disability: A systematic literature review
`Clara D.M. van Karnebeek, Sylvia Stockier
`
`REGULAR ARTICLES
`
`382 Recombination mapping using Boolean logic and high-density SNP ~e?otyping for exome sequence filtering
`Thomas c. Markello, Ted Han, H~nna~ Carlson-D?nohoe, Ch1d1 Ahaghotu, Ursu.la Harper, MaryPat Jones,
`Settara Chandrasekharappa, Vair Anikster, David R. Adams, NISC Comparative Sequencing Program,
`William A. Gahl, Cornelius F. Boerkoel
`390 Diet in phenylketonuria: A snapshot of special dietary costs and reimbursement systems in 10 international
`centers
`A. Belanger-Quintana, K. Doko.upil, H. Gokmen-Ozel, A.M. Lammardo, A. MacDonald, K. Motzfeldt, M. Nowacka,
`M. Robert, M. van Rijn, K. Ahrmg
`396 Long-term betaine therapy in a murine model of cystathionine beta-synthase deficient homocystinuria: Decreased
`efficacy over time reveals a significant ~hresh~ld effect between elevated homocysteine and thrombotic risk
`Kenneth N. Maclean, Hua Jiang, Lon S. Gremer, Robert H. Allen, Sally P. Stabler
`
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`ri,=ht Laws
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`404
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`408
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`416
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`421
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`428
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`433
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`438
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`443
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`450
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`457
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`463
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`472
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`479
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`484
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`489
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`494
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`502
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`508
`
`Impact of enzyme activity assay on indication in liver transplantation for ornithine transcarbamylase deficiency
`Taiichi Wakiya, Yukihiro Sanada, Taizen Urahashi, Yoshiyuki Ihara, Naoya Yamada, Noriki Okada, Kentaro Ushijima,
`Shinya Otomo, Koichi Sakamoto, Kei Murayama, Masaki Takayanagi, Kenichi Hakamada, Yoshikazu Yasuda,
`Koichi Mizuta
`Exploring the transcriptomic variation caused by the Finnish founder mutation of lysinuric protein
`intolerance (LPI)
`Maaria Tringham, Johanna Kurko, Laura Tanner, Johannes Tuikkala, Olli S. Nevalainen, Harri Niinikoski,
`Kirsti Nanto-Salonen, Marja Hietala, Olli Simell, Juha Mykkanen
`Combined extraction of acyl carnitines and 26:0 Iysophosphatidylcholine from dried blood spots: Prospective
`newborn screening for X-Iinked adrenoleukodystrophy
`Yana Sandlers, Ann B. Moser, Walter C. Hubbard, Lisa E. Kratz, Richard 0. Jones, Gerald V. Raymond
`Enzymatic activity and genetic variation in SCD1 modulate the relationship between fatty acids and inflammation
`Carolina Stryjecki, Kaitlin Rake, Shannon Clarke, Daiva Nielsen, Alaa Badawi, Ahmed EI-Sohemy, David W.L. Ma,
`David M. Mutch
`Early cognitive development in children with infantile Pompe disease
`Gail A. Spiridigliozzi, James H. Heller, Laura E. Case, Harrison N. Jones, Priya S. Kishnani
`Fanconi-Bickel syndrome: GLU12 mutations associated with a mild phenotype
`Sarah Catharina Gri.inert, Karl Otfried Schwab, Martin Pohl, Jorn Oliver Sass, Rene Santer
