Januari 09, 2017
[yaffa rubinstein]good afternoon everybody. thank you for coming here, and so nice to see so many of you here.before helen introduces the speakers, i would like to make a few announcements. this eventhas been sponsored by the biospecimens interest group and is supported by the office of raredisease research and the office of biospecimens and biorepositories research at the nci. ifyou would like to get involved in this group, please contact us or log on to our web site.i would like to mention also that our next presentation will be in january, and we aresoliciting names for future speakers. so, if you have any suggestions, please let usknow. also, i would like to let you know that weare lucky to be the first one to be using
the new state-of-the-art equipment that wasinstalled in this auditorium. today we have the privilege and honor to havethree outstanding speakers presenting an extraordinary program on the undiagnosed disease program,which helen is going to introduce to you. [helen moore]all right, thanks -- i add my thanks to your coming today. and i just want to take a momentand thank yaffa for organizing this. i'm only an accessory here today. she has done allthe work to make this happen today. and so we're not going to read lengthy bios thisafternoon but just tell you that the speakers today are, first, steve groft, the directorof the office of rare diseases research at the nih, john gallin, director of the nihclinical center, and william gahl, clinical
director of the nhgri and director for theundiagnosed disease program. so, dr. groft will start us off. [stephen groft]thank you, helen and yaffa, for this opportunity to present the program that has started maybea little bit over a year ago. but before i begin, i do want to first thank the staffhere at the clinical center. i think maybe sometimes you don't hear the comments thatcome in from the people, especially in the rare diseases community, but i really cansay without any question that the first question i get when i go and meet with a patient advocacygroup and their scientific and medical advisors, is how do we get a study started at nih? howdo we get into the nih system? so i think
you can see the esteem that so many peoplein the rare disease community really hold for you and the program that you representand the research that you conduct here at the nih. and it really is a tremendous testimonyto the dedication to all the rare diseases that you have become known for. and we certainlyappreciate the efforts of so many of the individuals who have helped with the program as we'veinitiated here at the clinical center. and so i'll just really give you a littlebit of the background and then we'll turn it over to the more experienced cliniciansand activities that we've been involved with, but i do want to thank the biospecimens interestgroup that invited us and have participated in developing the whole program, so yaffaand helen, thank you again. it's a real privilege
and honor to express this program to the nihcommunity because it has been one of a tremendous amount of public interest, and i think billwill tell you the level of interest that we've faced and that they've faced within the programof screening patients and physicians who have patients who would like to come here. just some background information, first, asfar as getting the diagnosis or the diagnostic odyssey that we talk about, particularly forthe rare diseases where so many times the symptoms do not manifest themselves at onetime, they're going to carry over a number of years and maybe several decades 'till wereally get the full picture of a disease. but back in 1989, when there was a nationalcommission on orphan disease, and then this
study was replicated in 2002 by the nationalorganization for rare disorders. we did some patient surveys and you can see there thenumbers that we -- tying to diagnosis. and it's that greater than five years that hadus really concerned as far as taking that long to actually obtain a diagnosis. and ithink all of us can understand the frustrations and the anxieties that go with not havinga diagnosis, not knowing what we have, what are the outcomes that we can even think about.so, when you start applying this to a pretty large population, you see that there a goodnumber of people who spend many, many years trying to obtain the diagnosis. we have a -- what we call the genetic andrare disease information center that we co-sponsor,
our office, the office of rare diseases research,with the national human genome research institute. and after about 10,000 inquiries, we wentback over a three-year period, looking at the inquiries that we received at the informationcenter, and approximately six percent of the request for information related to undiagnoseddiseases. so you can see that it is a very, very large problem that we're looking at.it's just we don't hear about it very often. and in 2000, the nih and our office publisheda report of a special emphasis panel on the coordination of rare diseases research. andin that, we talked about forming specialized centers of research and diagnosis. unfortunately,when we were looking at this when we implemented our rare diseases clinical research network,we didn't focus on the diagnosis. we were
focused on research, natural history studies,training of the next generation of physicians and then the active role of patient advocacygroups as well as doing clinical trials of the rare diseases. so, we never really gotinto developing these specialized centers, and we thought what we'd like to do is everybodyget a little bit of experience here at the nih. and so what we're really working towards isa better characterization and establishing diagnostic criteria for the rare diseases.and one of the ways that we do it within our office, and we try to extend to this to allof the institutes, and many of the intramural research program and investigators here inthe clinical center have taken advantage of
