Prevalence of the fragile X syndrome in four birth cohorts of children of school age

Summary The prevalence of the fragile X syndrome among 12,882 children (6594 boys and 6288 girls) born during the years 1969–1972 in Kuopio province in eastern central Finland has been studied retrospectively. Mentally retarded children were selected from normal schools by using school achievement tests and from registers of mentally retarded individuals. In the present study fragile X syndrome was found in 6/111 mentally retarded children (5.4%), in 4/61 boys and in 2/50 girls, respectively. It was not detected in the control group of 85 healthy children. The corrected prevalence of fragile X syndrome among boys in four successive birth cohorts was estimated to the 1 in 1210 or 0.8/1000, and that among girls, 1 in 2418 or 0.4/1000. The overall prevalence was calculated to be 1 in 1612 or 0.6/1000 children.     

Population cytogenetics of folate-sensitive fragile sites

Summary The frequencies of folate-sensitive autosomal rare fragile sites (ARFS) were compared in populations of mentally retarded, mentally subnormal, and mentally normal children and of patients referred for diagnostic chromosome study. The frequencies did not differ significantly. Altogether, an autosomal rare fragile site was found in 16 of 1445 individuals (1 in 90). Of six different folate-sensitive ARFS detected, the most common one was FRA9A, with a frequency of 1 in 241 individuals. In addition, FRA17A, classified as a distamycin A-inducible fragile site, was found with a frequency of 1 in 206. It was regarded as a spontaneously expressive fragile site. In 19 families in which transmission of an autosomal rare fragile site was studied, the mother was the carrier in 16 families and the father, in one family. The mean percentage (±SD) of cells expressing ARFS in 55 individuals was 19% (±11.4). The age did not affect the rate of expression. When the rate of expression was calculated separately in a group of mentally retarded (mean=23.4%) and in a group of mentally normal individuals (mean=16.0%), the difference was statistically significant.     

Angelman syndrome methylation screening of 15q11-q13 in institutionalized individuals with severe mental retardation

Among several genetic diseases that comprise mental retardation, Angelman syndrome (AS) has been extensively recognized and investigated. In the general population, the syndrome occurs in about 1 in 20,000 live births and its prevalence in severely mentally retarded individuals is 1.4%. These figures, however, may be an underestimate, because of the variable phenotype of AS. The main objective of this work was to investigate AS patients among a group of mentally retarded subjects, using the methylation pattern of the SNRPN gene, as determined by Southern blotting molecular analysis. The molecular investigation of 75 institutionalized individuals with severe to profound mental retardation resulted in the detection of 1 case with an abnormal methylation pattern of the SNRPN gene, corresponding to AS. The patient's phenotype was classified as atypical, without outbursts of inappropriate laughter or a happy disposition; the patient would not have been diagnosed in the usual screens for AS, which only select patients who demonstrate the typical clinical findings characteristic of the disease.     

Population cytogenetics of folate-sensitive fragile sites

Summary The location and frequency of folate-sensitive common fragile sites (CFS) were studied in three populations: (1) 111 mentally retarded children of school age, (2) 240 mentally subnormal children attending special schools, and (3) 85 healthy children attending normal schools. Common fragile sites were found at 54 chromosomal bands including also the band Xq27, where gaps and breaks were detected in 4% of the children. The most frequent CFS were FRA3B (at 3p14.2), FRA6E (at 6q26), and FRA16D (at 16q23) seen in 73%, 65%, and 58% of the individuals totally studied. The frequencies of CFS-positive individuals did not differ among the populations. The variation found in the distribution of CFS among the populations was primarily assumed to be due to sampling differences and study method. The rate of expression of the most frequent CFS varied significantly among the individuals, seeming to suggest that polymorphism exists at those CFS.     

Observations on Community School Facilities for the Mentally Retarded and Admissions to Institutions in Ontario, 1954-63

The relationship between community school facilities and first admissions of mentally retarded children to Ontario Institutions was investigated for the period 1954-1963. The number of educable (I.Q. 50-75) mentally retarded children aged 6-16 years in community schools rose consistently (92.1/100,000 population in 1954 to 190.1 in 1963), while first admissions of educable mentally retarded persons aged 5-19 years to Ontario Hospital Schools showed no consistent trend (2.0/100,000 in 1954 and 2.0 in 1963). The number of trainable (I.Q. 20-50) mentally retarded children aged 5-18 years in community retarded children''s schools rose steadily (10.9/100,000 population in 1954 to 42.8 in 1963), while first admissions in this category aged 5-19 years demonstrated no consistent trend (2.6/100,000 in 1954 and 2.2 in 1963).No indication was found that the age distribution of these first admissions had changed from 1954 to 1963. Any effect that increased school facilities might have had in reducing first admissions may have been nullified by the very large demand for a limited number of beds.     

