1 http://www.med.wayne.edu/neurology/clin_programs/Labs/PMD/PMD_brochure.

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About PMD
Clinical features of PMD Pelizaeus-Merzbacher disease (PMD), named after two German physicians who first described its most important clinical features, is a rare condition caused by mutations affecting the gene for proteolipid protein 1 (PLP1, formerly called PLP) !he PLP1 gene lies on the " chromosome so that most affected indi#iduals are males who inherit the mutant or abnormal gene from their mothers $arely, females can ha#e symptoms %linically, Pelizaeus-Merzbacher disease usually begins during infancy and signs of the disease may be present at birth or in the first few wee&s of life !he first recognizable sign is a form of in#oluntary mo#ement of the eyes called nystagmus !he eye mo#ements can be circular, as if the child is loo&ing around the edge of a large circle, or horizontal to-and-fro mo#ements !he nystagmus tends to impro#e with age 'ome infants ha#e stridor (labored and noisy breathing) (nfants may show hypotonia (lac& of muscle tone) floppiness) at first, but most e#entually, o#er se#eral years, de#elop spasticity (a type of increased muscle tone or stiffness of the muscles and *oints) Motor and intellectual milestones are delayed, howe#er the intellectual delay is often more apparent than real, if care and time are ta&en to e#aluate the children Most PMD indi#iduals learn to understand speech, but #erbal output can #ary from normal speech to almost complete mutism +ead and trun& control may be a problem and wa#ering or tremor of the upper body (titubation)when sitting is common !rouble with coordination (ataxia) is also common, and de,terity of the arms and fingers is usually reduced -ision is usually reduced to some degree, probably from the effects of the myelin abnormality, but also from the nystagmus as well .lthough the following terms are somewhat artificial, they are used in many te,tboo&s and medical reports Connatal PMD refers to the most se#ere form of the disease, with neurological signs, such as nystagmus, stridor and hypotonia, being noticeable from birth to within the first few wee&s of life 'eizures may occur only in these children !hese children usually are unable to tal& or wal&, although they may comprehend /uite well !he Classical PMD syndrome is the most commonly seen form of the disease 0ystagmus usually begins in the first 1 months to 2 months Later, delay in the usual de#elopmental milestones, such as rolling o#er, sitting up, standing, wal&ing and speech are seen Muscle tone may be hypotonic, although this is not as noticeable as in the connatal child Most of these children do learn to tal&, although they may ha#e slurred speech (dysarthria) 'ome of these children learn to wal& with assistance, such as wal&ers, but most are not able to -irtually all PMD patients ha#e ata,ia 3e now &now that some mutations of the PLP1 gene may result in a less se#ere syndrome, called spastic paraparesis (wea&ness and stiffness of the legs) or 'PG1, where the ma*or sign is gait difficulty due to wea&ness and spasticity of the legs 4ne family has been reported with a mutation that causes tremor and5or attention deficit disorder as the ma*or abnormalities Peripheral ner#e myelin is usually not affected, howe#er we ha#e disco#ered that in the rare families whose mutations pre#ent the synthesis of any PLP6 (the PLP6 null syndrome) ha#e a mild peripheral myelin disorder, but ha#e less se#ere o#erall neurologic difficulties !he clinical diagnosis generally includes the clinical findings listed abo#e along with a family history consistent with " chromosome transmission (that is, being passed down by mothers, and ne#er being passed from an affected father to his son) !he most useful screening test after the neurologic e,amination and family history, is a

