ORIGINAL AR TICLES
Multi-Institutional Survey of the Rett Syndrome in Japan Noriko Oguro, MD, Mariko Momoi, MD, Terutoshi Nakamigawa, MD, Shinya Miyamoto, MD, Shigeichi Kobayashi, MD, Masutomo Miyao, MD and Shigehiko Kamoshita, MD
The results of the first multi-institutional survey of the Rett syndrome in Japan are reported. The survey was performed during 1985 and 1986. Eighty-nine cases were collected, of which 54 cases were confirmed to have the Rett syndrome. The ages of the patients ranged between 1 and 26 years. The clinical onsets occu"ed after 18 months of age in 28 cases, and before the age of one year in 26. No familial cases nor consanguinity was found. The incidence of perinatal abnormalities among the patients was not significantly higher than in other diseases in which no perinatal factors are involved. Key words: Rett syndrome, mental retardation, stereotypic hand movement. Oguro N, Momoi M, Nakamigawa T, Miyamoto S, Kobayashi S, Miyao M, Kamoshita S. Multi-institutional survey of the Rett syndrome in Japan. Brain Dev 1990;12:753-9
The Rett syndrome (RS) has recently been a focus of interest in pediatric neurology because of its characteristic clinical features and exclusive occurrence in females. In 1966, Rett first described a progressive neurological disease that was seen only in females [1]. Since Hagberg and associates redefined this disorder in 1983 [2], clinical reports on this syndrome have accumulated [3-10]. The prevalence of RS in southwestern Sweden was reported by Hagberg to be approximately 0.65 in 10,000 girls in 1985 [11]. The prevalence in West Scotland was estimated to be one in 15,000 girls as reported by Kerr and associates in 1985 [12]. Since these reports, the high prevalence of this syndrome has drawn attention. By 1986, more than 1,000 cases of RS had been recognized worldwide [13]. In Japan, Ishikawa and associates first described 3 cases of this syndrome in 1978 [14] and Nomura and associates reported 6 cases in 1984 [3]. Suzuki and associates studied the prevalence of RS in Tama area, the suburbs of Tokyo including seven cities. They reported that the
From the Department of Pediatrics, Jichi Medical School, Tochigi (NO, MM, TN, SM, SK, MM); and Department of Pediatrics, Faculty of Medicine, The University of Tokyo, Tokyo (SK). Received for publication: October 20, 1989. Accepted for publication: August 16, 1990. Corresponding address: Dr. Shigehiko Kamoshita, Department of Pediatrics, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku Tokyo 113, Japan.
prevalence of RS was 0.67 in 10,000 girls and it was similar to those in Europe [15]. Hagberg and co-workers proposed clinical criteria for RS in 1985 [16]. One of these criteria was that normal psychomotor development should be present throughout the first 6 months; in many cases it is seen throughout the first 12 to 18 months of life. These criteria were only for finding typical cases to elucidate the pathogenesis of RS for the clinical and epidemiological research. Hagberg and associates also proposed clinical staging of RS to facilitate understanding of the characterization of disease profIles [17]. It consisted of 4 stages from infancy to adolescence. These criteria and this staging system were used to diagnose and collect the patients in our study. In 1988, the Rett Syndrome Diagnostic Criteria Work Group proposed revised clinical criteria, the female sex being excluded [18] . One of these criteria was that normal psychomotor development had to last throughout the first 6 months. Because the etiology of RS is completely unknown and because clinical criteria are still one of the foci of the discussion, the accumulation of detailed clinical information is of great importance as to determination of the right direction for investigations of this disease. To clarify the incidence and the clinical details of RS in Japan, the first multi-institutional survey was performed during 1985 and 1986 as a research project supported by a grant from National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare, Japan. Here we report
Table 1 Major clinical features of the Rett syndrome described in the first inquiry sheet Rett syndrome: Major clinical features 1. Mostly female 2. Autistic tendency 3. Stereotyped hand movements (washing-hand manner)
4. 5. 6. 7.
Gait disturbance Epileptic seizures Microcephaly Mental deterioration
the results of this first multi-institutional survey of RS in Japan.