A Survey of Toxoplasmosis Among Mentally Retarded Children

To determine what role, if any, toxoplasmosis plays in the mental retardation of children, sera from 345 mentally retarded children were tested for the presence of antibodies to Toxoplasma gondii. The serological tests employed were the complement-fixation, the Sabin-Feldman dye test and the immunofluorescence test. The donors were also skin-tested with toxoplasmin.Of 345 mentally retarded donors nine gave a positive skin reaction, 15 possessed complement-fixing antibodies, 21 had immunofluorescent antibodies and 45 had dye test antibodies to T. gondii.The incidence of antibodies to T. gondii in the mentally retarded group was approximately the same as in the normal control group of the same age, and less than in the group suspected of having toxoplasmosis. It is concluded that in the children in this study toxoplasmosis played little or no role as a predisposing factor in the occurrence of congenital mental deficiency.     

The frequency of X-linked mental retardation

600 mentally retarded children, 339 boys and 261 girls aged 5-9 years were examined. Boys to girls ratio (B:G) was found in the total group to be 1.3. Among 257 children with mental retardation of confirmed genetic origin B:G = 1.4, in 129 children with confirmed exogenous defects B:G = 1.04. The significant prevalence of boys over girls was characteristic of children with monogenic forms. The frequency of X-linked mental retardation in the total group, in all mentally retarded boys and in boys with genetic forms was 12.5 +/- 1.3%, 22.1 +/- 2.2% and 28.5 +/- 2.8%, respectively. The frequency of X-linked mental retardation was higher in boys with genetic forms of imbecility.     

Survey of Scalp Dermatophyte Carriage in a Day Care Center in Turkey

The prevalence of tinea capitis and the symptom-free colonisation of the scalp with dermatophytes were examined in 502 mentally retarded participants who attended day care centers in the Tarsus district, Mersin, Turkey. Between December 2006 and May 2007, a screening study was conducted in three centers on a total of 316 (62.9%) male and 186 (37.1%) female participants aged 12 ± 6.2 years. The examinations were carried out in parallel with the hairbrush, toothbrush, and cotton swab methods by inoculation onto Sabouraud glucose agar. No participant was diagnosed with tinea capitis; however, we detected three carriers, all of whom were boys aged 2–16 years. The total prevalence of carrier state was 0.6%. Of three boys, T. tonsurans was seen in two cases (66.7%), and in one case a zoophilic variant of T. mentagrophytes (33.3%) was isolated. The diagnosis was made via the hairbrush method in all three carriers. We also did a screening study on ten households of the three asymptomatic carriers. T. mentagrophytes also was isolated in a 5-year-old sister of the boy with T. mentagrophytes colonisation. All the carriers were followed-up without any antimycotic treatment. In two of the participants, the carrier state persisted at the 13th and 17th week follow-ups, and mycological clearance was documented at the 20th and 24th week for these individuals. The third case and the household’s culture were found negative at the 7- and 12-week follow-ups. Despite poor hygienic conditions and the participants’ difficulties in performing basic hygiene practices, asymptomatic carriage was found to be surprisingly less prevalent among the mentally retarded individuals.     

Screening for FMR1 and FMR2 mutations in 222 individuals from Spanish special schools: identification of a case of FRAXE-associated mental retardation

Fragile X syndrome is the most common inherited form of familial mental retardation. It results from a (CGG) _n trinucleotide expansion in the FMR1 gene leading to the typical Martin-Bell phenotype. Clinical features vary depending on age and sex. Expansion of a (CCG) _n repeat in the FMR2 gene corresponds to the FRAXE fragile site which lies distal to FRAXA and is also associated with mental retardation, but it is less frequent and lacks a consistent phenotype. Analysis of repeat expansions in these two genes allows the molecular diagnosis of these different entities. We report here the screening of the FRAXA and FRAXE mutations in 222 unrelated mentally retarded individuals attending Spanish special schools. PCR and/or Southern blotting methods were used. We detected full mutations in the FMR1 gene in 11 boys (4.9%) and 1 boy (0.5%) with a CCG repeat expansion in the FMR2 gene. The latter shows mild mental retardation with psychotic behaviour and no remarkable physical traits. Molecular studies revealed a mosaicism for methylation in the FMR2 gene. This case supports the observation that expansions greater than 100 repeats can be partially methylated and cause the phenotype. Received: 11 February 1997 / Accepted: 9 June 1997     