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brain magnetic resonance imaging (M$() scan, which is a #ery sensiti#e test for leukodystrophies (diseases of the white matter), most reliable if it is done after one or two years of age (the times when the ma*or white matter pathways in the brain are de#eloping) 4ther tests to e,clude other leu&odystrophies such as the lysosomal storage diseases (such as metachromatic leu&odystrophy, 'alla disease and 7rabbe disease) and adrenoleu&odystrophy should also be done 8#o&ed potentials testing is also helpful and should show abnormal central conduction but normal or near normal peripheral conduction !he definiti#e test is demonstration of a pathologic mutation of the PLP gene PMD genetics !here are two ma*or aspects of the disease that are important to really understand it !he first is the genetics of PMD and the second relates to the effect of PLP1 mutations on the ner#ous system 9irst (:ll describe the genetics PMD occurs when there is a change (or mutation) in the body:s ;blueprint; material !hese blueprint materials, called genes, control the way a body is made, what it loo&s li&e, and how it wor&s Most genes come in pairs 4ne gene of each pair comes from the mother:s egg and the other from the father:s sperm (n the tens of thousands of gene pairs, sometimes one will be changed !he mutation may be inherited or may happen by itself 'ometimes a mutated gene will not cause problems 4ther times a gene with a mutation will cause the body not to wor& correctly, and that a person will ha#e a genetic condition such as PMD Genes are carried on chromosomes Most indi#iduals ha#e <2 chromosomes in each cell in their body !he chromosomes come in 1= pairs with the first 11 pairs being identical in males and in females !he last pair is the se, chromosomes) females ha#e two " chromosomes, while males ha#e one " and one > chromosome !he chromosome can be thought of li&e a boo&case and the gene as a boo& located on the boo&case D0. (deo,yribonucleic acid) which is the basic component of the gene, is li&e the letters in the boo& Genetic information is stored, and passed down from generation to generation, in the form of the precise se/uence of D0. letters or bases 'ince the gene for PMD is located on the " chromosome, the disease typically affects only boys or men in a family !echnically, this is called " lin&ed inheritance $emember that females ha#e two " chromosomes while males ha#e one " and one > chromosome (f there is a gene on the " chromosome which is not wor&ing properly, males will be affected more often than females, since females li&ely ha#e a gene on the other " chromosome which does wor& properly and this usually compensates for the defecti#e " chromosome 9emales who carry the gene for PMD therefore typically are not affected since the PLP gene on the other " chromosome is normal Males with PMD are usually not able to ha#e children, so the disease when it occurs in se#eral generations is passed on by women who are carriers for the PMD mutation 3omen who carry the PMD gene ha#e a ?@A or 6 in 1 chance of passing it on to their sons and their daughters !hese odds are the same for e#ery pregnancy 3hat happened in one pregnancy does not in any way influence the odds for the ne,t pregnancy 'ons who inherit the gene would be affected, whereas daughters would be carriers (f a daughter did not inherit the PMD gene, then she would not pass PMD on to her children Some basic molecular biology Deo,yribonucleic acid (D0.), which carries the instructions that instruct cells to ma&e proteins, is made up of four chemical bases or letters, abbre#iated %, !, G, and . (for cytosine, thymidine, guanine and adenine) . D0. molecule is simply a long chain of these bases strung together !he information is the se/uence of bases !his is li&e all the information stored in a boo& in the order of specific letters of the alphabet, or the information on a computer dis& represented by a long string of

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zeroes and ones (n fact, each chromosome is basically a single molecule of D0. !he largest human chromosome (the first) has about 61@,@@@,@@@ bases

9igure 6 !ightly coiled strands of D0. are pac&aged in units called chromosomes, housed in the cell:s nucleus 3or&ing subunits of D0. are &nown as genes !he four types of bases are colored orange, pin&, blue and green here !his and other figures are from ;Bnderstanding Genetic testing; from the 0ational %ancer (nstituteC Bsed with permission of the 4ffice of %ancer Pre#ention, 0ational %ancer (nstitute . mutation (any alteration of the D0.) that affects only a single base (one letter) is called a point mutation 4ther types of mutations can occur as well, including insertions (additions of D0. into a gene), deletions (remo#al of part of a gene), and duplications where entire genes are present in one or more additional copies !he gene responsible for PMD is the proteolipid protein 6 gene (PLP1) and it is located on the " chromosome PLP1 duplication !he types of mutations that are &nown to cause PMD fall into two general categoriesC point mutations and duplications (n *ust the past few years it has been disco#ered that most PMD is caused by duplications (or rarely triplication or e#en /uintuplication) of the entire PLP1 gene !his seems to be the case for PMD families around the world and we still do not understand why it occurs !he duplications appear to account for about ?@ to as much as D? A of those families with PMD 3e currently belie#e that the duplication results in too much otherwise normal proteolipid protein being made 9urthermore, this e,cessi#e PLP6 is to,ic to the cells (called oligodendrocytes) trying to ma&e myelin !here can be /uite a lot of difference in the neurologic difficulties between families with duplications 4ne reason for this may be due to the differences in the size of the duplication in different families 3hile we belie#e that members of the same family will ha#e the same size duplication, there is &now to be a big difference in duplication size between different families !he smallest duplications &nown are around 6@@,@@@ D0. bases in length, but the biggest ones found so far are around ? million bases !he PLP1 gene is about =@,@@@ bases long 4ther factors that may e,plain the differences in families are what genes other than PLP1 are also duplicated, and whether some of these genes that come before or after PLP on the " chromosome are mutated by the duplication 9urther research will be needed to understand the #ariability between families (and e#en within families) affected by PMD PLP1 point mutations