METHODS The survey involved two steps. First, for rough screening, inquiry sheets with simple diagnostic criteria (Table 1) were distributed to 175 institutions where pediatric neurologists were on service. They included departments of pediatrics of medical schools and associated hospitals, national sanatoriums, children's hospitals and a private clinic. The second inquiry sheets, which included 135 detailed questions on the family history, perinatal history, clinical course, laboratory data and treatments, were sent to the institutions that reported cases in the first survey.
RESULTS Collected cases One-hundred and twenty-nine institutions (73.7%) responded and 89 cases were collected. They included 25 cases in university hospitals, 26 cases in national sanatoriums, 25 in public hospitals, and 13 in a private clinic. All cases were diagnosed by pediatricians or pediatriC neurologists, and all were female. The collected cases were classified into three groups as to clinical features: twenty-eight cases showed clinical courses most often seen in patients with RS as reported by Hagberg et al [16]. Their clinical deterioration started after they acquired the ability to walk by 18 months of age. In 26 other cases, the deterioration started after 8 months, i.e. before they acquired the ability to walk. All of them acquired the ability to sit unsupported by 8 months of age and started to deteriorate thereafter. Three cases in this group never walked unsupported. The remaining 35 cases did not satisfy the diagnostic criteria and most of them showed clinical deterioration from their early infancy. Thus, these 3 groups were arbitrarily named the typical, early-onset, and questionable cases, respectively. The first two groups, the 28 typical and 26 early-
754 Brain & Development, Vol 12, No 6, 1990
Table 2 The residence at the onset, the current residence and the location of institutions which reported cases Prefecture Hokkaido Aomori Iwate Miyagi Akita Yamagata Fukushima Ibaragi Tochigi Gunma Saitama Chiba Tokyo Kanagawa Niigata Toyama Ishikawa Fukui Yamanashi Nagano Gifu Shizuoka Aichi Mie Shiga Kyoto Osaka Hyogo Nara Wakayama Tottori Shimane Okayama Hiroshima Yamaguchi Tokushima Kagawa Ehime Koehl Fukuoka Saga Nagasaki Kumamoto Oita Miyazaki Kagoshima Okinawa Other countries Unknown Total
Residence at the onset* 2
Present resident *
Location of institute *
o o o o o o o o o
2
2
0 0 0 0 0 0 0
o o
0 0 0 0 0 0 0
o o
6
o
8
5 2 7
8
10
2
o
o
o
o
o o o I 4
o I
2
o o o o o 0 3
2 I
1 0 0 0 2 0 0 0
o
o o o o o 12
o o 2
2
20 3
o o o o o o o 13
o 2
o o o o o o
o o o o o
3
4 I
2 1 I
o o
o 2
o
o 1
o o o 3
o
o
o
o
0 0 0 0 10
o o
o
54
54
* Number of cases were shown.
o
o o
o 1
o o
o o 54
Table 3 The age distribution at February 1, 1987
Age (year)
Typical cases
Early-onset cases
0 1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16 17 18 19 20 21 22 23 24 25 26
Table 4 Parental ages at the birth of patients
Questionable cases 1
Maternal age (year, mean ± SD)
Paternal age (year, mean ± SD)
29.4 ± 6.5 26.4 ± 3.6 29.7 ± 4.4
31.0±6.7 30.4 ± 3.6 31.5 ± 5.3
Typical cases Early-onset cases The remaining cases
1
3 5 3 3 2
2 2 3 2 1 3 1 2
2 4 3 3 3 6 2 1 3
Table 5 The family history
(1) Consanguineous marriage
(2) Rett syndrome
3 3 2
(3) Other neurological diseases 1
(-)
28
21
0
5
(-)
28 0
24 2
22 5 1
20 4 2
1/5 1/5
1/4 0/4
1/5
0/4 0/4
(-)
(+)
Unknown
1
(26)
Unknown Unknown
4 2
(28)
Early· onset cases
Typical cases
Cerebral palsy Mental retardation Epilepsy Leukodystrophy Autism Others
0/5 0/5
0/4
3/5
3/4
1
Table 6 Prenatal problems
onset cases were analyzed in detail.
