Movement Disorders Vol. 5, No. 3, 1990, pp. 195-202. 0 1990 Movement Disorder Society
Rett Syndrome and Associated Movement Disorders Patricia M. FitzGerald, Joseph Jankovic, and *Alan K. Percy Baylor College of Medicine Department of Neurology and *Department of Pediatrics, Houston, Texas, U.S.A.
Summary: Rett syndrome, a progressive neurodegenerativedisorder described only in female subjects, is manifested by a wide spectrum of behavioral and motor abnormalities. We studied 32 patients with this disorder, ages 30 months to 28 years old, and characterized their extrapyramidal disturbance. The most common motor abnormalities were stereotyped movements and gait disturbance, seen in all patients. Bruxism, oculogyric crises, parkinsonism, and dystonia were also common, but myoclonus and choreoathetosis were seen only infrequently. The hyperkinetic movement disorders tended to dominate in younger patients, while bradykinetic disorders were more evident in the older patients. This study provides evidence that movement disorders seen in Rett syndrome reflect age-related neurodegenerative changes in the basal ganglia. Key Words: Rett syndrome-Stereotypies-Gait disturbance-BruxismOculogync crisis-Parkinsonism-Dystonia-Myoclonus-Chorea.
PATIENTS AND METHODS
In 1966, Rett described 22 girls with progressive cerebral atrophy and characteristic clinical features including stereotyped hand movements, oligophrenia, alalia, gait apraxia, spasticity, mental retardation, and a tendency to convulsive attacks (1,2). This disorder was subsequently named Rett’s Syndrome by Hagberg et al. (3), who studied 35 female subjects and emphasized autistic behavior, acquired microcephaly , jerky truncal ataxia, and vasomotor disturbance. Hagberg et al. (4), later proposed inclusion and exclusion criteria for Rett syndrome, and described a staging system (5). Diagnostic criteria for this syndrome were further defined in 1988 (6). Stereotyped hand movements, gait disturbance, and dystonia have been previously noted in Rett syndrome and are included in the necessary or supportive diagnostic criteria (6a). However, other movement disorders are less well documented. We therefore studied 32 Rett patients to characterize the full spectrum of extrapyramidal involvement in this neurodegenerative disease.
Of 41 female patients seen with Rett syndrome at the Baylor College of Medicine Movement Disorder Clinic, 32 had a complete data base including ratings on the Motor-Behavioral Assessment Scale and at least two separate videotapes. They ranged in age from 30 months to 28 years and satisfied the diagnostic criteria for Rett syndrome (6). The patients were arbitrarily divided into three groups according to age at the time of evaluation: Group 1, 8 years old. Different motor characteristics were rated on the Motor-Behavioral Assessment Scale: 0, normal or never; 1, mild or rare; 2, moderate or occasional; 3, marked or frequent; and 4, very severe or constant (Appendix). All patients were videotaped at least once, and some several times, over a 2-year follow-up period. Extensive electrophysiologic studies and sleep studies have been performed as part of a multi-disciplinary Rett project, and these results will be reported separately.
A videotape segment accompanies this article. Address correspondence and reprint requests to Dr. Joseph Jankovic, Professor of Neurology at Department of Neurology, Baylor College of Medicine, 6550 Fannin, #1801, Houston, Texas 77030, U.S.A.
STATISTICAL METHODS The differences between the three groups in terms of severity scores were assessed using non-
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parametric analysis of variance and the Kruskal Wallis test. Intercorrelations among the clinical variables were evaluated using the Spearman rank order correlation test. ILLUSTRATIVE CASES
Patient 1 This 3%-year-old girl was the product of a fullterm normal delivery. Developmental milestones were normal through the first year of life, at which time she was thought to be “slow in walking.” Additionally, she was noted to repetitively touch her eyelids and look upwards. From 15 to 18 months, her social interaction deteriorated, she lost her vocabulary, became irritable and clumsy, and stopped playing with her toys. She walked alone, but had a very broad-based and unsteady gait. Stereotyped wiggling finger movements were present almost constantly and she frequently placed her fingers and hands over her mouth. At evaluation she smiled and appeared to be aware of her environment, but did not obey verbal commands. She had no intelligible speech and exhibited total indifference to painful stimuli including pinching or having blood drawn. There was severe bruxism, with moderate drooling and air saliva expulsion. She continuously moved her hands over her mouth or licked her hands. There were intermittent choreoathetotic movements of her arms and hands. She frequently rocked and walked with a broad-based and ataxic gait (videotape segment 2). Patient 2 This girl was 5 years and 7-months old. She was delivered at 7 months because of premature rupture of membranes. There was normal postnatal development, but at 1 year of age bilateral hand shaking was noted. Although she could stand, she could not walk. She then became progressively more unstable, and lost her ability to sit. At 2 years and 6 months, she completely lost her limited vocabulary, no longer used her hands in a purposeful fashion, and had repetitive stereotyped movements of the fingers of her left hand and bilateral hand-washing and wringing. On examination, she did not sustain any interest in objects or people, had poor eye contact, and produced no sounds except for loud bruxism. Oculogyric crises, manifested by conjugate deviations of her eyes upward and laterally, were intermittently observed. She had moderate rigidity of
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all extremities, with brisk knee and ankle jerks. She did not reach for or hold things with her hands, but repetitively performed handwashing and wringing movements. Severe dystonic posturing of both feet precluded even bearing weight on her lower limbs (videotape segment 5 ) . Occasional spontaneous generalized myoclonic jerks were seen. She had a moderate degree of scoliosis, and vasomotor skin changes with coldness and livedo reticularis were evident in both legs. She was completely insensitive to painful stimuli. Patient 3 This is a girl 5 years and 6 months old whose developmental milestones were appropriate until 9 months of age, when she no longer could sit or crawl. She used about 15 words, but by 14 months she no longer spoke, and had developed some autistic features and irritability. She had brief episodes of repetitive blinking, loud laughing, and momentary falling forward. She stopped reaching for toys and did not appear to understand verbal commands. From that time, no new skills were learned. During examination she interacted poorly and did not verbalize. She had severe bruxism, with hyperventilation and breathholding. There were almost constant ocular deviations and she either mouthed her hands or made repetitive waving movements or sequential finger movements, but was unable to grasp any objects. Although she could stand with support, she was unable to walk, and had continuous myoclonic jerking of all extremities, with dystonic posturing of both feet (videotape segment 6). Moderate rigidity with hyperreflexia was present in all extremities. Patient 4 This 20-year-old woman developed normally until 18 months of age when she became withdrawn,
