Trends in the prevalence and characteristics of unilateral spastic cerebral palsy in patients born between 1988 and 2007 in Okinawa, Japan.

Objective: The objective of this study was to investigate the trends in the prevalence and characteristics of unilateral spastic cerebral palsy among children born between 1988 and 2007 in Okinawa, Japan. Method: We conducted a surveillance of children with cerebral palsy using the local cerebral palsy registration system. For analysis purposes, the study was divided into two periods: periodⅠ (from 1988 to 1997) and periodⅡ (from 1998 to 2007). We performed a chi-squared test and Poisson regression analysis. Result: We observed a significant trend for an increased prevalence of unilateral spastic cerebral palsy in periodⅡ (p<0.01). The number of children with unilateral spastic cerebral palsy who were born with birth weights of 1500 g or more and/or a gestational age of 32 weeks or more was increased in periodⅡ. In addition, brain magnetic resonance imaging and computed tomography scans showed that porencephaly and periventricular white matter damage were common findings in preterm children of gestational age less than 31 weeks in period II. The most frequently observed neuroimaging feature in children with a gestational age of over 32 weeks was brain infarction. Conclusion: We found a trend for an increased prevalence of unilateral spastic cerebral palsy in periodⅡ. However, the cause of this increase is as yet unknown.

Trends in the prevalence of cerebral palsy in children born between 1988 and 2007 in Okinawa, Japan.

AIM: This study aimed to describe trends in CP prevalence among children born between 1988 and 2007 in Okinawa, Japan. METHOD: This study was conducted during two time periods, Period I (from 1988 to 1997) and Period II (from 1998 to 2007), using data from the local CP registration system. We assessed cerebral palsy gestational age and birth weight specific trends in prevalence and analyzed these with Poisson regression analysis. RESULTS: Overall crude CP prevalence was 1.88 per 1000 live births. Approximately 70% of children with CP were born preterm or with low birth weight (LBW). Overall CP prevalence increased in Period I and decreased significantly in Period II (P<0.05). Additionally, CP prevalence among children born with a birth weight between 1000 and 1999g increased in Period I and decreased significantly in Period II (P<0.05). A significant decrease was found among the children born between 1995 and 2007 with a gestational age between 28 and 31weeks (P<0.01). CONCLUSIONS: There was a decrease in CP prevalence from 1998 to 2007, especially among LBW children and preterm infants. The high CP proportions among LBW and preterm infants are unique features of the population of Okinawa, Japan.

Long-term survival of children with cerebral palsy in Okinawa, Japan.

AIM: The aim of this study was to describe the survival prognosis of children with cerebral palsy (CP) in Okinawa, Japan. METHOD: A cohort study was conducted on all children with CP born between 1988 and 2005 in Okinawa, Japan. Survival proportions were determined with a life table and Kaplan-Meier survival curves were plotted. The effect of each predictor variable was estimated using Cox regression analysis. RESULTS: This study included 580 children with CP (332 males, 248 females). In the cohort, 119 (20.5%) children were classified in Gross Motor Function Classification System (GMFCS) level I, 65 (11.2%) were classified in level II, 40 (6.9%) in level III, 189 (32.6%) in level IV, 166 (28.6%) in level V and GMFCS level was unknown for one. Of the 34 children who died, 29 were classified in GMFCS level V and GMFCS level was unknown for one. Mean age at start of follow-up was 24.5 months (SD 2.6 mo); mean length of follow-up was 8 years 8 months (standard error of the mean 0.214 y). The 5 year- and 18-year survival percentages of the entire cohort were 98% and 89% respectively. In children with CP, significantly lower survival rates were associated with multiple factors, including a birthweight of at least 2500 g (p=0.009), a gestational age of at least 37 weeks (p=0.004), and the most severe gross motor limitation, GMFCS level V (p<0.001). However, multivariate analysis showed GMFCS level V was the only significant predictor variable (p<0.001) for survival of CP. INTERPRETATION: This study is the first to describe survival of children with CP in Japan. Our results are similar to those previously reported in other countries. These results are important in planning adequate provision of social and medical services for individuals with CP.

Missense mutations in the DNA-binding/dimerization domain of NFIX cause Sotos-like features.

