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The Genetics of Alternating Hemiplegia of Childhood A long and winding road Matthew T. Sweney, MD MS Clinical Instructor, University of Utah AHC Family Meeting 7/22/11 Overview Introduction to AHC Significant Familial cases Early investigation Comparative Genomic Hybridization Whole Genome Sequencing Introduction Initial Characterization Verret & Steele 1971 8 cases linked by hemiparesis and headache Migraine variant Disease evolution Estimated 1-2 affected children per 1 million Eye movements, focal dystonia Hemiparesis/plegia, ataxia Developmental impact Diagnostic Criteria 1. 2. 3. 4. 5. 6. Onset of symptoms prior to 18 months of age Repeated attacks of hemiplegia involving either side of the body Other paroxysmal disturbances, including tonic or dystonic spells, oculomotor abnormalities and autonomic phenomena, during hemiplegic bouts or in isolation Episodes of bilateral hemiplegia or quadriplegia as generalization of a hemiplegic episode or bilateral from the beginning Immediate disappearance of symptoms upon sleeping, which later may resume after waking Evidence of developmental delay and neurologic abnormalities including choreoathetosis, dystonia, or ataxia Introduction Diagnostic challenge Relationship to known paroxysmal diseases Familial Hemiplegic Migraine Episodic Ataxias Periodic Paralysis Relationship to epilepsy Typical events not epileptic Suspected epileptic events in ~50% of cases As yet unknown pathophysiology Suspected channelopathy University of Utah AHC database Affected individuals referred by Physicians, Family Support Organizations Clinical data and DNA/cell line collection via IRB approved protocol since 1999 Contact with patients by phone/written communication/in-person at regional meetings University of Utah AHC database Pediatrics, March 2009 172 patients consented to enrollment 103 patients met diagnostic criteria Largest database of AHC patients in the world Familial cases 5 kindreds with multiple children affected Others reported, however inadequate medical records or no blood specimen available Familial Cases Translocation T(3;9)(p14.3;q34.3) BAC 370G13 Contig human tear prealbumin cos3-T7 5.9 kb AA683210 hNT neuron R52874 KIAA0649 F11681 U46429 (brain) (infant brain) cpG island BAC-T7 BAC-sp6 cos3-T7 24 kb 22.4 kb KIAA0649 cos27-T3 8.4 kb cos3-T3 cos55-T7 LCN1c Total length largest contig 83 kb cos55 37 kb 26.5 kb fragment with germ cell cDNA AI662518 AA778411 (fetal heart) cos55-T3 Odorant binding protein Candidate Genes Translocation breakpoint MRPS2, mitochondrial ribosomal protein KIAA1422 (KCNT1), calcium activated K+ channel, near translocation breakpoint 9q KIAA0649--Function unknown Looks promising, right?… Unaffected Carriers Gene Candidates CACNA1A, Calcium channel associated with FHM, 19p13.2--bridge phenotypes? ATP1A2, Positive lod score and shared haplotype for K7940; mutations in two families associated with FHM2 phenotype SCN1A, mutations found in 3 families with familial hemiplegic migraine (FHM3) SLC1A3-EAAT1, Glutamate transporter. Joana Jen identified a point mutation in one sporadic affected individual. More Genes CACNA1D, Brain expressed calcium channel, near translocation breakpoint 3p SLC6A11, Distal 3p near breakpoint ATP2B2, Near breakpoint in K4323 CACNA1I, Calcium channel, Positive lod in K4323 In all, from 1999 to 2008, 25 candidate genes screened Comparative Genomic Hybridization AKA Microarray Analysis Assesses copy number changes in DNA content Uses 244,000 known probes Covers genes and noncoding regions CGH 10 subjects in small pilot trial All met classic criteria Numerous single-probe copy number variations shared across all 10 No contiguous probe deletion or duplication shared by all subjects No clear answers revealed Current work AHC: Pepsi Refresh Grant $250,000 grant awarded for the purposes of identifying the genetic cause of AHC 23 samples sent for whole genome sequencing Sent via ISB to Complete Genomics, Inc Provides sequenced data and variant reports Preliminary data in August, 2011, complete analysis may take additional 6-12 months Why is this important? Sequencing represents the standard by which other modes are judged Finally the cost of sequencing is practical The service we use provide both genetic sequencing as well as preliminary statistical analysis Data will hopefully serve as foundation for therapy or cure Where do we go from here? Wait for sequencing to be completed Statistical analysis of the sequencing Identify if it is one gene or combination of genes Identify the function of those gene(s) and model them Once the function is delineated, identify ways to modify/improve it Conclusions Complicated, rare disease Highlights the rationally haphazard approach in a gene hunt Exemplifies the challenges present with under-recognized disease, underfunded research, understaffed workforce Presents great opportunity to make an impact Acknowledgments Kathryn J. Swoboda, MD Pediatric Motor Disorders Group: Sandy Reyna, MD, Aga Lewelt, MD, Abby Smart, RN Fran Filloux, MD, Stefan Pulst, MD, Art Brothman, PhD Alternating Hemiplegia of Childhood Foundation