Autism spectrum disorder in a girl with a de novo x;19 balanced translocation

Balanced X-autosome translocations are rare, and female carriers are a clinically heterogeneous group of patients, with phenotypically normal women, history of recurrent miscarriage, gonadal dysfunction, X-linked disorders or congenital abnormalities, and/or developmental delay. We investigated a patient with a de novo X;19 translocation. The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. Her measurements are within normal range, and no other abnormalities were found during physical, neurological, or dysmorphological examinations. Conventional cytogenetic analysis showed a de novo balanced translocation, with the karyotype 46,X,t(X;19)(p21.2;q13.4). Replication banding showed a clear preference for inactivation of the normal X chromosome. The translocation was confirmed by FISH and Spectral Karyotyping (SKY). Although abnormal phenotypes associated with de novo balanced chromosomal rearrangements may be the result of disruption of a gene at one of the breakpoints, submicroscopic deletion or duplication, or a position effect, X; autosomal translocations are associated with additional unique risk factors including X-linked disorders, functional autosomal monosomy, or functional X chromosome disomy resulting from the complex X-inactivation process.

An evaluation of a community-based program for homeless adults with mental disorders and comorbid alcohol drug and mental disorders

Limited research has been conducted evaluating programs that are designed to improve the outcomes of homeless adults with mental disorders and comorbid alcohol, drug and mental disorders. This study conducted such an evaluation in a community-based day treatment setting with clients of the Harris County Mental Health and Mental Retardation Authority's Bristow Clinic. The study population included all clients who received treatment at the clinic for a minimum of six months between January 1, 1995 and August 31, 1996. An electronic database was used to identify clients and to track their program involvement. A profile was developed of the study participants and their level of program involvement included an examination of the amount of time spent in clinical, social and other interventions, the type of interventions encountered and the number of interventions encountered. Results were analyzed to determine whether social, demographic and mental history affected levels of program involvement and the effects of the levels of program involvement on housing status and psychiatric functioning status.^ A total of 101 clients met the inclusion criteria. Of the 101 clients, 96 had a mental disorder, and five had comorbidity. Due to the limited numbers of participants with comorbidity, only those with mental disorders were included in the analysis. The study found the Bristow Clinic population to be primarily single, Black, male, between the ages of 31 and 40 years, and with a gross family income of less than $4,000. There were more persons residing on the streets at entry and at six months following treatment than in any other residential setting. The most prevalent psychiatric diagnoses were depressive disorders and schizophrenia. The Global Assessment of Functioning (GAF) scale which was used to determine the degree of psychiatric functioning revealed a modal GAF score of 31--40 at entry and following six months in treatment. The study found that the majority of clients spent less than 17 hours in treatment, had less than 51 encounters and had clinical, social, and other encounters. In regard to social and demographic factors and levels of program involvement, there were statistically significant associations between gender and ethnicity and the types of interventions encountered as well as the number of interventions encountered. There was also a statistically significant difference between the amount of time spent in clinical interventions and gender. Relative to outcomes measured, the study found female gender to be the only background variable that was significantly associated with improved housing status and the female gender and previous MHMRA involvement to be statistically associated with improvement in GAF score. The total time in other (not clinical or social) interventions and the total number of encounters with other interventions were also significantly associated with improvement in housing outcome. The analysis of previous services and levels of program involvement revealed significant associations between time spent in social and clinical interventions and previous hospitalizations and previous MHMRA involvement.^ Major limitations of this study include the small sample size which may have resulted in very little power to detect differences and the lack of generalizability of findings due to site locations used in the study. Despite these limitations, the study makes an important contribution to the literature by documenting the levels of program involvement and the social and demographic factors necessary to produce outcomes of improved housing status and psychiatric functioning status. ^

Differential spatial and structural organization of the X chromosome underlies dosage compensation in C. elegans.

The adjustment of X-linked gene expression to the X chromosome copy number (dosage compensation [DC]) has been widely studied as a model of chromosome-wide gene regulation. In Caenorhabditis elegans, DC is achieved by twofold down-regulation of gene expression from both Xs in hermaphrodites. We show that in males, the single X chromosome interacts with nuclear pore proteins, while in hermaphrodites, the DC complex (DCC) impairs this interaction and alters X localization. Our results put forward a structural model of DC in which X-specific sequences locate the X chromosome in transcriptionally active domains in males, while the DCC prevents this in hermaphrodites.

