Unexplained Mental Retardation Research Articles

Case report of a 7-year-old CIPA child with multiple debridement's and amputations.

Background: Congenital Insensitivity to Pain (CIPA), otherwise known as Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV), is a rarely occurring autosomal recessive disorder encompassed by a group of hereditary and sensory autonomic neuropathies, which was initially described as pure analgesia present congenitally. Its clinical manifestation includes recurrent episodes of infections with unexplained behavior, anhidrosis, mental retardation, and damage to oral structures.
 Case Presentation: In this case report, we have demonstrated the signs and symptoms of a 7-year-old boy presented to the pediatric out-patient department of Memon Medical Institute Hospital with complaints of multiple fluid-filled blisters since the age of 1 year. He had a history of multiple hospital admissions due to infections, where he was diagnosed with a case of CIPA.
 Management & Results: Since the diagnosis of this medical condition, the child has undergone multiple debridements of his wound and amputations. The treatment plan was aimed to manage the blisters, prevent self-injuries, and treat orthopedic problems by regular dermal and orthopedic follow-ups.
 Conclusion: There is no cure for CIPA patients, the families that have CIPA patients must undergo prenatal testing and screening to prevent the birth of another affected child.

Analysis and prenatal diagnosis of FMR1 gene mutations among patients with unexplained mental retardation

To analyze the (CGG)n repeats of FMR1 gene among patients with unexplained mental retardation. For 201 patients with unexplained mental retardation, the (CGG)n repeats of the FMR1 gene were analyzed by PCR and FragilEaseTM PCR. Prenatal diagnosis was provided to carriers of pre- and full-mutations. The pattern of X chromosome inactivation (XCI) was determined for women with mental retardation and full mutations. For the 201 patients with unexplained mental retardation, 15 were identified with full mutations of the FMR1 gene. The prevalence of fragile X syndrome (FXS) in patients with unexplained mental retardation was determined as 7.5% (15/201). Prenatal diagnosis was provided for 6 pregnant women with pre- or full mutations. Analysis revealed that women with mental retardation and full FMR1 mutations exhibited a skewed XCI pattern with primary expression of the X chromosome carrying the mutant allele. FXS has a high incidence among patients with unexplained mental retardation. Analysis of FMR1 gene (CGG)n repeats in patients with unexplained mental retardation can facilitate genetic counseling and prenatal diagnosis for their families. FMR1 gene (CGG)n repeats screening should be recommended for patients with unexplained mental retardation.

Cri-du-Chat syndrome diagnosed in a 21-year-old woman by means of comparative genomic hybridization

El síndrome de cri du chat o del maullido de gato es causado por una deleción en el brazo corto del cromosoma 5; el tamaño de la pérdida de material genético varía desde solo la región 5p15.2 hasta el brazo entero. La prevalencia va desde 1 por 15 000 habitantes hasta 1 por 50 000 habitantes. Su diagnóstico se puede confirmar con cariotipo con bandas G de alta resolución, hibridación fluorescente in situ o hibridación genómica comparativa por microarreglos (HGCm); este se sospecha en infantes con un llanto similar al maullido de un gato, fascies dismórficas, hipotonía y retardo del desarrollo psicomotor; sin embargo, en los adultos afectados los hallazgos fenotípicos son menos específicos.Se presenta el caso de una mujer de 21 años con retardo mental severo y tricotilomanía, que no controla esfínteres y no se baña ni come sola; solo emite ruidos y tiene facies dismórficas. El cariotipo de bandas G es reportado 46, XX y la HGCm muestra microdeleción de 18.583Mb en 5p15.33p14.3, incluyendo región crítica de cri du chat. En pacientes de este tipo se debe realizar HGCm para hacer un diagnóstico etiológico, establecer un pronóstico, ordenar pruebas médicas adicionales y tratamientos específicos y realizar la adecuada asesoría genética.

Novel NTRK1 mutations associated with congenital insensitivity to pain with anhidrosis verified by functional studies.

