Future Research Directions in Joubert Syndrome

Table of Contents (click to jump to sections)

I. Overview and Introduction
II. Clinical Approaches to Diagnosis and Management
III. Genetics of Brain Development and Behavior
IV. Autism and Joubert Syndrome
V. Recommendations for Future Research Directions
Agenda
Participant List

Future Research Directions in Joubert Syndrome

June 27 - 28, 2002
New Orleans, Louisiana

 

I. Overview and Introduction

This conference was funded by the National Institute of Neurologic Disorders and Stroke (NINDS), the Office of Rare Disorders, and the Joubert Syndrome Foundation. It took place on June 27-28, 2000 in New Orleans, and was a follow-up to a 1998 symposium on this disorder. Bernard L. Maria, M.D., M.B.A., chairperson, and Robert Finkelstein, Ph.D., Program Director, Neurogenetics Cluster, NINDS, outlined three goals for the conference. The first goal was to provide an overview of current knowledge during three sessions: clinical approaches to diagnosis and management, genetics of brain development and behavior, and Autism and Joubert syndrome. The second goal was to introduce established researchers from backgrounds in genetics, brain development, and behavior to the disorder. Finally, family representatives and research panelists were to engage in discussion culminating in the definition of future research goals.

Joubert syndrome is a rare autosomal recessive disorder caused by a set of cerebellar and brainstem abnormalities, termed the .molar tooth sign. due to their radiologic appearance. Other clinical features commonly include hypotonia, ataxia, and developmental delay. Additional symptoms may include breathing abnormalities (apnea and hyperpnea), problems with eyesight (retinal dystrophy) and visual tracking (ocular-motor apraxia ), kidney problems (renal cystic disease), and a variety of other associated difficulties.

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II. Clinical Approaches to Diagnosis and Management

The meeting began with welcoming messages from leaders of the sponsoring NIH Institutes:

Bernard L. Maria, M.D., M.B.A
Eugen Boltshauser, M.D.
William B. Dobyns, M.D.

Bernard L. Maria, M.D., M.B.A. provided an overview of the past 30 years of research on Joubert Syndrome. In 1969, Dr. Marie Joubert first identified the disorder in four siblings in a French-Canadian Family. Although all four siblings shared core characteristics of the syndrome, variability in symptom severity and presentation was remarkable across the children. In 1984, Dr. Maria diagnosed a child with the disorder in the United States and the child.s mother founded the Joubert Syndrome Foundation in 1992.

With the help of the foundation, Dr. Maria assembled a team of researchers to investigate the clinical features of the disorder. The team first described neuro-ophthalmological characteristics, including ocular motor apraxia and difficulties with ocular pursuit (hypometric saccades, impaired smooth pursuit, vestibular-ocular reflex cancellation deficits) and linked these characteristics to cerebellar and brain-stem functioning. Second, researchers described the developmental and behavioral characteristics of the syndrome. Third, Dr. Maria coined the term .Molar Tooth Sign. to describe four essential features: deep interpeduncular fossa, thick and straight superior cerebellar peduncles, and vermis hypoplasia. In addition, abnormalities were identified in the areas beginning at the caudal midbrain and extending to the to rostral medulla. Furthermore, autopsy results suggested that the cerebellar peduncles were uncrossed, leading to speculation that Joubert syndrome was a .non-decussation of major tracts..

The 1998 CNS symposium sponsored by NINDS, ORD, and the Joubert Syndrome Foundation resulted in the first general description of facial and oral-motor characteristics for persons with Joubert syndrome (e.g., prominent forehead, rounded eyebrows, upturned nares, triangular lips, inability to move tongue laterally, etc.). However, it remains unclear whether features are related to hypotonia. Furthermore, diagnostic criteria were revised.

Since 1998, researchers further described the relationships between brain structure and clinical characteristics (e.g., breathing and tongue abnormalities linked to the medulla). However, the relationship between neurobehavior/developmental delay and the hindbrain has not yet been defined. The development of a severity rating scale for brain structure abnormalities on imaging and a quantitative analysis of brainstem structures proved helpful in differentiating Joubert and Dandy-Walker syndromes. In the area of genetics, several candidate genes have been ruled out. Future directions in research on Joubert Syndrome were introduced.