A novel mutation in BCS1L associated with deafness, tubulopathy, growth retardation and microcephaly

We report a novel homozygous missense mutation in the ubiquinol-cytochrome c reductase synthesis-like (BCS1L) gene in two consanguineous Turkish families associated with deafness, Fanconi syndrome (tubulopathy), microcephaly, mental and growth retardation. All three patients presented with transitory metabolic acidosis in the neonatal period and development of persistent renal de Toni-Debré-Fanconi-type tubulopathy, with subsequent rachitis, short stature, microcephaly, sensorineural hearing impairment, mild mental retardation and liver dysfunction. The novel missense mutation c.142A>G (p.M48V) in BCS1L is located at a highly conserved region associated with sorting to the mitochondria. Biochemical analysis revealed an isolated complex III deficiency in skeletal muscle not detected in fibroblasts. Native polyacrylamide gel electrophoresis (PAGE) revealed normal super complex formation, but a shift in mobility of complex III most likely caused by the absence of the BCS1L-mediated insertion of Rieske Fe/S protein into complex III. These findings expand the phenotypic spectrum of BCS1L mutations, highlight the importance of biochemical analysis of different primary affected tissue and underline that neonatal lactic acidosis with multi-organ involvement may resolve after the newborn period with a relatively spared neurological outcome and survival into adulthood. CONCLUSION Mutation screening for BCS1L should be considered in the differential diagnosis of severe (proximal) tubulopathy in the newborn period. What is Known: • Mutations in BCS1L cause mitochondrial complex III deficiencies. • Phenotypic presentations of defective BCS1L range from Bjornstad to neonatal GRACILE syndrome. What is New: • Description of a novel homozygous mutation in BCS1L with transient neonatal acidosis and persistent de Toni-Debré-Fanconi-type tubulopathy. • The long survival of patients with phenotypic presentation of severe complex III deficiency is uncommon.

El estado del peso corporal en sujetos con retraso mental en un centro de día

La investigación del peso corporal en sujetos con retraso mental (RM) ha sido emparentada con la obesidad y, en menor medida, con el bajo peso. Con el motivo de determinar el estado del peso corporal y establecer si existen desviaciones respecto al peso normal, es que se realizó un estudio con diseño descriptivo transversal teniendo en cuenta las diferentes variables que afectan a sujetos con retraso mental, tomando como indicadores de evaluación el Índice de Masa Corporal y el IMC para la Edad, recolectándose los datos en concurrentes a un Centro de Día. Según este trabajo, el estado de peso corporal en sujetos con RM varía entre el peso normal y el exceso de peso en forma de sobrepeso y de obesidad, en menor medida el bajo peso. Los grupos de mujeres, individuos mayores de edad, sujetos con capacidad ambulatoria, discapacidad mental, menor grado de retraso mental, poseen mayor riesgo de sobrepeso y obesidad según los porcentuales obtenidos; mientras que los conjuntos de sujetos menores de 20 años, discapacidad motora, mayor grado de retraso mental, parálisis cerebral, individuos cuyo desplazamiento ambulatorio es nulo o casi nulo, y en menor medida varones y personas con discapacidad visual, presentaron tendencia al peso normal y el bajo peso como grupo. En los sujetos que recibían medicación su peso corporal se distribuía en valores proporcionales entre los diferentes estados. Nuevas investigaciones que muestren preocupación por las personas con discapacidad intelectual favorecerán la calidad de vida y el desenvolvimiento de este conjunto en la sociedad

El estado del peso corporal en sujetos con retraso mental en un centro de día

La investigación del peso corporal en sujetos con retraso mental (RM) ha sido emparentada con la obesidad y, en menor medida, con el bajo peso. Con el motivo de determinar el estado del peso corporal y establecer si existen desviaciones respecto al peso normal, es que se realizó un estudio con diseño descriptivo transversal teniendo en cuenta las diferentes variables que afectan a sujetos con retraso mental, tomando como indicadores de evaluación el Índice de Masa Corporal y el IMC para la Edad, recolectándose los datos en concurrentes a un Centro de Día. Según este trabajo, el estado de peso corporal en sujetos con RM varía entre el peso normal y el exceso de peso en forma de sobrepeso y de obesidad, en menor medida el bajo peso. Los grupos de mujeres, individuos mayores de edad, sujetos con capacidad ambulatoria, discapacidad mental, menor grado de retraso mental, poseen mayor riesgo de sobrepeso y obesidad según los porcentuales obtenidos; mientras que los conjuntos de sujetos menores de 20 años, discapacidad motora, mayor grado de retraso mental, parálisis cerebral, individuos cuyo desplazamiento ambulatorio es nulo o casi nulo, y en menor medida varones y personas con discapacidad visual, presentaron tendencia al peso normal y el bajo peso como grupo. En los sujetos que recibían medicación su peso corporal se distribuía en valores proporcionales entre los diferentes estados. Nuevas investigaciones que muestren preocupación por las personas con discapacidad intelectual favorecerán la calidad de vida y el desenvolvimiento de este conjunto en la sociedad

