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Cracking the code
Cracking the code Cracking the code Houston, we have a problem. - - PowerPoint PPT Presentation
Cracking the code Cracking the code Houston, we have a problem. - - PowerPoint PPT Presentation
Cracking the code Cracking the code Houston, we have a problem. Consanguineous Marriage Tay Brain T2-Hyperintensity Sachs Stem Pelizaeus- B12 Metabolism U-Fibres Merzbacher Hypomyelination T1-Hypointensity CSF Salla LEUKODYSTROPHY
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Cracking the code
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Houston, we have a problem.
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Strange Diet MRI B12 Metabolism Consanguineous Marriage Myelin White Matter T1-Hypointensity T2-Hyperintensity High Signal
LEUKODYSTROPHY
U-Fibres Corpus Callosum Internal Capsule Brain Stem Cerebellum Contrast Differential Diagnosis Pelizaeus- Merzbacher Salla Disease CSF Hypomyelination Hypomyelination Tay Sachs Fucosidosis Gangliosidosis Atrophy Basal Ganglia
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Leukodystrophy comes from the Greek roots leuko (white), dys (lack of) and troph (growth).
SLIDE 17 Signals are unable to travel down this broken pathway
SLIDE 18 electron micrograph
- f myelinated axons
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How Does Leukodystrophy Occur ?
Leukodystrophies are genetic disorders.
autosomal recessive x-linked
25% Autosomal recessive disorders affect both boys and girls and require both parents to be carriers (heterozygotes). Carriers themselves have no disability, however on average there is a 25% chance of their children having the illness and a 50% chance of their children being a carriers. 50% X-linked disorders are carried on the X chromosome, with only the mother being the carrier. Carriers themselves have no disability, however on average 50% of the daughters of a woman who is a carrier will also be carriers and 50% of the sons- f a woman who is a carrier will have the disorder.
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MRI / Genetics Diagnosis
An MRI-based approach to the diagnosis of white matter disorders. Raphael Schiffmann and Marjo S. van der Knaap Professor Marjo van der Knaap Paediatric Neurologist VU Medisch Centrum Amsterdam Netherlands Dr Richard Leventer Paediatric Neurologist Royal Children’s Hospital Melbourne Australia SLIDE 22
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44 times around the Earth
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4.6 times from the Earth to the Moon
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MRI / Genetics Diagnosis
306 Days
An MRI-based approach to the diagnosis of white matter disorders. Raphael Schiffmann and Marjo S. van der Knaap Professor Marjo van der Knaap Paediatric Neurologist VU Medisch Centrum Amsterdam Netherlands Dr Richard Leventer Paediatric Neurologist Royal Children’s Hospital Melbourne Australia SLIDE 28
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Massimo | Whole Genome
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MRI / Genetics Diagnosis
472 Days
An MRI-based approach to the diagnosis of white matter disorders. Raphael Schiffmann and Marjo S. van der Knaap SLIDE 32
Undiagnosed vs. Unclassified
The Burden of Inherited Leukodystrophies in Children Neurology 75 | 24th August 2010Although children can be diagnosed with a Leukodystrophy based on imaging alone >50% of variants of this debilitating condition remain genetically unclassified offering little hope of treatment, an unknown future and an almost certain tragic outcome
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11,481 Single Nucleotide Variations 175 Insertions 206 Deletions 7,814 Heterozygous 4,084 Homozygous 5,726 Genes
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Familial Trio Genome Analysis
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SLIDE 39 Dr Leah Kaminsky Medical Director Elwood Family Clinic Melbourne Australia
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Familial Trio Genome Analysis
Step 1 Step 2 Step 3 Step 4 B SIFT C Mutation Taser A PolyPhen Candidate Genes Mapping, mate joining and alignment Filtering (sort, duplicate removal, merge and index) Realignment and Quality Score Assessment (GATK) Identification of potentially damaging SNPs Prediction of pathogenicity Dr Ryan Taft Senior Research Fellow University of Queensland Brisbane Australia SLIDE 42
Familial Trio Genome Analysis
Filter out variants common to Massimo and either Mum or Dad (non pathogenic) Screen for compound heterozygotes (predictive pathogenic combinations)
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Familial Trio Genome Analysis : DARS
Inheritance Rationale Variant Position Massimo P M Compound Heterozygous DARS:NM_001349:exon11:c.G1099T:p.D367Y DARS:NM_001349:exon10:c.C821T:p.A274V chr2:136673803 chr2:136678161 Dad P Heterozygous DARS:NM_001349:exon11:c.G1099T:p.D367Y chr2:136673803 Mum M Heterozygous DARS:NM_001349:exon10:c.C821T:p.A274V chr2:136678161 SLIDE 44
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Validation | Candidate Gene
How do we prove DARS variants are causal?
- Option 1 - Knock In / Knock Out Mouse Model
- incredibly costly
$250,000
- time-consuming
3 years
- uncertain result
it’s still a mouse
- Option 2 - Find a cohort of patients with the same presentation (phenotype)
- variants in the same gene and / or pathway
- easier said than done
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Validation | Patient Cohort
MDBP is an established bioregistry of almost 700 registered patients All have detailed clinical information - MRIs and genetic material available Most have genetic material available from both biological parents Collaborating clinicians identified several “Massimo Like” patients Four families with one affected child One family with two affected children
Dr Adeline Vanderver Paediatric Neurologist Childrens National Medical Centre Washington DC United States Professor Marjo van der Knaap Paediatric Neurologist VU Medisch Centrum Amsterdam Netherlands Dr Nicole Wolf Paediatric Neurologist VU Medisch Centrum Amsterdam Netherlands Dr Richard Leventer Paediatric Neurologist Royal Children’s Hospital Melbourne Australia SLIDE 48
“After 1,161 days we achieved a confirmed diagnosis for Massimo and in the process discovered a new disorder. Both children in a family of five from the United States were confirmed as having the same genetic variations, as were several from Europe, and potentially many, many more from across the world. What was more exciting than achieving the diagnosis itself was discovering some
- f these children are in their teens and stable. Massimo is no longer alone and now we have hope.”
MISSION ACCOMPLISHED
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Affected and carrying compound heterozygous mutations in DARS Unaffected and not carrying a compound heterozygous mutation in DARS
The McLaughlin Family
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In addition to Massimo, 9 more children were identified with mutations in the DARS gene. This validated the diagnosis and identified a disease entirely new to medicine called Hypomyelination of the Brain stem and Spinal cord leading to Leg spasticity (HBSL). The research team was published in the American Journal of Human Genetics Volume 92 / Number 5 / 2nd May 2013.
From One Child to a New Disease
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Massimo effect
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The Foundation
Promote the prevention, diagnosis and treatment of childhood leukodystrophies. Accelerate the discovery of novel genetic variations responsible for childhood leukodystrophies and to translate these findings into clinical trials and treatments.
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Making Science Fiction, Science Fact
When a disease is perceived as rare the level of attention and funding it receives is almost non-existent. However, childhood Leukodystrophies, whilst individually rare, appear to be not altogether uncommon. In fact these conditions may affect up to 1 in 3,000 births, a prevalence not dissimilar to Cystic Fibrosis, yet their existence remains almost unknown.
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Making Science Fiction, Science Fact
If we can reduce the number undiagnosed cases to less than 10% within five years and show that a common delivery platform, known as a vector, can treat multiple disorders the game suddenly changes and will drive public and private investment into research.
SLIDE 58 missionmassimo.com
JOIN OUR MISSION
TO END CHILDHOOD LEUKODYSTROPHIES and win a trip into space SLIDE 59
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Scientific crew
Brainy bunch
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