The Rett Syndrome Program Project at Baylor College of Medicine Alan K Percy, MD
The Baylor Rett syndrome (RS) program project has enrolled more than 60 of the anticipated 70 children to be evaluated over 5 years. The program is composed of 6 individual projects and a Core center for coordinating the evaluations and managing the data. The projects consist of I) Qinical assessment of RS; II) Status of communication skills in RS; III) Clinical neurophysiology and sleep in RS; IV) Epidemiology of RS; V) Molecular genetics in RS; and VI) Neuropathology of RS. This program project and a similar program at the Johns Hopkins University School of Medicine are complementary. Key words: Rett syndrome, research program, Baylor College of Medicine, neurophysiology, neuropathology, drug trial. Percy AK, The Rett syndrome program project at Baylor College of Medicine. Brain Dev 1990;12:8-10
The Rett syndrome (RS) report of Hagberg et al in 1983 [1] led to an explosion of interest in this remarkable disorder currently limited to females. Within a short time, the initial patients with RS were evaluated at the Baylor College of Medicine [2] and preliminary data developed regarding the possible role of the biogenic amine neurotransmitters in this disorder. These studies prompted the formation of the Rett Study Group (RSG) at Baylor. Through the efforts of the International Rett Syndrome Association, funding was provided for research in RS from the National Institute of Child Health and Human Development. The RSG formulated a program project application which was approved and became operational in May, 1988. This program project has enrolled more than 60 of the anticipated 70 children to be evaluated over five years. The studies, consisting of six research components (Table 1) and a Core center for data management, are described below. These research elements complement a similar program project at Johns Hopkins University School of Medicine. PROJECT I Project I is the clinical evaluation component and is the hub around which the other projects revolve. The studies
From the Rett Center, Baylor College of Medicine, Houston,TX. Correspondence address: Dr. Percy, 1 Baylor Plaza, Houston, TX 77030, USA.
in this project consist of five principal elements (Table 2). The first element represents the initial clinical contact with the RS patient at which time the diagnosis is confirmed according to established criteria [3,4] and the patient is staged according to the system of Hagberg and Witt-Engerstrom [5]. Appropriate testing is conducted to rule out other neurodegenerative disorders. Motor-behavioral assessment, the second element, consists of an analysis of the movement disorder using videotape and a scoring system of specific parameters as previously reported [6]. Initial results substantiate the clinical impression of progressive parkinsonian features [7]. The third element is an evaluation of cognitive junction by a team of child development specialists. The aim is to track components of psychomotor development over time using standardized testing modalities. In addition, alternative testing schemes which do not rely on a motor response are being employed in an attempt to isolate higher cortical processes from the limitations of motor function. Neurotransmitter analysis, the fourth element, indicates the measurement in cerebrospinal fluid of the biogenic amine metabolites (homovanillic acid, hydroxymethoxyphenyl glycol, and 5-hydroxYindoleacetic acid), biopterin, the crucial cofactor in the synthesis of the biogenic amines, and (3-endorphin, an endogenous opiate reported by Myer [8] to be elevated in RS. The fifth element, neuropharmacologic intervention, currently consists of a double-blind, placebo-controlled evaluation of the opiate antagonist, Naltrexone (Trexan-DuPont). In this study, 24 RS children in stages II and III [5] will be enrolled and treated for 4 months each with placebo
Table 1 Rett syndrome program project Baylor College of Medicine Project I.
Participants
Clinical assessment of the Rett Syndrome
Status of communication skills in the Rett syndrome III. Clinical neurophysiology and sleep in the Rett syndrome IV. Epidemiology of the Rett syndrome V. Molecular genetics in the Rett syndrome VI. Neuropathology of the Rett syndrome
II.
