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Rett syndrome: Discrimination of typical and variant forms
Rett Syndrome: Discrimination of Typical and Variant Forms Alan K Percy, MD, Huda Y Zoghbi, MD and Daniel G Glaze, MD
Eighteen female patients are described with the clinical features of Rett syndrome. Fifteen patients fulfill the criteria established by Hagberg et al [IJ whereas three represent clinical variants. Detailed biochemical and neurodiagnostic assessment was conducted in all patients. Reduction in cerebrospinal biogenic amine metabolites and characteristic alterations in respiratory, sleep, and EEG patterns were helpful in supporting the clinical diagnosis in the fifteen patients with typical features of Rett syndrome. In the remaining three patients, the modalities were much less helpful in establishing the diagnosis. Until a molecular marker is defined, diagnosis must depend on careful clinical assessment. Key words: Rett syndrome, variant form, biogenic amines, CSF, EEG, breathing patterns. Percy AK, Zoghbi HY, Glaze DG. Rett syndrome: discrimination of typical and variant forms. Brain Dev 1987; 9:458-61
Since the elaboration of strict criteria for the diagnosis of Rett syndrome by Hagberg et al [1] at the second symposium on Rett syndrome in 1984, the recognition of variant forms has become increasingly more common. In order to understand the relationship of these variant forms to those children with Rett syndrome following , the typical clinical pattern, we have compared the results of biochemical and neurodiagnostic studies. These results indicate some differences in the parameters studied between patients with typical Rett syndrome and patients with variant features.
PATIENTS AND REPORT Our patient population with Rett syndrome consists of 18 children, all females. Fifteen of these patients satisfy the criteria established by Hagberg et al [1] and had a mean age at onset of 10 months. Three of the patients differed from the others in having a later age at onset with a mean of 22 months and an apparently slower pace of progression. All patients were evaluated by computed brain tomography, sleep polygraphic analysis of electroencephalographic and cardiorespiratory parameters, and biogenic
From the Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, USA. Correspondence address: Dr. Alan K. Percy, Departments of Pediatrics and Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
amine metabolite analysis in cerebrospinal fluid. The following case report is typical of our three patients with variant features. KA is a 13-year-old female who was the product of a normal pregnancy and delivery and a normal neonatal course. Her development proceeded apparently normally for the first 18 months of life. She was smiling at 4 weeks of age, sitting at 572 months, crawling at 9 months, taking steps at 1 year, walking at 13 months, and saying phrases at 18 months. The parents first suspected difficulty at 22 months of age when she began to have non-consolable night screaming which would last 2 to 4 hours and occur 2 to 4 times weekly. By two years of age she had begun to regress sOcially, motorically, and verbally. At 472 years of age she began to hyperventilate admixed with breath-holding spells. Her head circumference at birth was in the 50th percentile and measurements at 372 and 8 years were at the 25th percentile. Subsequently, there was a clear decline to the 10th percentile at age 11 and the second percentile at age 13. A CT scan of the head at 3 years of age was within normal limits. A second scan at age 7 showed mild atrophy and a third scan at age 12 showed moderate and symmetrical atrophy without other abnormalities. She began to have generalized seizures at 11 years and was placed on a variety of medications including the ketogenic diet. With a combination of divalproex and clorazepate, seizure control was obtained, the screaming was minimized, she was more alert anq her interactions improved. A sleep study performed at 12 years of age showed a normal percentage of rapid eye movement (REM) sleep, disorganized breathing patterns
while awake with apneic periods during which the p02 was reduced to 45 mmHg (78% saturation). The EEG during this study revealed a diffusely slow background activity without evidence of epileptiform pattern and with well-defined sleep spindles. KA lives with her parents who are in good health, two brothers, ages 4 and 15, and one sister, age 11, all of whom are also in good health. Examination reveals a seemingly alert female who is able to give some meaningful eye contact but who is unable to communicate in other ways. There is an absence of purposeful hand movements and stereotypic hand movements as seen in other patients with Rett syndrome. She was able to sit without support and ambulated on a fairly broad base without evident truncal ataxia but with mild apraxia. Tone was regarded as within normal limits, deep tendon reflexes were normal and symmetrical and the plantar responses were flexor. The general physical examination was within normal limits.