Congenital insensitivity to pain with anhidrosis (CIPA), also known as hereditary sensory and autonomic neuropathy type IV, features loss of pain sensation, decreased or absent sweating (anhidrosis), recurrent episodes of unexplained fever, self-mutilating behavior, and variable mental retardation. Mutations in neurotrophic receptor tyrosine kinase 1 (NTRK1) have been reported to be associated with CIPA. We identified four novel NTRK1 mutations in six Korean patients from four unrelated families. Of the four mutations, we demonstrated using a splicing assay that IVS14+3A>T causes aberrant splicing of NTRK1 mRNA, leading to introduction of a premature termination codon. An NTRK1 autophosphorylation assay showed that c.1786G>A (p.Asp596Asn) abolished autophosphorylation of NTRK1. In addition, Western blotting showed that c.704C>G (p.Ser235*) and c.2350_2363del (p.Leu784Serfs*79) blunted NTRK1 expression to undetectable levels. The four novel NTRK1 mutations we report here will expand the repertoire of NTRK1 mutations in CIPA patients, and further our understanding of CIPA pathogenesis.

Analysis pathogenicity of chromosome micro imbalance in children with unexplained mental retardation or development delay

Objective To investigate clinically chromosome micro imbalance in children with unexplained mental retardation(MR) or development delay(DD) by using high resolution microarray comparative genomic hybridi-zation(Array-CGH), to identify chromosome micro imbalance which might be associated with MR/DD, and evaluate the effectiveness of Array-CGH in etiological diagnosis of children with unexplained MR/DD. Methods One hundred and twenty-six children with unexplained MR/DD were recruited for this study by Array-CGH to detect chromosome micro imbalance.All chromosome micro imbalances were verified with database of genomic variation(DGV), Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources(DECIPHER) and literature review, to determine if the chromosome micro imbalances found in these children were associated with MR/DD. Results Twenty-eight clinically relevant chromosome micro imbalances were detected among 26 children out of 126 children with unexplained MR/DD.The diagnostic yield for the MR/DD children was 20.6%(26/126 cases). These chromosome micro imbalances were undetectable by chromosome analysis.All MR/DD children with chromosome micro imbalances had face dysmorphism and/or surface, organ dysmorphism.The most common abnormality was Prader-Willi syndrome/Angelman syndrome(3/26 cases, 11.5%), which was followed by DiGeroge syndrome(2/26 cases, 7.6%), Cri-du-chat syndrome(2/26 cases, 7.6%) and 16p11.2 deletion syndrome(2/26 cases, 7.6%). Conclusions Chromosome micro imbalance is one of the most common causes of unexplained MR/DD.Array-CGH can detect disease associated with chromosome micro imbalance as a useful evaluation to help differential diagnosis of children with unexplained MR/DD.Screening for chromosome micro imbalance should be firstly carried out in those MR/DD children with face dysmorphism and/or surface, organ dysmorphism. Key words: Mental retardation/development delay; Chromosome micro imbalance; Pathogenicity; Microarray comparative genomic hybridization

Application of BoBs technique for detecting common chromosome microdeletion and microduplication syndromes

To establish a strategy for screening and diagnosing common microdeletion and microduplication syndromes among children with idiopathic mental retardation and development abnormalities. Potential chromosomal variations among patients with unexplained mental retardation, cardiac anomalies, particular facial features, learning disabilities and other clinical characteristics were detected with bacterial artificial chromosome BACs-on-Beads (BoBs) technique and karyotyping. Positive results were verified with array-based comparative genomic hybridization (Array-CGH). Fifty eight of the 60 patients had a normal chromosome karyotype. Ten patients with microdeletion and microduplication syndromes were detected by BoBs, which included two positive cases identified through chromosome karyotyping. Two patients were respectively diagnosed as Smith-Magenis syndrome and Prader-Willi/Angelman syndrome by BoBs and the results were confirmed by Array-CGH. BoBs is capable of detecting chromosome microdeletion and microduplication with high specificity and throughput, which can compensate the shortcomings of conventional cytogenetic technology and will be widely applied for clinical diagnosis.