Eugene Boltshauser, M.D. reviewed challenges in the diagnosis of Joubert syndrome, which lead to occasional false positive diagnoses in the literature. First, a variety of characteristics are associated with cardinal symptoms of Joubert in the literature, including short stature, scoliosis, congenital cataracts, hydrocephalus, corpus callosum agenesis, hepatic fibrosis, and sinus inversus. However, reports are inconsistent and the relationship of these symptoms to Joubert is unclear. Second, siblings with Joubert may vary widely in breathing patterns, neuroimaging features, presence of occipital encephalocele, presence of hexadactyly, and length of survival, as observed in the original probands described by Marie Joubert. Third, the difficulty in making a clinical diagnosis is increased by descriptions of syndromes with very similar and overlapping features.

Dr. Boltshauser discussed three features that may be associated with Joubert syndrome: retinal, liver, and kidney dysfunction. Among children with Joubert, retinal dystrophy is quite common and exists along a continuum, from no impairment to marked impairment. Information regarding the long-term prognosis for vision is not available. Dr. Boltshauser also described a subgroup of young children with core symptoms of Joubert syndrome and congenital amaurosis (congenital blindness despite an intact retina). Among these children, no significant visual improvement was observed and varying degrees of kidney involvement were described. Dr. Boltshauser suggested that these children might demonstrate either a subtype of Joubert syndrome or a completely separate syndrome, such as Senior-Loken syndrome.

The presence of liver fibrosis has been discussed in some single case reports, but no systematic study is available. In cases where liver fibrosis is present, liver function is not impaired and is not associated with kidney dysfunction. Liver fibrosis in conjunction with core symptoms of Joubert syndrome may constitute either a subgroup of Joubert syndrome or a separate, overlapping condition (e.g., COACH, Arima).

Finally, Dr. Boltshauser described nephronophthisis, an autosomal recessive condition leading to end stage kidney failure, in children with Joubert syndrome. Description of nephronophtisis in this population is complicated by difficulties in diagnosis of the kidney disorder. In addition, Senior-Loken syndrome is an overlapping condition, which includes characteristics of Joubert as well as kidney involvement and is linked to genes associated with nephronophthisis. Despite difficulties in studying nephronophthisis among children with Joubert syndrome, existing information suggests that nephronophthisis in this population is typically juvenile in onset, with end stage renal failure occurring rarely. Among those children who reach renal failure, the course of nephronophthisis is variable, as is the association between renal and retinal function. Longitudinal study is necessary to understand the relationship between Joubert syndrome and retinal, liver, and kidney functioning.

William B. Dobyns, M.D. reviewed syndromes overlapping with Joubert, noting that the .molar tooth sign. may be related to a variety of hindbrain/midbrain syndromes, as malformations are rarely associated with a single syndrome. A potential set of hindbrain/midbrain syndromes was discussed. First, the distinction between Dandy-Walker syndrome and Joubert syndrome using MRI was described. Second, Dr. Dobyns described .true. Joubert as the molar tooth sign, ataxia, hypotonia, apnea/hyperpnea, and developmental delay without kidney or retinal involvement. Pre-axial polydactyly may also be observed. In cases where congenital blindness is observed, the term .Joubert Lemer Amaurosis. is suggested. Third, Dekiban-Arima syndrome is described as a potentially separate syndrome involving core characteristics of Joubert syndrome in combination with visual problems and cystic dysplastic kidneys. Cystic dysplastic kidneys are described as distinguishable from nephronopthisis, which is apparent in Senior-Loken syndrome. The occasional incidence of polymicrogyria is reported, as well. Fourth, Dr. Dobyns described COACH syndrome as a diagnosis that is in question. Core symptoms include cerebellar vermis hypoplasia, oligophrenia, ataxia, coloboma, and hepatic fibrosis. Next, Dr. Dobyns described Malta syndrome as a possible variant of Joubert syndrome or as a separate syndrome that includes the molar tooth sign, cerebral abnormalities (occipital cephalocele, hydrocephalus), colobomas in both eyes, visual problems, and normal kidneys and liver. Another variant includes characteristics of Joubert syndrome in combination with polymicrogyri, normal kidneys, liver, and retinal function. Seventh, Senior-Loken syndrome consists of retinal dystrophy, possible juvenile nephronophthisis and facial dysmorphology, skeletal anomalies, and early lethality. Finally, a new syndrome (Varadi) involving hypoplastic vermis, molar tooth sign, hyperpnea/apnea, a small cleft in the lip, multiple alveolar phrenula, multiple tongue hamartomas, midaxial polydactyly on the hands and preaxial polydactaly on the feet, and hypothalamic hamartoma is provided as an example of a syndrome which is clearly different from Joubert despite the appearance of the molar tooth.

