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Friday, May 5, 1100-1130
- Second family with Mabry Syndrome caused by PIGL mutation
- A viable mouse model of severe mitochondrial disease: adipose-specific fumarate hydratase deficiency
Friday, May 5, 1600-1615
- Disorders of intracellular cobalamin metabolism: phenotype, genotype and long-term treatment outcome
Saturday, May 6, 0900-0915
Saturday, May 6, 1050-1105
- The application of a magnetic resonance imaging algorithm in the clinical diagnosis of white matter abnormalities
Friday, May 5, 1100-1115
Second family with Mabry Syndrome caused by PIGL mutation
Ruqaiah S Altassana, Chantal Poulinb, Daniela Buhasa,c,*
aDepartment of Medical Genetics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, Canada.
bDepartment of Pediatric Neurology, Montreal Children’s Hospital, McGill University Health Center, Montreal, Quebec, Canada.
cDepartment of Human Genetics, McGill University, Montreal, Quebec, Canada.
Objectives: To describe the second family with Mabry syndrome (Hyperphosphatasia mental retardation syndrome-HPRMS) caused by PIGL mutation.
Design and Methods: Clinical evaluation and molecular testing of two siblings presented to our institution with distinctive facial features, developmental delay, mental retardation, seizure disorder, skeletal deformities, and high alkaline phosphatase.
Results: Molecular testing for the index case showed two heterozygous mutations in PIGL gene (C.60G>A; p.TRP20*, and c.262C>T; p.ARG88Cys). Segregation analysis confirmed compound heterozygous inheritance of the two alleles. Same changes found in the other affected sibling.
To date, six mutations in PIGL gene have been identified in seven patients presenting with CHIME syndrome (coloboma, heart defect, early-onset ichthyosiform dermatosis, mental retardation and ear anomalies /hearing loss alternate with epilepsy) and only one patient with Mabry phenotype (Am J Med Genet A.2015Apr:167A(4):777-85).
In our patients, some of the clinical features overlap between CHIME and Mabry syndrome especially the CNS involvement; however, they do not have coloboma, heart defect or hearing impairment. The distinctive skeletal phenotype of short terminal phalanges and the high alkaline phosphatase diverged our diagnosis to Mabry syndrome.
Conclusions: Our clinical, biochemical and molecular findings support the previous report of Mabry syndrome caused by PIGL mutation, which is another PhosphatidylInositol Glycan (PIG) anchor biosynthesis class that should be considered in the differential diagnosis of the known PIG classes (PIGV, PIGO, and PIGW) and the Post GPI Attachment to Proteins genes (PGAP2, PGAP3) that are currently linked to Mabry syndrome.
Keywords: Hyperphosphatasia mental retardation syndrome (HPMRS), Mabry syndrome, PIGL gene, CHIME syndrome, autosomal recessive intellectual disability.
Friday, May 5, 1115-1130
A viable mouse model of severe mitochondrial disease: adipose-specific fumarate hydratase deficiency
Hao Yang1, Shupei Wang1, Pierre Allard1, Catherine Brunel-Guitton1, Saverio Cinti2, and Grant A. Mitchell1.
1Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine.
2Department of Experimental and Clinical Medicine, Center of Obesity, United Hospitals, University of Ancona, Ancona, Italy.
Objective: To obtain a viable animal model of severe mitochondrial disease (MD). The disease-causing potential of mutations in many mitochondrial proteins is unknown and poses a major challenge for interpreting genomic data. A corresponding animal model would be useful to understand the biological impact of mutations. We hypothesized that mice with severe mitochondrial disease only in fat tissues would be viable and would allow evaluation of tissues with high and low energy utilization: brown and white adipose tissues (BAT and WAT), respectively. We tested this with the Krebs cycle enzyme fumarate hydratase (FH). Systemic FH deficiency is clinically severe in humans and embryonically lethal in mice.
Method: We created adipose tissue-specific FH knockout (AFHKO) mice using adipocyte-specific Cre-mediated excision driven by the adiponectin promoter.