the program to put together scientific conferenceson specific rare diseases or a group of rare disorders, so if you have an interest andyou haven't heard about our scientific conference program, please contact the office. just senda quick note, and we'll start talking to you about a conference and everything that youcan do and how it all works, so we're happy to help with this. we've seen in recent years this expansionin newborn screening programs here in the united states, and we think that this is goingto continue to grow. i believe there are about 29 disorders now that are screened in thestates here, here in the united states, and we think that number's going to grow. we alsohave -- our programs also focus on the development
of genetic diagnostic tests that should beaccompanied by appropriate counseling and information to go back to the patient andfamilies as well as to the practitioner. but we have a pilot project that actually we startedhere in the clinical center with bill gahl and other investigators, that we've triedto figure out a way to develop genetic tests and to move them out of the research laboratoryinto a clia-certified laboratory, so we've had a nice program, and again, we do makeresources available, so if you're in the gene discovery mode and you'd like to -- and youthink that there is some significance, clinical significance of what we're looking at as faras a diagnosis and other information that might be and should be made available to thepatients and the families, we'll help put
together a genetic test and develop the informationthat will accompany that test. so, again, please just contact the office and we'll worktogether on that. but what we're dealing with really is witha program such as this, there's a tremendous amount of interest in this program. i thinkwe're developing truly a global approach to rare diseases as more and more nations arecoming on board with a focus on rare diseases. for so many years, it seems like the unitedstates was the only country working in the rare disease area. then in 1999, the europeanunion passed their legislation, and so, we've had a tremendous amount of effort. there shouldbe a good number of collaborations with the european union investigators and individualcountries, so it's growing.
the program itself, we would like to see itgrow into more -- and maybe bill will talk about this, or john, about expanding intomore of the intramural research program. most of the patients are being seen by a smallnumber of investigators, but i think we'd like to see how this could be extended intoother protocols and new protocols and the clinics here at the clinical center. at somepoint, if additional resources were ever made available, and that's really money, we'd liketo expand this into the extramural research program and use the clinical center here asa hub of activities that we could, perhaps, extend this out to a lot of the extramuralresearch community. we have a very large clinical and translational science awards program,the old general clinical research centers,
that are very, very fertile ground for introducinga program like this. and our rare disease clinical research network is also anotherarea that we think we could extend this and expand the initiative, so it's something we'dlike to look at. again, as i mentioned, there's a tremendousinterest in the program throughout the world, and again, with -- when i do go and speakwith partners through the world, this is probably the number one area of interest. how is theundiagnosed diseases program? how is it working? is it really functioning? are you seeing patients,and what are the results? and so, the partnerships are available. i think it's just a matterof us figuring out some way how we can really link up with them. there's been some proposedlegislation that would develop a national
undiagnosed diseases registry, and that hassome complications where, you know, that's still in the hopper, but we're not sure whereit's going. but it is certainly an area of interest as we continue to watch it to seeexactly what they're going to ask us to produce. and throughout all of this, we have seen theincrease, as many of you probably have observed, the continued involvement of patient advocacygroups as research partners. and two new groups have started up. one is inod, in need of diagnosis.and the other is swan, the symptoms without a name. and again, as i mentioned, these arepeople who have lived for many years without a diagnosis, and the name to their disease,they know it's not -- most of them are not really good diseases. they're not doing well,but they've devoted their energy to try to
bring an emphasis to obtaining diagnosis fora lot more patients. so with that i will end, and i'm going toturn it over to dr. john gallin, who is a director of the clinical center. i'll seeif i can get the slides. we may need some help...finding john's slides. okay. are yougetting it from back there? here we go...okay, got it. thank you very much, and john, we'll turnit over to you and then to bill. [john i. gallin]okay, thank you very much. it's a pleasure to be here, and i want to thank first theoffice of rare diseases for sponsoring the whole program of the undiagnosed disease program,and specifically i want to thank the special
interest group for hosting this session today.i'm just going to spend a few minutes reminding you what kind of facility we have here andwhy this makes a special home, and then we'll turn it over to dr. gahl who's going to reallyprovide the excitement for today. so what is the vision of the clinical center?in case you don't know, it's very simple. as america's research hospital, we will leadthe global effort in training today's investigators in discovering tomorrow's cures. now, we spenta lot of time writing this sentence, believe it or not, and things like "america's" isa key word. and our hope is that as time evolves, the facility will transform from not onlya national hospital for patients, but also an institution that serves investigators bothhere at the clinical center and across the