Dr. Dobyns summarized by noting that multiple problems are inherent to the definition of Joubert syndrome and the location of a genetic cause for the disorder, including the presence of phenotypic variability and probability of the involvement of multiple genes. Some observed features are not very specific (e.g., cephalocele, coloboma) while others are more useful in differentiating between syndromes (e.g., congenital amaurosis, nephronophthisis, cystic dysplastic kidneys, and post-axial vs. mid-axial polydactyly). He suggests the presence of at least five distinct syndromes involving midbrain/hindbrain malformations similar to those seen in Joubert.

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III. Genetics of Brain Development and Behavior

Anthony Winshaw-Boris, M.D., Ph.D.
Phillip F. Chance, M.D. and Melissa A. Parisi, M.D., Ph.D.
Thomas H. Wassink, M.D.

In order to enhance understanding of cerebellar development and the genetics related to midbrain and hindbrain development, Anthony Winshaw-Boris, M.D., Ph.D. reviewed studies involving mice. Cerebellar development occurs in a series of steps, including the specification of the cerebellar primordial layer, granule cell generation and migration from the rhombic lip, purkinje cell generation, maintenance, migration from the ventricular zone, and neuronal survival. Each of these stages is directed by specific genes and proteins, many of which may be candidate genes for Joubert syndrome. All types of genes and proteins may be involved, including transcription factors, signal molecules etc.

The brain divides into general regions early in development. The isthmus organizer is a region that plays an important role in the further development of midbrain, hindbrain, and cerebellum and the genes and proteins directing the isthmus organizer may be related to Joubert syndrome. For example, gbx2, obx2, and fgf8 work together to determine where the isthmus organizer will be located. Removal of any one of these genes in knockout studies causes the isthmus organizer to shift in location.

As regions of the brain become increasingly differentiated over time, the rhombic lip, located at the midbrain/hindbrain junction, generates most of the cells that will form the cerebellum. Granule cells proliferate and migrate laterally from rhombic lip to create the cerebellar hemispheres. The cells merge at the midline, where the vermis is formed. After birth of the mouse, cells continue to migrate inward from the external granule cell layer to the internal granule cell layer. Although granule and purkinje cell generation and migration occur in different areas of the brain, several basic processes may be common to both types of cells. Molecules controlling general migration patterns may be important, as well as molecules controlling patterns specific to cerebellar development. The genetic control of migration of neurons past purkinje cell layers (e.g., Lis1), decussation (e.g., dccmetrin pathway), and of neuronal survival may be important in Joubert syndrome.