Table I Rett syndrome: polygraphic-EEG video studies
(N = 15)
Nocturnal sleep characteristics:
Reduced % stage REM IS/IS
Respiratory pattern: Awake:
Sleep:
IS/IS had periods of disorganized breathing followed by increased rate and effort; oxygen drops to 38-81% (21-47 mmHg).
1/15 apnea (REM) 14/15 continuous, regular breathing no oxygen drops
RESULTS Computed tomography of the brain was performed on all 18 patients and was normal in 11. Mild atrophy was noted in 4, moderate atrophy in 2, and severe atrophy in 1. Two of the patients with later onset had normal studies and one demonstrated moderate and symmetrical atrophy. Polygraphic-EEG video studies were performed in all 18 patients. The results of the 15 patients with typical Rett syndrome are summarized in Table 1 [2]. All 15 patients demonstrated a reduction in the percentage of stage REM sleep. In terms of respiratory pattern while awake, all 15 patients demonstrated periods of disorganized breathing followed by periods of increased rate and effort. During the periods of apnea, oxygen saturations were reduced to between 38 and 81 % or to p02 values between 21 and 48 mmHg. In contrast during sleep, breathing remained continuous and regular without apnea in 14 of 15 patients. In the remaining patient, one apneic episode was noted during REM sleep. In all 15 patients there was no evidence of a fall in oxygen saturation during sleep. With regard to the three variant patients, one demonstrated the disorganized respiratory pattern during wakefulness and reduction in REM sleep noted above. One demonstrated an occasional period of disorganized breathing during wakefulness while her percentage of REM sleep was normal. The third patient had normal REM sleep and normal respiratory patterns both during wakefulness and sleep. Recently Hagberg and Witt-Engerstr6m [3] developed a staging format to describe the clinical progression of children with Rett syndrome. The ontogenesis of EEG findings in patients with Rett syndrome has been corre-
Table 2 Rett syndrome: ontogenesis of EEG findings EEG characteristics Asleep
Stage
Awake
Early onset stagnation 6-18 mos
Normal or minimal slowing of background and occipital dominant
Normal-well-defined vertex transien ts and sleep spindles
II Rapid destructive 1-4 yrs
Marked slowing of background and occipital dominant; rare focal spike or sharp-wave discharges
Poorly-defined vertex transients and spindles with loss of sleep characteristics; focal or multifocal spike and/ or sharp wave discharges
III Pseudo stationary 4-8 yrs
Further slowing with loss of occipital dominant; multifocal spike and sharp-wave discharges becoming generalized
Absent vertex transients and spindles during NREM; multifocal spike and/or sharp wave discharges, then appearance of generalized slow spike and wave during NREM
IV Late motor deterioration after 8 yrs
Absent occipital dominant; marked background slowing (delta frequencies); multifocal spike and sharp wave or generalized slow spike and wave
Almost continuous generalized slow spike and wave
Percy et al: Rett syndrome - typical and variant 459
lated [4] with the clinical stages described by Hagberg and Witt-Engerstrom. The results of tills analysis for the 15 patients with typical features of Rett syndrome are detailed in Table 2. The EEG characteristics progress from a virtually normal pattern in stage I to a markedly abnormal pattern in stage IV featuring an absence of occipital dominant rhythm and marked background slowing during wakefulness and almost continuous generalized slow spike and wave activity while asleep . None of the three patients with the variant presentation of Rett
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The demonstration of variant forms of a given disease process can hardly be regarded as a new phenomenon . One only needs to look at the sphingolipidoses for examples. Indeed, the absence of clinical variants in the sphingolipidoses would be regarded as the exception rather than the rule. Therefore , it was to be expected that variant forms of Rett syndrome would be forthcoming once attention was focused on tills remarkable phenotype. The present report describes 18 patients of whom 3 represent variant patterns of presentation. Methods of clinical and laboratory assessment which had been useful in supporting the diagnosis of Rett syndrome in patients with typical features were assessed as to their applicability to children with variant patterns. The results demonstrate that these modalities are less helpful in establishing the diagnosis of Rett syndrome in tills group. In only one of the three patients were there consistent abnormalities in the polygraphic and biochemical studies typical of other cillldren with Rett syndrome . As has
•
:1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Age In Yelr.
