Mental Retardation Of Unknown Etiology Research Articles

Shotgun proteomics reveals possible mechanisms for cognitive impairment in Mucopolysaccharidosis I mice.

Mucopolysaccharidosis type I (MPS I) is due to deficient alpha-L-iduronidase (IDUA) which leads to storage of undegraded glycosaminoglycans (GAG). The severe form of the disease is characterized by mental retardation of unknown etiology. Trying to unveil the mechanisms that lead to cognitive impairment in MPS I, we studied alterations in the proteome from MPS I mouse hippocampus. Eight-month old mice presented increased LAMP-1 expression, GAG storage in neurons and glial cells, and impaired aversive and non-aversive memory. Shotgun proteomics was performed and 297 proteins were identified. Of those, 32 were differentially expressed. We found elevation in proteins such as cathepsins B and D; however their increase did not lead to cell death in MPS I brains. Glial fibrillary acid protein (GFAP) was markedly elevated, and immunohistochemistry confirmed a neuroinflammatory process that could be responsible for neuronal dysfunction. We didn't observe any differences in ubiquitin expression, as well as in other proteins related to protein folding, suggesting that the ubiquitin system is working properly. Finally, we observed alterations in several proteins involved in synaptic plasticity, including overexpression of post synaptic density-95 (PSD95) and reduction of microtubule-associated proteins 1A and 1B. These results together suggest that the cognitive impairment in MPS I mice is not due to massive cell death, but rather to neuronal dysfunction caused by multiple processes, including neuroinflammation and alterations in synaptic plasticity.

Comparison of methods for the analysis of lysosomal enzyme activities in quality control dried blood spot specimens

Mucopolysaccharidosis type I (MPS I) is due to deficient alpha-Liduronidase (IDUA) which leads to storage of glycosaminoglycans (GAG). The severe form of MPS I is characterized by mental retardation of unknown etiology. Trying to unveil the mechanisms of cognitive impairment, we studied alterations in the proteome from MPS I mouse hippocampus. Eight-month-old MPS I mice had GAG storage in neurons and glial cells, and impaired aversive and non-aversive memory. Shotgun proteomics was performed and 296 proteins were identified. Of those, 32 were differentially expressed (pb0.05). We found elevation in proteins such as the pro-apoptotic cathepsin D (CtsD, 7-fold normal). Glial fibrilary acid protein (GFAP) was 4.5-fold normal, and immunohistochemistry for GFAP as well as quantitative PCR for TNF-alpha and MIP-1-alpha confirmed a neuroinflammatory process that could be responsible for neuron dysfunction. We did not observe differences in ubiquitin or other proteins related to protein folding, suggesting that the ubiquitin system is working properly. We observed alterations in several proteins involved in synaptic plasticity, including overexpression of post synaptic density-95 (PSD-95) and reduction of microtubuleassociated proteins A and B. IDUA (laronidase, Genzyme, 1.2 mg/kg) was injected i.v. and was able to reduce GAG storage as well as CtsD levels in the brain, suggesting that CtsD can be used as a biomarker for efficacy of preclinical treatments and that a small fraction of laronidase can reach the brain. These results suggest that the cognitive impairment in MPS I is due to multiple processes, including neuroinflammation and alterations in synaptic plasticity.

Molecular diagnostic dilemmas in Rett syndrome

Rett syndrome (OMIM 312750) is a progressive, X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene located on chromosome Xq28. The disorder is characterized by a period of normal development during the first 6–18months of life, followed by gradual loss of skills already gained, such as speech and purposeful movement of the hands. The majority of cases are sporadic and represent “de novo” mutations.In this study we summarize the results of diagnostic testing of 30 patients with Rett syndrome (RTT) or mental retardation of unknown etiology using bidirectional sequencing of the open reading frame of the MECP2 gene. Twenty different variants were identified in those patients including 12 missense (R133C, P152R, T158M, V300I, I303M, R306C, T311M, R344W, A358T, P384L, A443T, V481M), four nonsense (R168X, K192X, R255X, R270X), two deletion (E137_L386del, I293_S350del), and two frameshift (S291QfsX26, G343AfsX6) mutations. Seven of the twenty variants identified were novel mutations (E137_L386del, K192X, S291QfsX26, G343AfsX6, I293_S350del, P384L, and A443T). In the cases with novel or non-recurrent missense mutations, family studies were performed to investigate genotype–phenotype correlations. Our results demonstrate the importance of family studies and highlight the complexity of interpretation of MECP2 alterations, which may or may not be disease-associated.