Diagnosises progresses of gene chip technology in unexplained mental retardation

Gene chip technology is a large amount of information,simple operation,fast speed of the nucleic acid sequence determination and quantitative analysis technique.The advantages of this technology include high integration and high content of micromation,parallelism,diversification and automatization.Currently,gene chip technology is increasingly being used in clinic,including disease diagnosis,treatment guidelines and prognosis.The progresses of the diagnosis of the gene chip technology in unexplained mental retardation are summarized in this paper. Key words: Gene chip; Mental retardation; Diagnosis

TBX4 mutations (small patella syndrome) are associated with childhood-onset pulmonary arterial hypertension

BackgroundChildhood-onset pulmonary arterial hypertension (PAH) is rare and differs from adult-onset disease in clinical presentation, with often unexplained mental retardation and dysmorphic features (MR/DF). Mutations in the major PAH gene,...

Study on subtelomeric aberrations in children with mental retardation

Objective To make an etiology study on children with unexplained mental retardation (MR) by using combined multiplex ligation-dependent probe amplification (MLPA), and to explore associations between subtelomeric aberrations and phenotypes in local children. Methods Sixty-seven children with unexplained MR were enrolled in study group from Jul.2009 to Dec.2011 in Guangdong Women and Children's Hospital.Peripheral blood of patients and their parents were collected as samples of subtelomeric test by MLPA.Two kinds of probes of MLPA were combined to verify the aberration results.After confirmed test the parent of positive children were tested by the same way, then to analyze associations between test data and the clinical feature. Results Among sixty-seven children enrolled in the study aged 6 months to 15 years, where were 42 male and 25 female; the intelligence of 47 children belonged to mild degree(IQ≥50 scores), that of 20 children belonged to severe degree(IQ 0.05). The aberration rate in moderate to severe degree group was higher than those mild degree group.The rates of features including physical developmental retardation, malformation and organ aberrations in positive children were higher than those of the negative cases.There were significant differences between the 2 severity groups (all P<0.05). Conclusions Aberrations in subtelomeric region can be one of the important causes of unexplained MR.The MR patients were supposed to have subtelomeric region tested so as to provide the evidence for diagnosis and genetic counseling. Key words: Mental retardation; Subtelomeric region; Multiplex ligation-dependent probe amplification; Child

Identification, functional analysis, prevalence and treatment of monocarboxylate transporter 8 (MCT8) mutations in a cohort of adult patients with mental retardation

Monocarboxylate transporter 8 (MCT8) is an essential thyroid hormone (TH) transporter as humans with MCT8 mutations have severe neurological and endocrine abnormalities. The objectives are (i) to identify novel MCT8 mutations and (ii) to assess their functional relevance; (iii) to describe the effects of block-and-replace treatment in an MCT8 patient. The TOP-R study is a cross-sectional nation-wide multicentre study. Subjects with unexplained mental retardation (MR) were screened for MCT8 mutations. We identified three mutations: p.F501del (previously described), p.L492P and p.T162T. The F501del and L492P mutants, but not the T162T mutant, showed diminished T3, T4 and rT3 transport in transfected cells. TH transport in T162T fibroblasts was also not affected. One patient was treated with block-and-replace therapy to normalize serum TH levels. The results indicated a slow onset of the decrease in serum T4 and T3 by successive treatment with methimazole and PTU, and eventually their complete normalization by administration of LT4 with PTU but not with methimazole. The frequency of MCT8 mutations in males with X-linked MR approximately 3·9%. We identified several MCT8 mutations in a cohort of subjects with unexplained MR. We demonstrated the pathogenicity of two missense mutations. The synonymous variant did not affect TH transport. Block-and-replace therapy of one patient reversed the TH abnormalities. Our data suggest a decreased TH secretion rate and an increased T4 to T3 conversion by the type I deiodinase in patients with MCT8 mutations. Our study indicates that MCT8 mutations are a relatively frequent cause of X-linked MR.