Melissa A. Parisi, M.D., Ph.D. presented an overview of research knowledge regarding the genetics of Joubert syndrome. First, she reviewed basic information regarding the clinical characteristics of the disorder and its transmission. Joubert syndrome is known to be an autosomal recessive disorder, where unaffected parents pass on genes resulting in Joubert syndrome. The initial French-Canadian probands may have represented a founder effect, where genetic drift resulted in changed copy of a gene, which was passed down on both sides of the family. The prevalence rate of the disorder is one in 100,000, as estimated using consanguineous families, and distribution occurs worldwide. Although prevalence rates were originally described as higher for males than females, current estimates suggest more equal gender distribution.Second, Dr. Parisi reviewed findings in Joubert syndrome using traditional genetics approaches. A genome wide study of ten families using standard linkage analysis (LOD score method) which estimates the linkage between genetic markers, such that a parent's characteristic should be more common among children than a non-parent's characteristic, did not result in a gene loci. This may have been due to widely spaced markers, indicating that children from different families may not have all had Joubert syndrome, but displayed similar, overlapping syndromes. Another method involves identifying identical genetic regions within affected individuals in consanguineous families (identity by descent mapping; IBD). Review of a consanguineous Arab family with symptoms of Joubert syndrome suggested a gene locus on chromosome 9, with two families linked to 9q34.3 by homozygosity mapping. However, two of the four Arab families didn’t map onto the gene, suggesting this was not the cause for all families. Examination of 26 families with children with Joubert syndrome and did not implicate 9q34.3. However, other conditions in which cerebellar hypoplasia is a characteristic map onto this gene, suggesting there be a clustering of genes in this region. Chromosomal rearrangement in children with the disease using positional cloning at breakpoints is another frequently used approach. Although a patient with Smith-Magenis syndrome and features of Joubert showed a chromosome deletion 17p11.2, examination of 26 families did not implicate the involvement of 17p. A gene within this area may be important or a gene on the other chromosome that shows up because of this deletion. Finally, analysis of candidate genes and mutation studies can be useful. As reported earlier in the conference, studies of mice have identified genes related to patterning, signaling, and/or neuronal adhesion at the rhombic lip. Using screening techniques (e.g., heteroduplex analysis, sequencing for mutations, dideoxy fingerprinting, and dHPLC), the following genes have been ruled out: WNT1, FGF8, EN1, EN2, and Bar HL1. Dr. Parisi reviewed challenges to using standard genetics approaches in Joubert syndrome, including the difficulty in making a clear clinical diagnosis (e.g., possible subtypes and overlapping syndromes), the probability of genetic heterogeneity involving multiple loci and multiple genes, the relative lack of families with more than two affected children, and heterogeneity of the presentation of the disease within families. In the future, strategies including testing mutation in candidate genes among existing families, performing a genome-wide screen, and looking in fetal brain samples may be helpful. However, adequate power must be obtained by collecting information from sufficient numbers of families (from 62 to 270 families, depending on the number of genes involved). In addition, advanced imaging techniques and more informative markers with higher resolution may improve research findings. Thomas H. Wassink, M.D. discussed the diagnosis of autism, the types of investigations which have been conducted in the area of genetics and autism, related research findings, challenges in this research, and strategies for meeting these challenges. First, he reviewed the diagnostic criteria for Autism, a developmental disorder characterized by deficits in communication, reciprocal social interaction, and stereotyped and repetitive behaviors and interests. Social difficulties can include impaired non-verbal communication (e.g., eye to eye gaze), lack of social or emotional reciprocity, decreased sharing of interests (e.g., joint attention), and problems with peer relationships. In the domain of communication, children with autism may show delays in language development, stereotyped use of language (e.g., echolalia), and difficulty initiating and sustaining conversation. Finally, difficulties with repetitive behavior can include intense preoccupations, rigid adherence to routines and rituals, and stereotyped motor mannerisms. The prevalence rate of the disorder ranges from 1-2 in every 1000 children and is more common among boys than among girls. The disorder is developmental in nature, and in 10% of cases can be attributed to a definable genetic cause.Heritability estimates are higher than .9, with siblings of a child with autism 50-100 times more likely to inherit the disease than someone in the general population. As in Joubert syndrome, the pattern of heritability is complex. In Autism, anywhere from three to more than fifteen genes may be involved. In addition, epigenetic factors, or non-genetic factors that mediate the effect of the genes on phenotype expression, may be operating.

Seven genome wide screens (look across all chromosomes to try to find regions of the chromosome which might have relevant genes) involving families with two or more affected children have been conducted and the following regions identified as of interest: 7q, 2q, and 13q. Study of 7q suggests an association with autism (LOD 1-3.2). 7q has also been related to specific language impairment (SLI; disorder of language in the absence of other associated features) and a small number of cases of autism have been identified with chromosomal malformations in this region. WNT2, in a 7q linked region, may be implicated in autism. In addition, chromosome 15q11-13 is implicated in Prader-Willi and Angelman syndromes.