Distribution of patients The patients were unevenly distributed throughout Japan (Table 2). The prevalence was higher around the large cities, such as Tokyo, Yokohama, or Nagoya. There was no report from the northern half of mainland Honshu. Several institutions reported many cases, which suggests that the number of cases considerably depends on the degree of interest. Therefore, there must be not a few unreported or undiagnosed cases. Ages of patients The ages of patients at the time of the study (February 1, 1987) ranged from 1 to 26 years (Table 3). Forty-seven out of 54 cases were between 5 to 17 years of age.
Family histories The average ages of the parents at the time of birth of the patients are shown in Table 4. Compared with the national averages of the parents' ages (28.1 years for mother and 31.0 years for father) [19], they did not differ signifi-
History of maternal pregnancy and delivery Spontaneous abortion Artificial abortion Others Prenatal abnormalities Infection Drug Threatened abortion Abnormalities of quickening
Typical cases (28)
Early onset cases (26)
2 2
3 1
0
0
7/28
7/26 0/7 7/7 3/7 0/7
2/7 2/7 5/7 5/7
cantly. No consanguinity or familial cases were found, as shown in Table 5. Cerebral palsy, mental retardation, epilepsy and other neurological abnormalities were found in family members. It is not clear whether these conditions in family members are related to RS. Prenatal abnormalities, although not serious, were noted in 25% of the typical cases and 27% of the early-
Oguro et al: Survey of Rett syndrome 755
onset cases (Table 6). These numbers were slightly higher than those reported for Duchenne muscular dystrophy and the Tourette syndrome, 20.9% and 18.6%, respectively [20]. The rates of spontaneous abortions were 3.0% in pregnancies in the typical cases and 4.7% in the earlyonset cases. They were not increased.
Because RS only affects girls, it can easily be assumed that RS is fatal when present in males. Therefore, the numbers of male and female siblings of the patients were examined. The numbers of siblings of the 28 typical patients were 18 brothers and II sisters. The 26 earlyonset cases had 10 brothers and 20 sisters. The total num-
(4) rltandard deviation at birth (Early-onset cases; 26 cases)
_
Multi-Institutional Survey of the Rett Syndrome in Japan Noriko Oguro, MD, Mariko Momoi, MD, Terutoshi Nakamigawa, MD, Shinya Miyamoto, MD, Shigeichi Kobayashi, MD, Masutomo Miyao, MD and Shigehiko Kamoshita, MD
The results of the first multi-institutional survey of the Rett syndrome in Japan are reported. The survey was performed during 1985 and 1986. Eighty-nine cases were collected, of which 54 cases were confirmed to have the Rett syndrome. The ages of the patients ranged between 1 and 26 years. The clinical onsets occu"ed after 18 months of age in 28 cases, and before the age of one year in 26. No familial cases nor consanguinity was found. The incidence of perinatal abnormalities among the patients was not significantly higher than in other diseases in which no perinatal factors are involved. Key words: Rett syndrome, mental retardation, stereotypic hand movement. Oguro N, Momoi M, Nakamigawa T, Miyamoto S, Kobayashi S, Miyao M, Kamoshita S. Multi-institutional survey of the Rett syndrome in Japan. Brain Dev 1990;12:753-9
The Rett syndrome (RS) has recently been a focus of interest in pediatric neurology because of its characteristic clinical features and exclusive occurrence in females. In 1966, Rett first described a progressive neurological disease that was seen only in females [1]. Since Hagberg and associates redefined this disorder in 1983 [2], clinical reports on this syndrome have accumulated [3-10]. The prevalence of RS in southwestern Sweden was reported by Hagberg to be approximately 0.65 in 10,000 girls in 1985 [11]. The prevalence in West Scotland was estimated to be one in 15,000 girls as reported by Kerr and associates in 1985 [12]. Since these reports, the high prevalence of this syndrome has drawn attention. By 1986, more than 1,000 cases of RS had been recognized worldwide [13]. In Japan, Ishikawa and associates first described 3 cases of this syndrome in 1978 [14] and Nomura and associates reported 6 cases in 1984 [3]. Suzuki and associates studied the prevalence of RS in Tama area, the suburbs of Tokyo including seven cities. They reported that the
From the Department of Pediatrics, Jichi Medical School, Tochigi (NO, MM, TN, SM, SK, MM); and Department of Pediatrics, Faculty of Medicine, The University of Tokyo, Tokyo (SK). Received for publication: October 20, 1989. Accepted for publication: August 16, 1990. Corresponding address: Dr. Shigehiko Kamoshita, Department of Pediatrics, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku Tokyo 113, Japan.