Fig 1 CSF biogenic amine metabolites in Rett syndrome. Panel A: MHPG levels, Panel B: HVA levels, and Panel C: 5-HlAA levels. Values are expressed in ng/ml CSF. Control values (.) are ex· pressed as means ± standard error where N =16 for 2.5 years, JJ for 5-10 years and 10 for 10-16 years, respectively. Patient values were obtained from samples obtained at Baylor ( • ) or at outside facilities ( &).
460
syndrome demonstrated any spike or spike and wave activity on their EEGs . All three patients were regarded by clinical assessment as being in Hagberg stage III and according to the findings in Table 2 should have demonstrated a loss of occipital dominant rhythm during wakefulness and an absence of vertex transients and spindles during NREM sleep as well as spike and wave discharges. Although slowing was noted in each patient's EEG, none of the other features was noted . Analysis of biogenic amine metabolites in cerebrospinal fluid [5} was conducted in 18 patients seen in our facility as well as in 11 patients whose samples were received from outside sources (Table 3). As noted in the figure there was a consistent reduction in the levels of MHPG and INA, the metabolites for norepinephrine and dopamine, respectively, whereas levels for 5 -HIAA, the serotonin metabolite, were reduced in approximately one-half the patients. With regard to the patients demonstrating a variation in their clinical presentation , one of them had reduction in all three metabolites , the remaining two had completely normal studies for all three metabolites .
Brain & Development, Vol 9, No 5, 1987
Table 3 Rett syndrome: reduction of biogenic amine metabolites in cerebrospinal fluid Patient source
MHPG
HVA
5-HIAA
Baylor
16/18 11/14
15/18 13/14
10/18 3/14
27/ 32
28/ 32
13/ 32
Outside Total
been stated repeatedly, clarity in the diagnosis and understanding of this fascinating syndrome awaits the definition of a molecular marker. Until such time diagnosis rests on careful clinical assessment. As part of the continuing search for biochemical abnormalities in patients with Rett syndrome, Dr Edwin Myer (personal communication) of the Medical College of Virginia, has evaluated endorphin levels in cerebrospinal fluid from 11 patients. Ten of the 11 patients had increased endorphin levels, a feature which Dr Myer had associated only with status epilepticus and the childhood apnea syndromes. Clearly, further studies must be undertaken to confirm these results. Should the abnormalities remain consistent, it would be appropriate to investigate the effect of opiate antagonists in these patients. ACKNOWLEDGMENTS The authors were supported in this study by funds from the Texas Children's Hospital. The neurotransmitter metabolite
studies in cerebrospinal fluid were kindly provided by Dr. Ian Butler in the Department of Neurology, University of Texas School of Medicine in Houston. The authors are especially grateful to Nancy Ivy for her assistance in preparation of this manuscript.
REFERENCES 1. Hagberg B, Goutieres F, Hanefeld F, Rett A, Wilson 1. Rett syndrome: criteria for inclusion and exclusion. Brain Dev (Tokyo) 1985;7:3n-3.
2. Glaze DG, Frost JD Jr, Zoghbi HY, Percy AK. Rett syndrome: characterization of respiratory pattern and sleep. Ann Neurol 1987;21: 377-82. 3. Hagberg B, Witt-Engerstrom 1. Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence. Am J Med Genet 1986; 24:47-59. 4. Glaze DG, Frost JD Jr, Zoghbi HY, Percy AK. Rett syndrome: correlation of EEG characteristics with clinical staging. Arch Neurol 1987;44: 1053-6. 5. Zoghbi HY, Percy AK, Glaze DG, Butler IJ, Riccardi VM. Reduction of biogenic amine levels in the Rett syndrome. N Engl J Med 1985;313:921-4.