`Morquio A syndrome due to Maternal Uniparental Isodisomy of the telomeric end of chromosome 16
`S. Catarzi, L. Giunti, F. Papadia, 0. Gabrielli, R. Guerrini, M.A. Donati, M. Genuardi, A. Morrone
`Anti-cx-galactosidase A antibody response to agalsidase beta treatment: Data from the Fabry Registry
`William R. Wilcox, Gabor E. Linthorst, Dominique P. Germain, Ulla Feldt-Rasmussen, Stephen Waldek,
`Susan M. Richards, Dana Beitner-Johnson, Marta Cizmarik,J. Alexander Cole, Wytske Kingma, David G. Warnock
`Lysosomal lipase deficiency: Molecular characterization of eleven patients with Wolman or cholesteryl ester
`storage disease
`Tommaso Fasano, Livia Pisciotta, Letizia Bocchi, Ornella Guardamagna, Paola Assandro, Claudio Rabacchi,
`Paolo Zanoni, Mirella Filocamo, Stefano Bertolini, Sebastiano Calandra
`Non-invasive evaluation of buccal respiratory chain enzyme dysfunction in mitochondrial disease: Comparison
`with studies in muscle biopsy
`Michael J. Goldenthal, Teddy Kuruvilla, Shirish Damle, Leon Salganicoff, Sudip Sheth, Nidhi Shah, Harold Marks,
`Divya Khurana, Ignacio Valencia, Agustin Legido
`Metabolic consequences of mitochondrial coenzyme A deficiency in patients with PAN1(2 mutations
`Valerio Leoni, Laura Strittmatter, Giovanna Zorzi, Federica Zibordi, Sabrina Dusi, Barbara Garavaglia, Paola Venco,
`Claudio Caccia, Amanda L. Souza, Amy Deik, Clary B. Clish, Marco Rimoldi, Emilio Ciusani, Enrico Bertini,
`Nardo Nardocci, Vamsi K. Mootha, Valeria Tiranti
`ALS patients with mutations in the SOD1 gene have an unique metabolomic profile in the cerebrospinal fluid
`compared with ALS patients without mutations
`Anna Wuolikainen, Peter M. Andersen, Thomas Moritz, Stefan L. Marklund, Henrik Antti
`A novel splicing mutation causes analbuminemia in a Portuguese boy
`Gianluca Caridi, Monica Dagnino, Marco Di Duca, Helena Pinto, Maria do Ceu Espinheira, Antonio Guerra,
`Susana Fernandes, Monica Campagnoli, Monica Galliano, Lorenzo Minchiotti
`Dyrkla activates antioxidant NQOl expression through an ERl(1/2-Nrf2 dependent mechanism
`Christophe Noll, Asma Tlili, Clementine Ripoll, Ludovic Mallet, Jean-Louis Paul, Jean-Maurice Dela bar, Nathalie Janel
`Genetic association between WNT10B polymorphisms and obesity in a Belgian case-control population is
`restricted to males
`J.K. Van Camp, S. Beckers, D. Zegers, A. Verrijken, L.F. Van Gaal, W. Van Hui
`Genetic contribution to (-reactive protein levels in severe obesity
`Genevieve Faucher, Frederic Guenard, Luigi Bouchard, Veronique Garneau, Valerie Turcot, Alain Houde, Andre Tchernof,
`Jean Bergeron, Yves Deshaies, Frederic-Simon Houle!, Stefane Lebel, Picard Marceau, Marie-Claude Vohl
`Population variability in CD38 activity: Correlation with age and significant effect of TNF-a -308G>A and CD38
`184C>G SNPs
`Valeria Polzonetti, Francesco M. Carpi, Daniela Micozzi, Stefania Pucciarelli, Silvia Vincenzetti, Valerio Napolioni
`Associati~~ st~tdy of common variants in the sFRPl gene region and parameters of bone strength and body
`compos1t1on m two independent healthy Caucasian male cohorts
`E~eline Boudin, Elke Piters, Erik Fransen, Torben Leo Nielsen, Marianne Andersen, Greet Raef, Youri Taes,
`Kun Brixen, Wim Van Hui
`
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`BRIEF COMMUNICATIONS
`
`516 S-adenosylmethionine treatment in methionine adenosyltransferase deficiency, a case report
`Mahoko Furujo, Masako Kinoshita, Masayoshi Nagao, Toshihide Kubo
`519 A novel fluorometric enzyme analysis method for Hunter syndrome using dried blood spots