prevalence of RS was 0.67 in 10,000 girls and it was similar to those in Europe [15]. Hagberg and co-workers proposed clinical criteria for RS in 1985 [16]. One of these criteria was that normal psychomotor development should be present throughout the first 6 months; in many cases it is seen throughout the first 12 to 18 months of life. These criteria were only for finding typical cases to elucidate the pathogenesis of RS for the clinical and epidemiological research. Hagberg and associates also proposed clinical staging of RS to facilitate understanding of the characterization of disease profIles [17]. It consisted of 4 stages from infancy to adolescence. These criteria and this staging system were used to diagnose and collect the patients in our study. In 1988, the Rett Syndrome Diagnostic Criteria Work Group proposed revised clinical criteria, the female sex being excluded [18] . One of these criteria was that normal psychomotor development had to last throughout the first 6 months. Because the etiology of RS is completely unknown and because clinical criteria are still one of the foci of the discussion, the accumulation of detailed clinical information is of great importance as to determination of the right direction for investigations of this disease. To clarify the incidence and the clinical details of RS in Japan, the first multi-institutional survey was performed during 1985 and 1986 as a research project supported by a grant from National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare, Japan. Here we report
Table 1 Major clinical features of the Rett syndrome described in the first inquiry sheet Rett syndrome: Major clinical features 1. Mostly female 2. Autistic tendency 3. Stereotyped hand movements (washing-hand manner)
4. 5. 6. 7.
Gait disturbance Epileptic seizures Microcephaly Mental deterioration
the results of this first multi-institutional survey of RS in Japan.
METHODS The survey involved two steps. First, for rough screening, inquiry sheets with simple diagnostic criteria (Table 1) were distributed to 175 institutions where pediatric neurologists were on service. They included departments of pediatrics of medical schools and associated hospitals, national sanatoriums, children's hospitals and a private clinic. The second inquiry sheets, which included 135 detailed questions on the family history, perinatal history, clinical course, laboratory data and treatments, were sent to the institutions that reported cases in the first survey.
RESULTS Collected cases One-hundred and twenty-nine institutions (73.7%) responded and 89 cases were collected. They included 25 cases in university hospitals, 26 cases in national sanatoriums, 25 in public hospitals, and 13 in a private clinic. All cases were diagnosed by pediatricians or pediatriC neurologists, and all were female. The collected cases were classified into three groups as to clinical features: twenty-eight cases showed clinical courses most often seen in patients with RS as reported by Hagberg et al [16]. Their clinical deterioration started after they acquired the ability to walk by 18 months of age. In 26 other cases, the deterioration started after 8 months, i.e. before they acquired the ability to walk. All of them acquired the ability to sit unsupported by 8 months of age and started to deteriorate thereafter. Three cases in this group never walked unsupported. The remaining 35 cases did not satisfy the diagnostic criteria and most of them showed clinical deterioration from their early infancy. Thus, these 3 groups were arbitrarily named the typical, early-onset, and questionable cases, respectively. The first two groups, the 28 typical and 26 early-
754 Brain & Development, Vol 12, No 6, 1990
Table 2 The residence at the onset, the current residence and the location of institutions which reported cases Prefecture Hokkaido Aomori Iwate Miyagi Akita Yamagata Fukushima Ibaragi Tochigi Gunma Saitama Chiba Tokyo Kanagawa Niigata Toyama Ishikawa Fukui Yamanashi Nagano Gifu Shizuoka Aichi Mie Shiga Kyoto Osaka Hyogo Nara Wakayama Tottori Shimane Okayama Hiroshima Yamaguchi Tokushima Kagawa Ehime Koehl Fukuoka Saga Nagasaki Kumamoto Oita Miyazaki Kagoshima Okinawa Other countries Unknown Total
Residence at the onset* 2
Present resident *
Location of institute *
o o o o o o o o o
2
2
0 0 0 0 0 0 0
o o
0 0 0 0 0 0 0
o o
6
o
8
5 2 7
8
10
2
o
o
o
o
o o o I 4
o I
2
o o o o o 0 3
2 I
1 0 0 0 2 0 0 0
o
o o o o o 12
o o 2
2
20 3
o o o o o o o 13
o 2
o o o o o o
o o o o o
3
4 I
2 1 I
o o
o 2
o
o 1
o o o 3
o
o
o
o
0 0 0 0 10
o o
o
54
54
* Number of cases were shown.