nation more so than it has even in the past.and that particularly relates to the comments dr. groft just made. so we opened, you know, in 1953. and sincethen we've seen more than 350,000 patients, and about half of them have been patientswith rare diseases. our new hospital opened in 2005. currently we have 234 beds open.there are about 1,850 people who work for the clinical center, and i should add thatthere's about 4,000 people who work for the 17 different institutes that use the clinicalcenter, so in these walls, there's about 6,000 people working and my hope is that they allwork well together. my sense is that they do. of those people, there's about 1,220 credentialedphysicians, which is a rather remarkable number
for 234 beds. i don't think you'll find thatanywhere in the world. the engine that drives this place are theclinical protocols, and there are 1,450 active clinical protocols. and the budget for thisyear is $362.3 million dollars. so, our nurses say there's no other hospitallike it. so, what makes this place different? well, as you all know, every patient is enrolledon a protocol. care is free. our nurses are very highly educated. every one of them isa registered nurse. about 15 percent have a master's degree, and about five percenthave phds. the hospital is embedded in an environment with research labs surroundingit with some of the world's greatest investigators. our theme is often first in human and clinicaltrials. we can do long-term, high intellectual,
and economic risk studies. because we don'twrite grants, we can respond rapidly to public health emergencies as we have done in thepast, for example, in aids and the sars epidemic. and we have these unique cohorts of patientswith rare diseases. so, we've had a long tradition of studyingrare diseases and patients with unknown diagnosis. so what's new with this undiagnosed diseaseprogram? well, from my perspective, there are two major things that are new. first ofall, there's a call for undiagnosed diseases with no phenotype restrictions. so we're invitinganybody who has an unexplained problem to make an inquiry. second, is that, really forthe first time, at least since i've been here, a multidisciplinary approach is given to everypatient. and this is shown by this list of
consultants which you're not supposed to read,but be impressed by the number, so although dr. groft said it's relatively few peoplewho are involved in this program, i think it's a very large, robust group representingalmost all the different components of the nih. but indeed, it could be bigger, and wehope it gets bigger over time. so, what does the clinical center do? well,we have an office of patient recruitment and public liaison which triages patient calls.and since may of 2008, there's been about 1,700 inquiries, and every patient receivesa preliminary screening. all the clinical center departments are primed to be helpful,and i think most of them have been key collaborators, but particularly our general medicine andpediatrics consult services among others.
we have a very large amount of outside inquiriesabout this program. you've read about it in "nature;" you've read about it in "the newyork times;" and you'll be hearing and reading about it more. and the communications stafffrom both the clinical center and predominantly the human genome institute, as well as thenih in general, have been very engaged in trying to help the public understand betterwhat we do. the clinical center obviously provides a certainamount of space and supplies and special resources, and it's really the special resources thati think make this such a marvelous facility. and these resources have evolved the courseof our long tradition of phenotyping patients. so, let me just, in one slide, show you whati think are some highlights. we have a brand
new gmp facility that's going to open in afew weeks here on the first floor for making candidate drugs. this is a fabulous resourcethat can help once the diagnosis is made and new therapeutic strategies are contemplatedwhen industry is not capable or interested in helping making a candidate drug. we have a phenomenal amount of imaging equipmentin this facility, working closely with the nmr center. there are over 27 mri machines,for example, in this hospital, some of which serve animals, but the nmr center's a facilityto make new machines. a new 7-tesla machine is about to be unveiled for clinical use,and we have multi-modality minimally invasive procedural suites, rather unique for the country.we have a biomechanics lab in the rehab medicine
movement for testing and assessing movement,which leighton chan's group runs. our blood bank is phenomenal in terms of helping preparespecial kinds of cells for research purposes, both in the lab and the clinic. we are nowpriming up to be able to do stem cell therapy when the investigators want to do that. andthe phenotyping capability includes the metabolic sweep for -- originally designed to assessobesity, but is available for testing -- wasting syndromes or any syndrome where you want tocharacterize the metabolic state of the patient with great precision. we also have some it tools, and one i wantto mention, and i'm going to end my comments with, is the biomedical translational researchinformation system, or btris, which jim cimino
has been building. and what is btris? well,it's a data and tissue repository, and in view of the interest of this interest groupi wanted to show you in one slide what it does. so, from the clinical center, there'sinput into this system from the laboratories, the pharmacy, the imaging facilities, thecris system, the old nimss system, and from all the different institutes, they will bedepositing whatever they want to deposit into this system that relates to patients. in the future, the ctsa network, we hope,will also contribute to this system. and we will be taking all the biospecimens and tissueinformation that's available at nih. and i am told there's over 30 million specimensout there in freezers and things all over
the place. our goal is to eventually haveall that information linked into this system. and so, what we hope in the future is thatadditional institute research data and images will be added every year. the addition ofthe stored sample data which comes from these patients with rare diseases will allow investigatorsto search samples along with related clinical research data. so you'll have tissue information.you'll have clinical information. you'll have phenotyping information, genetic information,et cetera, all available in one place. and hopefully this will be a valuable resourceto the community. and finally, as we begin to partner with theextramural community, our dream is that this kind of a system will become a national resourcecontaining a vast amount of information that