Similar to Joubert syndrome, problems with genetic complexity make the search difficult. Approaches to furthering this line of research include narrowing the phenotype by identifying subtypes (e.g., use specific characteristics of autism such as severity of language impairment, IQ, stereotypic/rigid behaviors) or broadening the phenotype by looking at traits present among first-degree relatives. In addition, strategies include looking at related disorders with known genetic causes (e.g., tuberous sclerosis) and using technological approaches to molecular study (e.g., DNA pooling, etc.).

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IV. Autism and Joubert Syndrome

Judith H. Miles, M.D., Ph.D.
Eileen B. Fennell, Ph.D.

Dr. Judith Miles, University of Missouri-Columbia, discussed issues regarding heterogeneity in autism. First, she described the challenge to genetics studies due to variable expression of symptoms, potentially overly broad diagnostic criteria, and the presence of several genetically discrete disorders related to the autism phenotype (e.g., Fragile X syndrome, Tuberous Sclerosis, and chromosome disorders).

In the past, researchers attempted to create subgroups to reduce heterogeneity in this population. Although the most common approach is to form subgroups on the basis of behavioral characteristics, Dr. Miles suggests a different approach, separating children who experienced central nervous system insult during embryogenesis from those who did not. In a study of 465 consecutive referrals to an outpatient clinic, features related to CNS insult (dysmorphic facial features and microcephaly) were examined among children with autism. First, children with dysmorphic facial features exhibited increased rates of microcephaly, seizure, brain abnormalities, and intelligence quotients (IQ.s) of less than 55 than children without such features. Furthermore, children with dysmorphic features demonstrated a more equivalent male to female ratio and less recurrence among siblings than did children who were not dysmorphic. Similar findings were present when children with microcephaly were compared to children without microcephaly.

These findings suggested that among children with autism, children with CNS insult during embryogenesis differed from those without CNS insult. Thus, Dr. Miles and colleagues divided children with autism into two subgroups. The first group contained children with .complex autism. (30% of the total group), defined as autism in combination with dysmorphology, brain abnormalities, or microcephaly. In contrast, children with .essential autism. were defined as those without dysmorphology, brain abnormalities, or microcephaly. Comparison of the subgroups suggested higher IQ.s, fewer seizures and abnormal EEG.s, a regressive pattern of onset, higher prevalence for males than females, and higher family recurrence risk for children with essential autism. In contrast, children with complex autism had lower IQ.s, more seizures and abnormal EEG.s, a gradual onset, a more even gender distribution, poorer outcome, and a lower familial recurrence risk. This method of reducing heterogeneity in children diagnosed with autism is useful to researchers and clinicians because it is based on a sound developmental premise and identifies those children who are likely to have a poorer outcome and lower familial recurrence rates. In addition, all genetic syndromes known to contribute to autism are included in this group. Thus, costly and invasive testing may be limited to children who are microcephalic and/or dysmorphic.

In addition to distinguishing complex from essential autism, gender, macrocephaly, and family history of autism related syndromes might provide useful distinctions. Comparison of males and females with autism reveals similar intellectual functioning, despite somewhat different distribution of scores. Girls are more likely to exhibit features of complex autism (44%) than boys (25%). However, females are, in general, less severely affected (e.g., higher IQ.s, more pretend play, less repetitive behavior). Twenty three percent of children with autism exhibit macrocephaly. In 44% of the children, macrocephaly is familial, suggesting that macrocephaly may be a marker for a common autism gene. Finally, family history studies of autism suggest increased risk for autism, alcoholism, depression, cognitive disorders, language disorders, and ADHD in families of children with autism. In families where history of alcoholism is significant, there is a higher rate of macrocephaly and of regressive autism. More specifically, regressive autism is more frequent among children whose mothers are alcoholic. Thus, alcoholism may be a marker for another common autism gene. Dr. Eileen Fennell, Florida State University, discussed prior studies of behavior and cognition in children with Joubert. Initial study indicated that out of 20 studied children, six were tested and had difficulty with information (60%), picture completion (40%), digits forward (20%), digits backwards (67%), and immediate and delayed recall of stories (75%). Children had difficulties with finger, toe, and heal-toe movements and with visual motor integration due to problems with motor output. Verbal fluency was also a problem. Caregivers described their children as clumsy, demanding, having visual and speech problems, overactive, cries, growth problems, dependent, clingy, problems with eating, and aggressions. In 1998, 32 caregivers rated their children on a developmental inventory. Over half of the children scored below their chronological age with no children scoring in the normal range. When children were classified by severity on MRI, 1/3 of children had problems above the brainstem, including abnormal mylination. However, no relationship was found between behavioral and neuroanatomical data. Future research includes full neuropsychological and behavioral assessment that can be related to MRI.s looking for subtypes among children with Joubert syndrome.