Percy et al: Rett syndrome - typical and variant 461
Eighteen female patients are described with the clinical features of Rett syndrome. Fifteen patients fulfill the criteria established by Hagberg et al [IJ whereas three represent clinical variants. Detailed biochemical and neurodiagnostic assessment was conducted in all patients. Reduction in cerebrospinal biogenic amine metabolites and characteristic alterations in respiratory, sleep, and EEG patterns were helpful in supporting the clinical diagnosis in the fifteen patients with typical features of Rett syndrome. In the remaining three patients, the modalities were much less helpful in establishing the diagnosis. Until a molecular marker is defined, diagnosis must depend on careful clinical assessment. Key words: Rett syndrome, variant form, biogenic amines, CSF, EEG, breathing patterns. Percy AK, Zoghbi HY, Glaze DG. Rett syndrome: discrimination of typical and variant forms. Brain Dev 1987; 9:458-61
Since the elaboration of strict criteria for the diagnosis of Rett syndrome by Hagberg et al [1] at the second symposium on Rett syndrome in 1984, the recognition of variant forms has become increasingly more common. In order to understand the relationship of these variant forms to those children with Rett syndrome following , the typical clinical pattern, we have compared the results of biochemical and neurodiagnostic studies. These results indicate some differences in the parameters studied between patients with typical Rett syndrome and patients with variant features.
PATIENTS AND REPORT Our patient population with Rett syndrome consists of 18 children, all females. Fifteen of these patients satisfy the criteria established by Hagberg et al [1] and had a mean age at onset of 10 months. Three of the patients differed from the others in having a later age at onset with a mean of 22 months and an apparently slower pace of progression. All patients were evaluated by computed brain tomography, sleep polygraphic analysis of electroencephalographic and cardiorespiratory parameters, and biogenic
From the Department of Pediatrics and Neurology, Baylor College of Medicine, Houston, USA. Correspondence address: Dr. Alan K. Percy, Departments of Pediatrics and Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
amine metabolite analysis in cerebrospinal fluid. The following case report is typical of our three patients with variant features. KA is a 13-year-old female who was the product of a normal pregnancy and delivery and a normal neonatal course. Her development proceeded apparently normally for the first 18 months of life. She was smiling at 4 weeks of age, sitting at 572 months, crawling at 9 months, taking steps at 1 year, walking at 13 months, and saying phrases at 18 months. The parents first suspected difficulty at 22 months of age when she began to have non-consolable night screaming which would last 2 to 4 hours and occur 2 to 4 times weekly. By two years of age she had begun to regress sOcially, motorically, and verbally. At 472 years of age she began to hyperventilate admixed with breath-holding spells. Her head circumference at birth was in the 50th percentile and measurements at 372 and 8 years were at the 25th percentile. Subsequently, there was a clear decline to the 10th percentile at age 11 and the second percentile at age 13. A CT scan of the head at 3 years of age was within normal limits. A second scan at age 7 showed mild atrophy and a third scan at age 12 showed moderate and symmetrical atrophy without other abnormalities. She began to have generalized seizures at 11 years and was placed on a variety of medications including the ketogenic diet. With a combination of divalproex and clorazepate, seizure control was obtained, the screaming was minimized, she was more alert anq her interactions improved. A sleep study performed at 12 years of age showed a normal percentage of rapid eye movement (REM) sleep, disorganized breathing patterns
while awake with apneic periods during which the p02 was reduced to 45 mmHg (78% saturation). The EEG during this study revealed a diffusely slow background activity without evidence of epileptiform pattern and with well-defined sleep spindles. KA lives with her parents who are in good health, two brothers, ages 4 and 15, and one sister, age 11, all of whom are also in good health. Examination reveals a seemingly alert female who is able to give some meaningful eye contact but who is unable to communicate in other ways. There is an absence of purposeful hand movements and stereotypic hand movements as seen in other patients with Rett syndrome. She was able to sit without support and ambulated on a fairly broad base without evident truncal ataxia but with mild apraxia. Tone was regarded as within normal limits, deep tendon reflexes were normal and symmetrical and the plantar responses were flexor. The general physical examination was within normal limits.
Table I Rett syndrome: polygraphic-EEG video studies
(N = 15)
Nocturnal sleep characteristics:
Reduced % stage REM IS/IS
Respiratory pattern: Awake:
Sleep:
IS/IS had periods of disorganized breathing followed by increased rate and effort; oxygen drops to 38-81% (21-47 mmHg).