will enable hypothesis generation, hypothesistesting before even going and doing experiments. so, if you're interested in btris, and it'sjust been unveiled and become activated, you can learn more about it at this site. so, those are my comments, and now i'd liketo introduce dr. gahl who's going to tell you about what's happening in this clinic. [william a. gahl]well, thanks you very much. i want to thank the special interest group for biospecimensfor their invitation and john and steve, especially my institute, but most of all, all of youwho have contributed to this program so much. if there's one message i want to send outto all of you, it's that we have cases up
here that have not been fully explored, andif any of you are interested, i would like you to come up to us and tell us your interest,your specialty area. and if you want to pursue any of these disorders, please do becausethey still remain mysteries, and we can use all the help we can get. so, i guess it's this one. all right, i'lluse the bottom one. i'm fine. yeah, that's what i was hitting. so this started with the office of rare diseasegetting all sort of inquiries that really couldn't be answered, and steve mentionedthat already. but in addition, there was a retreat in 2007 at which the directors ofthe ics thought of ways in which to sort of
enhance or rejuvenate the clinical center,and one of those ways was to recreate the fascinoma clinics of the 60s and 70s. you'llprobably recall that most of the leadership of the nih is now in the members of the secondhalf-century club, so they remember back to the 60s and 70s when they did this themselves.and i think they remember that fondly, so they wanted to do that. and so we have thegoals of the program to assist patients, come to a diagnosis, but also discover new diseasesthat will reveal something to us about biochemistry, about pathways, about cell biology. and i'dlike to show you today about how we're moving towards some of those goals. the way this programs works is that we receivemedical records and also a summary letter
from the physician. actually, sometimes wedon't receive that and we have to ask for it, but we're supposed to get it. and thenwe triage the submitted records and send them out to specialists in the area that the coverletter and the records indicate. they get back to us and we'll make a decision aboutwhether to accept or decline the patient and then tell the patients and the physicians.and then if the -- for the accepted patients, they come back to us for about a week admission,and we have delay time now for admission, probably about two to three months for bothpediatrics and adults. so this got a lot of press and actually dr.zerhouni was part of the announcement almost a year and half ago now. and you can justsort of read all the people who are interested
in this. this struck a cord with people. ithink it's because many of them had trouble reaching, let's say, a team that would lookat everything comprehensively and sort of universally. instead, they'd have to go toone specialist and then another specialist, et cetera. so there was a significant amountof press. fine. so, this is what happened. basically we'reinundated and couldn't really handle it. and, in fact, another way of looking at it is sortof lucy without the candy. so out of desperation we sought more support and actually receivedsupport from the leadership at the nih and from individual institutes and especiallyfrom individual investigators, many of whom are in the audience.
the number of inquiries we've had since mayof 2008 is really 2,300. the number of medical records is clearly over 900. i don't evenactually know. we do have a database, however. most of the patients we've been able to reject,and many of them eminently rejectable, any of us would reject. some of them are a littlebit more questionable, and i'm sure that occasionally we make mistakes. but we have accepted about190 individuals on -- many on my service, many on other services throughout the nihto existing protocols. we have about 150 charts that are currently active and under evaluation.and 13 of the patients that we have either seen or were about to see have died beforethey got here or shortly after they got here, which really speaks to the severity and criticalityof the patients that apply to this, as well
as a number of the patients who don't havethat criticality. most of the cases are actually neurological cases, and many of the casesare pediatric cases that are very complicated. we now have expanded our personnel hired bythe udp to these numbers here, so we have a reasonable contingent of individuals. andthese are the personnel who are currently with us as paid personnel and we're acquiringmore sort of as we speak, just working on a couple of other contracts. and the consultantshere -- again, a significant list of individuals from all the disciplines of the nih. we have planning meetings in which we triagesome of these charts and update the database. and often, we have to ask for specific furtherinformation in the form of slides or images.
and we get it. people really do not resistthis. after all, they get free medical care here. of course, there may be some other reasons,too. and the pediatrics group now is headed bydr. cynthia tifft who's in the second row here. she just came on board as the deputyclinical director in nhgri, and she's conducting the pediatric portion of this now. then we have open meetings once a month, whichis basically to sort of show off many of the interesting cases that we have with imagesand slides and a lot of contributing individuals here, many of whom spend a considerable amountof time preparing for these meetings. and then i sort of conduct the meeting, and welearn about new cases that are of interest.