Alan Percy, Huda Zoghbi, Joseph Jankovic, W. Daniel Williamson Brad Stach, James Jerger, Roberta DiDonato Daniel Glaze, James Frost, Peter Hiatt Thomas J ones, Claudia Kozinetz Huda Zoghbi Dawna Armstrong, Makoto Igarashi, Jeffrey Browning
Table 2 Rett syndrome program project Baylor College of Medicine Project I: Clinical assessment of the Rett syndrome Clinical pa ttem Motor-behavioral assessment Cognitive function Neurotransmitter analysis Neuropharmacologic intervention
and Naltrexone with an intervening washout period of 1 month. The complete clinical assessment as well as the assessments in Projects II and III will be performed prior to entry into the study and at the end of each drug treatment phase. This model is suitable for the evaluation of other potential therapeutic modalities as well. As a control group, children with the diagnosis of infantile autism will undergo the same protocol.
PROJECT II Project II is designed to assess the status of communication skills in children with the Rett syndrome. This evaluation consists of two major elements. The first is an examination of receptive language function using standardized testing instruments under the direction of a speech pathologist. The aim is to utilize techniques which do not require a verbal response. The second element tests the clinical neurophysiology of the auditory system. In this element, standard audiologic testing is coupled with evoked brain stem responses as well as the middle and late latency components of the evoked responses. In the initial group of more than 20 RS girls, peripheral auditory function and ABR responses were normal whereas late latency responses were uniformly
abnormal indicating dysfunction at the level of auditory processing and integration (B Stach, personal communication).
PROJECT 1lI Project III examines clinical neurophysiology and sleep in the Rett syndrome. Building on available results [9, 10], this project seeks to extend our understanding of the temporal relationships between the encephalographic changes and the clinical patterns in RS. This is accomplished through longterm video/EEG/polygraphic recordings. As part of the neuropharmacological intervention in Project I, the short-acting opiate antagonist, Naloxone, has been evaluated during the recording sessions. Reductions in stereotypic behaviors and respiratory irregularities have been noted consistently between 30-60 minutes following administration of the Naloxone (D Glaze, personal communication). In addition, careful examination of pulmonary function has been carried out. In the first 25 girls examined, 21 had cessation of airflow during inspiration, expiration, or both, and direct laryngoscopy demonstrated obstruction of airflow at the level of the vocal cords in 5 of 7 girls examined [11].
PROJECT IV Project IV is an epidemiological study designed to identify all existing cases of RS in the state of Texas. This will be accomplished through the aid of relevant health care providers including" physicians, therapists, state agencies, and chronic health care facilities. At present, the network of contacts has been established and referrals are being received. All suspected cases of RS identified in this manner will be evaluated by one of the pediatric neurologists in the RSG following the acquisition of available medical information and a videotape recording, if feasible.
PROJECT V Project V is a laboratory-based examination of possible genetic mechanisms underlying RS. Using molecular biology techniques, this study is directed at finding a genetic marker for RS. Current efforts are concentrated to the X chromosome because of the sex-limited nature of RS, at least to the present time. Other studies will explore the possible role of mitochondrial DNA which is transmitted by the female.
PROJECT VI Project VI is devoted to the neuropathology of RS. This project has already yielded important information on the neuropathology of RS [12, 13], and continuing collaborations with other neuropathologists are ongoing.
Percy et al: Rett syndrome program project 9
CORE This segment of the program project is responsible for patient identification, coordination of the inpatient and outpatient evaluations, and data collecting, storage and retrieval, and analysis. The responsibility for patient intake and coordination of evaluations has been capably assumed by Rebecca Schultz, RN, PNP. The inpatient evaluations have been conducted by admission into the pediatric clinical research center at Texas Children's Hospital. This allows the smooth completion of the studies outlined in Projects I, II, and III while the child is in the medical center, obviating the need for daily trips to the various examination sites. Outpatient evaluations are carried out in the Blue Bird Clinic of the Methodist Hospital.
ACKNOWLEDGMENTS Support was provided by USPHS grants HD 24,234 and RR 00188, the Blue Bird Circle of Houston, the Texas Children's Hospital, and Compaq Computer Corporation. Dr. Percy is currently a Visiting Professor in the Department of Psychiatry and Neurochemistry, Gothenburg University, Gothenburg, Sweden.
REFERENCES 1. Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann Neurol 1983;14:471-9.