“acted deaf,” and had an unsteady gait. She lost her previous vocabulary of 15-20 words, and by 24 months was unable to walk. At 26 months she had completely lost the use of her hands and speech, rocked constantly, and frequently screamed for no apparent reason. Stereotyped hand movements characterized by clenching her hands together, either in front of or behind her body, or clapping, became prominent and almost constant. Her gait slowly improved, but was remarkable for a wide base, shuffling, toe-walking, and postural instabil-
RETT SYNDROME AND ASSOCIATED DISORDERS ity. For the past 3 years she has had progressive motor slowing and has developed blepharospasm, facial grimacing, and jaw clenching. On examination, she avoided eye contact and made moaning and occasionally shrieking sounds. She was markedly bradykinetic and except for some facial dystonic movements including blepharospasm and trismus, she had no facial expression. Assistance to arise from a chair was needed, but she could walk alone with a broad-based gait. She had marked dystonic flexion of her fingers and hands (videotape segment 7). Hyperreflexia with rigidity was present in all limbs. Patient 5 This 28-year-old woman was first noted to have neurologic difficulty at 12 months, when she developed truncal instability. She then began to lose previously attained milestones: grasp, speech, and stable gait. By 4 years of age, she completely lost purposeful use of her hands and had stereotyped movements including rubbing her palms together, clapping, and hand wringing. From that time, she had been unable to communicate, but has regained some grasping ability. Harrington rods were placed at 16 years for severe scoliosis. Examination showed marked hypomimia with drooling and no verbalization. She was moderately bradykinetic and rigid, but could arise from a chair without assistance, and walked with a broad-based unsteady gait (videotape segment 9). RESULTS Gait abnormalities were seen in all patients. A “jerky gait ataxia” was seen in 10 of 32 (31%) patients, nine (28%) were unable to walk, four (13%) had a broad-based gait, one toe walked, and eight
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had mixed features including toe walking and a broad base. Of the stereotyped hand movements, also seen in all patients, clapping, wringing, and clenching were most common. We divided the other movement abnormalities into two major groups: hyperkinetic (Table 1) and hypokinetic (Table 2). Of the hyperkinetic disorders, bruxism was most common, seen in 97%. This occurred chiefly during daytime and was only rarely seen during sleep. Oculogyric crises, seen in 63%, generally consisted of brief eye deviations in an upward direction. Although some parents described these as “seizures,” they occurred without associated epileptiform electroencephalographic activity, or clinical epileptiform features. Of the 19 patients with dystonia, crural involvement was the most common, followed by generalized dystonia and then focal dystonia of either foot. Scoliosis, possibly indicative of truncal dystonia, was seen in 50%. Head or truncal jerking was most common in the 11 patients with myoclonus, while those with choreoathetosis (13%) had predominantly distal involvement. In the hypokinetic group, hypomimia was the most common finding, seen in 63%. Drooling was seen in 75% of patients, but we did not include it among the hypokinetic symptoms because we felt that this was a nonspecific finding, possibly due to poor posterior pharyngeal control. Some degree of rigidity and bradykinesia was seen in 44% and 41% of patients, respectively. Tremor, although historically reported in one patient, was not seen in any patient during the examination. A statistically significant difference in the occurrence of the various movement disorders between the groups was found only for hypomimia (p < 0.05), which was more common and more severe in older patients. The individual variables that were
TABLE 1. Extrapyramidal involvement in Rett syndrome: hyperkinetic disorders Group I (N = 10)
Group 2 (N = 11)
Group 3 (N = 11)
Characteristic
MeanVSD
N
MeadSD
N
MeadSD
N
Bruxism Oculogyric crises Dystonia Scoliosis Myoclonus Athetosis
3.010.8 1.511.3 0.811.1 0.510.8 0.010.0 0.410.7
10 7 4 4 0 3
2.510.9 1.811.5 1.511.4 1.210.9 1.211.2 0.010.0
11 7 7 8 6 0
2.111.3 0.9/1.1 1.70.2 1.111.4 0.911.1 0.2/0.6
10 6 8 4 5 1
a
Mean, mean value on the Motor-Behavioral Assessment Scale.
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TABLE 2. Extrapyramidal involvement in Rett syndrome: hypokinetic disorders Group 1 (N = 10)
Group 2 (N = 11)
Group 3 (N = 11)
Characteristic
Mean“1SD
N
MeanlSD
N
MeadSD
N
Hypomimia Rigidity Bradykinesia
0.511.0 0.411.0 0.6/1.1
3 2 3
1.611.2 1.111.2 0.711.3
9
2.011.6 1.411.5 1.311.4
8 6 6
6 4
Mean, mean value on the Motor-Behavioral Assessment Scale.
found to correlate positively with each other were bradykinesia with hypomimia and rigidity, and rigidity with dystonia, hypomimia, and myoclonus (p < 0.05). Although parkinsonian findings (bradykinesia and rigidity) seemed to be more common in older girls, this trend did not reach statistical significance.
DISCUSSION Stereotypic hand movements and “gait apraxia” have been well described in Rett snydrome, and are included in the necessary criteria for diagnosis of this disorder (1-6). The stereotypic movements include apposition of hands, finger kneading and rubbing, hand clapping and washing, wringing, squeezing, twisting, and pillrolling (1-14) (Fig. 1). The gait disorder has been difficult to characterize. Rett described slow, short steps with wide swaying movements, and later appearance of tiptoe walking (1,2). In Hagberg et al.’s series (3), the gait was described as unstable, rigid, and shuffling, associated with a jerky truncal ataxia while sitting unsupported. Similar gait disturbances have been described in other series (7-11). Of 52 ambulatory patients studied by Coleman et al. (7), 42% had toe walking. Naidu et al. (11), noted evolution in gait from a wide-based clumsy gait, through toe-walking with gait apraxia. However, the term “gait apraxia” may not be an appropriate designation in these patients because they are invariably cognitively impaired and have additional motor disturbances. Of our ambulatory patients, the most common disturbance was gait ataxia with marked unsteadiness, followed by a broad-based gait. After stereotypies and gait disturbance, bruxism was otherwise the most common motor disturbance seen in our patients, present in 97% (Table 3). This form of oromandibular dystonia has been also encountered frequently in other series (3,7,8,10-14). In contrast to nocturnal bruxism, jaw clenching, and tooth grinding in our patients was most evident
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during daytime, and ceased in sleep. In one study, 95% of Rett patients had grinding of teeth, which was viewed by us as a self-abusive behavior (7). Others have described bruxism in the context of stereotyped movements (3,12), or in association with the respiratory abnormalities of hyperventilation and breath holding @,IO,ll). Bruxism is common in mentally retarded individuals, with a prevalence of 21.5% in one series (15). Often thought to be a manifestation of dental pathology, occuring in
FIG. 1. This 71h-year-old girl with Rett syndrome has moderate parkinsonia findings, manifested here by hypomimia and typical stereotyped hand movements.
