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Genetic aspects of stuttering

Genetic aspects of stuttering. Dr Bert Bast ( ex-University Hospital Utrecht Nl), with Dr Dennis Drayna (NIH, Bethesda Md) and Dr Simon Fisher (Max Planck Inst ., Nijmegen Nl) . Own experience. PWS, persistent but can manage Pharmacist → Immunology → Genetics

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Genetic aspects of stuttering

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  1. Geneticaspects of stuttering Dr Bert Bast (ex-UniversityHospital Utrecht Nl), withDr Dennis Drayna (NIH, Bethesda Md) and Dr Simon Fisher (Max PlanckInst., Nijmegen Nl)

  2. Ownexperience • PWS, persistent butcan manage • Pharmacist → Immunology → Genetics • Head of LaboratoryUniversityHospital Utrecht Nl • Science • Health care • Quality system • Teaching • Organisation • Local, national, international

  3. FIRSTCONTRIBUTORS GENETICSEnvironment Speech Language Planning Production LATER CONTRIBUTORS Experience EXACERBATION Emotional Reactivity & Regulation OVERT BEHAVIOR Conture et al 2006 Instances of Stuttering

  4. Genes in Stuttering? • Known: it runs in families • Taken in the past as due to environment & education • Studies on mono/dizygotictwins and adoption: 45-84% inherited • How to find relevant genes? • Basicinformationexplained

  5. How to find relevant genes? • Genetictrait • Studies in families • Linkagechromosomal marker • Western families toosmall • Western society too diverse • Special families? • Consanguinous (inbred) forages in e.g. secludedvalleys

  6. Pakistani stuttering family PKST72 • ○: f; □: m; ∕: †; •▪: st • ==: consanguinous • Chromosomal markers ̴ stuttering • Cloningfragments • Sequencinggenes:

  7. Cells, chromosomes & genes • Body consists of cells • Eachcellcontains a nucleus • 46 chromosomes (human) • 2 m DNA in 10 μm nucleus (~ 20 km in tennis ball) • DNA: Nucleotides • Stretch N’s maybe a gene • 22.000 genes (human) • Duplicatedduringcelldivision • Sometimeserrors: mutation

  8. Severity of mutation • Most are repaired • Ifnot, lethal forcellitself • Or lethal beforebirth (abortus) • Or ̴ lethal duringchildhood • Orgivedisease in adults • Dependingonaffectedamino acid & mono vsdizygosity • Orpositive: evolution

  9. Mutatedgenes • Genesencode (via RNA) proteins (aminoacids) • Mutated gene maygiveaberrantprotein • Sometimesadvantage • In PKST72 mutations in gene calledGNPTAB • & otherenzymes (proteins) in lysosomalpathway • Cellclearance

  10. These mutations and stuttering • Action=reaction ̴ Newton? • Genesdon’tworkthatway • In PKST71 exeptions ↔ • Studies in USA & GB: • p=0.0004 significant not100%

  11. Significant, buthow? • FromPathology: in severemutationsenzymes ‘absent’: • Rare fatalchildhood disorder • Heremildmutations present • In laboratory studies mutant enzymes made & expressed: • Activitydecreased ̴ 50%

  12. Furthersignificance?? • These are commonenzymes • Howthenspecific effect? • More expressedlocally in brain • Little more known at present • Examplefuture studies • Martin Sommer & Gerry Maguire

  13. Where are we now? • HeredityStuttbeingfilled in • Known to existforyears • First geneselucidated • Found in different populationsworldwide • Statistically significant • Function ̴ stuttering studied • Accounts for ̴ 10% PWS • Othergenes?

  14. Stuttering loci and genes

  15. Somanygenesonedisease? • My own research in myeloma ( ̴ leukemia): • 7 firstlyimplicatedgenes; A 50 secondarygenes • Basedonthat: Diagnosis & therapy >>>> • E.g. in deafness 150 genes

  16. Working hypothesis • Specificbrainnervecells are unique to speech and uniquely sensitive to this mild metabolic deficit • Identify these cells, discover whatthey do, theirconnections and howthisinherited deficit affectsthem • It is not a black vs white pattern: learn to understand and utilize the plasticity of the (young) brain

  17. Implications • Society: stuttering is a medical issue, likemany • Parents: don’tfeelguilty, itisn’tyourfault • PWS: genes do notgive a doom, keep working • Scientists: diagnostic/prognosticsignificance? • SLP’s: therapeuticalsignificance? • Reinforce the medicalposition ̴physicaltherapist • Utilizeplasticity: earlyintervention (M-C Franken) • Understanding of pathophysiologywill help to improve diagnosis and treatment

  18. Acknowledgements • Dr Dennis Drayna NIH • Dr Simon Fisher MPI • 100’s of scientists • 1000’s of PWS • Millions of bucks • Insight and hope

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