Place de l’EEG dans le diagnostic des troubles neurodéveloppementaux

Most electroencephalograms (EEG) are requested in the work-up of an epileptic disorder and in its follow-up. In the absence of epilepsy, the study of EEG characteristics is documented in mental retardation (MR), specific language impairment (SLI) and autistic spectrum disorder (ASD). In this review, we will discuss separately the indications for and limitations of an EEG in these three major neurodevelopmental situations. Despite being most often of limited value, EEG can provide useful aetiological clues in cases of mental retardation of unknown aetiology and remains an important diagnostic procedure in children with language regression when an acquired epileptic aphasia (Landau-Kleffner syndrome) is suspected. The finding of interictal epileptiform activity (IEA) in SLI and ASD is not uncommon and usually has to be considered as an epiphenomenon not related to the cognitive and behavioural symptoms despite an on-going debate.

Is there a relationship between attention deficit/hyperactivity disorder and manic symptoms among children with mental retardation of unknown etiology?

Mental retardation (MR) is common and lifelong. In children and adolescents with MR, the rate of attention deficit/hyperactivity disorder (ADHD) and bipolar disorder is higher than that in the general population. However, there are no previous sufficient data that exist in establishing a relationship between ADHD and manic symptoms. The aim of the present study was to examine the relationship between manic symptoms and ADHD as well as oppositional-defiant disorder (ODD) and conduct disorder (CD) in children with MR of unknown etiology (MR-UE). A total of 167 children with MR-UE attending a rehabilitation and training school in Erzurum, Turkey, were included in the study. We administered the Child Disruptive Behavior Screening and Rating Scale related to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition and the Young Mania Rating Scale–Parent Version (P-YMRS) to parents. The age range of children and adolescents with MR-UE was between 5 and 21 years, with a mean age of 11.13 ± 3.75 years. In total, 5.8% of children and adolescents with MR-UE showed a border intelligence quotient (IQ), with 58.4% having a mild IQ, 29.2% having a moderate IQ, and 6.6% having severe IQ. According to the Child Disruptive Behavior Screening and Rating Scale related to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, 40.1% of children and adolescents with MR-UE had inattention, 19.9% had hyperactivity, 28.7% had ODD, and 13.3% had CD. A total of 7.2% of the children and adolescents with MR-UE had probable mania, and 1.8% had mania according to Young Mania Rating Scale–Parent Version. A positive correlation existed between the mean scores of Young Mania Rating Scale–Parent Version and the mean scores of inattention, hyperactivity, ODD, and CD ( P = .000). Hyperactivity and ODD were predictors of being manic/probably manic. Diagnosing psychiatric disorders in children and adolescents with MR-UE is difficult but essential for better functioning. Manic symptoms and disruptive behaviors as well as ADHD symptoms were prevalent among children and adolescents with MR-UE and hyperactivity, and oppositional-defiant symptoms were predictors of manic symptoms in these patients.

Distribution of CGG/GCC Repeats at the FMR1 and FMR2 Genes in an Indian Population with Mental Retardation of Unknown Etiology

Fragile X syndrome is one of the X-linked disorders associated with moderate to severe mental retardation. Fragile X A syndrome (FRAXA) and fragile X E syndrome (FRAXE) are caused by trinucleotide repeat expansion of CGG and GCC repeats at the 5' untranslated region of the FMR1 and FMR2 genes, respectively. The present study was undertaken to identify the repeat polymorphism and to estimate the risk of transmission in Andhra Pradesh and surrounding states of South India. The FRAXA and FRAXE allelic polymorphisms were studied by radioactive polymerase chain reaction that revealed 25 FRAXA among 344 X-chromosomes and 20 FRAXE allelic variants among 212 X-chromosomes in our population. The most frequent FRAXA allele size was of 29 CGG repeats (27.5%) followed by allele sizes of 28 (20.8%) and 31 (7.2%), and that of FRAXE was 15 GCC repeats (24.0%) followed by allele containing 18 repeats (18.4%) and 16 repeats (11.3%). CGG/GCC repeat polymorphism at the FMR1 and FMR2 loci observed in this study demonstrated a racial and ethnic variation among the populations.