RETT SYNDROME AND ASSOCIATED DISORDERS TABLE 3 . Extrapyramidal involvement in Rett syndrome Characteristic
Percent of total
Stereotyped movements Gait disorder Bruxism Drooling Oculogyric crises H ypomimia Dystonia Scoliosis Rigidity Bradykinesia Myoclonus Athetosis
100 100 97 75 63 63 59 50 44 41 34 13
-20% of dental patients, bruxism has also been viewed as a psychophysiological disorder, a sign of organic brain damage, or a familial disorder (16). We believe that bruxism, which is often accompanied by facial grimacing, seen in some Rett patients represents a form of oro-facial-mandibular dystonia. Oculogyric crises, another form of focal dystonia, were evident in 63% of our patients. Other authors have mentioned staring episodes (7,17), and “upward eye rolling or a vacant stare” (3). These ocular movements may be difficult to differentiate from seizures (3,18). However, in our patients these episodes did not correlate with electroencephalographic epileptiform activity. Other dystonic movements and postures, seen in 59% of our patients, included generalized, crural, and focal dystonia. Progressive dystonia and dystonic movements, often accompanied by choreoathetosis, were also noted in other, smaller series of Rett patients (12,17). Scoliosis, a possible complication of chronic axial dystonia, was seen in 50% of our patients. This skeletal abnormality has been previously emphasized in Rett syndrome, but the mechanism is still unknown (2,3,7,1&12,14,19-22). Scoliosis has been typically seen in the thoracolumbar region and is generally unresponsive to bracing (20,21). Of the hyperkinetic disorders, myoclonus and choreoathetosis were least common in our patients, and tremor was not seen in any patient. The predominantly proximal myoclonus, present in 34% of the total group, has been mentioned, but not well documented, in other series (3,7,19). Hagberg et al. (3) described a “jerky truncal ataxia” that also often involves the limbs. A careful analysis of our
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patients with this “jerky ataxia” suggests that this peculiar movement disorder represents a combination of cerebellar ataxia and myoclonus. Others have also noted myoclonic jerks (7) or “jerky and writhing movements” (19). Al-Matten et al. (12) described choreoathetosis in 8 of 15 patients, but this hyperkinesia was seen in only 13% of our patients. We considered hypomimia, bradykinesia, drooling, and rigidity to represent parkinsonian findings. Drooling, the most common of these findings seen in 75% of our patients, has been seen frequently in other series (2,8). Rett (2) commented on the presence of diminished facial expression, with a masklike face in older children. In our patients, this was the only abnormality that correlated significantly with age. Although rigidity (seen in 44%) and bradykinesia (41%) tended to be more prevalent in older girls, this trend did not reach statistical significance. The gait disturbance seen in older girls, although resembling a parkinsonian gait (3,%lo), is characterized by a broad stance rather than the narrow-based gait typically seen in Parkinson’s disease. The underlying pathophysiologic basis for these extrapyramidal disturbances has not been established. Neuropathologic studies have been remarkable for brain atrophy and microcephaly, spongy changes in the cerebral and cerebellar white matter, lipofuscin deposition, and hypopigmentation of the substantia nigra (2,23,24). Incomplete melanization of the locus coeruleus has also been noted (25,26). Postmortem neurochemical studies are difficult to interpret because many of the Rett patients have severe malnutrition before death. Brucke et al. (25), in a single postmortem study, showed severe reduction in dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in most regions studied, with increases in the 3-4-dihydroxyphenyl acetic acid (DOPAC)/DA, homovanillic acid (HVA)/DA, and the 5-hydroxyindole acetic acid (5-HIAAh-HT ratios, suggesting increased turnover of DA and 5HT. Sofic et al. (261, found considerable reductions in ascorbic acid and reduced glutathione in most areas studied, but suggested that this might be a secondary phenomenon, related to malnutrition. Cerebrospinal fluid (CSF) monoamine metabolites of NE and DA were significantly reduced in the Zoghbi et al. (27) study of 6 patients with Rett syndrome. In a follow-up study of 32 patients, reductions were also noted in 5-HT metabolites, but total CSF biopterin levels were increased (28). In con-
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trast, Sahota et al. (29) reported normal serum and urinary biopterin levels with normal dihydropteridine reductase activity. Normal CSF monoamine metabolites, y-aminobutyric acid and amino acid levels have been reported by Riederer et al. (30) and Perry et al. (31). Positron emission tomographic scanning and neuroimaging studies have not been helpful in delineating any specific abnormalities (24,32). In this study of 32 patients with Rett syndrome we found that the expression of underlying extrapyramidal dysfunction seemed to be age determined, with a trend toward progression from a hyperkinetic to a bradykinetic state. This evolution in the spectrum of extrapyramidal findings may reflect a more rapid maturation of the striatum in Rett patients as compared with the normal age-related changes. Administration of levodopa to neonatal 6-hydroxydopamine (6-OHDA)-treated rats results in stereotypies and self-mutilating behavior (33). In contrast, adult 6-OHDA-treated rats display paw treading and head nodding. These findings of age-dependent effects of dopamine agonists on experimental stereotypic behaviors may provide insight into the curious evolution of clinical findings in Rett syndrome. Acknowledgment: We thank Dr. Deborah del Junco and Ms. Yue-Chune Lee for their technical assistance. This study was supported in part by the NIH/HDMR, grant number HD24234, and in part by a grant to the General Clinical Research Center, Texas Children’s Hospital, NIH grant number MOIRR00188.