Results: AFHKO mice survived despite having severe mitochondrial dysfunction. ATP content was low: in BAT (3.5% of control content, p<0.001) and WAT (30.4%, p<0.01), with swollen mitochondria and disrupted cristae. Krebs cycle metabolite profiles were abnormal in AFHKO BAT and WAT, with low acetyl- and succinyl-CoA and high succinate and fumarate. AFHKO mice have distinct, easily-measurable phenotypes: cold-sensitivity, leanness, small white adipocytes (modal diameter, 5-mo-old AFHKO 50μm vs controls, 70µm). Brown AFHKO adipocytes were monovesicular and hypertrophic. AFHKO BAT mass was 1.4-fold higher than controls. 10-mo-old AFHKO mice were insulin sensitive and glucose tolerant.
Conclusion: AFHKO mice provide proof of principal that an adipose knockout can permit study of the biological effects of mutations and possibly treatment for a severe MD.
Keywords: mitochondrial disease, adipose tissue, animal model, FH deficiency
Friday, May 5, 1600-1615
Disorders of intracellular cobalamin metabolism: phenotype, genotype and long-term treatment outcome
Lizbeth Mellin-Sanchez1, Garrett Bullivant1, Vivian Cruz1, Julian Raiman2, Andreas Schulze1,3, Komudi Siriwardena4, Saadet Mercimek-Mahmutoglu1,3.
1Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto
2Birmingham’s Children Hospital, Birmingham, England
3Genetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, Canada
4Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
Objective: To determine the phenotype, genotype, and treatment outcome of all patients with disorders of intracellular cobalamin (cbl) metabolism and to compare the treatment outcome of patients diagnosed by newborn screening (NBS) and symptomatically, we performed a retrospective cohort study.
Background: Disorders of intracellular cobalamin (cbl) metabolism are the result of defects in the synthesis of metabolically active coenzymes including methylcobalamin and adenosylcobalamin from dietary cobalamin. These disorders are grouped into: A, B, C, D, D1, D2, E, F, G, J.
Methods: All patients were included. Electronic charts were reviewed. We compared treatment outcome of patients identified by NBS versus symptomatically.
Results: There were 33 patients: 26 cblC, 3 cblG, 2 cblE, one cblD1 and one cblB. Sixteen patients were identified by newborn screen. Twenty-five patients had developmental delay and 11 patients had seizures. Brain magnetic resonance imaging (MRI) revealed cerebral atrophy in 10 patients. Developmental delay was present in 69% of patients identified by NBS versus 82% of symptomatic patients. Seizures were present in 19% of the patients identified by NBS versus 47% of symptomatic patients. Cerebral atrophy in brain MRI was present in 6% of the patients identified by newborn screening versus 53% of symptomatic patients. All patients were treated with daily intramuscular hydroxcobalamin (dose 0.5-10mg) and/or betaine and/or l-carnitine.
Conclusion: We report 33 new patients with disorders of intracellular cbl metabolism s retrospective cohort study. cblC was the most common subtype. Patients identified by newborn screening and treatment started in the neonatal period appear to have better neurodevelopmental outcome.
Keywords: Cobalamin, New born screening, homocystinuria, methylmalonic aciduria
Saturday, May 6, 0900-0915
Expanding the phenotypic spectrum of POLR3-related leukodystrophy
Laurence Gauquelin MD1, Stefanie Perrier BSc1,2, Luan T. Tran MSc1,2, Kether Guerrero MSc1,2, Norberto Rodriguez Espinosa MD3, Ingrid Tejera Martin MD4, Nicole I. Wolf MD PhD5, Daniela Pohl MD PhD6, Savithri Nageswaran MBBS MPH7, Annette E. Grefe MD8, Genevieve Bernard MD MSc FRCPC1,2,9.
1Department of Neurology and Neurosurgery, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Canada.
2Child Health and Human Development Program, Research Institute of the McGill University Health Center, Montreal, Canada.
3Unidad de Neurologia de la Conducta y Memoria, Hospital Universitario Nuestra Sra De Candelaria, Santa Cruz de Tenerife, Canary Islands, Spain.
4Neurologia, Hospital Quironsalud Tenerife, Santa Cruz de Tenerife, Canary Islands, Spain.
5Department of Child Neurology, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.
6Department of Neurology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.
7Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
8Department of Neurology, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States of America.
9Department of Medical Genetics, Montreal Children’s Hospital, McGill University Health Center, Montreal, Canada.
Background: RNA polymerase III-related leukodystrophy (POLR3-HLD) is the second most common hypomyelinating leukodystrophy and is caused by recessive mutations in POLR3A, POLR3B and POLR1C.
Objective: To describe the extremes of the clinical and magnetic resonance imaging (MRI) phenotypic spectrum of POLR3-HLD.