Point mutations are usually mista&es in the gene where one of the bases or :letters: is replaced by the wrong one (technically called a base substitution) 9igure 1 below might help you understand this

9igure 1 9or a cell to ma&e protein, the information from a gene is copied, base by base, from D0. into new strands of messenger $0. (m$0.) !hen m$0. tra#els out of the nucleus into the cytoplasm, to cell organelles called ribosomes !here, m$0. directs the assembly of amino acids that fold into completed protein molecule Depending upon where the letter is and what it is replaced by, the mutation could result inC E 0o effect E 4ne amino acid in the protein encoded by the gene is replaced by the wrong amino acid (amino acid substitution) Depending on the place and nature of the amino acid substitution, these mutations can ha#e mild or se#ere effects PLP6 with *ust one wrong amino acid at a critical location is to,ic to myelin forming cells, *ust as is o#erabundance of normal PLP6 (and may e#en be more to,ic than o#erabundance) E !he protein is prematurely terminated (ends at the wrong place) E Disturbance in the regulation of the gene E Disturbance in splicing of the gene Mutations can also result in the gain or loss of more than one base (f this occurs in the region of the gene that codes for protein then this might not only result in the gain or loss of one or more amino acids in the protein, but also might cause the protein to be completely disturbed after the place the mutation occurs because the machinery that decodes the genetic information into protein (called ribosomes) gets out of register with the proper code and *ust ma&es scrambled protein after the mutation site 'ince there are only < letters in the genetic alphabet and they are read in words = letters long, there are 2< possible genetic words or codons possible 4f these 2< codon possibilities, 26 of them code for one of 1@ possible amino acids !he remaining = codons are called termination codons and tell the protein synthesis machinery to stop ma&ing protein 0otice that there are more codon possibilities

than there are amino acids 'ome amino acids ha#e more than one codon that can encode them, whereas others ha#e only one or two codon possibilities Proteins are simply chains of amino acids hoo&ed together li&e beads on a chain !o ma&e a simple analogy, ta&e the following simple sentenceC !he red fo, ran far and sat 0ow if one of the letters is mistyped, li&e what happens with a base substitution mutation, the meaning of the sentence changesC !he red so, ran far and sat !hese missense mutations may sometimes not be harmful or cause mild disease, but if they occur at an important location in the protein can be /uite harmful (f, as in the case of a base deletion, all the words get *umbled up after the mutation, because the protein synthesis machinery has to read the code three letters at a time (these are called frame shift mutations)C !he red o,r anf ara nds at !he se#erity of this type of mutation depends mostly upon where the mutation is located (f the frame shift occurs at the end of the gene, it may not cause se#ere problems, whereas a mutation near the beginning of the gene will typically ha#e se#ere conse/uences .lthough not strictly point mutations, the effects of mutations that delete or insert a small number (for e,ample two to a couple of dozen) of bases, are similar to what happens with single base mutations Many PLP1 mutations ha#e been identified Most of these point mutations are uni/ue to a specific family 'ince these are uni/ue mutations, it is not easy to predict for a PMD patient with one of these mutations what will happen o#er the course of his life, especially if there is no prior history of the disease in the family . ma*or goal of genetic research on PMD focuses on the clinical signs caused by specific mutations in PLP1 !his is called genotype-phenotype correlation 3e ha#e compiled a list of the mutations described in scientific *ournals and published it at this web siteC PLP6 mutation table !o ma&e matters e#en more complicated, we now &now that most genetic information coding for proteins is bro&en up into chun&s that are separated, sometimes by #ery large distances, from each other !hese chun&s are called e,ons, and the D0. segments that separate the e,ons are called introns !he genetic information in the nucleus of a cell is first transcribed to molecules of ribonucleic acid ($0.), then the introns are remo#ed from the $0. to generate the messenger $0. (m$0.) molecules that ha#e all the protein coding information nicely spliced together !he m$0. then lea#es the nucleus to ser#e as the blueprint for the protein synthesis machinery in the cytoplasm (the rest of the cell that surrounds the nucleus) of the cell

9igure = 3hen a gene contains a point mutation (shown as a red star), the protein encoded by that gene will be abnormal 'ome protein changes are insignificant, others are disabling 3e &now that the PLP1 gene is bro&en up into D e,ons, and it turns out that one of the e,ons (the third one) sometimes is partially spliced out, resulting in a protein that loo&s li&e PLP, but is missing =? amino acids in the middle of the protein !he smaller protein is called DM1@ !here are some PMD causing mutations that affect how the PLP6 m$0. is spliced together