so i wanted to tell you about some geneticaspects of this pursuit and then give you some cases. the genetic analysis, in additionto using targeted diagnostics that are clia-certified and molecular and are send-out tests thatwe pay for. besides that, we do some unbiased screening with snp analysis. and these snpsare done by dr. tom markello through the nhgri genomics core, which we have access to. andthere's some significant software that's involved that was really developed in part by tom andin part was able to be purchased. we're able to determine two things. one isthe copy number variance. in other words, you're supposed have two copies. do you haveonly one? do you have none? in other words, are there deletions? or do you have a duplicationand have three copies? and runs of homozygosity
or heterozygosity -- is no longer, no longerexists in this individual patient. and that can speak towards autosomal recessive diseaseor genes in the region of, let's say inappropriate homozygosity, that would be candidates. so,the way that this works as a single nucleotide polymorphism is an area within the genomethat has a natural variation in many of us. and it isn't a one percent to 99 percent ratio;it's really a 30/70, 60/40, 50/50 or so, so these are common variants, and they're definedby a single nucleotide but surrounded by other bases so that one can determine whether aperson has, for example, the a or the t in the first case, or the c or the g in the secondcase. and so, these snps are selected by illumina,in this case, across the board. and they're
selected approximately every 3,000 bases sothat one can determine to basically use these as signals or as markers for the absence ofa region of sequence. and that absence can be on one allele or on two alleles, or itcan be a duplication. and we can determine that, and i'll sort of show you how in this.and, so if you have, for example, 10 snps in a row that are missing, you know you'vegot roughly 30 kilobases missing and maybe a portion of a gene that's missing. thingsof that sort are what we can do. and it turns out by convention that the lessfrequent allele is called the b allele, and so everybody of us who is diploid is aa, bb,or ab. and this is a picture of the distribution of some of these individuals, so that wouldbe bb, ab, aa, and a and b, and these are
essentially intensity plots of the signalthat comes out of a snp analysis of the genomics core. so, here, for example, is a listing of a numberof snps with their r ratios. and an r ratio is the ratio of the a to b -- or actually,b to a. and if the ratio is 1 -- in other words, you're heterozygous -- you're log tothe base-2 of r is going to be 0. so, for example, this means that the person is heterozygotebecause that reads .0084, which is close enough to zero. so the way that one uses this isto determine the intensity, and if you have an intensity that's logs below the 0 to 1,or -1 to +1 range, namely here -- if the intensity is that low, it means it's deleted. and thenyou can line this up with a human genome database
to determine what genes are in that region,what genes could be deleted, therefore, what genes could be candidates to be looked atfor the causative gene. and in this case, when you expand the previousslide where there were only a couple of snps visible. here you have really all of thesesnps that are -- have very low intensity, indicating a deletion. that deletion is 32snps, 60 kilobases involved, and in fact, it corresponds to the particular deletionthat we see in a disease that i study, which is cystinosis, a very common 57,257 base pairdeletion which accounts for half of the north american and european individuals who havecystinosis. so this is sort of proof of principle that we can pick these things out.
the other issue is that you can measure heterozygosityversus homozygosity. and this illustrates that, so this now is the b allele frequencyplotted on the ordinate. and over here are the aas. their b allele frequency is 0. here'sthe bbs. their b allele frequency is 1. and the b allele frequency is .5 for heterozygotes.so, you can see that these are homozygotes. these are homozygous snps, and these are heterozygoussnps. and this is a centromere for which there are no snps. so, if you were to expand this on the nextslide, you're only going to see the middle line, only you're going to see the middleline for all sorts of different chromosomes. and here, for example, is a loss of heterozygosity,or an absence of heterozygosity. so, if you
thought that this was an autosomal recessivedisorder, you could look in this region, see what genes are there, and they could be candidates.now, in general, this type of analysis will give you more candidates than you can possiblyuse, so that, really, this is a first step towards pursuing a genetic diagnosis. so here's another area that you may have seen.and here's an individual whom we saw very early in the course of this program who gaveno history of consanguinity, but if you look at all these spots, it does have consanguinityall over the place and has approximately a three to four percent -- a three to four percentage-- percent of all this person's genome is homozygous, which could correspond to roughlya second-cousin relationship among the parents.