1/15 apnea (REM) 14/15 continuous, regular breathing no oxygen drops
RESULTS Computed tomography of the brain was performed on all 18 patients and was normal in 11. Mild atrophy was noted in 4, moderate atrophy in 2, and severe atrophy in 1. Two of the patients with later onset had normal studies and one demonstrated moderate and symmetrical atrophy. Polygraphic-EEG video studies were performed in all 18 patients. The results of the 15 patients with typical Rett syndrome are summarized in Table 1 [2]. All 15 patients demonstrated a reduction in the percentage of stage REM sleep. In terms of respiratory pattern while awake, all 15 patients demonstrated periods of disorganized breathing followed by periods of increased rate and effort. During the periods of apnea, oxygen saturations were reduced to between 38 and 81 % or to p02 values between 21 and 48 mmHg. In contrast during sleep, breathing remained continuous and regular without apnea in 14 of 15 patients. In the remaining patient, one apneic episode was noted during REM sleep. In all 15 patients there was no evidence of a fall in oxygen saturation during sleep. With regard to the three variant patients, one demonstrated the disorganized respiratory pattern during wakefulness and reduction in REM sleep noted above. One demonstrated an occasional period of disorganized breathing during wakefulness while her percentage of REM sleep was normal. The third patient had normal REM sleep and normal respiratory patterns both during wakefulness and sleep. Recently Hagberg and Witt-Engerstr6m [3] developed a staging format to describe the clinical progression of children with Rett syndrome. The ontogenesis of EEG findings in patients with Rett syndrome has been corre-
Table 2 Rett syndrome: ontogenesis of EEG findings EEG characteristics Asleep
Stage
Awake
Early onset stagnation 6-18 mos
Normal or minimal slowing of background and occipital dominant
Normal-well-defined vertex transien ts and sleep spindles
II Rapid destructive 1-4 yrs
Marked slowing of background and occipital dominant; rare focal spike or sharp-wave discharges
Poorly-defined vertex transients and spindles with loss of sleep characteristics; focal or multifocal spike and/ or sharp wave discharges
III Pseudo stationary 4-8 yrs
Further slowing with loss of occipital dominant; multifocal spike and sharp-wave discharges becoming generalized
Absent vertex transients and spindles during NREM; multifocal spike and/or sharp wave discharges, then appearance of generalized slow spike and wave during NREM
IV Late motor deterioration after 8 yrs
Absent occipital dominant; marked background slowing (delta frequencies); multifocal spike and sharp wave or generalized slow spike and wave
Almost continuous generalized slow spike and wave
Percy et al: Rett syndrome - typical and variant 459
lated [4] with the clinical stages described by Hagberg and Witt-Engerstrom. The results of tills analysis for the 15 patients with typical features of Rett syndrome are detailed in Table 2. The EEG characteristics progress from a virtually normal pattern in stage I to a markedly abnormal pattern in stage IV featuring an absence of occipital dominant rhythm and marked background slowing during wakefulness and almost continuous generalized slow spike and wave activity while asleep . None of the three patients with the variant presentation of Rett
A
CSF BIOGENIC AMINE METABOLITES IN RETT SYNDROME
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U
:.
16 14 12
1
10
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6
CI
4
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11-
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8
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•. . .. . . • •• • •
• • •
• •
•
•
I
•
t
•
IPo lI.nts:
2
DISCUSSION
Baylor OUI &lde
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Controls
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100 80 60 40
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• e. ".
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• • • •
.
1Pallonls: Controls
I Baylor Outsldo
The demonstration of variant forms of a given disease process can hardly be regarded as a new phenomenon . One only needs to look at the sphingolipidoses for examples. Indeed, the absence of clinical variants in the sphingolipidoses would be regarded as the exception rather than the rule. Therefore , it was to be expected that variant forms of Rett syndrome would be forthcoming once attention was focused on tills remarkable phenotype. The present report describes 18 patients of whom 3 represent variant patterns of presentation. Methods of clinical and laboratory assessment which had been useful in supporting the diagnosis of Rett syndrome in patients with typical features were assessed as to their applicability to children with variant patterns. The results demonstrate that these modalities are less helpful in establishing the diagnosis of Rett syndrome in tills group. In only one of the three patients were there consistent abnormalities in the polygraphic and biochemical studies typical of other cillldren with Rett syndrome . As has
•
:1
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Age In Yelr.