Deficiencia cerebral de creatina: primeros pacientes españoles con mutaciones en el gen GAMT

Background and objetive Brain creatine (Cr) deficiencies are a group of inborn errors of metabolism that are characterized by an absence or severe reduction of brain Cr. Clinically, these patients can display psychomotor/mental retardation and language disorders, commonly associated with epilepsy or movement disorders. Three metabolic defects are known: two affect synthesis – guanidinoacetate metiltransferase (GAMT) and glycine amidinotransferase (AGAT) deficiencies– and one affect the Cr transporter (CRTR). We present the first three Spanish patients with GAMT deficiency, and we compare their clinical phenotype and treatment response with other published cases. Patients and method The three patients presented mental retardation, epilepsy and autistic behaviour. Patient 1 also had severe chorea. Diagnosis was done by biochemical and genetic procedures (guanidinoacetate quantification, determination of GAMT activity and mutation analysis in the GAMT gene). Results An increase of guanidinoacetate was detected in urine and plasma. Brain magnetic resonance spectroscopy revealed low Cr levels. Enzymatic studies revealed a decreased GAMT activity in fibroblasts. Molecular analysis detected pathogenic mutations in the GAMT gene. After the deficiency was confirmed, the patients started treatment with Cr. In addition, patient 2 and 3 received an arginine-restricted diet and ornithine supplements. All them showed a partial improvement. Conclusions Patients with GAMT deficiency have an unspecific but relatively constant clinical presentation. Brain Cr deficiency should be considered in patients with mental retardation of unknown aetiology, specially in those with movement disorders or epilepsy. Early diagnosis is important in cases with known treatment such as GAMT deficiency.

Assessment of a clinical checklist in the diagnosis of fragile X syndrome in India

Fragile X syndrome (FRAXA) is one of the most common forms of mental retardation. It is caused by the expansion of cytosine-guanine-guanine (CGG) repeats in the 5′ untranslated region of the fragile X mental retardation 1 ( FMR1) gene, located at Xq27.3. The number of CGG repeats in the FMR1 gene occurs in four distinct ranges: 2–50 (normal), 50–60 (gray zone), 60–200 (premutation), and > 200 (full mutation). When the number of CGG repeats exceeds 200, the gene becomes hypermethylated and transcriptionally silenced, which results in the loss of FMR protein and causes FRAXA. The key clinical features of FRAXA are mental retardation, macro-orchidism, long face, prominent jaw, connective tissue abnormalities, and behavioral problems. A modified 15-item checklist was used to assess the clinical features in 337 individuals (316 males and 21 females) who have mental retardation of unknown etiology. These patients were in institutions. Molecular diagnosis was performed using polymerase chain reaction and Southern blot analysis and revealed that 14 males were positive for FRAXA. Studies of the families of the affected males revealed an additional 11 affected males and 20 carrier females. Retrospective analysis of clinical features was performed in a total of 327 males and 41 females. Six clinical features were statistically significant in FRAXA individuals when compared to non-FRAXA individuals. These features were hyperactivity ( p < 0.05), poor eye contact ( p < 0.001), hyper extensibility of joints ( p < 0.001), large ears ( p < 0.001), macro-orchidism ( p < 0.001), and a family history of mental retardation ( p < 0.001). When a total score of 5 out of 15 was used as the threshold clinical score, 73.18% of the patients with total scores < 5 could be eliminated as FRAXA-negative patients, thereby improving the reliability of FRAXA testing using the clinical checklist.