LEGENDS TO THE VIDEOTAPE SEGMENT 1. Hand stereotypies and irregular breathing are seen in this 3-year-old girl with Rett syndrome. SEGMENT 2. This 3-year and 6-month-old girl demonstrates complex stereotyped hand movements with mouthing, choreic movements in arms, and a broad-based gait (illustrative case 1). SEGMENT 3. This is a 3-year and 10-month-old girl with severe bruxism, mouthing, and breathholding. SEGMENT 4. This 5-year-old girl demonstrates stereotyped hand movements, breath-holding, hyperventilation, rocking, and toe-walking. SEGMENT 5. Severe crural dystonia and stereotyped hand movements are seen in this 5-year and 6-month-old girl (illustrative case 2). SEGMENT 6. This 5-year and 7-month-old girl demonstrates generalized myoclonus, foot dystonia, and a broad-based stance (illustrative case 3). SEGMENT 7. In addition to the typical broadbased gait, this 20-year-old woman with Rett syndrome also has hand and facial dystonia with blepharospasm (illustrative case 4). SEGMENT 8. Severe hypomimia, body bradykinesia, and toe-walking are evident in this 28year-old woman. SEGMENT 9. This 20-year-old woman demonstrates moaning, hypomimia, hand stereotypies, body rocking, scoliosis, foot dystonia, and toewalking (illustrative case 5).
APPENDIX Rett Syndrome Motor-Behavioral Assessment Current assessment score I. BehaviorallSocial Assessment 1. Regression of motor skills 2. Regression of verbal skills 3. Poor eyelsocial contact 4. Lack of sustained interest 5. Imtability, crying tantrums 6 . Overactiveloverpassive (Circle one) 7. Does not reach for objects or people 8. Does not follow verbal commands, acts as deaf 9. Feeding difficulties 10. Chewing difficulties 1 1 . Lack of toilet training 12. Masturbation
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Age in months condition was at its worst
Assessment score at that time
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
3 3 3 3 3 3 3
4 4 4 4 4 4 4
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
3 3 3 3 3 3 3
4 4 4 4 4 4 4
0 0 0 0 0
1 1 1 1 1
2 2 2 2 2
3 3 3 3 3
4 4 4 4 4
0 0 0 0 0
1 1 1 1 1
2 2 2 2 2
3 3 3 3 3
4 4 4 4 4
Comment
201
RETT SYNDROME AND ASSOCIATED DISORDERS APPENDIX
13. Self-mutilation (pulling hair or ears, scratching, etc.) 14. Aggressive behavior (head banging, throwing, spitting, etc.) 15. Seizures 16. Apparent insensitivity to pain 17. Subtotal (TOTAL OF EACH ITEM ABOVE) 11. Orofuciul/Respirutory Assessment 18. Speech disturbance 19. Bruxism 20. Breath holding 2 1. Hyperventilation 22. Air-saliva expulsioddrooling 23. Mouthing of hands and objects 24. Biting self or others 25. Subtotal (TOTAL OF EACH ITEM ABOVE) 111. Motor AssessmentlPhysicul Signs 26. Hand clumsiness 27. Stereotypic hand washing, rubbing, clapping, stroking, kneading. 28. Ataxidapraxia (gait and trunk) 29. Truncal rockingfshifting weight 30. Oculogyric movements 3 1. Bradykinesia 32. Dystonia 33. Hypomimia 34. Scoliosis 35. Myoclonus 36. Choredathetosis 37. Hypertonidrigidity 38. Hyperreflexia 39. Vasomotor disturbance 40. Subtotal (TOTAL OF EACH ITEM ABOVE)
continued
Current assessment score
Age in months condition was at its worst
Assessment score at that time
0 1 2 3 4
---
0 1 2 3 4
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
-------
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
--
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
Comment
3 3 3 3 3 3 3
4 4 4 4 4 4 4
---------------
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
3 3 3 3 3 3 3
4 4 4 4 4 4 4
--
__
0 1 2 3 4 0 0 0 0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3 3 3 3 3 3
4 4 4 4 4 4 4 4 4 4 4 4 4
-
0 0 0 0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3 3 3 3 3 3
4 4 4 4 4 4 4 4 4 4 4 4 4
--
0, Normal or never; I , mild or rare; 2, moderate or occasional; 3, marked or frequent; 4, very severe or constant.
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6. The Rett Syndrome Diagnostic Criteria Work Group. Diagnostic criteria for Rett syndrome. Ann Neurol 1988;23:425428. 6a. FitzGerald PM, Jankovic J, Glaz DG, Schultz R, Percy AK. Extrapyramidal involvement in Rett’s syndrome. Neurology 1990;40:293-295. 7. Coleman M, Brubaker J, Hunter K, Smith G. Rett syndrome: a survey of North American patients. J Ment D e j k Res 1988;32:117-124. 8. Suzuki H, Matsuzaka T, Hirayama Y, et al. Rett’s syndrome: progression of symptoms from infancy to childhood. J Child Neurol 1986;1:137-141. 9. Nomura Y, Segawa M, Hasegawa M. Rett’s syndromeclinical studies and pathophysiological considerations. Bruin Dev 1984;6:475486. 10. Ho HH, Wong PKH, Robertson R. Rett syndrome: clinical profile and EEG abnormalities. Clin Znvest Med 1988;ll: 234-241. 11. Naidu S, Murphy M, Moser HW, Rett A. Rett syndromenatural history in 70 cases. A m J Med Genet 1986;24:61-72.