`Adviye A. Tolun, Carrie Graham, Qun Shi, Ramakrishna S. Sista, Tong Wang, Allen E. Eckhardt, Vamsee K. Pamula,
`David S. Millington, Deeksha S. Bali
`522 Progressive mesenteric lymphadenopathy with protein-losing enteropathy; a devastating complication in
`Gaucher disease
`Beom Hee Lee, Dae-Yeon Kim, Gu-Hwan Kim, Kyung-Ja Cho, Hye-Kyung Yoon, Han-Wook Yoo
`525 Association between a common I<CNJ11 polymorphism (rs5219) and new-onset posttransplant diabetes in patients
`treated with Tacrolimus
`Beatriz Tavira, Eliecer Coto, Armando Torres, Carmen Diaz-Corte, Beatriz Diaz-Molina, Francisco Ortega,
`Manuel Arias, Juan M. Diaz, Rafael Selgas, Carlos Lopez-Larrea, Marta Ruiz-Ortega, Alberto Ortiz, Elena Gonzalez,
`Josep M. Cam pistol, Victoria Alvarez, The Pharmacogenetics of tacrolimus REDINREN study group
`
`LETTERS TO THE EDITOR
`
`528
`
`Is E326K glucocerebrosidase a polymorphic or pathological variant?
`Benjamin Liou, Gregory A. Grabowski
`530 Sample blank subtraction outreachs hemoglobin interferences in flurorometric methods for DBS
`Eser Y. Sozmen
`
`531 ABSTRACT INDEX
`
`Language services. Authors who require information about language editing and copyediting services pre- and post-submission
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`342
`
`Abstracts/ Molecular Genetics a11c/ Metabolism 105 (2012) 273-366
`
`urinary PAGN (U-PAGN) and morning spot U-PAGN (p<0.001 for all correlations), the strongest correlation was found with 24-h U-PAGN (r~ 0.821
`for GPB and 0.788 for NaPBA), followed by plasma PAGN AUC0 _2 4 h ( r = 0.716), and PAGN trough levels (r = 0.673 ); plasma PBA and PAA either as
`AUC0 _24 or trough/peak levels showed weaker correlations (r values ranging from 0.247 to 0.534). Similar to 24-h U-PAGN, morning spot U-PAGN
`correlated strongly with GPB dose (r= 0.730) in adults; no spot urine samples were collected in the pediatric study (HPN-100-005). In protocol
`HPN-100-006, which enrolled adults, plasma PAA exposure was significantly lower on GPB vs. NaPBA (AUC0 _24 (~1g h/mL) 447 ( 130.4) vs. 599
`(91.6); ratio of geometric means 0.625; 90% Cl 0.523-0.748; p = 0.001) despite nearly identical output of U-PAGN ( 13502745 (52.5) ug vs.
`13627515 (52.0) ug) and previously reported equivalent ammonia control.
`
`Conclusion: The considerable variability of blood metabolite levels. their weaker correlation with dose, and the inconsistency between PM
`and U-PAGN as a marker of waste nitrogen scavenging, as well as practical considerations, limit their utility for therapeutic monitoring. By con(cid:173)
`trast, both 24-h U-PAGN and morning spot urine PAGN correlate strongly with close and appear to be clinically useful non-invasive biomarkers
`for monitoring compliance and the need for close adjustment.
`
`79) Elevated phenylacetic acid (PAA) levels appear linked to neurological adverse events in healthy adults but not in urea cycle disorder
`(UCO) patients
`
`, J Bartley4
`, A Feigenbaum 5
`M. Mokhtarani 1• GA Diaz 2, W Rhead 3
`
`• N Longo 6, W Berquist 7, SA Berry8, R Gallagher9, U Lichter-Konecki 10, D Bartho(cid:173)
`• W Smith 15. J Vockley 15
`, S Bart 17, MS Korson 18, D Kronn 19, R Zori 20, JL Merritt21 , San(cid:173)
`lomew 11 , CO Harding 12, S Cederbaum 13, SE McCandless 14
`clesh Sreenath-Nagamani 22· J Mauney23 , K Dickinson 1, T Moors 3. D Coakley 1
`, B Lee22, BF Scharschmidt 1
`
`1flyperion
`2Mt. Sinai., NY
`3Med College WI
`4Long Beach
`5Univ of Toronto
`6Univ of UT
`7Stanforc/
`8Univ of MN
`9Denver C/1i/dre11's
`1°CNMC, Washington. DC
`11 Nationwide Cl!ildre11's, Co/!lmb!ls
`120HSU
`13UCIA
`14CWRU
`15ME Med Ctr.