10 Brain & Development, Vol 12, No 1, 1990
2. Percy AK, Zoghbi H, Riccardi VM. Rett syndrome: initial experience with an emerging clinical entity. Brain Dev (Tokyo) 1985;7:300-4. 3. Hagberg B, Goutieres F, Hanefeld F, Rett A, Wilson J. Rett syndrome: criteria for inclusion and exclusion. Brain Dev (Tokyo). 1985;7:372-3. 4. The Rett Syndrome Diagnostic Criteria Work Group. Diagnostic criteria for Rett syndrome. Ann Neurol 1988;23: 425-8. 5. Hagberg B, Witt-Engerstrom I. Rett syndrome. A suggested staging system for describing impairment profIle with increasing age towards adolescence. Am J Med Genet 1986;24: 47-59. 6. Percy AK, Zoghbi HY, Lewis KR, Jankovic J. Rett syndrome: qualitative and quantitative differentiation from autism. J Child Neurol 1988;3:S65-7. 7. FitzGerald PM, Jankovic J, Percy A. Extrapyramidal involvement in Rett syndrome. Neurology 1989;39(suppll):140. 8. Budden S, Myer EC. CSF endorphins. 5th International Conference on Rett Syndrome. Vienna. 1988. 9. Glaze DG, Frost Jr JD, Zoghbi HY, Percy AK. Rett's syndrome: characterization of respiratory patterns and sleep. Ann Neurol 1987;21:371-82. 10. Glaze DG, Frost Jr JD, Zoghbi HY, Percy AK. Rett's syndrome: correlation of electroencephalographic characteristics with clinical staging. Arch Neurol 1987 ;44: 1053-6. 11. Hiatt PW, Glaze DG, Frost Jr JD. Airflow obstruction in children with Rett syndrome. Pediatr Res 1989;25 (part 2): 356A. 12. Jellinger K, Armstrong D, Zoghbi HY, Percy AK. Neuropathology of Rett syndrome. Acta Neuropathol 1988;76: 142-58. 13. Armstrong D. Neuroendocrine pathology. 5th International Conference on Rett Syndrome. Vienna. 1988.
The Baylor Rett syndrome (RS) program project has enrolled more than 60 of the anticipated 70 children to be evaluated over 5 years. The program is composed of 6 individual projects and a Core center for coordinating the evaluations and managing the data. The projects consist of I) Qinical assessment of RS; II) Status of communication skills in RS; III) Clinical neurophysiology and sleep in RS; IV) Epidemiology of RS; V) Molecular genetics in RS; and VI) Neuropathology of RS. This program project and a similar program at the Johns Hopkins University School of Medicine are complementary. Key words: Rett syndrome, research program, Baylor College of Medicine, neurophysiology, neuropathology, drug trial. Percy AK, The Rett syndrome program project at Baylor College of Medicine. Brain Dev 1990;12:8-10
The Rett syndrome (RS) report of Hagberg et al in 1983 [1] led to an explosion of interest in this remarkable disorder currently limited to females. Within a short time, the initial patients with RS were evaluated at the Baylor College of Medicine [2] and preliminary data developed regarding the possible role of the biogenic amine neurotransmitters in this disorder. These studies prompted the formation of the Rett Study Group (RSG) at Baylor. Through the efforts of the International Rett Syndrome Association, funding was provided for research in RS from the National Institute of Child Health and Human Development. The RSG formulated a program project application which was approved and became operational in May, 1988. This program project has enrolled more than 60 of the anticipated 70 children to be evaluated over five years. The studies, consisting of six research components (Table 1) and a Core center for data management, are described below. These research elements complement a similar program project at Johns Hopkins University School of Medicine. PROJECT I Project I is the clinical evaluation component and is the hub around which the other projects revolve. The studies
From the Rett Center, Baylor College of Medicine, Houston,TX. Correspondence address: Dr. Percy, 1 Baylor Plaza, Houston, TX 77030, USA.