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12. Al-Mateen M, Philippart M, Shields D. Rett syndrome. A commonly overlooked progressive encephalopathy in girls. Am J Dis Child 1986;140:761-765. 13. Verma NP, Chheda RL, Nigro MA, Hart ZH. Electroencephalographic findings in Rett syndrome. Eleciroencephalogr Clin Neurophysiol 1986;64:394401. 14. Coleman M, Naidu S, Murphy M, Pines M, Bias W. A set of monozygotic twins with Rett syndrome. Brain Dev 1987;9: 475-478. 15. Blount RL, Drabman RS, Wilson N, Stewart D. Reducing severe diurnal bruxism in two profoundly retarded females. J Appl Behav Anal 1982;15:565-571. 16. Glaros AG, Rao SM. Bruxism: a critical review. Psycho1 Bull 1977;84:767-781. 17. Philippart M. Clinical recognition of Rett syndrome. Am J Med Genet 1986;24:111-118. 18. FitzGerald PM, Jankovic J. Tardive oculogyric crises. Neurology 1989;39:143k1437. 19. Kerr AM, Stephenson JBP. A study of the natural history of Rett syndrome in 23 girls. Am J Med Genet 1986;24:77-83. 20. Keret D, Bassett GS, Bunnell WP, Marks HG. Scoliosis in Rett syndrome. J Pediat Orthop 1988;8:138-142. 21. Hennessy MJ, Haas RH. The orthopedic management of Rett syndrome. J Child Neurol 1988;3:S43-S48. 22. Trevathan E, Naidu S. The clinical recognition and differential diagnosis of Rett syndrome. J Child Neuroll988;3:S6S16. 23. Jellinger K, Seitelberger F. Neuropathology of Rett syndrome. Am J Med Genei 1986;24:259-288. 24. Burd L, Gascon GG. Rett syndrome: review and discussion
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of current diagnostic criteria. J Child Neurol 1988;3:263268. 25. Brucke T, Sofic E, Killian W, Rett A, Riederer P. Reduced concentrations and increased metabolism of biogenic amines in a single case of Rett syndrome: a postmortem brain study. J Neural Transm 1987;68:315-324. 26. Sofic E,Riederer P, Killian W, Rett A. Reduced concentrations of ascorbic acid and glutathione in a single case of Rett syndrome: a postmortem brain study. Brain Dev 1987;9:529531. 27. Zoghbi HY,Percy AK, Glaze DG, Butler IJ, Riccardi VM. Reduction of biogenic amine levels in the Rett syndrome. N Engl J Med 1985;313:921-924. 28. Zoghbi HY, Milstien S, Butler IJ, et al. Cerebrospinal fluid biogenic amines and biopterin in Rett syndrome. Ann Neurol 1989;25:56-60. 29. Sahota A, Leeming R, Blair J , Hagberg B. Tetrahydrobiopterin metabolism in Rett disease. Brain Dev 1985;7:34%350. 30. Riederer P, Brucke T, Sofic E, et al. Neurochemical aspects of the Rett syndrome. Brain Dev 1985;7:351-360. 31. Perry TL, Dunn HG, Ho HH, Crichton JU. Cerebrospinal fluid values for monoamine metabolites, y-aminobutyric acid, and other amino compounds in Rett syndrome. J Pediatr 1988;112:234-238. 32. Naidu S, Wong DF, Sanche Roa P, et al. Rett syndrome: positron emission tomography: metabolic-clinical correlates. Ann Neurol 1988;24:305. 33. Breese GR, Baumeister AA, McCown TJ, et al. Behavioral differences between neonatal and adult 6-hydroxydopamine-treated rats to dopamine agonists: Relevance to neurological symptoms in clinical syndromes with reduced brain dopamine. J Pharmacol Exp Ther 1984;231:343-354.
Rett Syndrome and Associated Movement Disorders Patricia M. FitzGerald, Joseph Jankovic, and *Alan K. Percy Baylor College of Medicine Department of Neurology and *Department of Pediatrics, Houston, Texas, U.S.A.
Summary: Rett syndrome, a progressive neurodegenerativedisorder described only in female subjects, is manifested by a wide spectrum of behavioral and motor abnormalities. We studied 32 patients with this disorder, ages 30 months to 28 years old, and characterized their extrapyramidal disturbance. The most common motor abnormalities were stereotyped movements and gait disturbance, seen in all patients. Bruxism, oculogyric crises, parkinsonism, and dystonia were also common, but myoclonus and choreoathetosis were seen only infrequently. The hyperkinetic movement disorders tended to dominate in younger patients, while bradykinetic disorders were more evident in the older patients. This study provides evidence that movement disorders seen in Rett syndrome reflect age-related neurodegenerative changes in the basal ganglia. Key Words: Rett syndrome-Stereotypies-Gait disturbance-BruxismOculogync crisis-Parkinsonism-Dystonia-Myoclonus-Chorea.
PATIENTS AND METHODS
In 1966, Rett described 22 girls with progressive cerebral atrophy and characteristic clinical features including stereotyped hand movements, oligophrenia, alalia, gait apraxia, spasticity, mental retardation, and a tendency to convulsive attacks (1,2). This disorder was subsequently named Rett’s Syndrome by Hagberg et al. (3), who studied 35 female subjects and emphasized autistic behavior, acquired microcephaly , jerky truncal ataxia, and vasomotor disturbance. Hagberg et al. (4), later proposed inclusion and exclusion criteria for Rett syndrome, and described a staging system (5). Diagnostic criteria for this syndrome were further defined in 1988 (6). Stereotyped hand movements, gait disturbance, and dystonia have been previously noted in Rett syndrome and are included in the necessary or supportive diagnostic criteria (6a). However, other movement disorders are less well documented. We therefore studied 32 Rett patients to characterize the full spectrum of extrapyramidal involvement in this neurodegenerative disease.
Of 41 female patients seen with Rett syndrome at the Baylor College of Medicine Movement Disorder Clinic, 32 had a complete data base including ratings on the Motor-Behavioral Assessment Scale and at least two separate videotapes. They ranged in age from 30 months to 28 years and satisfied the diagnostic criteria for Rett syndrome (6). The patients were arbitrarily divided into three groups according to age at the time of evaluation: Group 1, 8 years old. Different motor characteristics were rated on the Motor-Behavioral Assessment Scale: 0, normal or never; 1, mild or rare; 2, moderate or occasional; 3, marked or frequent; and 4, very severe or constant (Appendix). All patients were videotaped at least once, and some several times, over a 2-year follow-up period. Extensive electrophysiologic studies and sleep studies have been performed as part of a multi-disciplinary Rett project, and these results will be reported separately.
A videotape segment accompanies this article. Address correspondence and reprint requests to Dr. Joseph Jankovic, Professor of Neurology at Department of Neurology, Baylor College of Medicine, 6550 Fannin, #1801, Houston, Texas 77030, U.S.A.