Molecular analysis of the (CGG)n expansion in the FMR-1 gene in 59 Spanish fragile X syndrome families

The fragile X mental retardation syndrome is caused by an expansion of a trinucleotide repeat (CGG)_n in the FMR-1 gene. Molecular genetic study of fragile X provides accurate diagnosis and facilitates genetic counseling in families with affected members. We present here the molecular study of 59 Spanish fragile X syndrome families using probe StB 12.3 and the polymerase chain reaction (PCR) of the (CGG)_n repeat sequence of the FMR-1 gene. The results obtained have allowed us to characterize 455 individuals, including eight prenatal diagnoses. The clinical diagnosis of fragile X in 89 affected males was confirmed, 137 female carriers were identified (48 of whom were mentally retarded), 176 individuals at risk were found not to have the expansion, and 12 cases of normal transmitting males (NTM) were detected. In the sample studied, no de novo mutations were detected, nor any mutation different from that described for the (CGG)_n expansion. One nonmentally retarded male was detected as having an unmethylated CpG island for the FMR-1 gene, but with more than 200 CGG repeats (high functioning male). The analysis of the (CGG)_n repeat in 208 normal chromosomes gave an allele distribution similar to that in other Caucasoid population groups, with alleles of 29 and 30 CGG repeats accounting for 46% of the chromosomes. The combination of Southern analysis and PCR of the (CGG)_n repeat is highly efficient for diagnosis, compared with cytogenetic techniques, especially in the detection of female carriers, NTMs, and prenatal diagnosis, enabling accurate genetic counseling to be provided in all cases.     

Analysis of socio-demographic and systemic health factors and the normative conditions of oral health care in a population of the Brazilian elderly

doi: 10.1111/j.1741‐2358.2010.00446.x
Analysis of socio‐demographic and systemic health factors and the normative conditions of oral health care in a population of the Brazilian elderly Objective: To investigate the association of socio‐demographic and systemic health factors according to the normative conditions of oral health care (dental caries, edentulism, periodontal disease and oral mucosal lesion) in elderly individuals. Material and methods: A cross‐sectional study was carried out in a group of elderly with access to community health care (n = 200). The normative conditions of oral health were then investigated according to the WHO and the SB Brazil criteria. Bivariate analyses were evaluated by the chi‐square test and Fisher’s exact test. An estimation of prevalence for the covariates was performed using Poisson’s regression models. Results: The prevalence of edentulism and oral mucosal lesions was detected in 58% and 21.5% of elderly patients, respectively. In the dentate subjects, the prevalence of dental caries and periodontal disease was 51.2% and 20.8%, respectively. Older men and individuals from lower‐income groups exhibited a higher prevalence of dental caries. Elderly women, illiterate individuals, and individuals over the age of 65 years exhibited a higher prevalence of edentulism. Elderly 60–64 years old and those who are employed had a significant association with periodontal disease. Conclusion: Socio‐demographic factors were associated with some notable oral diseases in the elderly.     

Frequency of the fragile X syndrome in institutionalized mentally retarded females in Japan

Summary The fragile X [fra(X)] syndrome was screened on 190 Japanese institutionalized females with moderate to severe mental retardation. Two inmates with severe mental retardation (IQ 20) had the fra(X) chromosome in 26% and 15% of the cells examined, indicating that the prevalence of the fra(X) syndrome was about 1% in all female inmates and was about 3.27% in severely mentally retarded females with known causes. However, no female with fra(X) syndrome was found in 35 moderately retarded females. Both had brothers with the fra(X) syndrome and the prevalence was 10% in females with a family history of mental retardation. In addition, the replication study of the fra(X) chromosome in the patients supported the proposal that an excess of the early replicated fra(X) chromosome is related to the mental capacity in heterozygous females. Therefore, the fra(X) syndrome should not be ignored even in severely mentally retarded females with a family history, though the heterozygotes are commonly normal to subnormal in their mental development. in addition, the replication study of the fra(X) chromosome may help to estimate mental development in the carrier children.     

FISH diagnosis of the common 57-kb deletion in <Emphasis Type="Italic">CTNS</Emphasis> causing cystinosis

Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in CTNS. The most prevalent CTNS mutation, a 57-kb deletion, occurs in ~60% of patients in the United States and northern Europe and removes exons 1–9, most of exon 10, the CTNS promoter region, and all of an adjacent gene of unknown function called CARKL. CTNS codes for the lysosomal cystine transporter, whose absence leads to intracellular cystine accumulation, widespread cellular destruction, renal Fanconi syndrome in infancy, renal glomerular failure in later childhood, and other systemic complications. Because treatment with oral cysteamine can prevent or delay these complications significantly, early and accurate diagnosis is critical. This study describes the generation of fluorescence in situ hybridization (FISH) probes for the 57-kb deletion in CTNS, enabling cytogenetics laboratories to test for this common mutation. The probes would also be able to detect a less frequent 11.7-kb deletion. A blinded study was performed using multiplex PCR analysis as the gold standard to determine the presence or absence of the 57-kb deletion. The FISH probes, evaluated on 12 lymphoblastoid cell lines from singly deleted, doubly deleted, and nondeleted patients, made the correct diagnosis in every case. This appears to be the first FISH-based diagnostic method described for any lysosomal storage disorder. It can assist in the antenatal and perinatal diagnosis of cystinosis and promote earlier salutary therapy with cysteamine.     

Uncoupling protein 2 polymorphisms as risk factors for NTDs

BACKGROUND: Both environmental and genetic factors are involved in the etiology of NTDs. Inadequate folate intake and obesity are important environmental risk factors. Several folate‐related genetic variants have been identified as risk factors; however, little is known about how genetic variants relate to the increased risk seen in obese women. Uncoupling Protein 2 (UCP2) is an attractive candidate to screen for NTD risk because of its possible role in obesity as well as energy metabolism, type‐2 diabetes, and the regulation of reactive oxygen species. Interestingly, a previous study found that a common UCP2 compound homozygous genotype was associated with a threefold increase in NTD risk. METHODS: We evaluated three polymorphisms, ‐866G>A, A55V, and the 3′UTR 45 bp insertion/deletion, as risk factors for NTDs in Irish NTD cases (n = 169), their mothers (n = 163), their fathers (n = 167), and normal control subjects (n = 332). RESULTS: Allele and genotype frequencies were not significantly different when comparing NTD mothers, NTD fathers, or affected children to controls. Additionally, the previously reported risk genotype (combined homozygosity of 55VV and 3′UTR 45 bp deletion/deletion) was not present at a higher frequency in any NTD group when compared to controls. CONCLUSIONS: In our Irish study population, UCP2 polymorphisms did not influence NTD risk. Moreover, the prevalence of this allele in other populations was similar to the Irish prevalence but far lower than reported in the previous NTD study, suggesting that this previous finding of an association with NTDs might have been due to an unrepresentative study sample. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

A Unified Rapid PCR Method for Detection of Normal and Expanded Trinucleotide Alleles of CAG Repeats in Huntington Chorea and CGG Repeats in Fragile X Syndrome

We report on a unified rapid betaine-based-PCR protocol for amplification of the (CAG)n region in Huntington disease (HD) and the (CGG)n region in Fragile X syndrome (FXS), followed by an electrophoretic separation on automated sequencer for precise determination of the triplet numbers. The high betaine concentration (2.5 M betaine) permits precise amplification of the CAG and CGG repeats. Ten HD affected patients and 10 healthy individuals from HD families were re-evaluated. For FXS the CGG region in normal individuals and premutations of about 100 repeats were precisely amplified by this protocol. Ten unrelated FXS premutation carriers and 24 mentally retarded non-FXS affected boys were re-examined by this method. The results totally coincided with the previous ones. This protocol is a good choice as a fast screening test. Within 24 h we can have preliminary information on the patient’s genetic status. Normal individuals, CGG premutation carriers up to 100 repeats, as well as HD patients carrying an expansion up to 50 CAG repeats can be easily clarified. This accounts for a relatively large proportion (about 90%) of the suspected HD and FXS patients, referred to our laboratory for genetic analysis. The calculation of the repeat’s number is more accurate for the correct interpretation of the results, screening tests and genetic counselling.     

Broken ribs: Paleopathological analysis of costal fractures in the human identified skeletal collection from the Museu Bocage,Lisbon, Portugal (late 19th to middle 20th centuries)

Although rarely reported in the anthropological literature, rib fractures are commonly found during the analysis of human skeletal remains of past and modern populations. This lack of published data precludes comparison between studies and restricts an accurate understanding either of the mechanisms involved in thoracic injuries or their impact on past societies. The present study aimed: 1) to report rib fracture prevalence in 197 individuals, 109 males, and 88 females, with ages at death ranging from 13 to 88 years old, from the Human Identified Skeletal Collection, Museu Bocage, Portugal (late 19th‐middle 20th centuries); 2) to test the hypothesis that a higher prevalence of rib stress fractures existed in the 133 individuals who died from respiratory diseases, in a period before antibiotics. The macroscopic analysis revealed 23.9% (n = 47) of individuals with broken ribs. 2.6% (n = 124) out of 4,726 ribs observed were affected. Males presented more rib fractures, and a significantly higher prevalence was noted for older individuals. Fractures were more frequently unilateral (n = 34), left sided (n = 19) and mainly located on the shaft of ribs from the middle thoracic wall. Nineteen individuals presented adjacent fractured ribs. Individuals who died from pulmonary diseases were not preferentially affected. However, a higher mean rate of fractures was found in those who died from pneumonia, a scenario still common nowadays. Since rib involvement in chest wall injury and its related outcomes are important issues both for paleopathology and forensic anthropology, further investigations are warranted. Am J Phys Anthropol 2009. © 2009 Wiley‐Liss, Inc.     

Improvement in Lipid and Protein Trafficking in Niemann‐Pick C1 Cells by Correction of a Secondary Enzyme Defect

Different primary lysosomal trafficking defects lead to common alterations in lipid trafficking, suggesting cooperative interactions among lysosomal lipids. However, cellular analysis of the functional consequences of this phenomenon is lacking. As a test case, we studied cells with defective Niemann‐Pick C1 (NPC1) protein, a cholesterol trafficking protein whose defect gives rise to lysosomal accumulation of cholesterol and other lipids, leading to NPC disease. NPC1 cells also develop a secondary defect in acid sphingomyelinase (SMase) activity despite a normal acid SMase gene (SMPD1). When acid SMase activity was restored to normal levels in NPC1‐deficient CHO cells through SMPD1 transfection, there was a dramatic reduction in lysosomal cholesterol. Two other defects, excess lysosomal bis‐(monoacylglycerol) phosphate (BMP) and defective transferrin receptor (TfR) recycling, were also markedly improved. To test its relevance in human cells, the acid SMase activity defect in fibroblasts from NPC1 patients was corrected by SMPD1 transfection or acid SMase enzyme replacement. Both treatments resulted in a dramatic reduction in lysosomal cholesterol. These data show that correcting one aspect of a complex lysosomal lipid storage disease can reduce the cellular consequences even if the primary genetic defect is not corrected.     

A cytogenetic study of mentally retarded school children in taiwan with special reference to the fragile X chromosome

Summary A cytogenetic study was made on 341 mentally retarded children in the Provincial Nantou Rehabilitation Center for the Mentally Retarded and the St. Raphael Opportunity Center in Tainan. Of the 89 mentally retarded children with chromosomal abnormalities, 63 had Down syndrome, 13 had the fragile X [fra(X)] syndrome, and the remaining had other aneuploid constitutions. Family studies were possible for 2 of the 13 fra(X) probands. The results of this study illustrate the contribution of chromosomal abnormalities to the pathogenesis of mental retardation in children.     

Founder mutation R245H of Sanfilippo syndrome type A in the Cayman Islands

Sanfilippo A syndrome is an autosomal recessive lysosomal storage disease. This disease was reported in the Cayman Islands population with carrier frequency of 1/7 to 1/10 in the West Bay district of Grand Cayman. The carrier testing of Sanfilippo A disease for families at risk was carried out using the thermal characteristics of sulfamidase activity. In the present study, a search for mutations in the sulfamidase gene in an index family was performed. In addition, 77 individuals, relatives of children with Sanfilippo A syndrome, were also studied by single-strand conformation polymorphism (SSCP), restriction fragment-length polymorphism (RFLP) analyses, and sequencing. A single mutation, G746A (R245H), was found in the family, with the patient being homozygous and both parents and 1 of the 3 siblings being carriers. Among the 77 family members of the patient with Sanfilippo syndrome, the same mutation was found among carriers of the disease. The finding of a single mutation supports the idea of a founder effect, which facilitates accurate carrier identification of Sanfilippo A syndrome in the population of Cayman Islands.