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V. Recommendations for Future Research Directions

During a morning session of the conference, researchers and family representatives convened to discuss future research directions. The following suggestions were offered:

• Seek funds to develop a national registry. With appropriate data sharing policies in place, a registry would establish a centralized data collection and distribution site and promote collaborative, interdisciplinary, and international research efforts.
• In order to promote identification of homogeneous subgroups for future study:
  • Delineate the Joubert syndrome phenotype further through continued study of the following characteristics: dysmorphology, sleep, breathing, cortical and subcortical characteristics, retinal and kidney function, neurobehavioral characteristics, communication skills, oral-motor functioning, headaches, and cognitive/neuropsychological functioning.
  • Develop a common set of rating criteria for MRIs, preferably based on normative, age-matched data regarding the isthmus and other relevant midbrain/hindbrain structures.
  • Develop a consortium for central review of MRI findings and clinical features to increase diagnostic consistency across studies.
  • Expand research to include related disorders (e.g., .hindbrain related disorders.) and use the information gathered above to identify discrete syndromes and/or subtypes of Joubert syndrome.
• Develop longitudinal, natural history studies using the registry to characterize development over the lifespan and factors related to positive outcome.
• Collect data from a sufficient number of families (particularly multiply-affected/consanguineous families) through the registry to increase the power of analysis for studies of phenotype and of genetic etiology.
• Continued study of animal models and mutant mice studies to rule out candidate genes and further investigate midbrain/hindbrain development.
• Addition of a neuropathologist and a nephrologist to the Joubert Syndrome Foundation scientific advisory board and to any scientific panel in the future.
• Conduct research relevant intervention, including study of family, community, and social factors as well as specific intervention strategies.

In addition, the panel generated a series of recommendations for translation of research for the community in hopes of reducing the burden for families through improved community response and support. The following vehicles for communication were suggested:

• An article for the Joubert Syndrome Foundation newsletter addressing issues regarding diagnosis, subtyping/overlapping conditions, and standards for monitoring relevant body systems.
• A written statement for the Joubert Syndrome Foundation website providing basic information about Joubert and basic standards of care (e.g., monitoring of retina and kidneys) for physicians
• A page for the Joubert Syndrome Foundation website providing contact information for key agencies supporting and treating children with special health care needs and their families.
• Creation of a system linking local professionals to experts in Joubert syndrome to promote better standards of care.

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Agenda

FUTURE RESEARCH DIRECTIONS IN JOUBERT SYNDROME

June 27-28 2002
New Orleans, Louisiana

Sponsors: the National Institute of Neurologic Disorders and Stroke (NINDS), the Office of Rare Diseases, and the Joubert Syndrome Foundation

AGENDA

Thursday June 27, 2002 (Southshore Room)

6:30 AM - 8:00 AM - Buffet Breakfast (Hotel Restaurant)

8:00 AM - 8:10 AM
Welcome and Statement of Workshop Goals
Bob Finkelstein and Bernard Maria

Current Approaches to Diagnosis and Management

8:10 AM - 8:50 AM
Clinical Manifestations and Management
Eugen Boltshauser and Bernard Maria

8:50 AM - 9:10 AM
Overlapping Conditions and Mimicry
Bill Dobyns

9:10 AM - 10:00 AM
Panel Discussion and Question and Answer Session

Break 10:00 AM - 10:30 AM

Genetics of Brain Development and Behavior

10:30 AM - 10:50 AM
Genetics of hindbrain and midbrain development
Tony Wynshaw-Boris

10:50 AM - 11:10 AM
Genetics of Joubert syndrome
Phil Chance

11:10 AM - 11:30 PM
Genetics of Autism
Tom Wassink

11:30 PM - 12:00 PM
Panel Discussion and Question and Answer Session

Lunch 12:00 PM - 1:00 PM (on your own)