STATISTICAL METHODS The differences between the three groups in terms of severity scores were assessed using non-
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parametric analysis of variance and the Kruskal Wallis test. Intercorrelations among the clinical variables were evaluated using the Spearman rank order correlation test. ILLUSTRATIVE CASES
Patient 1 This 3%-year-old girl was the product of a fullterm normal delivery. Developmental milestones were normal through the first year of life, at which time she was thought to be “slow in walking.” Additionally, she was noted to repetitively touch her eyelids and look upwards. From 15 to 18 months, her social interaction deteriorated, she lost her vocabulary, became irritable and clumsy, and stopped playing with her toys. She walked alone, but had a very broad-based and unsteady gait. Stereotyped wiggling finger movements were present almost constantly and she frequently placed her fingers and hands over her mouth. At evaluation she smiled and appeared to be aware of her environment, but did not obey verbal commands. She had no intelligible speech and exhibited total indifference to painful stimuli including pinching or having blood drawn. There was severe bruxism, with moderate drooling and air saliva expulsion. She continuously moved her hands over her mouth or licked her hands. There were intermittent choreoathetotic movements of her arms and hands. She frequently rocked and walked with a broad-based and ataxic gait (videotape segment 2). Patient 2 This girl was 5 years and 7-months old. She was delivered at 7 months because of premature rupture of membranes. There was normal postnatal development, but at 1 year of age bilateral hand shaking was noted. Although she could stand, she could not walk. She then became progressively more unstable, and lost her ability to sit. At 2 years and 6 months, she completely lost her limited vocabulary, no longer used her hands in a purposeful fashion, and had repetitive stereotyped movements of the fingers of her left hand and bilateral hand-washing and wringing. On examination, she did not sustain any interest in objects or people, had poor eye contact, and produced no sounds except for loud bruxism. Oculogyric crises, manifested by conjugate deviations of her eyes upward and laterally, were intermittently observed. She had moderate rigidity of
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all extremities, with brisk knee and ankle jerks. She did not reach for or hold things with her hands, but repetitively performed handwashing and wringing movements. Severe dystonic posturing of both feet precluded even bearing weight on her lower limbs (videotape segment 5 ) . Occasional spontaneous generalized myoclonic jerks were seen. She had a moderate degree of scoliosis, and vasomotor skin changes with coldness and livedo reticularis were evident in both legs. She was completely insensitive to painful stimuli. Patient 3 This is a girl 5 years and 6 months old whose developmental milestones were appropriate until 9 months of age, when she no longer could sit or crawl. She used about 15 words, but by 14 months she no longer spoke, and had developed some autistic features and irritability. She had brief episodes of repetitive blinking, loud laughing, and momentary falling forward. She stopped reaching for toys and did not appear to understand verbal commands. From that time, no new skills were learned. During examination she interacted poorly and did not verbalize. She had severe bruxism, with hyperventilation and breathholding. There were almost constant ocular deviations and she either mouthed her hands or made repetitive waving movements or sequential finger movements, but was unable to grasp any objects. Although she could stand with support, she was unable to walk, and had continuous myoclonic jerking of all extremities, with dystonic posturing of both feet (videotape segment 6). Moderate rigidity with hyperreflexia was present in all extremities. Patient 4 This 20-year-old woman developed normally until 18 months of age when she became withdrawn,
“acted deaf,” and had an unsteady gait. She lost her previous vocabulary of 15-20 words, and by 24 months was unable to walk. At 26 months she had completely lost the use of her hands and speech, rocked constantly, and frequently screamed for no apparent reason. Stereotyped hand movements characterized by clenching her hands together, either in front of or behind her body, or clapping, became prominent and almost constant. Her gait slowly improved, but was remarkable for a wide base, shuffling, toe-walking, and postural instabil-
RETT SYNDROME AND ASSOCIATED DISORDERS ity. For the past 3 years she has had progressive motor slowing and has developed blepharospasm, facial grimacing, and jaw clenching. On examination, she avoided eye contact and made moaning and occasionally shrieking sounds. She was markedly bradykinetic and except for some facial dystonic movements including blepharospasm and trismus, she had no facial expression. Assistance to arise from a chair was needed, but she could walk alone with a broad-based gait. She had marked dystonic flexion of her fingers and hands (videotape segment 7). Hyperreflexia with rigidity was present in all limbs. Patient 5 This 28-year-old woman was first noted to have neurologic difficulty at 12 months, when she developed truncal instability. She then began to lose previously attained milestones: grasp, speech, and stable gait. By 4 years of age, she completely lost purposeful use of her hands and had stereotyped movements including rubbing her palms together, clapping, and hand wringing. From that time, she had been unable to communicate, but has regained some grasping ability. Harrington rods were placed at 16 years for severe scoliosis. Examination showed marked hypomimia with drooling and no verbalization. She was moderately bradykinetic and rigid, but could arise from a chair without assistance, and walked with a broad-based unsteady gait (videotape segment 9). RESULTS Gait abnormalities were seen in all patients. A “jerky gait ataxia” was seen in 10 of 32 (31%) patients, nine (28%) were unable to walk, four (13%) had a broad-based gait, one toe walked, and eight
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had mixed features including toe walking and a broad base. Of the stereotyped hand movements, also seen in all patients, clapping, wringing, and clenching were most common. We divided the other movement abnormalities into two major groups: hyperkinetic (Table 1) and hypokinetic (Table 2). Of the hyperkinetic disorders, bruxism was most common, seen in 97%. This occurred chiefly during daytime and was only rarely seen during sleep. Oculogyric crises, seen in 63%, generally consisted of brief eye deviations in an upward direction. Although some parents described these as “seizures,” they occurred without associated epileptiform electroencephalographic activity, or clinical epileptiform features. Of the 19 patients with dystonia, crural involvement was the most common, followed by generalized dystonia and then focal dystonia of either foot. Scoliosis, possibly indicative of truncal dystonia, was seen in 50%. Head or truncal jerking was most common in the 11 patients with myoclonus, while those with choreoathetosis (13%) had predominantly distal involvement. In the hypokinetic group, hypomimia was the most common finding, seen in 63%. Drooling was seen in 75% of patients, but we did not include it among the hypokinetic symptoms because we felt that this was a nonspecific finding, possibly due to poor posterior pharyngeal control. Some degree of rigidity and bradykinesia was seen in 44% and 41% of patients, respectively. Tremor, although historically reported in one patient, was not seen in any patient during the examination. A statistically significant difference in the occurrence of the various movement disorders between the groups was found only for hypomimia (p < 0.05), which was more common and more severe in older patients. The individual variables that were
TABLE 1. Extrapyramidal involvement in Rett syndrome: hyperkinetic disorders Group I (N = 10)
Group 2 (N = 11)
Group 3 (N = 11)
Characteristic
MeanVSD
N
MeadSD
N
MeadSD
N
Bruxism Oculogyric crises Dystonia Scoliosis Myoclonus Athetosis
3.010.8 1.511.3 0.811.1 0.510.8 0.010.0 0.410.7
10 7 4 4 0 3
2.510.9 1.811.5 1.511.4 1.210.9 1.211.2 0.010.0
11 7 7 8 6 0
2.111.3 0.9/1.1 1.70.2 1.111.4 0.911.1 0.2/0.6
10 6 8 4 5 1
a
Mean, mean value on the Motor-Behavioral Assessment Scale.