o
o o
o 1
o o
o o 54
Table 3 The age distribution at February 1, 1987
Age (year)
Typical cases
Early-onset cases
0 1 2 3 4 5 6 7 8 9 10 11 12
13 14 15 16 17 18 19 20 21 22 23 24 25 26
Table 4 Parental ages at the birth of patients
Questionable cases 1
Maternal age (year, mean ± SD)
Paternal age (year, mean ± SD)
29.4 ± 6.5 26.4 ± 3.6 29.7 ± 4.4
31.0±6.7 30.4 ± 3.6 31.5 ± 5.3
Typical cases Early-onset cases The remaining cases
1
3 5 3 3 2
2 2 3 2 1 3 1 2
2 4 3 3 3 6 2 1 3
Table 5 The family history
(1) Consanguineous marriage
(2) Rett syndrome
3 3 2
(3) Other neurological diseases 1
(-)
28
21
0
5
(-)
28 0
24 2
22 5 1
20 4 2
1/5 1/5
1/4 0/4
1/5
0/4 0/4
(-)
(+)
Unknown
1
(26)
Unknown Unknown
4 2
(28)
Early· onset cases
Typical cases
Cerebral palsy Mental retardation Epilepsy Leukodystrophy Autism Others
0/5 0/5
0/4
3/5
3/4
1
Table 6 Prenatal problems
onset cases were analyzed in detail.
Distribution of patients The patients were unevenly distributed throughout Japan (Table 2). The prevalence was higher around the large cities, such as Tokyo, Yokohama, or Nagoya. There was no report from the northern half of mainland Honshu. Several institutions reported many cases, which suggests that the number of cases considerably depends on the degree of interest. Therefore, there must be not a few unreported or undiagnosed cases. Ages of patients The ages of patients at the time of the study (February 1, 1987) ranged from 1 to 26 years (Table 3). Forty-seven out of 54 cases were between 5 to 17 years of age.
Family histories The average ages of the parents at the time of birth of the patients are shown in Table 4. Compared with the national averages of the parents' ages (28.1 years for mother and 31.0 years for father) [19], they did not differ signifi-
History of maternal pregnancy and delivery Spontaneous abortion Artificial abortion Others Prenatal abnormalities Infection Drug Threatened abortion Abnormalities of quickening
Typical cases (28)
Early onset cases (26)
2 2
3 1
0
0
7/28
7/26 0/7 7/7 3/7 0/7
2/7 2/7 5/7 5/7
cantly. No consanguinity or familial cases were found, as shown in Table 5. Cerebral palsy, mental retardation, epilepsy and other neurological abnormalities were found in family members. It is not clear whether these conditions in family members are related to RS. Prenatal abnormalities, although not serious, were noted in 25% of the typical cases and 27% of the early-
Oguro et al: Survey of Rett syndrome 755
onset cases (Table 6). These numbers were slightly higher than those reported for Duchenne muscular dystrophy and the Tourette syndrome, 20.9% and 18.6%, respectively [20]. The rates of spontaneous abortions were 3.0% in pregnancies in the typical cases and 4.7% in the earlyonset cases. They were not increased.
Because RS only affects girls, it can easily be assumed that RS is fatal when present in males. Therefore, the numbers of male and female siblings of the patients were examined. The numbers of siblings of the 28 typical patients were 18 brothers and II sisters. The 26 earlyonset cases had 10 brothers and 20 sisters. The total num-
(4) rltandard deviation at birth (Early-onset cases; 26 cases)
_