El estado del peso corporal en sujetos con retraso mental en un centro de día

La investigación del peso corporal en sujetos con retraso mental (RM) ha sido emparentada con la obesidad y, en menor medida, con el bajo peso. Con el motivo de determinar el estado del peso corporal y establecer si existen desviaciones respecto al peso normal, es que se realizó un estudio con diseño descriptivo transversal teniendo en cuenta las diferentes variables que afectan a sujetos con retraso mental, tomando como indicadores de evaluación el Índice de Masa Corporal y el IMC para la Edad, recolectándose los datos en concurrentes a un Centro de Día. Según este trabajo, el estado de peso corporal en sujetos con RM varía entre el peso normal y el exceso de peso en forma de sobrepeso y de obesidad, en menor medida el bajo peso. Los grupos de mujeres, individuos mayores de edad, sujetos con capacidad ambulatoria, discapacidad mental, menor grado de retraso mental, poseen mayor riesgo de sobrepeso y obesidad según los porcentuales obtenidos; mientras que los conjuntos de sujetos menores de 20 años, discapacidad motora, mayor grado de retraso mental, parálisis cerebral, individuos cuyo desplazamiento ambulatorio es nulo o casi nulo, y en menor medida varones y personas con discapacidad visual, presentaron tendencia al peso normal y el bajo peso como grupo. En los sujetos que recibían medicación su peso corporal se distribuía en valores proporcionales entre los diferentes estados. Nuevas investigaciones que muestren preocupación por las personas con discapacidad intelectual favorecerán la calidad de vida y el desenvolvimiento de este conjunto en la sociedad

Evidence of evolutionary up-regulation of the single active X chromosome in mammals based on Clc4 expression levels in Mus spretus and Mus musculus

Previous studies have shown that the chloride channel gene Clc4 is X-linked and subject to X inactivation in Mus spretus, but that the same gene is autosomal in laboratory strains of mice. This exception to the conservation of linkage of the X chromosome in one of two interfertile mouse species was exploited to compare expression of Clc4 from the X chromosome to that from the autosome. Clc4 was found to be highly expressed in brain tissues of both mouse species. Quantitative analyses of species-specific expression of Clc4 in brain tissues from mice resulting from M. spretus × laboratory strain crosses, demonstrate that each autosomal locus has half the level of Clc4 expression as compared with the single active X-linked locus. In contrast expression of another chloride channel gene, Clc3, which is autosomal in both mouse species is equal between alleles in F1 animals. There is no evidence of imprinting of the Clc4 autosomal locus. These results are consistent with Ohno’s hypothesis of an evolutionary requirement for a higher expression of genes on the single active X chromosome to maintain balance with autosomal gene expression [Ohno, S. (1967) Sex Chromosomes and Sex-Linked Genes (Springer, Berlin)].

A first-generation X-inactivation profile of the human X chromosome

In females, most genes on the X chromosome are generally assumed to be transcriptionally silenced on the inactive X as a result of X inactivation. However, particularly in humans, an increasing number of genes are known to “escape” X inactivation and are expressed from both the active (Xa) and inactive (Xi) X chromosomes; such genes reflect different molecular and epigenetic responses to X inactivation and are candidates for phenotypes associated with X aneuploidy. To identify genes that escape X inactivation and to generate a first-generation X-inactivation profile of the X, we have evaluated the expression of 224 X-linked genes and expressed sequence tags by reverse-transcription–PCR analysis of a panel of multiple independent mouse/human somatic cell hybrids containing a normal human Xi but no Xa. The resulting survey yields an initial X-inactivation profile that is estimated to represent ≈10% of all X-linked transcripts. Of the 224 transcripts tested here, 34 (three of which are pseudoautosomal) were expressed in as many as nine Xi hybrids and thus appear to escape inactivation. The genes that escape inactivation are distributed nonrandomly along the X; 31 of 34 such transcripts map to Xp, implying that the two arms of the X are epigenetically and/or evolutionarily distinct and suggesting that genetic imbalance of Xp may be more severe clinically than imbalance of Xq. A complete X-inactivation profile will provide information relevant to clinical genetics and genetic counseling and should yield insight into the genomic and epigenetic organization of the X chromosome.