9igure < 'plicing of the PLP1 gene !he gene has se#en e,ons that are brought together in the m$0. molecule 8,on = can be spliced in two ways !he area shaded in blue is missing from DM1@ 'ome mutations can affect how the m$0. is spliced 3e also &now that in addition to the regions that code for protein, there are regions of genes that regulate their e,pression (n order for the right proteins to be made in the right organs and in the right amounts, there are many processes that ha#e to be regulated #ery precisely 4ne important type of regulation occurs in the nucleus,

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which has to decide which genes to turn on and which to turn off, and by how much 'ome D0. se/uences that lie near but usually outside of the protein coding regions function to regulate gene e,pression or transcription into $0. Mutations that change these regulatory se/uences can ha#e drastic affects on the gene, and might result in the protein being made in too high or too low an amount, or to be made in the wrong organ or at the wrong time of life PLP1 and myelin PMD is one of the leu&odystrophies, disorders that affect the formation of the myelin sheath, the fat and protein co#ering--which acts as an insulator--on neural fibers (a,ons) in the central ner#ous system or %0', which is the brain and spinal cord .bout D? A of myelin is made up of fats and cholesterol and the remaining 1? A is protein PLP6 constitutes about half of the protein of myelin and is its most abundant constituent other than the fatty lipids 0ew e,periments indicate that about half or more of affected indi#iduals ha#e a duplication of an otherwise normal PLP6 gene !hus, it appears that the presence of too much PLP6 in oligodendrocytes, the cells that ma&e myelin in the central ner#ous system, is harmful !he point and other small mutations usually cause the substitution of one of the amino acids for another somewhere in the protein or pre#ent PLP6 from reaching its full length !his probably results in the protein being unable to fold into the correct shape or to interact with other myelin constituents !hese mutant proteins are to,ic to oligodendrocytes and pre#ent them from ma&ing normal myelin

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9igure ? !his figure shows what the myelin made by a single myelin forming cell (called an oligodendrocyte) loo&s li&e !he myelin is shown in cross section, 9rom the side it would loo& more li&e a rolled up carpet around each a,on (picture in the upper right corner) . single oligodendrocyte can myelinate many different ner#e fibers (also called a,ons) PLP6 may act li&e a glue to &eep the ad*acent layers of cell membrane tightly stuc& together !he bottom figure shows that PLP6 crosses through the membrane (the double layer made up of fat molecules, shown as the gray balls with zig-zag tails) < times Treatment Bnfortunately, there is currently no cure for Pelizaeus-Merzbacher disease, nor is there a standard course of treatment Gene therapy and cell transplantation are being e,plored as possible therapies 9or now, howe#er, treatment is symptomatic and supporti#e, and may include medication for seizures and the stiffness or spasticity that most PMD patients ha#e Physical therapy can be helpful in maintaining strength and *oint fle,ibility, and occupational therapy is helpful in ma,imizing the abilities of a PMD patient Fraces or wal&ers may enable a child to wal& (f speech or swallowing is impaired, a speech5swallowing therapist should be able to pro#ide important guidelines to ma&e speech more understandable and to pre#ent cho&ing 4rthopedic surgery may help reduce contractures, or loc&ed *oints, that can result from spasticity . physical medicine specialist (also &nown as physiatrist or rehab doctor) may be the most effecti#e physician in e#aluating a child:s needs and coordinating all the different therapists . de#elopmental pediatrician should also e#aluate each child to assess his abilities and help to design an educational curriculum to ma,imize his learning and potential (t is important in these de#elopmental assessments to factor in the longer time it ta&es a PMD child to process information, and also to factor in the motor limitations most &ids with PMD ha#e Periodic de#elopmental assessments should be done to monitor each child:s progress enetic counseling 4nce a PLP1 gene mutation is identified in a family, it is possible to test family members for the mutation and to pro#ide prenatal diagnosis for parents who ha#e a ris& of transmitting this disorder 'uch testing, especially for a couple planning a family, or for a woman who wants to &now whether she is a carrier, should be done under the guidance of a medical geneticist and5or genetic counselor %arrier testing is usually deferred until the female is 6G years of age (t is now possible to do preimplantation genetic testing (PGD) for PMD, but this is often not co#ered by health insurance Prognosis !he prognosis for those with Pelizaeus-Merzbacher disease #aries 'ome mutations are more se#ere than others and may result in death during childhood, but most li#e into adulthood 'ur#i#al into the si,ties has been seen !he course of the disorder is usually #ery slow, with some indi#iduals reaching a plateau and remaining stable for years +owe#er, some do worsen o#er time, for reasons that we do not understand, and will need further research !esearch . international group of clinicians and researchers wor&ing on PelizaeusMerzbacher disease and proteolipid protein has been organized to promote research to facilitate understanding of disease pathogenesis and de#elopment of