A novel microdeletion syndrome involving 5q14.3-q15: clinical and molecular cytogenetic characterization of three patients

Molecular karyotyping is being increasingly applied to delineate novel disease causing microaberrations and related syndromes in patients with mental retardation of unknown aetiology. We report on three unrelated patients with overlapping de novo interstitial microdeletions involving 5q14.3-q15. All three patients presented with severe psychomotor retardation, epilepsy or febrile seizures, muscular hypotonia and variable brain and minor anomalies. Molecular karyotyping revealed three overlapping microdeletions measuring 5.7, 3.9 and 3.6 Mb, respectively. The microdeletions were identified using single nucleotide polymorphism (SNP) arrays (Affymetrix 100K and Illumina 550K) and array comparative genomic hybridization (1 Mb Sanger array-CGH). Confirmation and segregation studies were performed using fluorescence in situ hybridization (FISH) and quantitative PCR. All three aberrations were confirmed and proven to have occurred de novo. The boundaries and sizes of the deletions in the three patients were different, but an overlapping region of around 1.6 Mb in 5q14.3 was defined. It included five genes: CETN3, AC093510.2, POLR3G, LYSMD3 and the proximal part of GPR98/MASS1, a known epilepsy gene. Haploinsufficiency of GPR98/MASS1 is probably responsible for the seizure phenotype in our patients. At least one other gene contained in the commonly deleted region, LYSMD3, shows a high level of central nervous expression during embryogenesis and is also, therefore, a good candidate gene for other central nervous system (CNS) symptoms, such as psychomotor retardation, brain anomalies and muscular hypotonia of the 5q14.3 microdeletion syndrome.

CARDIAC MANIFESTATIONS IN A CHILD WITH A NOVEL MUTATION IN CREATINE TRANSPORTER GENE SLC6A8

The creatine-phosphocreatine shuttle serves to maintain a high-energy phosphate supply for normal cellular function. Most creatine is derived from the diet; the rest is synthesized primarily in the liver, pancreas, and kidneys. The transport of creatine in tissues is accomplished by the Na+-dependent transporter SLC6A8. Expression of the SLC6A8 gene is high in skeletal muscle, heart, and kidney, moderate in brain, and extremely low in liver and pancreas. X-linked creatine transporter (Crt) defect (OMIM 300352), originally described in 2001,1 has been linked to mutations in the SL6CA8 gene at Xq28. SLC6A8 deficiency may comprise up to 1% of cases of mental retardation of unknown etiology in males.2 Intellectual disability is the uniform feature in patients with creatine-deficiency syndromes.3,4 Some patients also have epilepsy, extrapyramidal movement disorder, failure to thrive, and sometimes autism and other behavioral problems.4 We report a novel mutation in the SLC6A8 gene in an 11-year-old boy with Crt defect, who presented with multiple premature ventricular contractions (PVCs) in the second year of life. ### Case report. This male child had poor weight gain since birth. By 18 months of age his weight dropped below the fifth percentile and he was admitted for investigation. When given midazolam IV and topical lidocaine before an endoscopy, he immediately developed frequent PVCs (bigeminy …

Fragile X: translation in action.

Fragile X is a synapsopathy--a disorder of synaptic function and plasticity. Recent studies using mouse models of the disease suggest that the critical defect is altered regulation of synaptic protein synthesis. Various strategies to restore balanced synaptic protein synthesis have been remarkably successful in correcting widely varied mutant phenotypes in mice. Insights gained by the study of synaptic plasticity in animal models of fragile X have suggested novel therapeutic approaches, not only for human fragile X but also for autism and mental retardation of unknown etiology.

Are cerebral creatine deficiency syndromes on the radar screen?

Cerebral creatine deficiency syndromes (CCDS) are responsible for a considerable proportion of the population affected with mental retardation. CCDS are caused by either an inborn error of the proteins involved in creatine biosynthesis or in the creatine transporter. Besides mental retardation, the clinical characteristics of CCDS are speech and language delay, epilepsy and features of autism. CCDS can be diagnosed by proton magnetic resonance spectroscopy of the brain and/or by biochemical and molecular analysis. Treatment of the defects in creatine biosynthesis has yielded favorable outcomes, while treatments for creatine transporter deficiency are still under investigation at this time. The relatively large contribution of the CCDS to the monogenic causes of mental retardation emphasizes the importance of including CCDS in the differential diagnosis of mental retardation of unknown etiology. Pathophysiology is not yet unravelled, although it is known that creatine plays an important role in energy storage and transmission. Moreover, in vitro data indicate that creatine acts as a neuromodulator in the brain.