in this project consist of five principal elements (Table 2). The first element represents the initial clinical contact with the RS patient at which time the diagnosis is confirmed according to established criteria [3,4] and the patient is staged according to the system of Hagberg and Witt-Engerstrom [5]. Appropriate testing is conducted to rule out other neurodegenerative disorders. Motor-behavioral assessment, the second element, consists of an analysis of the movement disorder using videotape and a scoring system of specific parameters as previously reported [6]. Initial results substantiate the clinical impression of progressive parkinsonian features [7]. The third element is an evaluation of cognitive junction by a team of child development specialists. The aim is to track components of psychomotor development over time using standardized testing modalities. In addition, alternative testing schemes which do not rely on a motor response are being employed in an attempt to isolate higher cortical processes from the limitations of motor function. Neurotransmitter analysis, the fourth element, indicates the measurement in cerebrospinal fluid of the biogenic amine metabolites (homovanillic acid, hydroxymethoxyphenyl glycol, and 5-hydroxYindoleacetic acid), biopterin, the crucial cofactor in the synthesis of the biogenic amines, and (3-endorphin, an endogenous opiate reported by Myer [8] to be elevated in RS. The fifth element, neuropharmacologic intervention, currently consists of a double-blind, placebo-controlled evaluation of the opiate antagonist, Naltrexone (Trexan-DuPont). In this study, 24 RS children in stages II and III [5] will be enrolled and treated for 4 months each with placebo
Table 1 Rett syndrome program project Baylor College of Medicine Project I.
Participants
Clinical assessment of the Rett Syndrome
Status of communication skills in the Rett syndrome III. Clinical neurophysiology and sleep in the Rett syndrome IV. Epidemiology of the Rett syndrome V. Molecular genetics in the Rett syndrome VI. Neuropathology of the Rett syndrome
II.
Alan Percy, Huda Zoghbi, Joseph Jankovic, W. Daniel Williamson Brad Stach, James Jerger, Roberta DiDonato Daniel Glaze, James Frost, Peter Hiatt Thomas J ones, Claudia Kozinetz Huda Zoghbi Dawna Armstrong, Makoto Igarashi, Jeffrey Browning
Table 2 Rett syndrome program project Baylor College of Medicine Project I: Clinical assessment of the Rett syndrome Clinical pa ttem Motor-behavioral assessment Cognitive function Neurotransmitter analysis Neuropharmacologic intervention
and Naltrexone with an intervening washout period of 1 month. The complete clinical assessment as well as the assessments in Projects II and III will be performed prior to entry into the study and at the end of each drug treatment phase. This model is suitable for the evaluation of other potential therapeutic modalities as well. As a control group, children with the diagnosis of infantile autism will undergo the same protocol.
PROJECT II Project II is designed to assess the status of communication skills in children with the Rett syndrome. This evaluation consists of two major elements. The first is an examination of receptive language function using standardized testing instruments under the direction of a speech pathologist. The aim is to utilize techniques which do not require a verbal response. The second element tests the clinical neurophysiology of the auditory system. In this element, standard audiologic testing is coupled with evoked brain stem responses as well as the middle and late latency components of the evoked responses. In the initial group of more than 20 RS girls, peripheral auditory function and ABR responses were normal whereas late latency responses were uniformly
abnormal indicating dysfunction at the level of auditory processing and integration (B Stach, personal communication).
PROJECT 1lI Project III examines clinical neurophysiology and sleep in the Rett syndrome. Building on available results [9, 10], this project seeks to extend our understanding of the temporal relationships between the encephalographic changes and the clinical patterns in RS. This is accomplished through longterm video/EEG/polygraphic recordings. As part of the neuropharmacological intervention in Project I, the short-acting opiate antagonist, Naloxone, has been evaluated during the recording sessions. Reductions in stereotypic behaviors and respiratory irregularities have been noted consistently between 30-60 minutes following administration of the Naloxone (D Glaze, personal communication). In addition, careful examination of pulmonary function has been carried out. In the first 25 girls examined, 21 had cessation of airflow during inspiration, expiration, or both, and direct laryngoscopy demonstrated obstruction of airflow at the level of the vocal cords in 5 of 7 girls examined [11].