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TABLE 2. Extrapyramidal involvement in Rett syndrome: hypokinetic disorders Group 1 (N = 10)
Group 2 (N = 11)
Group 3 (N = 11)
Characteristic
Mean“1SD
N
MeanlSD
N
MeadSD
N
Hypomimia Rigidity Bradykinesia
0.511.0 0.411.0 0.6/1.1
3 2 3
1.611.2 1.111.2 0.711.3
9
2.011.6 1.411.5 1.311.4
8 6 6
6 4
Mean, mean value on the Motor-Behavioral Assessment Scale.
found to correlate positively with each other were bradykinesia with hypomimia and rigidity, and rigidity with dystonia, hypomimia, and myoclonus (p < 0.05). Although parkinsonian findings (bradykinesia and rigidity) seemed to be more common in older girls, this trend did not reach statistical significance.
DISCUSSION Stereotypic hand movements and “gait apraxia” have been well described in Rett snydrome, and are included in the necessary criteria for diagnosis of this disorder (1-6). The stereotypic movements include apposition of hands, finger kneading and rubbing, hand clapping and washing, wringing, squeezing, twisting, and pillrolling (1-14) (Fig. 1). The gait disorder has been difficult to characterize. Rett described slow, short steps with wide swaying movements, and later appearance of tiptoe walking (1,2). In Hagberg et al.’s series (3), the gait was described as unstable, rigid, and shuffling, associated with a jerky truncal ataxia while sitting unsupported. Similar gait disturbances have been described in other series (7-11). Of 52 ambulatory patients studied by Coleman et al. (7), 42% had toe walking. Naidu et al. (11), noted evolution in gait from a wide-based clumsy gait, through toe-walking with gait apraxia. However, the term “gait apraxia” may not be an appropriate designation in these patients because they are invariably cognitively impaired and have additional motor disturbances. Of our ambulatory patients, the most common disturbance was gait ataxia with marked unsteadiness, followed by a broad-based gait. After stereotypies and gait disturbance, bruxism was otherwise the most common motor disturbance seen in our patients, present in 97% (Table 3). This form of oromandibular dystonia has been also encountered frequently in other series (3,7,8,10-14). In contrast to nocturnal bruxism, jaw clenching, and tooth grinding in our patients was most evident
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during daytime, and ceased in sleep. In one study, 95% of Rett patients had grinding of teeth, which was viewed by us as a self-abusive behavior (7). Others have described bruxism in the context of stereotyped movements (3,12), or in association with the respiratory abnormalities of hyperventilation and breath holding @,IO,ll). Bruxism is common in mentally retarded individuals, with a prevalence of 21.5% in one series (15). Often thought to be a manifestation of dental pathology, occuring in
FIG. 1. This 71h-year-old girl with Rett syndrome has moderate parkinsonia findings, manifested here by hypomimia and typical stereotyped hand movements.
RETT SYNDROME AND ASSOCIATED DISORDERS TABLE 3 . Extrapyramidal involvement in Rett syndrome Characteristic
Percent of total
Stereotyped movements Gait disorder Bruxism Drooling Oculogyric crises H ypomimia Dystonia Scoliosis Rigidity Bradykinesia Myoclonus Athetosis
100 100 97 75 63 63 59 50 44 41 34 13
-20% of dental patients, bruxism has also been viewed as a psychophysiological disorder, a sign of organic brain damage, or a familial disorder (16). We believe that bruxism, which is often accompanied by facial grimacing, seen in some Rett patients represents a form of oro-facial-mandibular dystonia. Oculogyric crises, another form of focal dystonia, were evident in 63% of our patients. Other authors have mentioned staring episodes (7,17), and “upward eye rolling or a vacant stare” (3). These ocular movements may be difficult to differentiate from seizures (3,18). However, in our patients these episodes did not correlate with electroencephalographic epileptiform activity. Other dystonic movements and postures, seen in 59% of our patients, included generalized, crural, and focal dystonia. Progressive dystonia and dystonic movements, often accompanied by choreoathetosis, were also noted in other, smaller series of Rett patients (12,17). Scoliosis, a possible complication of chronic axial dystonia, was seen in 50% of our patients. This skeletal abnormality has been previously emphasized in Rett syndrome, but the mechanism is still unknown (2,3,7,1&12,14,19-22). Scoliosis has been typically seen in the thoracolumbar region and is generally unresponsive to bracing (20,21). Of the hyperkinetic disorders, myoclonus and choreoathetosis were least common in our patients, and tremor was not seen in any patient. The predominantly proximal myoclonus, present in 34% of the total group, has been mentioned, but not well documented, in other series (3,7,19). Hagberg et al. (3) described a “jerky truncal ataxia” that also often involves the limbs. A careful analysis of our
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patients with this “jerky ataxia” suggests that this peculiar movement disorder represents a combination of cerebellar ataxia and myoclonus. Others have also noted myoclonic jerks (7) or “jerky and writhing movements” (19). Al-Matten et al. (12) described choreoathetosis in 8 of 15 patients, but this hyperkinesia was seen in only 13% of our patients. We considered hypomimia, bradykinesia, drooling, and rigidity to represent parkinsonian findings. Drooling, the most common of these findings seen in 75% of our patients, has been seen frequently in other series (2,8). Rett (2) commented on the presence of diminished facial expression, with a masklike face in older children. In our patients, this was the only abnormality that correlated significantly with age. Although rigidity (seen in 44%) and bradykinesia (41%) tended to be more prevalent in older girls, this trend did not reach statistical significance. The gait disturbance seen in older girls, although resembling a parkinsonian gait (3,%lo), is characterized by a broad stance rather than the narrow-based gait typically seen in Parkinson’s disease. The underlying pathophysiologic basis for these extrapyramidal disturbances has not been established. Neuropathologic studies have been remarkable for brain atrophy and microcephaly, spongy changes in the cerebral and cerebellar white matter, lipofuscin deposition, and hypopigmentation of the substantia nigra (2,23,24). Incomplete melanization of the locus coeruleus has also been noted (25,26). Postmortem neurochemical studies are difficult to interpret because many of the Rett patients have severe malnutrition before death. Brucke et al. (25), in a single postmortem study, showed severe reduction in dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in most regions studied, with increases in the 3-4-dihydroxyphenyl acetic acid (DOPAC)/DA, homovanillic acid (HVA)/DA, and the 5-hydroxyindole acetic acid (5-HIAAh-HT ratios, suggesting increased turnover of DA and 5HT. Sofic et al. (261, found considerable reductions in ascorbic acid and reduced glutathione in most areas studied, but suggested that this might be a secondary phenomenon, related to malnutrition. Cerebrospinal fluid (CSF) monoamine metabolites of NE and DA were significantly reduced in the Zoghbi et al. (27) study of 6 patients with Rett syndrome. In a follow-up study of 32 patients, reductions were also noted in 5-HT metabolites, but total CSF biopterin levels were increased (28). In con-
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trast, Sahota et al. (29) reported normal serum and urinary biopterin levels with normal dihydropteridine reductase activity. Normal CSF monoamine metabolites, y-aminobutyric acid and amino acid levels have been reported by Riederer et al. (30) and Perry et al. (31). Positron emission tomographic scanning and neuroimaging studies have not been helpful in delineating any specific abnormalities (24,32). In this study of 32 patients with Rett syndrome we found that the expression of underlying extrapyramidal dysfunction seemed to be age determined, with a trend toward progression from a hyperkinetic to a bradykinetic state. This evolution in the spectrum of extrapyramidal findings may reflect a more rapid maturation of the striatum in Rett patients as compared with the normal age-related changes. Administration of levodopa to neonatal 6-hydroxydopamine (6-OHDA)-treated rats results in stereotypies and self-mutilating behavior (33). In contrast, adult 6-OHDA-treated rats display paw treading and head nodding. These findings of age-dependent effects of dopamine agonists on experimental stereotypic behaviors may provide insight into the curious evolution of clinical findings in Rett syndrome. Acknowledgment: We thank Dr. Deborah del Junco and Ms. Yue-Chune Lee for their technical assistance. This study was supported in part by the NIH/HDMR, grant number HD24234, and in part by a grant to the General Clinical Research Center, Texas Children’s Hospital, NIH grant number MOIRR00188.