Autism and Joubert Syndrome

1:00 PM - 1:45 PM
Heterogeneity in Autism
Judith Miles

1:45 PM - 2:45 PM
Behavior in Joubert Syndrome
Eileen Fennell

Break 2:45 PM - 3:15 PM

3:15 PM - 5:00 PM

Panel Discussion and Synopsis

Moderator: Bob Finkelstein

Closing Comments: Bernard Maria

6:00 PM -7:00 PM Dinner and Awards (Southshore Room)

Friday, June 28, 2002 (The Tchefuncte Room - 15th Floor)

7:30 AM - 9:30 AM (Continental Breakfast will be available)
Recommendations for Future Research Directions

Moderators: Bob Finkelstein and Bernard Maria

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Participant List

Michelle Abdulaziz
Vice President
Joubert Syndrome Foundation
2481 Orangewood Place
Simi Valley, CA 93065
Phone: (805) 527-1007
Fax: (805) 526-4202
michii@pacificnet.net

Karen Barnett, M.S.
Genetic Counselor
Department of Pediatrics
University of Washington
Box 356320, Room RR247
Seattle, WA 98195
Phone: (206) 352-6240
klb9@u.washington.edu

Craig Bennett, Ph.D.
Senior Research Fellow
Division of Genetics and Development
School of Medicine
University of Washington
HSB RR Wing RR-249
1959 NE Pacific Street
Seattle, WA 98195
Phone: (206) 616-3788
Fax: (206) 221-5132

Eugen Boltshauser, M.D.
Professor
Department of Pediatric Neurology
Children's Hospital
Steinwiesstrasse 75
CH-8032 Zuerich, Switzerland
Phone: (01) 266 73 30 [71 11]
Fax: (01) 266 71 63
eugen.boltshauser@kispi.unizh.ch

Barbara Braddock, M.S.
Developmental Psychology
Department of Psychology
University of Missouri - Columbia
3717 Bray Court
Columbia, MO 65203
Phone: (573) 445-8151
Fax: (573) 884-3543
bab718@mizzou.edu

Stephen Braddock, M.D.
Associate Professor of Child Health
Division of Medical Genetics
Department of Child Health
University of Missouri - Columbia
NW504, DC05800
One Hospital Drive
Columbia, MO 65212
Phone: (573) 882-6991
Fax: (573) 884-3543
braddocks@health.missouri.edu

Phillip Chance, M.D.
Professor and Chief
Division of Genetics and Development
University of Washington
Box 356320
Seattle, WA 98195
Phone: (206) 616-3787
Fax: (206) 221-5132
pchance@u.washington.edu

William Dobyns, M.D.
Department of Human Genetics
The University of Chicago
920 E. 58th Street, CLSC 319C
Chicago, IL 60637
Phone: (773) 834-3597
Fax: (773) 834-8470
wbd@bsd.genetics.uchicago.edu

Cheryl Duquette
President
Joubert Syndrome Foundation
6931 South Carlinda Avenue
Columbia, MD 21046
Phone: (410) 997-8084
joubertduquette@comcast.net

Janet Farmer, Ph.D.
Associate Professor
Department of Health Psychology
Department of Child Health
University of Missouri
Health Sciences Center
One Hospital Drive, DCO46.46
Columbia, MO 65212
Phone: (573) 882-8847
Fax: (573) 884-4540
farmerje@health.missouri.edu

Eileen B. Fennell, Ph.D.
Professor of Clinical and Health Psychology and Neurology
University of Florida
Box 100165
Health Sciences Center
Gainesville, FL 32610
Phone: (352) 265-0680 ext. 4-6893
Fax: (352) 265-0468
efennell@hp.ufl.edu

Robert Finkelstein, Ph.D.
Program Director
Neurogenetics Cluster
National Institutes of Health
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2143
Bethesda, MD 20892
Phone: (301) 496-5745
Fax: (301) 402-1501
finkelsr@ninds.nih.gov

Jill Gitten, Ph.D.
Pediatric Neuropsychology Fellow
Department of Psychiatry
Brown University
101 Forest Street
Providence, RI 02906
Phone: (401) 729-6200
Fax: (401) 729-6203
jill_gitten@brown.edu

