Abstracts for the Lysosomal Disease Network's WORLD Symposium

Medical Comorbidities in Juvenile Neuronal Ceroid Lipofuscinosis(Batten Disease)

Heather Adams a, b, Erika Augustine a, Samantha Potter a, JenniferKwon a, Fred Marshall a, Nicole Newhouse a, Amy Vierhile a, JonathanMink a, aUniversity of Rochester Medical Center, Rochester, NY, USA,bSyracuse University, Syracuse, USA

Juvenile neuronal ceroid lipofuscinosis (JNCL) is a childhood-onset neurodegenerative, lysosomal storage disease. JNCL causesvision loss, seizures, motor and mental decline, and premature death.Although neurological and psychiatric aspects of JNCL are well-characterized, little is known about systemic medical comorbidities.The University of Rochester Batten Center therefore reviewed medicalhistory of 45 males and 41 females with genetically confirmed JNCLwho had completed the Unified Batten Disease Rating Scale (UBDRS).Participants’ mean age was 15.1 years old (SD=5.2 years). Excludingneurologic and psychiatric symptoms, the five most commonlyparent-reported medical comorbidities were constipation (N=23),incontinence (N=23), acne (N=18), ear infection (N=17), eczemaor dry/itchy skin (N=14), and pain (N=13). Fourteen children werereported to have medication allergies. On average, children experi-enced approximately 4 comorbid health problems (M=3.9, SD=3.0;range=0 to 7). The total number of medical problems (“medicalburden”) was positively correlated with age (r=.42, p< .01),psychosocial quality of life (r=.35, p<.05) and with clinician'sglobal impressions of cognitive (r=.35, p<.05) and motor (r=.36,p<.05) function. Although comorbid health problems have not beena focus in the study of children with juvenile Batten disease, they arecommon and may provide a broader understanding of diseasephenomenology and course.

doi:10.1016/j.ymgme.2011.11.009

Evaluation of GLB1 In a Novel Ovine Model of GM1-Gangliosidosis

Amelia Ahern-Rindell, Masis Isikbay, Bethany McInturff, MeganSupinski, University of Portland, Portland, Oregon, USA

A unique form of the lysosomal storage disorder GM1-gangliosidosis (GM1) has been identified in sheep. While tradition-ally GM1 is associatedwith decreased levels of the lysosomal enzymeß-galactosidase (ß-gal), this ovine model also has an apparentsecondary deficiency of alpha-neuraminidase (neur). Both of thesehydrolases are components of a lysosomal multienzyme complex(LMC) whose formation is required to protect these enzymes andprevent their premature degradation within the lysosome. Othersheep have been identified with the traditional form of GM1 leadingus to believe that the dual enzyme deficient sheep are unique.

Previous work on this model suggests a structurally altered ß-gal isproduced thus, we hypothesize that this abnormal ß-gal interfereswith LMC formation leading to the secondary deficiency of neur. Weare currently using the evolutionarily related bovine GLB1 gene tocreate PCR primers to amplify and then sequence the orthologousgene in affected sheep. The majority of mutations identified in thedifferent types of human GM1 patients result in amino acidsubstitutions, although a few splice site mutations have beenreported. To date, no nucleotide base differences were foundbetween normal and GM1-affected sheep exon sequence. However,sequencing efforts continue on a few remaining exons and, werecently initiated investigation of the intron-exon sequence bound-aries. Identification of the mutation responsible for these GM1-affected sheep should further understanding of this unique animalmodel while shedding light on the structure of the ß-gal protein, theLMC, and hopefully one day, lead to a treatment for this fatal,neurological disorder.

doi:10.1016/j.ymgme.2011.11.010

Medical Outcomes and Adaptive Functions in Severe andAttenuated MPS I

Alia Ahmed, Taylor Zuck, Kathleen Delaney, Brianna Yund, ChesterWhitley, Elsa Shapiro, University of Minnesota, Minneapolis, MN, USA

Mucopolysaccharidosis type I (MPS I) is a multi-organ systemdisease. Hearing difficulties, corneal clouding, skeletal abnormalities,cardio pulmonary problems, CNS problems such as hydrocephalusand sometimes cervical cord compression impede functionality on aday to day basis. Hematopoietic cell transplant (HCT) in the severeHurler syndrome group is known to ameliorate some of theseproblems. Similarly, enzyme replacement therapy (ERT) for theattenuated Hurler-Scheie and Scheie syndrome patients increasesrange of motion, decreases hepatosplenomegaly, but other benefitsare not clear.

Methods: To test our hypothesis that these two treatments havediffering medical and functional outcomes, we compared the baselinemedical history and adaptive behavior functioning (Vineland Adap-tive Behavioral Scales) for two groups of patients over 6 years of age,N=18 children who are post transplant for Hurler syndrome andN=14 children who have had ERT for attenuated MPS I. We alsoexamined years since the onset of both treatments as a covariate.

Results: In 14 patients who had ERT, 13 have corneal clouding, 10have hearing difficulties, 13 have hepatosplenomegaly, 3 havehydrocephalus with shunt placement and all have skeletal abnorm-alities and valvular diseases. In 18 patients who had HCT, 15 havecorneal clouding, 12 have hearing difficulties, 10 have hepatospleno-megaly, 2 have hydrocephalus and all have skeletal abnormalities and

Contents lists available at ScienceDirect

Molecular Genetics and Metabolism

j ourna l homepage: www.e lsev ie r.com/ locate /ymgme

1096-7192/$ – see front matter.

Molecular Genetics and Metabolism 105 (2012) S15–S69