because remember, people who are first cousinsshare one-eighth of their genes; first cousins, once removed, one-sixteenth; and second cousins,one-thirty-second, which would be about three percent or so. so, one can discover this typeof issue. so, let me tell you now about some of thecases that we've seen here. and remember, what i'm going to show you know is reallya distillate of a huge number of charts that people have gone through and discarded withcause the majority of them. and so, perhaps every decent case that we've seen here represents50 to 100 cases that have been looked through and culled. we don't know what's going on with this nextgroup of patients. this patient, in fact,
we haven't even seen yet, but she's fascinatingin a way because this is a before and this is the way she is now. and she feels thatthe room is so hot -- i'm sorry, i think i can do this like this, yeah -- the room feelsso hot but only on her face, not on the rest of her body, so she keeps the temperaturein the room at 58 degrees and has a fan blowing on her face. and her face is painful, andnobody knows exactly why she has this dysautonomic symptomatology but only in a segmental area.we haven't seen this patient yet. we have seen these kids, and they have shortstature, dysarthria, bowel and bladder dysfunctions and dysmorphisms and -- again, we've seenthese individuals, but we don't know what they have, and so, we're interested in havingbone experts look into this.
here's a little girl who has cranioectodermaldysplasia. and you can see the dysmorphisms in her face. in fact, she has sister, andher sister is under psychiatric care because her sister doesn't understand why people makefun of her sister. her problem is that she has no roots to her teeth. her sweat glandsare missing, so she has many signs of ectodermal dysplasia, but this doesn't really fit anyparticular of the 150 different types. in sort of summary here, her main problem isthat she has thickening of the skull, and this bony overgrowth is impinging on the opticnerve canal so that she has some papilledema as well, and that may need to be releasedat some point. again, we don't know what's going on, nordo we know what's happening with this girl
with microcephaly seizures and developmentaldelay. and believe me, there are many, many of these individual cases. or this five-year-oldgirl who has liver disease and pancreatitis and also some neurological delays, but theinteresting thing from a metabolic standpoint is that within her liver she has areas ofbeginning fibrosis. she has some inflammatory cells here, and she has copper accumulation.but the copper accumulation in her liver is not associated with wilson disease or anytypical pattern of that copper distribution, which is always in zone 1. instead, she hasit in zone 3, which is the furthest away from the vasculature. and our pathologists havesaid they've never seen this, and neither have other liver pathologists. so this isa -- particularly a different type of copper
accumulation. she also has a biliary canaliculus here, andyou can see the lumen. this is apparently abnormal. in other words, this should be avirtual space, not a real space that you can see. and this reflects the fact that the columnarcells are swollen and they're surrounding that lumen. again, we don't know what we'redoing in this case, nor do we know what we're doing with these individuals who have allthese different disorders, including one who has a major accomplishment and probably couldincrease that number. now i want to tell you about some interestingcases that we actually have a lead on and that some people are working on. and here'sa 21-year-old woman who has lung nodules,
which you can see here. you know, these thingsdo not belong there. and she has ascietes, and her ureter has been kinked, so she hadhydronephrosis. all these things are thought to be related to her main defect, which, again,we don't know about but on biopsy of the cheek overgrowth -- she has this type of a pattern,which is both fibrous and inflammatory. and she has some plasma cells there, eosinophils,and she has some of the hematopoietic-derived stem cell markers within that biopsy of hercheek and lung. in her liver it shows essentially the same thing, some fibrosis but a lot ofinflammatory material as well. and dr. kleiner has made the diagnosis of angiolymphoid hyperplasiawith eosinophilia and fibroinflammatory disease, a descriptive diagnosis, and dr. aksentinovichhas discovered that there's increased il-8
and il-1r intercirculation, so these are cluestowards the type of inflammatory reaction that might occurring. and now we have a lotof other tissue by virtue of really a biopsy that dr. carter van waes did on her in a four-houroperation here at the nih to collect material to try to find out what types of cytokinesare being emitted and what type of therapeutic efforts we may make directed towards thoseinflammatory molecules. here's a 46-year-old woman who has in herkidneys a thrombotic microangiopathy, but she also has granulomas on her skin, and interestinglyincreased circulating vascular endothelial growth factor. this is her kidney biopsy,and you can see that there is thickening along the vascular wall and that the mesangium isincreased within her glomerulus. she also
has blunted podocytes, and this really isreminiscent of preeclampsia, in which you know is due to the production by placentaof an inhibitor of vegf, so that there no longer is enough trophism by vegf of the kidneycells, and therefore the patients get renal disease, hypertension, and the treatment isessentially removal of that antibody by delivery. in other words, get rid of the placenta, getrid of the antibodies. so, here's a woman who shows some findingsof preeclampsia but due to a different cause besides the placenta. in other words, it'sprobably a genetic defect either in the vegf itself or possibly in a vegf receptor. sothat's currently under investigation along with a collaborator at beth israel. and thisis the woman who was in "the new york times"
