Platform Presentations

Are you presenting a Platform? Click here for Information for Presenters



Friday, May 20, 1130-1200

Friday, May 20, 1345-1400

Saturday, May 21, 1215-1245


Friday May 20, 1130-1145

Outcome with Enzyme replacement therapy for lysosomal storage disorders: Triumphs and challenges in India

Mamta N. Muranjan, MDa, Sunil C. Karande, MDa.

aGenetic Clinic, Department of Pediatrics, King Edward Memorial Hospital, Parel, Mumbai 400012, India.

ERT for LSDs is not commercially available India nor is it reimbursed through insurance or government health programs. Very few patients have access to ERT through manufacturer’s charitable access programs or employer reimbursement. The paper reports experience of ERT at a single center in Western India.

Objective: To study clinical characteristics of patients with LSDs and response to ERT.

Methods: Retrospective analysis for age at onset of symptoms, diagnosis and commencement of ERT. Response for Gaucher disease and Hunter syndrome was assessed in terms of published guidelines.

Results: Eleven children with Gaucher disease (four with type 3 disease) were treated with imiglucerase (average dose 23 – 53 units/kg/year) for an average duration of 55 months. Four with infantile onset Pompe disease [IOPD] and one with late onset disease were treated with alglucosidase α at an average age of 6.8 months and 25 years respectively. Idursulfase was initiated in a cognitively normal boy at 5½ years of age.

With Imiglucerase therapy, the short term outcomes in terms of hematological reconstitution was satisfactory but none of the 11 patients attained all therapeutic goals in the recommended time frame for visceral, skeletal and growth domains. Of the nine patients continuing therapy (two drop-outs due to socio-economic factors), one was enrolled in a clinical trial with Eliglustat. Four patients are adults, one employed as an accountant and two in the final year of graduation (medicine and commerce).

For Hunter syndrome, earliest response (reduction in urine GAG and liver and spleen volume) was evident by the 2nd month. Improvement in range of motion was remarkable at the shoulder joint. Late diagnosis contributed to poor outcome in IOPD with a sole survivor on ERT for 3 months.

Conclusions: Outcome for LSDs in India is determined by age at diagnosis, limited dosing and socio-economic factors.

Keywords: Enzyme replacement therapy, Gaucher disease, Hunter syndrome, Pompe disease

Back To Top


Friday May 20, 1145-1200

Lysine degradation studies and drug screens: a therapeutic approach for Pyridoxine Dependent Epilepsy

Izabella Penaa, Alan Mearsa, Clara van Karnebeekb, Sidney M. Gospe Jr.c, Levinus A Bokd, Paulo Arrudae, Osama Al-Dirbashif, Pranesh Chakrabortyg, Kym Boycotta, Alex Mackenziea.

aCHEO Research Institute.

bBC Children’s Hospital.

cSeattle Children’s Hospital.

dMaxima Medical Center.


fNewborn Screening Ontario.

gChildren’s Hospital of Eastern Ontario, University of Ottawa.

Pyridoxine-dependent epilepsy (PDE) is a rare autosomal recessive disorder characterized by recurrent seizures that, although resistant to conventional anticonvulsants, are alleviated by high doses of pyridoxine (vitamin B6). Mutations in the ALDH7A1 gene, which encodes the lysine-metabolizing enzyme antiquitin, cause PDE. The initial reaction of the lysine degradation pathway, catalysed by Aminoadipate-Semialdehyde Synthase (AASS), is the conversion of lysine to aminoadipate semialdehyde (AASA). AASA spontaneously cyclizes to form piperideine-6 carboxylate (P6C); both compounds are substrates for antiquitin. P6C is believed to be the primary pathogenic driver of PDE as it reacts with pyridoxal 5′-phosphate (PLP), leading to PLP depletion. Despite amelioration of seizures with pyridoxine treatment, most patients nonetheless suffer from neurodevelopmental problems.

We report here for the first time increased lysine sensitivity in primary skin fibroblasts from PDE patients and the use of this novel phenotype for preclinical analysis of novel PDE therapeutic approaches. In the first case, mutations in AASS (the enzyme upstream of ALDH7A1 in the lysine catabolism pathway ) results in hyperlysinemia, which is now considered a benign inborn error of metabolism. We therefore hypothesized that AASS represents a therapeutic target for PDE and have shown knock-down (KD) of AASS prevented the high P6C levels we have observed in PDE fibroblasts and also reduces their lysine sensitivity. We next used PDE cells lysine sensitivity to conduct a targeted FDA-approved drug screening which identified that fenofibrate rescues PDE cells from lysine death. The rescue is dose-dependent; moreover other fibrates confer a similar beneficial effect showing a drug class effect. Preliminary analyses suggest that fenofibrate reduces lysine degradation and thus P6C accumulation in the PDE fibroblast model. In vivo studies in wild type mice also suggest that fenofibrate reduces overall lysine degradation. We established a reliable quantification method of P6C in patient urine to be used in the future for a biomarker reduction trial using fenofibrate. An aldh7a1-/- model in zebrafish is being generated to both test the relation between P6C levels and seizure events and to assess the therapeutic value of fenofibrate and/or KD AASS therapies.