`16Univ of Pittsb!lrgh
`17SNBL
`18T!lfts, Baltimore
`19Westcl1ester Meclical Ctr.
`20U11iv of FL, 21Seatt/e Cliilc/ren's
`22Baylor
`
`PAA is an endogenous bodily constituent and the active moiety in sodium phenyl butyrate (NaPBA), approved for treatment of UCDs, and in
`glycerol phenyl butyrate (GPB, also GT4P or HPN-100), being developed as a treatment alternative to NaPBA for UCO patients. Many of the over
`30 reports of administration of NaPBA and/or sodium phenylacetic acid to humans describe adverse events (AEs), particularly when
`administered intravenously. Thibault ( 1994, 1995) administered IV PAA to cancer patients and reported that AEs, including fatigue.
`dizziness, clysgeusia, headache, somnolence, lightheadedness. pedal edema, nausea, vomiting, and rash, correlated with PAA levels from 499
`to 1285 pg/mL. Although NaPBA has been used in UCO treatment for over two decades and although AEs reportedly associated with PAA are
`similar to those associated with hyperammonemia, little is known about the relationship between PAA levels and neurological AEs in UCO
`patients.
`
`Study design: Three populations were studied: ( 1) 130 healthy adults dosed with 4 to 12 mL TIO of GPB in a thorough QTc study, (2) 54 adult
`and 11 pediatric UCO patients (ages 6-17) enrolled in one of 3 protocols involving short term (2-4 week) switchover comparisons of NaPBA vs.
`GPB, and (3) 77 patients enrolled in two nearly identical 12-month GPB treatment protocols. In populations 1 and 2, maximal PAA (i.e. Cmax)
`levels were analyzed in relation to neurological AEs as defined by MEDORA using an Exact non-parametric Mann-Whitney test and Generalized
`Estimating Equations (GEE) with a logit link function and effects for dose and PAA level. The relationship between PAA levels the occurrence of
`the AEs reported by Thiebault was also explored in population 3.
`
`Results: There was no statistically significant relationship among UCO patients between neurological AEs and PAA levels for either GPB or
`Nal'BA. The odds ratio of a neurological AE ocrnrring for each 20 pg/mL increase in PAA levels for the two drugs combined was 0.95, very
`close to 1. Thus, among UCO patients dosed with HPN-100 or NaPBA over the ranges used in these studies, increasing levels of PM, which
`ranged up to 244 pg/mL, were not associated with an increase in neurological AEs. Similarly in population 3, PAA levels did not increase over
`time and exhibited no apparent relationship to neurological AEs, which also did not increase in frequency over time. The pediatric subject
`with the highest PAA level ( 410 fig/mL) did not report neurological AEs close to the timing of the blood draw. Unlike UCO subjects, healthy
`adult volunteers who reported a nervous system AE had statistically significantly higher PM Cmax levels than those who did not. While this anal(cid:173)
`ysis in healthy adults is compromised by the fact that PAA levels were not always available at the time of occurrence of the AEs and the small
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`Abstracts I Molecular Genetics and Metabolism 105 (2012) 273-366
`
`343
`
`sample_ ~ize in the l~igh~r close groups, the odds ratio of 1.75 (p = 0.006) suggests that increasing levels of PM are associated with increased
`?robab1hty of expenenc111g a nervous sy_stem AE among these healthy adults. AEs reported by healthy adults generally began within 36 h of dos-
`111g and, among those adults who rema111ecl on study, most resolved with continued dosing.