article who has some of the similar findings.she also has the thrombotic microangiopathy in her kidney. she also has problems withher venous lakes within her skull, and she lost her right eye because of retinal vascularproblems, and you can see she has really systemic disease. she has actually died by stoppingtherapy because her therapy was so significant that she was losing a lot of blood throughher gut and decided not to continue with the transfusions, and three days later she died.but she sent us her body, and we have performed an autopsy on it and have that tissue to studynow. this is a 39-year-old man who had slowly progressiveneurological problems, and you can see that there is some diffuse leucoencephalopathy,which progressed, at this time, relatively
slowly, but since then -- i'll just show youa couple of areas where there's some abnormalities here. but since then you can see the extentof brain volume loss that this person has had over the last three years or so. and webrought him in on two occasions, and we'll probably bring him in again under dr. toro'sservice and essentially excluded the diagnosis of leucoencephalopathy and made the diagnosisof primary progressive multiple sclerosis based upon a number of oligoclonal bands,increased protein, increased igg within the csf. but camilo also measured the ebv antibodytiters and found them to be elevated, and also the pcr was increased, so this wasn'tjust the presence of antibodies. it was also the presence of the virus itself, and nowdrs. bielekova of ninds and jacobsen of ninds
and dr. cohen, jeffrey cohen, and camilo toroare investigating this ebv infection as a possible cause primary progressive multiplesclerosis, which is essentially hypothesized within the literature, and this may be anindex or sentinel case that might be able to demonstrate that. i just want to tell you about two successstories and then i'll sort of be finished. one is a 52-year-old woman who, without takingsteroids and without essentially working out -- well, she might have worked out a littlebit, but she didn't work out like this. and it did not have any of the standard endocrinologicalabnormalities that might cause this. it had the development of increased musculature toan incredible extent. and this was becoming
painful for her. she had strains in her muscles.of course, she didn't like her appearance either, but in addition she had real pain,and it was becoming problematic. you can see on the ct scan here how big her paraspinalmuscles are. now, some of us in the audience, perhaps half of us might not mind this realmuch, but this is not a good thing to have. and these are her rib muscles, and then soshe has incredible increase in the size of her muscles. and when we did cts of her head,even the muscles that are essentially not used very often, or that we can't hypertrophy,were hypertrophied. for example, the rectus muscles of her eye were huge, like three,four times as big as our neuroradiologist had ever seen. so, she has this for some reason.the emg was myopathic, but a muscle biopsy
was read as normal. we brought the patientin because this was fascinating. the referring physician from duke said, "in my 38 years,i've never seen..." blah, blah, blah, okay. so it turns out that we did a second biopsyeven though the last biopsy was done only a year ago. and dr. quan had it sent to afipand our pathologists here and together made the diagnosis of amyloid myopathy. in otherwords, the amyloid was seen in the thickened walls of the vessels, and stain on congo redand protein aggregates were there on em. this led us to consider - i'm sorry -- the possibilityof amyloidosis, and in fact, one of the most common causes of that would be multiple myeloma.so we looked for plasma cells in a bone marrow that we did here as well and found 10 percentplasma cells, which is sufficient to make
the diagnosis. and it hadn't been seen before. and the follow up that -- dr. minoli referredher to the mayo clinic. now, she was become short of breath and fatigued. she had involvement-- a little bit of controversy, but it was considered -- she had involvement of her atria,and if she would get involvement of her ventricles, that's considered to be very bad and couldeasily lead to death within months. but at the mayo clinic, she underwent a stem celltransplant, had some post-transplant complications, but then recovered, is feeling very well nowand is no longer having all the muscle pain and, i'm told, feels better day by day. wedo expect a full recovery. and in the very, very rare cases in the literature, the musclemass is said to go down to normal, so we feel
very good that we've caught this. and i just would draw one sort of lesson fromthis, and that is that this is a woman who on two occasions requested to be seen at themayo clinic and was turned down by the specialty clinics there and frankly, probably wouldhave been turned down by a specialty clinic here as well. so her access to medical carefor this particular disorder was because a broad net was cast for people like her. andthe irony of it is that when she finally was diagnosed, she was welcomed with open armsby mayo clinic. oops, yes. so, then the last case is this sibship thatwe saw with calcification of the large vessels
and also the joints. so, can anybody tellif there's an abnormality here? so this is, of course, the bone and the kneecap, but youknow, this vessel here is without contrast. so this is a plain film showing the outlineof her vessels, and here it is on a pelvic film. you can see all that. this hurts thepatients because there's poor circulation, and they can't -- if they walk for a block,they have to stop, and it hurts them a lot. and here you see it as well, also all theway down to the foot. and then in the hands there's calcification in the joints here,right here, here, here. it's all over -- i didn't want to put arrows all over the place.so, this is the pedigree. turns out there are five children. they're adults. they'rein their 50s, and they have this, all.