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specific treatments and, we hope, a cure (n 0orth .merica, please contact Hames Garbern for more information !hese articles, a#ailable from a medical library, are sources of in-depth information on Pelizaeus-Merzbacher diseaseC Foulloche, H and .icardi, H Pelizaeus-Merzbacher diseaseC clinical and nosological study Hournal of %hild 0eurology 6C1==-I (6IG2) J.bstractK %aillou,, 9 et al Genotype phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations 8uropean Hournal of +uman Genetics GCG=D-G<? (1@@@) J.bstractK %ambi, 9 et al $efined genetic mapping and proteolipid protein mutation analysis in "-lin&ed pure hereditary spastic paraplegia 0eurology <2C6661-D (6II2) J.bstractK #an der 7naap, M and 9al&, H !he reflection of histology in M$ imaging of Pelizaeus-Merzbacher disease .H0$ .m H 0euroradiol 6@(6)CII-6@= (6IGI) J.bstractK Garbern, H PLP6-related disorders, Genere#iews (1@@<) Garbern, H Pelizaeus-Merzbacher disease, eMedicine (1@@?) Garbern, H , %ambi, 9 , 'hy, M and 7amholz, H !he Molecular Pathogenesis of Pelizaeus-Merzbacher disease .rchi#es of 0eurology ?2C616@-616<, (6III) J.bstractK Garbern, H , %ambi, 9 et al Proteolipid protein is necessary in peripheral as well as central myelin 0euron 6IC1@?-16G (6IID) J.bstractK JpdfK Gencic ', .buelo D, .mbler M, +udson LD Pelizaeus-Merzbacher diseaseC an "lin&ed neurologic disorder of myelin metabolism with a no#el mutation in the gene encoding proteolipid protein .m H +um Genet 6IGI 'ep)<?(=)C<=?-<1 (6IGI) J.bstractK Gow, . and Lazzarini, $ . cellular mechanism go#erning the se#erity of Pelizaeus-Merzbacher disease 0ature Genetics 6=C<11-<1G (6II2) J.bstractK +udson LD, Puc&ett %, Ferndt H, %han H, Gencic ' Mutation of the proteolipid protein gene PLP in a human " chromosome-lin&ed myelin disorder Proc 0atl .cad 'ci B ' . G2CG61G-=6 (6IGI) J.bstractK JpdfK (noue, 7 et al . duplicated PLP gene causing Pelizaeus-Merzbacher disease detected by comparati#e multiple, P%$ .m H +um Genet ?IC=1-I (6II2) J.bstractK Mimault, % et al Proteolipoprotein gene analysis in G1 patients with sporadic Pelizaeus-Merzbacher diseaseC duplications, the ma*or cause of the disease, originate more fre/uently in male germ cells, but point mutations do not .merican Hournal of +uman Genetics 2?C=2@-=2I (6III) J.bstractK 'eitelberger, 9ranz, Brbanits, ' and 0a#e, 7 -. Pelizaeus-Merzbacher disease +andboo& of %linical 0eurology, #ol 11 (22) new series, + Moser, ed 8lse#ier 'cience, .msterdam, (6II2)