Fig 1 CSF biogenic amine metabolites in Rett syndrome. Panel A: MHPG levels, Panel B: HVA levels, and Panel C: 5-HlAA levels. Values are expressed in ng/ml CSF. Control values (.) are ex· pressed as means ± standard error where N =16 for 2.5 years, JJ for 5-10 years and 10 for 10-16 years, respectively. Patient values were obtained from samples obtained at Baylor ( • ) or at outside facilities ( &).
460
syndrome demonstrated any spike or spike and wave activity on their EEGs . All three patients were regarded by clinical assessment as being in Hagberg stage III and according to the findings in Table 2 should have demonstrated a loss of occipital dominant rhythm during wakefulness and an absence of vertex transients and spindles during NREM sleep as well as spike and wave discharges. Although slowing was noted in each patient's EEG, none of the other features was noted . Analysis of biogenic amine metabolites in cerebrospinal fluid [5} was conducted in 18 patients seen in our facility as well as in 11 patients whose samples were received from outside sources (Table 3). As noted in the figure there was a consistent reduction in the levels of MHPG and INA, the metabolites for norepinephrine and dopamine, respectively, whereas levels for 5 -HIAA, the serotonin metabolite, were reduced in approximately one-half the patients. With regard to the patients demonstrating a variation in their clinical presentation , one of them had reduction in all three metabolites , the remaining two had completely normal studies for all three metabolites .
Brain & Development, Vol 9, No 5, 1987
Table 3 Rett syndrome: reduction of biogenic amine metabolites in cerebrospinal fluid Patient source
MHPG
HVA
5-HIAA
Baylor
16/18 11/14
15/18 13/14
10/18 3/14
27/ 32
28/ 32
13/ 32
Outside Total
been stated repeatedly, clarity in the diagnosis and understanding of this fascinating syndrome awaits the definition of a molecular marker. Until such time diagnosis rests on careful clinical assessment. As part of the continuing search for biochemical abnormalities in patients with Rett syndrome, Dr Edwin Myer (personal communication) of the Medical College of Virginia, has evaluated endorphin levels in cerebrospinal fluid from 11 patients. Ten of the 11 patients had increased endorphin levels, a feature which Dr Myer had associated only with status epilepticus and the childhood apnea syndromes. Clearly, further studies must be undertaken to confirm these results. Should the abnormalities remain consistent, it would be appropriate to investigate the effect of opiate antagonists in these patients. ACKNOWLEDGMENTS The authors were supported in this study by funds from the Texas Children's Hospital. The neurotransmitter metabolite
studies in cerebrospinal fluid were kindly provided by Dr. Ian Butler in the Department of Neurology, University of Texas School of Medicine in Houston. The authors are especially grateful to Nancy Ivy for her assistance in preparation of this manuscript.
REFERENCES 1. Hagberg B, Goutieres F, Hanefeld F, Rett A, Wilson 1. Rett syndrome: criteria for inclusion and exclusion. Brain Dev (Tokyo) 1985;7:3n-3.
2. Glaze DG, Frost JD Jr, Zoghbi HY, Percy AK. Rett syndrome: characterization of respiratory pattern and sleep. Ann Neurol 1987;21: 377-82. 3. Hagberg B, Witt-Engerstrom 1. Rett syndrome: a suggested staging system for describing impairment profile with increasing age towards adolescence. Am J Med Genet 1986; 24:47-59. 4. Glaze DG, Frost JD Jr, Zoghbi HY, Percy AK. Rett syndrome: correlation of EEG characteristics with clinical staging. Arch Neurol 1987;44: 1053-6. 5. Zoghbi HY, Percy AK, Glaze DG, Butler IJ, Riccardi VM. Reduction of biogenic amine levels in the Rett syndrome. N Engl J Med 1985;313:921-4.
Percy et al: Rett syndrome - typical and variant 461