Back To Top


Friday May 20, 1345-1400

Plasma cell-free mitochondrial DNA: A novel and non-invasive method to detect mutations in mitochondrial DNA

Christopher Newella, Steven C. Greenwayb,c,d, Paul Gordone, Ryan Lamontf, Jillian Parboosinghf, Richard T. Pone, Jane Shearerg, Aneal Khanc,d,f.

aDepartment of Medical Science, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

bLibin Cardiovascular Institute of Alberta and Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

cDepartment of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

dAlberta Children’s Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada.

eCentre for Health Genomics and Informatics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

fDepartment of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Alberta.

gFaculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.

Objectives: Mitochondrial disease comprises a heterogeneous group of diseases affecting 1 in 5000 people and can be caused by gene mutations in either nuclear or mitochondrial DNA (mtDNA). Less-invasive methods to obtain mtDNA have involved collection from peripheral blood leucocytes, urine sediment and buccal swab. However, these methods are specific to the cell type collected and lack sensitivity. Research suggests that cellular apoptosis and cellular turnover release small 150-200 base pair fragments of DNA from all cell types, which can be extracted from plasma as cell-free DNA (cfDNA). Entire mtDNA has not been successfully extracted from the cell free fraction previously. As we suspect that the circular nature of mtDNA is protective, our objective was therefore to develop a methodology to extract entire cf-mtDNA from plasma.

Design & Methods: Blood samples from patients with known mitochondrial disease (n=3) and healthy controls (n=2) were collected and their cfDNA isolated. To demonstrate the presence of the mitochondrial genome within these samples, we amplified the isolated DNA using custom PCR primers specific to overlapping fragments of mtDNA. cfDNA samples were each sequenced using the Illumina MiSeq next-generation sequencing platform.

Results: We confirmed the presence of mtDNA, demonstrating that the full mitochondrial genome is in fact present within cell-free DNA isolated samples. Furthermore, sequencing yielded a positive match for mitochondrial haplogroup variability in each patient and control.

Conclusions: We report the first successful method showing positive identification of cf-mtDNA by haplotype analysis from plasma. This technique can have clinical application to identify donor mtDNA in plasma and to identify targets of mtDNA therapies.

Funding: This project was funded by MitoCanada and the Alberta Children’s Hospital Research Institute. Christopher Newell was also funded by a MitoCanada PhD Scholarship.

Back To Top


Saturday May 21, 1215-1230

Comparison of high resolution respirometry and UV-Vis spectrometry for clinical mitochondrial testing – a pilot study

Lauren MacNeila, Murray Pottera, Mark Tarnopolskya.

aMcMaster University.

Mitochondrial disease is predominantly an inherited condition resulting from mutations to either nuclear or mitochondrial DNA. Enzymology by UV-Vis spectrometry (UVS) measures the functional capacity of individual and paired electron transport chain complexes, often assisting in an accurate diagnosis. In vivo high resolution respirometry (HRR) is considered the gold standard of mitochondrial function testing, however degradation induced variability have prevented its use as a clinical diagnostic tool.

Objective: To compare UVS and HRR results from patients with possible mitochondrial disease.

Design & Methods: Skeletal muscle biopsies were collected from 30 patients (♀:15, ♂:15, ages: 4-73) with possible mitochondrial disease and assayed by UVS and HRR. Thresholds for abnormal activity were set at >30% or < 2 00% of reference values. Histological and/or genetic testing was completed on samples when clinically relevant.

Results: HRR and UVS results were in agreement for 10 patients determined free of mitochondrial disease. Results from 12 patients were normal by UVS but abnormal by HRR (low Complex I or II activity); 75% of whom were histologically identified with fibre atrophy or inflammation. The remaining patients (8) were abnormal by UVS and normal by HRR; 88% of whom were identified with either atrophic/necrotic fibres or genetic mutations.

Conclusion: Accurate diagnosis of mitochondrial disease is challenging and best accomplished using results from several testing methods. Although variability induced by organelle degradation remains a current limitation for its diagnostic utility, our data suggest that HRR may provide useful clinical information when performed immediately post-biopsy.

Keywords: skeletal muscle, mitochondrial respiration, spectroscopy

Funding: This research was funded in part by MitoCanada.