PROJECT IV Project IV is an epidemiological study designed to identify all existing cases of RS in the state of Texas. This will be accomplished through the aid of relevant health care providers including" physicians, therapists, state agencies, and chronic health care facilities. At present, the network of contacts has been established and referrals are being received. All suspected cases of RS identified in this manner will be evaluated by one of the pediatric neurologists in the RSG following the acquisition of available medical information and a videotape recording, if feasible.
PROJECT V Project V is a laboratory-based examination of possible genetic mechanisms underlying RS. Using molecular biology techniques, this study is directed at finding a genetic marker for RS. Current efforts are concentrated to the X chromosome because of the sex-limited nature of RS, at least to the present time. Other studies will explore the possible role of mitochondrial DNA which is transmitted by the female.
PROJECT VI Project VI is devoted to the neuropathology of RS. This project has already yielded important information on the neuropathology of RS [12, 13], and continuing collaborations with other neuropathologists are ongoing.
Percy et al: Rett syndrome program project 9
CORE This segment of the program project is responsible for patient identification, coordination of the inpatient and outpatient evaluations, and data collecting, storage and retrieval, and analysis. The responsibility for patient intake and coordination of evaluations has been capably assumed by Rebecca Schultz, RN, PNP. The inpatient evaluations have been conducted by admission into the pediatric clinical research center at Texas Children's Hospital. This allows the smooth completion of the studies outlined in Projects I, II, and III while the child is in the medical center, obviating the need for daily trips to the various examination sites. Outpatient evaluations are carried out in the Blue Bird Clinic of the Methodist Hospital.
ACKNOWLEDGMENTS Support was provided by USPHS grants HD 24,234 and RR 00188, the Blue Bird Circle of Houston, the Texas Children's Hospital, and Compaq Computer Corporation. Dr. Percy is currently a Visiting Professor in the Department of Psychiatry and Neurochemistry, Gothenburg University, Gothenburg, Sweden.
REFERENCES 1. Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann Neurol 1983;14:471-9.
10 Brain & Development, Vol 12, No 1, 1990
2. Percy AK, Zoghbi H, Riccardi VM. Rett syndrome: initial experience with an emerging clinical entity. Brain Dev (Tokyo) 1985;7:300-4. 3. Hagberg B, Goutieres F, Hanefeld F, Rett A, Wilson J. Rett syndrome: criteria for inclusion and exclusion. Brain Dev (Tokyo). 1985;7:372-3. 4. The Rett Syndrome Diagnostic Criteria Work Group. Diagnostic criteria for Rett syndrome. Ann Neurol 1988;23: 425-8. 5. Hagberg B, Witt-Engerstrom I. Rett syndrome. A suggested staging system for describing impairment profIle with increasing age towards adolescence. Am J Med Genet 1986;24: 47-59. 6. Percy AK, Zoghbi HY, Lewis KR, Jankovic J. Rett syndrome: qualitative and quantitative differentiation from autism. J Child Neurol 1988;3:S65-7. 7. FitzGerald PM, Jankovic J, Percy A. Extrapyramidal involvement in Rett syndrome. Neurology 1989;39(suppll):140. 8. Budden S, Myer EC. CSF endorphins. 5th International Conference on Rett Syndrome. Vienna. 1988. 9. Glaze DG, Frost Jr JD, Zoghbi HY, Percy AK. Rett's syndrome: characterization of respiratory patterns and sleep. Ann Neurol 1987;21:371-82. 10. Glaze DG, Frost Jr JD, Zoghbi HY, Percy AK. Rett's syndrome: correlation of electroencephalographic characteristics with clinical staging. Arch Neurol 1987 ;44: 1053-6. 11. Hiatt PW, Glaze DG, Frost Jr JD. Airflow obstruction in children with Rett syndrome. Pediatr Res 1989;25 (part 2): 356A. 12. Jellinger K, Armstrong D, Zoghbi HY, Percy AK. Neuropathology of Rett syndrome. Acta Neuropathol 1988;76: 142-58. 13. Armstrong D. Neuroendocrine pathology. 5th International Conference on Rett Syndrome. Vienna. 1988.