Sotos syndrome is characterized by prenatal and postnatal overgrowth, characteristic craniofacial features and mental retardation. Haploinsufficiency of NSD1 causes Sotos syndrome. Recently, two microdeletions encompassing Nuclear Factor I-X (NFIX) and a nonsense mutation in NFIX have been found in three individuals with Sotos-like overgrowth features, suggesting possible involvements of NFIX abnormalities in Sotos-like features. Interestingly, seven frameshift and two splice site mutations in NFIX have also been found in nine individuals with Marshall-Smith syndrome. In this study, 48 individuals who were suspected as Sotos syndrome but showing no NSD1 abnormalities were examined for NFIX mutations by high-resolution melt analysis. We identified two heterozygous missense mutations in the DNA-binding/dimerization domain of the NFIX protein. Both mutations occurred at evolutionally conserved amino acids. The c.179T>C (p.Leu60Pro) mutation occurred de novo and the c.362G>C (p.Arg121Pro) mutation was inherited from possibly affected mother. Both mutations were absent in 250 healthy Japanese controls. Our study revealed that missense mutations in NFIX were able to cause Sotos-like features. Mutations in DNA-binding/dimerization domain of NFIX protein also suggest that the transcriptional regulation is abnormally fluctuated because of NFIX abnormalities. In individuals with Sotos-like features unrelated to NSD1 changes, genetic testing of NFIX should be considered.

[Postoperative course of a patient undergoing selective dorsal rhizotomy for cerebral palsy].

Selective dorsal rhizotomy (SDR) is a surgical technique for reducing spasticity associated with cerebral palsy (CP). In the present study, we investigated the changes of clinical symptoms before and after SDR in a child with CP undergoing functional training at the Okinawa Child Development Center. Total score on the Gross Motor Function Measure significantly improved compared to preoperative values at approximately six months, one year, and two years postoperatively. The level of spasticity also significantly decreased postoperatively compared to preoperative levels according to evaluation using the Ashworth scale and the modified Ashworth scale. Based on these findings, SDR was considered effective for reducing spasticity associated with CP. In addition, orthopedic surgery was performed after SDR in 47% of patients, indicating the need to further investigate the timing of SDR.

[Prevalence of cerebral palsy in Okinawa between 1995 and 2001].

We report a population based study of prevalence of cerebral palsy in children born between 1995 and 2001 in Okinawa. The overall prevalence of cerebral palsy was 2.3 per 1,000 live-births; this result was higher than that reported in our previous study conducted between 1988 and 1994. We found a high prevalence of cerebral palsy in children weighing less than 2,500 g, especially in those weighing less than 1,500 g at birth. Moreover we found children weighing more than 1,800 g or those who had more than 33 weeks of gestation period at birth showed a lower risk for cerebral palsy.

Phenotypic consequences of genetic variation at hemizygous alleles: Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.

PURPOSE: We tested the hypothesis that Sotos syndrome (SoS) due to the common deletion is a contiguous gene syndrome incorporating plasma coagulation factor twelve (FXII) deficiency. The relationship between FXII activity and the genotype at a functional polymorphism of the FXII gene was investigated. METHODS: A total of 21 patients including those with the common deletion, smaller deletions, and point mutations, and four control individuals were analyzed. We examined FXII activity in patients and controls, and analyzed their FXII 46C/T genotype using direct DNA sequencing. RESULTS: Among 10 common deletion patients, seven patients had lower FXII activity with the 46T allele of the FXII gene, whereas three patients had normal FXII activity with the 46C allele. Two patients with smaller deletions, whose FXII gene is not deleted had low FXII activity, but one patient with a smaller deletion had normal FXII. Four point mutation patients and controls all had FXII activities within the normal range. CONCLUSION: FXII activity in SoS patients with the common deletion is predominantly determined by the functional polymorphism of the remaining hemizygous FXII allele. Thus, Sotos syndrome is a contiguous gene syndrome incorporating coagulation factor twelve (FXII) deficiency.

Fifty microdeletions among 112 cases of Sotos syndrome: low copy repeats possibly mediate the common deletion.

Sotos syndrome (SoS) is an autosomal dominant overgrowth syndrome with characteristic craniofacial dysmorphic features and various degrees of mental retardation. We previously showed that haploinsufficiency of the NSD1 gene is the major cause of SoS, and submicroscopic deletions at 5q35, including NSD1, were found in about a half (20/42) of our patients examined. Since the first report, an additional 70 SoS cases consisting of 53 Japanese and 17 non-Japanese have been analyzed. We found 50 microdeletions (45%) and 16 point mutations (14%) among all the 112 cases. A large difference in the frequency of microdeletions between Japanese and non-Japanese patients was noted: 49 (52%) of the 95 Japanese patients and only one (6%) of the 17 non-Japanese had microdeletions. A sequence-based physical map was constructed to characterize the microdeletions. Most of the microdeletions were confirmed to be identical by FISH analysis. We identified highly homologous sequences, i.e., possible low copy repeats (LCRs), in regions flanking proximal and distal breakpoints of the common deletion, This suggests that LCRs may mediate the deletion. Such LCRs seem to be present in different populations. Thus the different frequency of microdeletions between Japanese and non-Japanese cases in our study may have been caused by patient-selection bias.

Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome.

Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically.