Anthropology and mental retardation: Research approaches and opportunities

Although mental retardation is largely a sociocultural phenomenon, anthropological interest in this field has been slow to develop. In recent years, anthropological concepts and methods have been used in study of the community adaptation of mentally retarded persons and societal reactions to them. As an illustration, research developments at the Mental Retardation Research Center, UCLA, are discussed. The need for expanded, collaborative research by social and biomedical scientists is examined. The research puzzles include the links between poverty, ethnicity, schools, families and mental retardation, as well as the nature of intelligence and adaptation.     

Clinical genealogical and molecular genetic study of patients with mental retardation

The results of clinical, genealogical, cytogenetic and molecular genetic studies of 113 patients from 96 families with different forms of mental retardation from Ukraine are presented. This study was held as part of the CHERISH project of the 7-th Framework Program. The aim of the project is to improve diagnostics of mental retardation in children in Eastern Europe and Central Asia through detailed analysis of known chromosomal and gene's aberrations and to find the new gene-candidates that cause mental retardation. All patients have normal chromosome number (46XY or 46XX). The cases with fragile-X syndrome were eliminated using molecular genetic methods. Genome rearrangements were found among 28 patients using cytogenetic analysis, multiplex ligation-dependent probe amplification (MLPA analysis) ofsubtelomeric regions and array-based comparative genomic hybridisation (array CGH screening). In 10 cases known pathogenic CNV's were identified, 11 cases are unknown aberrations; their pathogenicity is being determined. The rest cases are known nonpathogenic gene rearrangements. Obtained results show the strong genetic heterogeneity of hereditary forms of mental retardation. The further studies will allow to identificate genes candidates and certain mutations in these genes that may be associated with this pathology.     

Fruit flies and intellectual disability

Mental retardation - more commonly known nowadays as intellectual disability - is a severe neurological condition affecting 3% of the general population. As a result of analysis of familial cases and recent advances in clinical genetic testing great strides have been made in our understanding of the genetic etiologies of mental retardation. Nonetheless, no treatment is currently clinically available to patients suffering from intellectual disability. Several animal models have been used in the study of memory and cognition. Established paradigms in Drosophila have recently captured cognitive defects in fly mutants for orthologs of genes involved in human intellectual disability. We review here three protocols designed to understand the molecular genetic basis of learning and memory in Drosophila and the genes identified so far with relation to mental retardation. In addition, we explore the mental retardation genes for which evidence of neuronal dysfunction other than memory has been established in Drosophila. Finally, we summarize the findings in Drosophila for mental retardation genes for which no neuronal information is yet available. All in all, this review illustrates the impressive overlap between genes identified in human mental retardation and genes involved in physiological learning and memory.     

Molecular screening of FRAXA and FRAXE in Indian patients with unexplained mental retardation

Fragile-X mental retardation is the commonest form of inherited mental retardation. We have studied 146 Indian patients (174 X chromosomes) with unexplained mental retardation by molecular methods. All study subjects were unrelated. Three of the 118 males were found to have the FMR1 full mutation. None of the patients tested were positive for the FMR2 full mutation. The Fragile X prevalence was 2.5% among males, which is lower than previously reported in Indian mentally retarded patients. Screening for Fragile X among patients with nonspecific mental retardation is important, even if there is no family history of mental retardation or typical behavioral or physical features associated with the Fragile-X phenotype. Identification of positive cases is also very important for the families, because of the high recurrence risk of the disease. Large multicenter screening programs with uniform criteria would be worthwhile to determine the prevalence of Fragile-X mental retardation in the Indian population.     

Childhood Psychosis or Mental Retardation: A Diagnostic Dilemma: I. Psychiatric and Psychological Aspects

A relatively large percentage of children seen at a mental retardation clinic demonstrated psychotic symptoms. The entire group with psychotic manifestations, 62 in all, were reviewed in order to clarify the diagnosis of childhood psychosis or mental retardation. The 1961 British criteria for childhood psychosis were used and are advocated by the authors. Childhood psychosis was the primary diagnosis in 38 cases, and psychosis secondary to brain damage in 24 cases. Onset of the condition under the age of three years and a poor prognosis for social recovery were characteristic of the entire group.Obvious emotional disorder was present in 21 mothers and 14 fathers. There was a continuum in terms of number of psychotic symptoms, level of intelligence and presence of organic signs. It is concluded that there is an overlap between the entities of childhood psychosis and mental retardation.     

Partial trisomy 4q due to familial 2/4 translocation

Summary The case of a 5-year-old boy with partial trisomy for the long arm of chromosome No. 4 is described. The pattern of abnormal development in this and in 12 previously reported cases is similar, but the phenotype is not as characteristic as that associated with some other types of chromosomal imbalance. The most consistent features are: growth and mental retardation, small head with narrow forehead, short philtrum, relatively large ears with incomplete differentiation of the pinnae, cryptorchidism, oedema of the hands and/or feet, and renal anomalies. Abnormal development of the thumb was present in 4 of 13 cases. Eleven of the 13 families had balanced translocation carriers whose future offspring would be at increased risk for a mental retardation syndrome.     

A cytogenetic survey of mentally retarded children in Taiwan: final report on the incidence of chromosome abnormalities

A cytogenetic survey of 470 mentally retarded children from three different sources is reported. Thirty-eight patients (8.08%) were found to have recognizable chromosome abnormalities, including 4 cases of sex chromosomes and 34 cases of autosomes. The most prominent category of abnormality was trisomic 21, a total of 26 cases of this type was found in this study. Sex chromosome abnormalities contribute very little to the etiology of mental retardation. From the results of our three groups of patients as well as from those surveyed by others, it is concluded that the more severe the degree of mental retardation, the higher the incidence of chromosome abnormalities.     

Rapid FMR1-protein analysis of fetal blood: an enhancement of prenatal diagnostics

Fragile-X syndrome, a frequent cause of inherited mental retardation, is characterised in almost all cases by a CGG-repeat expansion that is located within the FMR-1 gene and that prevents the expression of fragile-X mental retardation protein (FMRP). We describe a test that simultaneously allows the rapid detection of FMRP in fetal lymphocytes and distinguishes these from fetal erythrocytes. Routine molecular genetic methods fail in the rare cases where protein expression is blocked, although there is no repeat expansion. Furthermore, they are unsuitable in cases of advanced pregnancy. Our test proves extremely valuable under both these circumstances.     

Subtelomeric chromosomal rearrangements detected in patients with idiopathic mental retardation and dysmorphic features

Subtelomeric chromosomal rearrangements detected in patients with idiopathic mental retardation and dysmorphic features: Cryptic aberrations involving the subtelomeric regions of chromosomes are thought to be responsible for idiopathic mental retardation (MR) and multiple congenital anomalies, although the exact incidence of these aberrations is still unclear. With the advent of chromosome-specific telomeric Fluorescence In Situ Hybridization (FISH) probes, it is now possible to identify submicroscopic rearrangements of distal ends of the chromosomes that can not be detected by conventional cytogenetic methods. In this study, cryptic subtelomeric chromosomal aberrations were detected in two of ten patients with idiopathic MR and dysmorphic features by using FISH probes of subtelomeric regions of all chromosome arms. A cryptic unbalanced de novo translocation was detected between the subtelomeric regions of the chromosome 10p and 18p in a patient with severe mental retardation, sensorineuronal deafness and several dysmorphic features. In the other patient, with mild mental retardation and dysmorphic features, a de novo subtelomeric deletion of chromosome 2q was found. In conclusion, in both familial and sporadic cases with idiopathic MR and dysmorphic features, the detection of chromosomal aberrations including subtelomeric rearrangements is of great importance in offering genetic counseling and prenatal diagnosis.     

Balanced X-autosomal translocation and mental retardation. Mapping mental retardation linked to X (excluding fragile X)

From personal observations and reported cases of translocation X-Autosome, a study of the breakpoint showed that Xp11 is more frequently associated to mental retardation. This finding is in agreement with linkage analysis in families with X-linked mental retardation non X-fra.     

Infant C677T MTHFR polymorphism and severe mental retardation

BACKGROUND: We investigated whether infants with homozygous genotype TT of the MTHFR gene were at increased risk of severe mental retardation. METHODS: One hundred children with severe mental retardation (cases) were investigated from a large geographic-based study of infants born in California in 1992-1993. Cases were compared to 743 randomly selected nonmalformed control infants born in California during 1987-1991. DNA was extracted from newborn screening filter papers. Cases and controls were genotyped TT if homozygous for the MTHFR C677T allele, CT if heterozygous for the C677T allele, and CC if homozygous for the C677 (wild type) allele. RESULTS: Overall, case and control infants had similar percentages of TT and CT genotypes. Percentages between cases and controls differed somewhat across race/ethnic groups. Elevated ORs of 1.9 (95% CI: 0.7-5.0) and 2.6 (95% CI: 1.1-5.8) were observed for the TT and CT genotypes, respectively, among Hispanic children. Observed results were not substantially altered for analyses that removed 41 case children who also had structural birth defects. CONCLUSIONS: Folate-related mechanisms are important to investigate for etiologies of birth defects, and such lines of inquiry may be revealing for mental retardation given the relationships between mental retardation and birth defects and potential relationships between folate, DNA methylation, and mental retardation.     