LEGENDS TO THE VIDEOTAPE SEGMENT 1. Hand stereotypies and irregular breathing are seen in this 3-year-old girl with Rett syndrome. SEGMENT 2. This 3-year and 6-month-old girl demonstrates complex stereotyped hand movements with mouthing, choreic movements in arms, and a broad-based gait (illustrative case 1). SEGMENT 3. This is a 3-year and 10-month-old girl with severe bruxism, mouthing, and breathholding. SEGMENT 4. This 5-year-old girl demonstrates stereotyped hand movements, breath-holding, hyperventilation, rocking, and toe-walking. SEGMENT 5. Severe crural dystonia and stereotyped hand movements are seen in this 5-year and 6-month-old girl (illustrative case 2). SEGMENT 6. This 5-year and 7-month-old girl demonstrates generalized myoclonus, foot dystonia, and a broad-based stance (illustrative case 3). SEGMENT 7. In addition to the typical broadbased gait, this 20-year-old woman with Rett syndrome also has hand and facial dystonia with blepharospasm (illustrative case 4). SEGMENT 8. Severe hypomimia, body bradykinesia, and toe-walking are evident in this 28year-old woman. SEGMENT 9. This 20-year-old woman demonstrates moaning, hypomimia, hand stereotypies, body rocking, scoliosis, foot dystonia, and toewalking (illustrative case 5).
APPENDIX Rett Syndrome Motor-Behavioral Assessment Current assessment score I. BehaviorallSocial Assessment 1. Regression of motor skills 2. Regression of verbal skills 3. Poor eyelsocial contact 4. Lack of sustained interest 5. Imtability, crying tantrums 6 . Overactiveloverpassive (Circle one) 7. Does not reach for objects or people 8. Does not follow verbal commands, acts as deaf 9. Feeding difficulties 10. Chewing difficulties 1 1 . Lack of toilet training 12. Masturbation
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Age in months condition was at its worst
Assessment score at that time
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
3 3 3 3 3 3 3
4 4 4 4 4 4 4
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
3 3 3 3 3 3 3
4 4 4 4 4 4 4
0 0 0 0 0
1 1 1 1 1
2 2 2 2 2
3 3 3 3 3
4 4 4 4 4
0 0 0 0 0
1 1 1 1 1
2 2 2 2 2
3 3 3 3 3
4 4 4 4 4
Comment
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RETT SYNDROME AND ASSOCIATED DISORDERS APPENDIX
13. Self-mutilation (pulling hair or ears, scratching, etc.) 14. Aggressive behavior (head banging, throwing, spitting, etc.) 15. Seizures 16. Apparent insensitivity to pain 17. Subtotal (TOTAL OF EACH ITEM ABOVE) 11. Orofuciul/Respirutory Assessment 18. Speech disturbance 19. Bruxism 20. Breath holding 2 1. Hyperventilation 22. Air-saliva expulsioddrooling 23. Mouthing of hands and objects 24. Biting self or others 25. Subtotal (TOTAL OF EACH ITEM ABOVE) 111. Motor AssessmentlPhysicul Signs 26. Hand clumsiness 27. Stereotypic hand washing, rubbing, clapping, stroking, kneading. 28. Ataxidapraxia (gait and trunk) 29. Truncal rockingfshifting weight 30. Oculogyric movements 3 1. Bradykinesia 32. Dystonia 33. Hypomimia 34. Scoliosis 35. Myoclonus 36. Choredathetosis 37. Hypertonidrigidity 38. Hyperreflexia 39. Vasomotor disturbance 40. Subtotal (TOTAL OF EACH ITEM ABOVE)
continued
Current assessment score
Age in months condition was at its worst
Assessment score at that time
0 1 2 3 4
---
0 1 2 3 4
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
-------
0 1 2 3 4 0 1 2 3 4 0 1 2 3 4
--
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
Comment
3 3 3 3 3 3 3
4 4 4 4 4 4 4
---------------
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
3 3 3 3 3 3 3
4 4 4 4 4 4 4
--
__
0 1 2 3 4 0 0 0 0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3 3 3 3 3 3
4 4 4 4 4 4 4 4 4 4 4 4 4
-
0 0 0 0 0 0 0 0 0 0 0 0 0
1 1 1 1 1 1 1 1 1 1 1 1 1
2 2 2 2 2 2 2 2 2 2 2 2 2
3 3 3 3 3 3 3 3 3 3 3 3 3
4 4 4 4 4 4 4 4 4 4 4 4 4
--
0, Normal or never; I , mild or rare; 2, moderate or occasional; 3, marked or frequent; 4, very severe or constant.
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