`
`~onclusions: A sig~ificant relationship betw~en '.AA levels and occurrence of neurological AEs, which generally resolved with continued
`closmg, _w~s detected 111 healthy volunteers. Unlike 111 _healthy adults, PM Cm.ix did not correlate with nervous system AEs in UCO patients
`o~er a s1mil~r range of closes and P~A levels. These find111gs may reflect metabolic differences among the populations ( e.g. UCO patients exhibit
`high glutamme levels compared with healthy humans) and/or metabolic adaptation with continued closing.
`
`80) Populat~on pk analysis of glycerol phenylbutyrate (GPB) and sodium phenylbutyrate (NAPBA) in adult and pediatric patients with
`urea cycle disorders (UCD}
`
`, A Feigenbaum 7, N Longo 8
`ne 1. M Mokhtara~( GA Dia~ 3, W Rhead 4, U Lichter-Konecki 5
`, w Berquist9, SA Berry w.
`, J Bartley6
`JPR Montele
`. CO Harclmg 13, MS Korson 14. SE McCandless 15, W Smith 16, J Vockley 17, S Bart 18
`, o Kronn 19, R Zori20.
`R Gallagher
`. D Bartholome_w
`Sanclesh Sreenath-Nagama111 21 , M Summar22, K Dickinson2, D Coakley2, B Lee21 , BF Scharschmiclt2
`
`1~
`
`1 Plwrsig/1t Corp., Cary, NC
`2Hyperion Therapeutics, Inc., Sout/J San Francisco, CA
`3Mt. Sinai Sc/Joo/ of Medicine, NY, NY
`4Med College of WI, Milwaukee, WI
`5Children's National Medical Center, Was/Jington. DC
`6Long Beac/J, CA
`7Hospita/ for Sick C/Jildren. Toronto, Ontario, Canada
`8Univ of UT, Salt Lake City UT
`9Stanford, Palo Alto, CA
`10Univ of MN, Minneapolis, MN
`11 Denver C/Ji/dren's Hospital, Denver, CO
`12Nationwide C/Jildren's Hospital, Columbus. OH
`130regon Healt/J & Sciences Univ., Portland, OR
`14Tufts Medical Center, Boston, MA
`15UHCMC and CWRU, Cleveland, OH
`16Maine Medical Ctr., Portland, ME
`17Univ of Pittsburg/J, Pittsburg/J, PA
`18SNBL, Baltimore MD
`19Westc/Jester Medical Ctr., Westchester, NY
`20Univ of FL, Gainesville, FL
`21 Baylor College of Medicine, HHMI, Houston, TX
`
`Glycerol phenylbutyrate (GPB, also referred to as HPN-100 or GT4P) is being developed as a treatment alternative to sodium phenyl butyrate
`(NaPBA) for UCO patients. GPB is a short chain triglyceride (liquid), and 5.8 mL TIO is anticipated to be the equivalent of 40 tablets (20 g) of NaPBA.
`
`Study Design: Population PK model building was performed using NONMEM (version 7.2) based on 2981 (plasma phenylbutyric acid [PBA],
`phenylacetic acid [PAA], phenylacetylglutamine [PAGN] and urine PAGN [UPAGN])) data points from 53 adult and 11 pediatric UCO patients
`(ages 6-17) who participated in phase 2 (UP 1204-003; HPN-100-005) or phase 3 (HPN-100-006) switchover comparisons of the pharmacoki(cid:173)
`netics ofNaPBA and GPB. The median GPB dose, expressed as grams of PBA per 1112, was 8.85 and 7.01 for pediatric and adult subjects, respectively.
`Diagnostic plots and statistical comparisons were used to select among candidate models, and covariates were assessed by graphical analyses and
`covariate modelling. Using the final pop PK model and parameter estimates, Monte Carlo simulations were performed in -1000 virtual patients for
`a range of NaPBA and GPB doses to predict systemic metabolite exposure and UPAGN output.