and dr. boehm's lab with cynthia st. hilaireworked on this and got fibroblasts from a biopsy we did. and this shows the control,and this shows the affected woman, and this is the acquisition of calcium over the courseof three weeks, and in the control there is none after three weeks. this is all the stainfor calcium microcrystals by an assay they performed. and this is critically importantto point out to us that the problem is not with circulating calcium or phosphate abnormalities,but really it was intrinsic to the cells. so that was the first step. at the same time,dr. markello was doing a snp analysis and found a region of homozygosity here that wasshared by all five affected individuals but not by the parents. so, this spoke to a recessivedisorder and spoke to this region here which
could be affected. that region involved 22megabases in which there are almost 8,000 snps, so this is a large region. and again,that's the issue here; that is a large region, 92 genes. none sort of were pointed out -- nonestruck themselves to us as, you know, real helpful. but on the other hand, we had dr.st. hilaire and dr. boehm involved, so they suggested one, and they have now identifieda gene in concert with us. and this is going to be, i think important for learning thingsabout the mechanism of calcification of vessels in general. and all this required a collectionof specimens, all sorts of different specimens, which we continue to do. it really is an importantissue for us in our handling and distribution of specimens.
so, the good parts of this are that virtuallyevery patient is pleased with the attention and the hope that we provide to them, andoccasionally we solve a case. and can see some of the cases could be new diseases. ithink i've noticed that around the bedside, around the tables of discussion, this hasbrought specialists closer together over cases. it reminds me of when i was a resident asopposed to a bench researcher. it bolsters our protocols, we think, and there may benew protocols that come from this. not so good is the fact that our triage of necessityis a difficult process for us, and the patients who are rejected are not really happy, andin fact some of the patients who are rejected send me notes. i get a lot of notes. one ofthe notes says, "you are a jerk." and i think
that that's something -- maybe a topic offuture discussion, maybe a whole conference could be held on that. [laughter] but i would say that nobody has ever stoodup and said, "you lie." so this is your chance, everyone who'd liketo stand up. anybody? okay, so we'll let that go. one of the otherproblems is that we've gotten congressional inquiries, and most of the congressional inquiriesare from patients -- from representatives or senators whose constituents have not appliedto the program. so, they decided that they were going to go to their senator or representativefirst before actually applying. of course
this makes the response very easy, but it'sreally not the appropriate thing to do. okay, so we're a little bit late sometimeswith getting back to patients, and part of that is because we're overwhelmed, and partof it is because our consultants don't get back to us in a timely fashion. and, as isaid, the patients we see are at a distillate, and, again, many of the patients don't reallyhave the objective findings that correspond to their complaints. in the future, we needto expand our basic research investigations into some of these distilled cases, becausethey're really good cases and we worked hard on phenotyping them. we'd like to use thisprogram as a model for how we use genetics in the future for investigating rare diseases,and we'd like to post the cases to this community
here and ask you for your input. so, if anyof you have expertise in the disorders that may be related to the ones we have up here,please let us know, because we're reasonably anxious to offload some of these cases. andwe'd like to consult international experts via the web and create udp clinics throughoutthe united states if possible, that is to say, if there's support on the behalf of theextramural people or the leadership here. so, we found that in order to fulfill themission of the udp, we have to admit patients to our service and then consult other services,and that's one of the wonderful things about nih, is that people are generous about theirconsultatory services. again, many of the patients would not come here if they had tocome to a particular specialty, and this is
a program that really doesn't fit into thenatural paradigm of professional advancement. in other words, a young investigator, i wouldnot recommend get involved as the major part of his or her pursuit in this program, becauseit's so high risk, but the benefits can be enormous as well if you strike gold. triageis difficult, failure is common, and patients are desperate. and i'll just give you thefinal example of how desperate patients are. here's a 46-year-old man who began to haveneurological disease, both cerebellar and cerebral, and this is what he writes. and this is the letter that his daughter sentto us over this, and i'm not going to read this; i'm going to let you read this. i guess it's obvious that a program like ourscan't be influenced by anything of this sort,
but we will be seeing this patient in a weekor so. so, i think hemingway said it best about the patients that we see and the difficultiesin life. "the world breaks everyone, and afterwards some are stronger in the broken places." andi think thoreau also said "the mass of men lead lives of quiet desperation." and thisis a program that lets us see really the juxtaposition of science and sadness in the world, and letsus as investigators see the human condition in the person of all the patients who applyand whom we see for a week here at the clinical center. thank you for your attention. [applause]
so i suppose -- i think people should leave,but if anyone wants to -- if anyone wants to ask any questions, i will stay here andanswer them for the stragglers. [end of transcript]
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