Ian Glass, MB,Ch.B, M.D.
Associate Professor
University of Washington
Pediatrics and Medicine
CHRMC, CH-25
4800 Sand Point Way, NE
Seattle, WA 98105
Phone: (206) 528-5142
Fax: (206) 517-2495
iglass@chmc.org

Joe Gleeson, M.D.
Assistant Professor
Division of Pediatric Neurology
Department of Neurosciences
University of California, San Diego
9500 Gilman Drive, MTF 324
La Jolla, CA 92093
Phone: (858) 822-3535
Fax: (858) 534-1437
jogleeson@ucsd.edu

Kimberly Henley, B.S.
Medical Student - Research Assistant
Department of Child Health
University of Missouri Health Care
M741B, DC058.00
One Hospital Drive
Columbia, MO 65212
Phone: (573) 882-5738
Fax: (573) 884-5179
henleykm@health.missouri.edu

Ellen Horwitz, Ph.D.
Assistant Professor
Child Development and Neurology
University of Missouri
School of Medicine
One Hospital Drive
Columbia, MO 65212
Phone: (573) 882-2578
Fax: (573) 884-3543
horwitze@health.missouri.edu

Benson Hsu, A.B.
Department of Child Health
University of Missouri
1700 Forum Blvd., #1004
Columbia, MO 65203
Phone: (646) 245-4067
bshrz9@mizzou.edu

Adam Jackson, B.S., B.A.
Medical Student
Department of Child Health
University of Missouri
1514 S. Westminster Place
Columbia, MO 65203
Phone: (573) 445-7062
awj7a5@mizzou.edu

Danny Liu, B.S.
Research Specialist
Department of Child Health
University of Missouri
M741B, DC058.00
One Hospital Drive
Columbia, MO 65212
Phone: (573) 882-5738
Fax: (573) 884-5179
dtl9ac@mizzou.edu

Bernard Maria, M.D, MBA
Professor and Chairman
Department of Child Health
Universityof Missouri - Columbia
One Hospital Drive, DC058.00
Columbia, MO 65212
Phone: (573) 882-6882
Fax: (573) 884-5179
mariabl@missouri.edu

Kathleen McCann, Ph.D.
Post-Doctoral Fellow
Department of Health Psychology
University of Missouri - Columbia
One Hospital Drive, DCO46.46
Columbia, MO 65212
Phone: (573) 884-6446
Fax: (573) 884-4540
mccannk@missouri.edu

Judith Miles, M.D., Ph.D.
Professor and Director
Division of Medical Genetics
University of Missouri Hospitals and Clinics
One Hospital Drive
Columbia, MO 65212
Phone: (573) 882-8933
Fax: (573) 884-3543
milesjh@missouri.edu

Melissa Parisi, M.D., Ph.D.
Acting Instructor
Department of Pediatics
Children's Hospital and Regional Medical Center, CH-25
Division of Genetics and Development
4800 Sand Point Way, NE
Seattle, WA 98105
Phone: (206) 528-2689
Fax: (206) 517-2495
mparisi@u.washington.edu

Sussan Paydar, Ph.D.
Program Analyst
Neurogenetics Cluster
National Institutes of Health
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard, Room 2141
Bethesda, MD 20892
Phone: (301) 496-6012
Fax: (301) 402-1501
paydars@ninds.nih.gov

Nicole Takahashi, B.S.
Research Specialist
Division of Medical Genetics
University of Missouri
Columbia Hospital
One Hospital Drive
Columbia, MO 65212
Phone: (573) 884-1893
Fax: (573) 884-3543
takahashin@missouri.edu

Thomas Wassink, M.D.
Assistant Professor
Carver College of Medicine
Univeristy of Iowa
1-191 MEB
Iowa City, IA 52242
Phone: (319) 935-7743
Fax: (319) 353-3003
thomas-wassink@uiowa.edu

Anthony Wynshaw-Boris, M.D. Ph.D.
Associate Professor
Department of Pediatrics and Medicine
University of California
9500 Gilman Drive
La Jolla, CA 92093
Phone: (858) 822-3400
Fax: (858) 822-3409
awynshawboris@wcsd.edu

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