Back To Top


Saturday May 21, 1230-1245

Uncovering novel candidate genes in consanguineous families with pyridoxine-responsive epileptic encephalopathy

Hilal Al Shekailia, C. van Karnebeeka, K. Al Thihlib, R. Alic, C. Rossa, M. Tarailo-Graovaca, A. Matthewsa, M. Coulter-Makiea, X. Hana, M. Higginsona, L. Zhanga, J. M. Friedmana.

aChild & Family Research Institute, University of British Columbia, Vancouver BC, Canada.

bGenetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman.

cDepartment of Child Health, College of Medicine, Sultan Qaboos University, Muscat, Oman.

Background: Pyridoxine-responsive epileptic encephalopathies (PREE) represent a clinically and genetically heterogeneous group of rare, autosomal recessive disorders1,2. They are characterized by recurrent seizures in the prenatal, neonatal, or postnatal period, which are typically resistant to conventional anticonvulsant treatment but show remarkable response to the administration of pyridoxine (vitamin B6)1,3,4,5. One such example of these disorders is pyridoxine-dependent epilepsy (PDE), a neonatal seizure disorder with reported incidence rates that range from 1:750,000 to as high as 1:20,0006. In most affected infants, PDE is caused by mutations in the antiquitin gene (ALDH7A1)7 and subsequent inactivation of α-aminoadipic semialdehyde dehydrogenase (antiquitin, ATQ), an enzyme that functions within the cerebral lysine catabolism pathway, leading to accumulation of α-aminoadipic semialdehyde (α-AASA)8. Although ALDH7A1 is the only gene for which mutations are known to cause PDE, locus heterogeneity has been demonstrated, other genes appear to be responsible in some families9. About 5% of infants with clinically typical PDE have no detectable mutation of ALDH7A110.

Objectives: This study was carried out to characterize the genetic defect underlying PREE in five consanguineous Omani Arab families with total of six affected children who have PDE-like clinical picture but negative ATQ biomarkers and/or negative ATQ sequencing.

Materials & Methods: Whole-genome SNP genotyping was performed using Illumina HumanOmni5-Quad/MEGA array chip. Based on the obtained high density SNP dataset, genome-wide runs of homozygosity (RoH) mapping was carried out using SNP & Variation Suite (SVS) software (Golden Helix). Whole-exome sequencing (WES) was carried out on the affected children and parents by Perkin-Elmer (Waltham, Massachusetts).

Results: After analysis of WES and RoH results, the following genes were flagged as candidates in family 1. The first candidate gene belongs to the solute carrier (SLC) family of genes. Three members of the SLC super family have been already described as vitamin transporters. To date, no transporter for vitamin B6 has been identified in humans despite multiple experimental evidence indicating the existence of an efficient and specific carrier-mediated mechanism of vitamin B6 uptake by human cells11,12,13. The second gene encodes a peptidase enzyme which is highly expressed in distinct regions within the brain. This enzyme was described to cleave a neuropeptide that is hypothesized to function as a neurotransmitter14. WES results in other families are under processing.

Acknowledgement: This study is sponsored by the OMICS2TREATID project and by a research grant from the Rare Disease Foundation, BC Children’s Hospital Foundation.


1Baumgartner-Sigl, S., et al. 2007. Bone. 40: 1655–1661.

2Basura, G., et al. 2009. European Journal of Pediatrics. 168: 697–704.

3Striano, P., et al. 2009. Epilepsia. 50: 933–936.

4Mills, P., et al. 2005. Human Molecular Genetics. 14: 1077-1086.

5Walker, V., et al. 2000. 82: 236-237.

6Stockler et al. 2011. Mol Genet Metab. 104: 48-60.

7Mills, P., et al. 2006. Nature Medicine. 18: 307-309.

8Sadilkova, K., et al. 2009. J Neuroscience Methods. 184: 136–141.

9Bennett, C., et al. 2005. Neurogenetics. 6: 143–149.

10Gospe, S. 2012. In: Pagon, R., M. Adam, T. Bird, et al. [eds]. GeneReviews [e-book]. Available through:

11Said, H., et al. 2003. Am J Physiol Cell Physiol. 285: C1219–C1225.

12Said, Z., et al. 2008. Am J Physiol Cell Physiol. 294: C1192–C1197.

13Said, H., et al. 2002. Am J Physiol Renal Physiol. 282: F465–F471

14Gene Entrez database at the National Center for Biotechnology Information, available through:

Back To Top




Oral presentations will be 10 minutes long plus 5 minutes for Q&A. We advise you to keep the Introduction part of your presentation succinct – please realize that the Garrod Symposium audience is well-versed in inherited metabolic diseases and genetics.


A computer and full powerpoint set-up will be provided. Presenters must bring their presentation file on a USB stick. Details on the time and place to meet to load your presentation will be provided to you when you register at the conference. Please advise whether you will be using PowerPoint or Keynote, and whether audio is required.


If you submitted an abstract and have not yet received your acceptance notice please contact the office at

Back To Top