`
`Results: The final model that best fit the data was characterized by (a) partial conversion of PBA to PAGN prior to reaching the systemic
`circulation, (b) saturable conversion of PAA to PAGN (Km -161 ~tg/ml), and (c) -60% slower PBA absorption when cleliverecl as GPB vs.
`NaPBA. Body size (i.e. body surface area or BSA) was a significant covariate such that metabolite clearance was proportionally related to BSA,
`i.e. larger BSA corresponds to more rapid metabolite clearance. Fractional presystemic metabolism of PBA was higher for adults than for pediatric
`patients receiving GPB (43% vs. 14%), whereas the reverse was true for NaPBA (23% vs. 43%). As compared with NaPBA. predicted median PAA
`exposure based on simulated GPB closing at the PBA equivalent of 13 g/m2 of NaPBA (maximum labelled close, not to exceed 20 g NaPBA/clay
`total) was -13%-22% lower in adults (Cmax = 82 vs. 106 pg/mL; AUC0 _24 = 649 vs. 829 pg.him) and -13% higher in pediatric subjects ages
`6-17 ( Cmax = 154 vs. 138 ug/mL; AUC0
`_24 = 1286 vs. 1154 pg.h/ml): predicted upper 95th percentile PAA exposure was 25%-40% lower
`for adult subjects on GPB vs NaPBA ( Cmax = 341 vs. 558 pg/ml; AUC0 _24 = 1625 vs. 2572) and similar for pediatric subjects ( Cmax = 496 vs.
`_24 = 3751 vs. 3499). Simulated closing at the PBA equivalent of -5 g/1112 of NaPBA yielclecl generally similar and less variable
`494 ug/mL; AUC
`0
`predicted PAA exposure for both drugs and for pediatric as well as adult patients. Recovery of PBA as UPAGN was very similar whether delivered
`orally as GPB or NaPBA.
`
`Conclusions: GPB behaves as a slow-release version of NaPBA in that the rate of PBA absorption is slower but the extent of absorption,
`as assessed by UPAGN, is very similar. PAA to PAGN conversion is saturable, and the higher PAA levels in pediatric as compared with adult
`UCO patients for both drugs reflect BSA-related changes in PAA clearance and higher per weight closing in pediatric patients. Differences in
`the proportion of PBA metabolized presystemically appear to account for the cl rug-related differences in PAA levels, which are modest in relation
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`to inter-subject variability observed with both drugs. Even with dosing at the upper end of the labelled range for NaPBA (i.e. 13 g/m2 of NaPBA;
`not to exceed 20 g/day) where PAA exposure shows greatest variability, the upper 95th percentile for PAA exposure, assessed as Cmax, is less
`than 500 μg/ml.
`
`81) Adaptive functioning and health-related quality of life of patients with mucopolysaccharidosis type ii (hunter syndrome)
`
`Mary C. Needham1, Wendy Packman1,2, and Seymour Packman2
`
`1Palo Alto University
`2University of California, San Francisco, USA
`
`We investigated the adaptive functioning and health-related quality of life (HRQOL) of patients with Mucopolysaccharidosis type II (MPS II;
`Hunter syndrome) through interviews with parents/caregivers of 73 patients. To investigate adaptive functioning, the Vineland Adaptive Behav-
`ior Scales (2nd Ed.) Parent/Caregiver Rating Scale (Vineland-II) was administered and the results were compared to the normative sample. On the
`Vineland-II, the parents/caregivers of MPS II patients reported scores significantly lower than the normative sample in the domains of commu-
`nication, daily living skills, socialization, and motor skills, as well as for each subdomain of the measure. To examine health-related quality of
`life, the PedsQL Quality of Life, Parent Proxy Report was administered to 65 parents/caregivers of patients with MPS II; the results were compared
`to a healthy sample and an oncology sample. On the PedsQL, the reported HRQOL of the MPS II patients was significantly lower than the reported
`HRQOL of healthy children for the following scales: physical health, psychosocial health (including emotional functioning, social functioning,
`and school functioning), and the total score. Furthermore, statistically significant differences were found on all aforementioned PedsQL scales
`when comparing the scores reported by parents/caregivers of MPS II patients to the scores reported by parents of oncology patients. These
`findings demonstrate that individuals with MPS II have significant limitations in their adaptive functioning, as well as poorer HRQOL than healthy
`individuals and oncology patients in terms of physical, emotional, social, and school functioning. Professionals and caregivers involved in the lives
`of MPS II patients should be aware of, and attentive to, the limitations for MPS II patients within the realms of adaptive behavior and HRQOL.