Mutational screening of ARX gene in Brazilian males with mental retardation of unknown etiology

ARX gene mutations have been known as important causes of developmental and neurological disorders and are responsible for a large spectrum of abnormal phenotypes, includeing syndromic as well as nonsyndromic forms of mental retardation. We have screened the entire coding and flanking intronic sequences of ARX gene in 143 mentally impaired males in order to investigate the contribution of ARX mutations to mental retardation in the population of Rio de Janeiro, Brazil. Three sequence variants were identified: one patient had the most recurrent mutation already observed in ARX gene, the c.428_451dup(24 bp), two patients presented the c.1347C>T (p.G449G) in exon 4, and one patient had the intronic variant c.1074-3T>C. Although two of these alterations were considered polymorphisms, the known pathogenic variant c.428_451dup(24 bp) was found at a high rate (4.8%) among X-linked mental retardation (XLMR) families. Our results, the first in Latin America, reinforce the idea that ARX mutations are relevant to mental retardation and are indicative that molecular screening of exon 2 should be considered in males with mental retardation of unknown etiology, associated or not with neurological manifestations, especially in familial cases.

X-linked creatine transporter (SLC6A8) mutations in about 1% of males with mental retardation of unknown etiology

Mutations in the creatine transporter gene, SLC6A8 (MIM 30036), located in Xq28, have been found in families with X-linked mental retardation (XLMR) as well as in males with idiopathic mental retardation (MR). In order to estimate the frequency of such mutations in the MR population, a screening of 478 males with MR of unknown cause was undertaken. All 13 exons of SLC6A8 were sequenced using genomic DNA. Six novel potentially pathogenic mutations were identified that were not encountered in at least 588 male control chromosomes: two deletions (p.Asn336del, p.Ile347del) and a splice site alteration (c.1016+2C>T) are considered pathogenic based on the nature of the variant. A mutation (p.Arg391Trp) should be considered pathogenic owing to its localization in a highly conserved region. Two other missense variants (p.Lys4Arg, p.Gly26Arg) are not conserved but were not observed in over 300 male control chromosomes. Their pathogenicity is uncertain. A missense variant (p.Val182Met), was classified as a polymorphism based on a normal creatine/creatinine (Cr:Crn) ratio and cerebral creatine signal in proton magnetic resonance spectroscopy (H-MRS) in the patient. Furthermore, we found 14 novel intronic and neutral variants that were not encountered in at least 280 male control chromosomes and should be considered as unclassified variants. Our findings of a minimum of four pathogenic mutations and two potentially pathogenic mutations indicate that about 1% of males with MR of unknown etiology might have a SLC6A8 mutation. Thus, DNA sequence analysis and/or a Cr:Crn urine screen is warranted in any male with MR of unknown cause.

Psychological benefit of diagnostic certainty for mothers of children with disabilities: Lessons from Down syndrome

Diagnostic and prognostic uncertainty is one of the major psychological stressors for patients in acute and chronic illness, as well as for parents of children with disabilities or chronic disease. Whereas the parents' feeling of uncertainty is undoubtedly very strong shortly after the birth of a child with disabilities, the long-term effects on the parents of having or not having a precise genetic diagnosis, in terms of emotional stress, remain unclear. In this study, mothers of non-disabled children are compared to mothers of children with Down syndrome, and to mothers of children with a diagnostically unassigned mental retardation with regard to the level of anxiety, feelings of guilt, and emotional burden. While the mothers of children with Down syndrome score comparably to the mothers of non-disabled children, the results show broad psychoemotional disadvantages for mothers of children with a mental retardation of unknown etiology. Consequently, the value of genetic diagnosis of infantile disabilities encompasses, beyond clinical considerations like therapy planning and assignment of the recurrence risk for siblings, significant and long-lasting emotional relief for the parents.

Language abilities of siblings of children with autism.