Molecular basis of X-linked non-specific mental retardation

Mental retardation (MR) is a common disorder, affecting 1-3% of the total population. This condition results from failure to develop cognitive abilities and intelligence level appropriate for the age group. Mental retardation is basically a clinically as well as etiologically heterogeneous type of condition and both genetic and non-genetic factors have been found to be involved. There are more than 1000 entries in Online Mendelian Inheritance in Man (OMIM) database under the name of mental retardation. In recent years 15 genes for X linked non-specific mental retardation have been identified which provide important clues regarding molecular and cellular processes involved in signal transduction cascade in central nervous system. Recent advancements in identification and characterization of X-linked non-specific mental retardation genes have been discussed in this review. Understanding of the molecular pathways of disease causing genes would be helpful in developing effective therapeutic approaches for mental retardation.     

Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group.

The fragile X syndrome is an X-linked mental retardation disorder caused by an expanded CGG repeat in the first exon of the fragile X mental retardation (FMR1) gene. Its frequency, X-linked inheritance, and consequences for relatives all prompt for diagnosis of this disorder on a large scale in all affected individuals. A screening for the fragile X syndrome has been conducted in a representative sample of 3,352 individuals in schools and institutes for the mentally retarded in the southwestern Netherlands, by use of a brief physical examination and the DNA test. The attitudes and reactions of (non)consenting parents/guardians were studied by (pre- and posttest) questionnaires. A total of 2,189 individuals (65%) were eligible for testing, since they had no valid diagnosis, cerebral palsy, or a previous test for the FMR1 gene mutation. Seventy percent (1,531/2,189) of the parents/guardians consented to testing. Besides 32 previously diagnosed fragile X patients, 11 new patients (9 males and 2 females) were diagnosed. Scoring of physical features was effective in preselection, especially for males (sensitivity .91 and specificity .92). Major motives to participate in the screening were the wish to obtain a diagnosis (82%), the hereditary implications (80%), and the support of research into mental retardation (81%). Thirty-four percent of the parents/guardians will seek additional diagnostic workup after exclusion of the fragile X syndrome. The prevalence of the fragile X syndrome was estimated at 1/ 6,045 for males (95% confidence interval 1/9,981-1/ 3,851). On the basis of the actual number of diagnosed cases in the Netherlands, it is estimated that >50% of the fragile X cases are undiagnosed at present.     

A new case of Martsolf syndrome

Martsolf syndrome is an autosomal recessive syndrome characterized by microcephaly, mental retardation, cataract, hypogonadism and short stature. A seven-year-old boy was admitted to the hospital with growth retardation and difficulties in walking. His parents were first cousins. Bilateral lens extraction was performed during infancy because of congenital cataract. On physical examination he had short stature, microcephaly, micropthalmia, hypogonadism, mental retardation. Brain magnetic resonance imaging revealed alterations in the white matter. Up to date very few cases with this syndrome have been reported. This is the first case described in the Turkish population and may add valuable information to the literature.     

Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3)

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.     

Disabilities caused by unstable mutations in Costa Rica

Motonic dystrophy and fragile X syndrome are two genetically determined relatively common disabilities. Both are examples of a new type of mutation mechanism called unstable or dynamic mutations, triple repeats expansions or DNA amplification. Fragile X syndrome is recognized as the main cause of hereditary mental retardation and myotonic dystrophy is considered the most common muscular dystrophy of adults. This is a prospective non randomized study of clinically affected people, in order to confirm the diagnosis with molecular techniques (Southern blot and PCR) and to perform cascade screening of the rest of the family to offer them adequate genetic counseling. We were able to corroborate the initial diagnosis in most clinical cases of myotonic dystrophy, but in the cases of mental retardation more than half studies were negative for fragile X syndrome, stressing the difficulties encountered by medical practitioners to diagnose this syndrome. The reasons for this are several; probable the main culprit is the subtle and unspecific clinical picture affected individuals exhibit, particularly children before puberty. Cascade screening, genetic counseling and selective abortion are the only tools available to prevent these disabling diseases for the moment.     

Ring chromosome 15 in child with a minor dysmorphism of phenotype

Summary The analysis of a karyotype of a girl with slight mental retardation, without significant dysmorphism, showed the presence of a ring chromosome in group 13–15. By the application of G technique it was discovered that in this case it was an aberrant chromosome 15.Besides retardation in growth and a slight mental backwardness in this case, it was confirmed that in cases of ring 15 syndrome no preponderant change appears in phenotype.     

Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation

The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically detectable chromosomal abnormalities are the most frequently recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy-number variants. We studied 100 children with idiopathic mental retardation and normal results of standard chromosomal analysis, by use of whole-genome sampling analysis with Affymetrix GeneChip Human Mapping 100K arrays. We found de novo deletions as small as 178 kb in eight cases, de novo duplications as small as 1.1 Mb in two cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy-number variants as conventional cytogenetic analysis can in people with mental retardation.