`Additionally, it is important for those involved in the patients' lives to seek opportunities to improve the HRQOL of these patients.
`
`82) Brain volumes and cognitive function in MPS IIIA (sanfilippo syndrome type a): Cross-sectional study
`
`Igor Nestrasil1, Alia Ahmed1, Kyle Rudser1, Kate Delaney1, Patrick Haslett2, Charles Richard III2, Elsa Shapiro1, Chester B Whitley1
`
`1University of Minnesota, Minneapolis, MN, USA
`2Shire HGT, Lexington, MA, USA
`
`Background: MPS III is predominantly a neurological disease. Quantitative MRI and neurocognitive function may provide understanding of
`the disease and information about rate of decline.
`
`Goals: 1. Collect natural history data and develop outcome measures sensitive to treatment effects; 2. Identification of related changes in
`cognitive performance.
`
`Methods: Cross-sectional quantitative MRI data were collected for children with MPS IIIA during a natural history study sponsored by Shire
`Human Genetic Therapies, Inc. Volumetric analysis was performed by automated segmentation. All volumes were adjusted to intracranial
`volume. Developmental quotient (DQ) and age equivalent scores were utilized as cognitive outcome.
`Patients showed differing cognitive attributes depending on age at diagnosis. 19 children with classic symptoms were diagnosed before 6y of
`age; 6 were diagnosed with later onset/attenuated disease. Mean age was 6.2 y, mean DQ 45. DQ declined with age (p b0.01), grey matter loss
`(p b0.001), and increase in compound ventricular volume (p b0.001). A robust correlation with grey matter was found; because of continued
`development in the group diagnosed before 6y, the relationship of grey matter volumes to DQ was less than the older attenuated group, prob-
`ably due to lack of atrophy onset in the younger group. Grey matter loss was significantly related to increasing age (p b0.01).
`
`Discussion: Grey matter volume loss with enlarging ventricles is the leading MRI pattern linked to cognitive decline in MPS III. The
`pathomechanism causing neuronal death is still unknown and no treatment is available. We demonstrate a quantitative description of disease
`progression that is a first step to establish an evaluation tool for future therapies.
`
`83) Acute rhabdomyolysis following status dystonicus, renal failure, and cardiopulmonary arrest in a patient with glutaric aciduria type 1
`
`Stephanie A. Newton, Saumya S. Jamuar, Leah Hecht, David Harris, Irina Anselm, and Gerard T. Berry
`
`Children's Hospital Boston, Boston, MA, USA
`
`We present the third case report of a patient with Glutaric Aciduria type I (GA1) and rhabdomyolysis. The male infant was diagnosed with
`GA1 at 4 months of age when, in the setting of febrile illness, he experienced seizures, opisthotonic posturing, and intermittent dystonia. Brain
`MRI revealed characteristic basal ganglia lesions, and urine organic acid analysis showed markedly elevated glutarate and 3-OH-glutarate.
`He remained stable on a lysine and tryptophan restricted diet for several years, but did have severe spasticity and painful spasms. At
`7 years of age, dystonia worsened and was resistant to medications. At 8.5 years of age, he presented with fever, suspected pneumonia/sepsis,
`respiratory distress, and worsening dystonia which progressed to status dystonicus. Laboratory studies indicated renal failure and rhabdomy-
`olysis associated with elevated serum AST, ALT, and CK. Hypotension developed and was follo