Language abilities of siblings of children with autism were examined to explore the possibility that language abilities are behavioral markers specific to the genetic liability for autism, as part of the broader phenotype. Language abilities were compared among 27 siblings of children with autism, 23 siblings of children with mental retardation of unknown etiology (MR), and 22 siblings of children with developmental language disorders (DLD). Groups were matched by siblings' age, gender, birth order, family size, ethnicity, family income and by probands' gender and mental age. Siblings of children with autism achieved higher scores than siblings of children with DLD on receptive, expressive, and total language scales of the Children's Evaluation of Language Fundamentals and on verbal IQ. Moreover, within the DLD group, school problems in the domains of reading and arithmetic were more prevalent than within the other two groups. Only 2 siblings of children with autism received clinical diagnoses based on DSM-IV criteria compared to 3 siblings of children with MR and 7 siblings of children with DLD. After excluding data of the diagnosed siblings, no differences in language abilities could be discerned among the groups, except that more siblings in the DLD group were identified as having language difficulties. In summary, although language deficits characterize autism, siblings of children with autism were not found to demonstrate deficits in language skills assessed by formal language tests, IQ, or academic skills.

Prospective screening for subtelomeric rearrangements in children with mental retardation of unknown aetiology: the Amsterdam experience

Objective: The frequency of subtelomeric rearrangements in patients with unexplained mental retardation (MR) is uncertain, as most studies have been retrospective and case retrieval may have been biased towards cases...

X-Linked Mental Retardation with Seizures and Carrier Manifestations Is Caused by a Mutation in the Creatine-Transporter Gene (SLC6A8) Located in Xq28

A family with X-linked mental retardation characterized by severe mental retardation, speech and behavioral abnormalities, and seizures in affected male patients has been found to have a G1141C transversion in the creatine-transporter gene SLC6A8. This mutation results in a glycine being replaced by an arginine (G381R) and alternative splicing, since the G-->C transversion occurs at the -1 position of the 5' splice junction of intron 7. Two female relatives who are heterozygous for the SLC6A8 mutation also exhibit mild mental retardation with behavior and learning problems. Male patients with the mutation have highly elevated creatine in their urine and have decreased creatine uptake in fibroblasts, which reflects the deficiency in creatine transport. The ability to measure elevated creatine in urine makes it possible to diagnose SLC6A8 deficiency in male patients with mental retardation of unknown etiology.

Fragile X founder effect and distribution of CGG repeats among the mentally retarded population of Andalusia, South Spain

Abstract Fragile X syndrome is the most common inherited form of mental retardation. We investigated the prevalence of theFragile X syndrome in the population with mental retardation of unknown etiology in Andalusia, South Spain. Weanalyzed 322 unrelated patients (280 males and 42 females), and found a fragile X syndrome frequency of 6.5%.Among the non-fragile X chromosomes, the 29 CGG repeat was the most common allele. At the linked microsatelliteDXS548 locus, we found a new allele which we called “allele 10” (17 CA). Similar to other south Europeanpopulations, allele 2 (25 CA) at the DXS548 locus and the fragile X allele were in linkage disequilibrium supportingthe idea of a common founder chromosome predisposing to the CGG expansion. Keywords :mentalretardation,fragileXsyndrome,CGGrepeats,geneticscreeningReceived:March5,2002;accepted:March25,2002. Introduction FragileXsyndromeisthemostcommoncauseofhe-reditarymentalretardation.Itischaracterizedbymentalhandicap,facialdysmorphismandexpressionofafragilesiteatXq27.3(MartinandBell,1943;Lubs,1969;Esca-lante and Frota-Pessoa, 1969; Escalante

Klinefelter syndrome is a common cause for mental retardation of unknown etiology among prepubertal males.

Klinefelter syndrome (KS) has not typically been associated with mental retardation (MR), however, in recent years a growing body of evidence suggested that KS boys often experience language deficits and academic difficulties. In this study, we screened DNA samples from 1205 patients originally referred for fragile X syndrome (FRAX) testing, because of MR of unknown etiology and detected 8 KS patients. A similar number of males in the same age group were found to have FRAX; 3 of them had a family history of FRAX. Based on these findings, KS might be the most common cause of MR of unknown etiology among prepubertal males. Because of the significant benefits of early recognition and treatment of KS, we emphasize the importance of cytogenetic testing of all prepubertal males with cognitive impairment even without dysmorphic features.