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!rofatter H., Dlouhy '$, DeMyer 3, %onneally PM, +odes M8 PelizaeusMerzbacher diseaseC tight lin&age to proteolipid protein gene e,on #ariant Proc 0atl .cad 'ci B ' . G2CI<1D-=@ (6IGI) J.bstractK JpdfK 3olf 0(, 'istermans 8., %undall M, +obson GM, Da#is-3illiams .P, Palmer $, 'tubbs P, Da#ies ', 8ndziniene M, 3u >, %hong 37, Malcolm ', 'urtees $, Garbern H>, 3oodward 7H !hree or more copies of the proteolipid protein gene PLP6 cause se#ere Pelizaeus-Merzbacher disease Frain 61GCD<=-?6 (1@@?) J.bstractK 3oodward, 7 and Malcolm, ' Proteolipid protein geneC Pelizaeus-Merzbacher disease in humans and neurodegeneration in mice !rends in Genetics, ?C<C61?61G (6III) J.bstractK >ool, D., 8dgar, HM, Montague, P and Malcolm, ' !he proteolipid protein gene and myelin disorders in man and animal models +uman Molecular Genetics ICIGD-II1 (1@@@) J.bstractK .dditional information is a#ailable from the following organizations and indi#idualsC Ms Patti Da#iau ?1? ' +arris (ndianapolis, (0 <2111 (=6D) 2=?-D=?I PDa#iauLclarian org Ms Laura 'pear 1 Hohn Hames .udobon Marlton, 0H @G@?= !he PMD 9oundation, (nc Marlton, 0H PMD 9oundation dhobsonLpmdfoundation org . German PMD 3eb site httpC55home t-online de5home5+ei&o$oem&e5#erein htm !he Myelin Pro*ect Myelin Pro*ect 8uropean Leu&odystrophy .ssociation 8L. 0at 4rg for $are Disorders (04$D) P 4 Fo, GI1= 0ew 9airfield, %! @2G61-6DG= (1@=) D<2-2?6G (G@@) III-22D= 04$D +unter:s +ope 9oundation P4 Fo, 2<= 4rchard Par&, 0> 6<61D

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!oll 9reeC 6-GDD-IG<-+4P8 (D62) 22D-6161 huntersLhuntershope org +unter:s +ope .ssociation for 0euro-Metabolic Disorders c5o ?11= Froo&field Lane 'yl#ania, 4+ <=?2@ (<6I) GG?-6<ID Bnited Leu&odystrophy 9oundation 1=@< +ighland Dri#e 'ycamore, (L 2@6DG (G6?) GI?-=166 (G@@) D1G-?<G= BL9 0at !ay-'achs M .llied Diseases .ssoc 1@@6 Feacon 't , 'te 1@< Froo&line, M. @16<2 (26D) 1DD-<<2= (G@@) I@2-GD1= !ay-'achs .lliance -ery technical information on PMD and 'PG1 can be found at the 4nline Mendelian (nheritance in Man !he 0ational +uman Genome $esearch (nstitute has a great deal of information on a wide #ariety of genetics topics that you might find useful !he Public Froadcasting 'ystem has a nice site that help e,plain geneticsC !he +uman Genome !he 0ational %enter for Fiotechnology (nformation has e,cellent online te,tboo&s Please email (at *garbernLmed wayne edu) if you or any of your family need additional information !he following clinicians and researchers are members of the PMD groupC Drs Hames Garbern *garbernLmed wayne edu Department of 0eurology and %enter for Molecular Medicine and Genetics 3ayne 'tate Bni#ersity 'chool of Medicine <16 8 %anfield $oom =16D Detroit, M( <G1@6 (=6=) ?DD-12<G Hohn 7amholz Michael 'hy .le, Gow Department of 0eurology and %enter for Molecular Medicine and Genetics

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3ayne 'tate Bni#ersity 'chool of Medicine Ms 7aren 7ra*ews&i, M', %G% &m&ra*ewLmed wayne edu <16 8 %anfield room =16D 3ayne 'tate Bni#ersity 'chool of Medicine Detroit, M( <G1@6 (=6=) ?DD-62GI Ms .ngela !repanier, M', %G% atrepaniLgenetics wayne edu %enter for Molecular Medicine and Genetics 3ayne 'tate Bni#ersity 'chool of Medicine Dr Grace +obson ghobsonLnemours org duPont (nstitute for %hildren 3ilmington, D8 Dr 9ranca %ambi Department of 0eurology Bni#ersity of 7entuc&y Le,ington, 7> Dr 7en (noue Department of Mental $etardation and Firth Defect $esearch 0ational (nstitute of 0euroscience 0ational %enter of 0eurology and Psychiatry (0%0P) !o&yo, Hapan Dr 4dile Foespflug-!anguy (0'8$M BM$ =G< 9acultN de MNdecine %lermont-9errand cede,, 9rance Dr Hutta GOrtner %linic of Pediatrics and Pediatric 0eurology Bni#ersity of GPttingen GPttingen, Germany Dr .lfried 7ohlschQtter Department of Pediatrics Bni#ersity +ospital 8ppendorf +amburg, Germany Last updated .pril G, 1@@? %omments appreciated Please email Hames Garbern

R 1@@? %opyright 3ayne 'tate Bni#ersity Foard of Go#ernors