Methods: A retrospective chart review of five mutations proven patients with very atypical phenotypes: 2 infants with very severe clinical features and 3 adults with an extremely mild phenotype.
Results: Patients 1 and 2 presented within the first months of life with failure to thrive and developmental delay and regression. They died before 18 months of age from respiratory failure. Their MRI did not reveal the typical characteristics of POLR3-HLD. Both patients had a combination of a pathogenic variant leading to a premature stop codon in POLR3A (patient 1 c.2119C>T, p.Q707* and patient 2 c.1681C>T, p.R561*), as well as an intronic variant leading to aberrant splicing: c.1771-7C>G. Patients 3 and 4 were adult siblings with severe myopia who were diagnosed with hypomyelination on MRI performed for an unrelated reason. Their MRI pattern was typical for POLR3-HLD but with more residual myelin than typically seen. Patient 5 is an adult with an extremely mild phenotype who was diagnosed in the context of affected offsprings. These three patients are homozygous for the common POLR3B mutation (c.1568T>A, p.Val523Glu).
Conclusions: These findings are a good illustration of the expansion of a known phenotype in the era of next generation sequencing. At both ends of the spectrum, genotype-phenotype correlation is present.
Keywords: POLR3-related leukodystrophy, 4H leukodystrophy, hypomyelination, magnetic resonance imaging (MRI).
Funding Acknowledgement: GB has received a Research Scholar Junior 1 award from the Fonds de Recherche du Québec en Santé (FRQS) 2012-2016 and a Canadian Institute of Health Research New Investigator salary award (2017-2022) (201512MSH-360766-171036). This work was supported by operating grants from Réseau de Médecine Génétique Appliquée of the FRQS. SP is supported by the Max Stern recruitment fellowship from McGill University.
Saturday, May 6, 1050-1105
The application of a magnetic resonance imaging algorithm in the clinical diagnosis of white matter abnormalities
Ravi Datar BMScg, Asuri N. Prasad MBBS MD FRCPC FRCPEc,d,f, Keng Y. Tay MBBS BSc FRCPRb, Charles A. Rupar PhD FCCMGa,d,e,f, Pavlo Ohorodnyk MDb, Michael Miller PhDd,f, Chitra Prasad MD FRCPC FCCMG FACMGd,f.
Departments of aBiochemistry, bMedical Imaging, cNeurology, dPaediatrics, ePathology and Laboratory Medicine, London Health Sciences Centre, London, ON
fChildren’s Health Research Institute, London, ON
gWestern University, London, ON
Background: White matter abnormalities (WMA) reported on cranial magnetic resonance imaging (MRI) often pose a diagnostic challenge when trying to establish an etiologic diagnosis. During childhood and adult years, genetic and metabolic disorders in addition to acquired conditions are included in differential diagnoses. To help clinicians and radiologists, a structured algorithmic has been recommended to aid in establishing working diagnoses that will facilitate appropriate biochemical and genetic investigations.
Objective: This retrospective pilot study investigated the validity and diagnostic utility of such an algorithm for patients seen in our clinics.
Methods: The MRI algorithm was applied to thirty-one patients selected at random from patients attending the neurogenetic and neurometabolic clinic at a tertiary care hospital. These patients varied in age from 5 months to 79 years old, and presented confirmed white matter signal abnormalities (WMSAs) on cranial MRIs. Twenty-one patients had a confirmed biochemical genetic diagnosis and 10 patients had confirmed non-specific WMA diagnoses (etiology unknown). Two radiologists, blinded to confirmed diagnoses, used patient MRI scans and clinical abstractions to classify possible WMA diagnoses through utilizing the algorithm.
Results: : The MRI algorithm displayed a sensitivity of 100%, a specificity of 30.0% and a positive predicted value of 74.5%. Cohen’s kappa statistic for inter-radiologist agreement was 0.733, suggesting “good” agreement between radiologists.
Conclusions: Although a high diagnostic utility was not observed, results suggest that this MRI algorithm has promise as a clinical tool for clinicians and radiologists. This study has identified various benefits and limitations of this approach for future directions.
Keywords: white matter abnormalities, myelination, magnetic resonance imaging, diagnostic utility, diagnostic neuroradiology
INFORMATION FOR PRESENTERS
Oral presentations will be 11 minutes long plus 4 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.
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