Simple tandem DNA repeats and human genetic disease.

The human genome contains many repeated DNA sequences that vary in complexity of repeating unit from a single nucleotide to a whole gene. The repeat sequences can be widely dispersed or in simple tandem arrays. Arrays of up to 5 or 6 nt are known as simple tandem repeats, and these are widely dispersed and highly polymorphic. Members of one group of the simple tandem repeats, the trinucleotide repeats, can undergo an increase in copy number by a process of dynamic mutation. Dynamic mutations of the CCG trinucleotide give rise to one group of fragile sites on human chromosomes, the rare folate-sensitive group. One member of this group, the fragile X (FRAXA) is responsible for the most common familial form of mental retardation. Another member of the group FRAXE is responsible for a rarer mild form of mental retardation. Similar mutations of AGC repeats give rise to a number of neurological disorders. The expanded repeats are unstable between generations and somatically. The intergenerational instability gives rise to unusual patterns of inheritance--particularly anticipation, the increasing severity and/or earlier age of onset of the disorder in successive generations. Dynamic mutations have been found only in the human species, and possible reasons for this are considered. The mechanism of dynamic mutation is discussed, and a number of observations of simple tandem repeat mutation that could assist in understanding this phenomenon are commented on.

Micrornas 9a, 9b, 9c And 315 Regulate Expression Of A Reporter For The Neuronal Microtubule-Associated Protein Futsch/map1b

Fragile X syndrome (FXS) is the most common form of inherited mental retardation in humans. FXS is caused by loss of the Fragile X Mental Retardation Protein (FMRP), an important regulator of neuronal mRNA translation. Patients with FXS display cognitive deficits including memory problems. Protein synthesis-dependent long-term changes in synaptic plasticity are involved in the establishment and maintenance of long-term memory. One prevalent theory of FXS pathology predicts that FMRP is required to negatively regulate the translation of important mRNAs at the synapse. We are investigating microRNAs (miRNAs) as a potential regulator of synaptic FMRP-regulated mRNAs that have previously been described as being crucial to the process of synaptic plasticity. The general hypothesis underlying this thesis is that FMRP may negatively regulate the expression of futsch (the Drosophila homologue of the microtubule-associated protein gene MAP1B) via the miRNA pathway. The first step we took in testing this hypothesis was to confirm that futsch is subject to miRNA-mediated translational control. Using in silico target analysis, we predicted that several neuronally expressed miRNAs target the futsch mRNA 3'UTR and repress expression of Futsch protein. Then, using an in vitro luciferase reporter system, we showed that miR-315 and members of the miR-9 family selectively down-regulated futsch reporter translation. We have confirmed by site- directed mutagenesis that the miRNA interaction with the futsch 3'UTR is specific to the miRNA seed region binding site. Interestingly, reduction of FMRP levels by RNAi had no effect on futsch 3'UTR reporter expression. Together, these data suggest regulation of futsch expression by the miRNA pathway might be independent of FMRP activity. However, additional experiments need to be completed to confirm these preliminary results.

Regulation of Synaptogenesis by the miRNA Pathway and FMR/P Bodies

Post-transcriptional regulation of mRNA is facilitated by different mechanisms, such as microRNA (miRNA) induced gene silencing or fragile X mental retardation protein (FMRP) mediated repression either independent of or acting through cytoplasmic RNA Processing bodies (P bodies). DPTP99A, Lar, and Wg have known functions during synaptogenesis and may be targets of miR-8. Here, we provide evidence that miR-8 regulates DPTP99A in vitro. Non-endogenous miR-8 expressed using an UAS driver regulates Lar. Endogenous miR-8 may regulate DPTP99A in vivo. Here we show that FMRP is capable of colocalizing with the P body components: DCP1, HPat, and Me31B, but not CCR4. We also show that RNAi against HPat and Me31B but not CCR4 and DCP1 are required for FMRP’s repression of a translational reporter in vivo. This functional analysis provides additional insight into another aspect of FMRP’s and P bodies’ ability to cooperatively control repression of mRNA targets.

American journal of mental deficiency.

Includes the association's conference proceedings and addresses.

Annual report - Illinois Commission on Mental Health and Developmental Disabilities.

Mode of access: Internet.

Mental health and developmental disabilities in Illinois : an examination /

Includes bibliographical references.