Dr Bert Bast (ex-University Hospital Utrecht Nl), with Dr Dennis Drayna (NIH, Bethesda Md) and Dr Simon Fisher (Max Planck Inst., Nijmegen Nl)

 PWS, persistent but can manage  Pharmacist → Immunology → Genetics  Head of Laboratory University Hospital Utrecht Nl ◦ Science ◦ Health care ◦ Quality system ◦ Teaching ◦ Organisation ◦ Local, national, international

FIRST CONTRIBUTORS LATER CONTRIBUTORS EXACERBATION OVERT BEHAVIOR Conture et al 2006 GENETICS Environment Speech Language Planning Production Experience Emotional Reactivity & Regulation Instances of Stuttering

 Known: it runs in families  Taken in the past as due to environment & education  Studies on mono/dizygotic twins and adoption: 45-84% inherited  How to find relevant genes?  Basic information explained

 Genetic trait  Studies in families  Linkage chromosomal marker  Western families too small  Western society too diverse  Special families?  Consanguinous (inbred) for ages in e.g. secluded valleys

 ○: f; □: m; ∕: †; ▪: st  ==: consanguinous  Chromosomal markers ̴ stuttering  Cloning fragments  Sequencing genes: Mutated gene Non PWSPWS

 Body consists of cells  Each cell contains a nucleus  46 chromosomes (human)  2 m DNA in 10 μm nucleus (~ 20 km in tennis ball)  DNA: Nucleotides  Stretch N’s may be a gene  genes (human)  Duplicated during cell division  Sometimes errors: mutation

 Most are repaired  If not, lethal for cell itself  Or lethal before birth (abortus)  Or ̴ lethal during childhood  Or give disease in adults  Depending on affected amino acid & mono vs dizygosity  Or positive: evolution

 Genes encode (via RNA) proteins (amino acids)  Mutated gene may give aberrant protein  Sometimes advantage  In PKST72 mutations in gene called GNPTAB  & other enzymes (proteins) in lysosomal pathway  Cell clearance

 Action=reaction ̴ Newton?  Genes don’t work that way  In PKST71 exeptions ↔  Studies in USA & GB:  p= significant not 100%

 From Pathology: in severe mutations enzymes ‘absent’:  Rare fatal childhood disorder  Here mild mutations present  In laboratory studies mutant enzymes made & expressed:  Activity decreased ̴ 50%

 These are common enzymes  How then specific effect?  More expressed locally in brain  Little more known at present  Example future studies  Martin Sommer & Gerry Maguire

 Heredity Stutt being filled in  Known to exist for years  First genes elucidated  Found in different populations worldwide  Statistically significant  Function ̴ stuttering studied  Accounts for ̴ 10% PWS  Other genes?

 My own research in myeloma ( ̴ leukemia):  7 firstly implicated genes; A 50 secondary genes  Based on that: Diagnosis & therapy >>>>  E.g. in deafness 150 genes

 Specific brain nerve cells are unique to speech and uniquely sensitive to this mild metabolic deficit  Identify these cells, discover what they do, their connections and how this inherited deficit affects them  It is not a black vs white pattern: learn to understand and utilize the plasticity of the (young) brain

 Society: stuttering is a medical issue, like many  Parents: don’t feel guilty, it isn’t your fault  PWS: genes do not give a doom, keep working  Scientists: diagnostic/prognostic significance?  SLP’s: therapeutical significance? ◦ Reinforce the medical position ̴physical therapist ◦ Utilize plasticity: early intervention (M-C Franken)  Understanding of pathophysiology will help to improve diagnosis and treatment

 Dr Dennis Drayna NIH  Dr Simon Fisher MPI  100’s of scientists  1000’s of PWS  Millions of bucks  Insight and hope