565: Predictors of carrier screening for Fragile X syndrome

individual diagnoses, the following test characteristics were considered: cases where MRI confirmed a correct diagnosis obtained by US, cases where MRI improved diagnostic accuracy by diagnosing anomalies that US did not, cases where MRI failed to confirm a diagnosis that was accurately obtained by US, and cases where MRI offered no benefit because neither MRI nor US accurately diagnosed the anomaly. RESULTS: 799 MRIs were performed, of which 406 subjects possessed documented neonatal or pathologic outcomes. MRI agreed with ultrasound in 68% of cases. Overall, MRI confirmed the neonatal diagnosis in 56.4% of cases, improved the diagnosis in 12.8% of cases, detracted from the diagnosis in 5.9% of cases, and had no benefit in 24.9% of cases. Among individual anomalies, there were no cases of diaphragmatic hernia, omphalocele, vein of Galen malformation, or Dandy Walker complex where MRI correctly changed the ultrasound diagnosis. Findings varied for all other diagnoses (Table). CONCLUSION: Fetal MRI generally agrees with US performed at a tertiary care center, which may limit its adjunct diagnostic benefit. For most diagnoses, MRI gains must be weighed against potential drawbacks prior to clinical use. Notably, this study does consider potential cost, prognostic, or surgical-planning benefits of fetal MRI.

MECP2 duplication syndrome in both genders

BackgroundDuplications involving the methyl-CpG-binding protein 2 gene (MECP2) locus at Xq28 have been frequently identified in male patients who exhibit a phenotype unique from that of Rett syndrome, which is mainly characterized by severe mental retardation, recurrent infections, and epilepsy. This combination of features is recognized as MECP2 duplication syndrome. MethodsGenomic copy number was investigated for patients with unexplained mental retardation, and phenotypic features of the patients having interstitial duplications including MECP2 were analyzed. ResultsThree male and one female patients with MECP2 duplication were identified. The phenotypic features of all the four patients were compatible with MECP2 duplication syndrome. The X-chromosome inactivation (XCI) pattern was analyzed in the female patient, identifying a skewed XCI that activated the X-chromosome containing the MECP2 duplication. Her mother possessed the same MECP2 duplication and a random XCI pattern but exhibited no phenotypic features, indicating a nonsymptomatic carrier. The brain magnetic resonance imaging revealed periventricular cystic lesions in all four patients, including the female patient. ConclusionThis study suggested clinical implications of the MECP2 duplication syndrome not only in the male but also in female patients with unexplained mental retardation.

Severe intellectual disability, omphalocele, hypospadia and high blood pressure associated to a deletion at 2q22.1q22.3: case report

BackgroundRecently, array-comparative genomic hybridization (aCGH) platforms have significantly improved the resolution of chromosomal analysis allowing the identification of genomic copy number gains and losses smaller than 5 Mb. Here we report on a young man with unexplained severe mental retardation, autism spectrum disorder, congenital malformations comprising hypospadia and omphalocele, and episodes of high blood pressure. An ~ 6 Mb interstitial deletion that includes the causative genes is identified by oligonucleotide-based aCGH.ResultsOur index case exhibited a de novo chromosomal abnormality at 2q22 [del(2)(q22.1q22.3)dn] which was not visible at the 550 haploid band level. The deleted region includes eight genes: HNMT, SPOPL, NXPH2, LOC64702, LRP1B, KYNU, ARHGAP15 and GTDC1.DiscussionaCGH revealed an ~ 6 Mb deletion in 2q22.1 to 2q22.3 in an as-yet unique clinical case associated with intellectual disability, congenital malformations and autism spectrum disorder. Interestingly, the deletion is co-localized with a fragile site (FRA2K), which could be involved in the formation of this chromosomal aberration. Further studies are needed to determine if deletions of 2q22.1 to 2q22.3 define a new microdeletion syndrome.

Increased frequency of occult fragile X-associated primary ovarian insufficiency in infertile women with evidence of impaired ovarian function

The FMR1 premutation is associated with overt primary ovarian insufficiency (POI). However, its prevalence in women with occult POI (i.e. menstrual cycles, but impaired ovarian response) has not been examined. We hypothesized that both the FMR1 premutation and intermediate allele is more frequent in infertile women with occult POI than in controls, and that a repeat length cutoff might predict occult POI. All subjects were menstruating women <42 years old and with no family history of unexplained mental retardation, autism or fragile X syndrome. Cases had occult POI defined by elevated FSH or poor response to gonadotrophin therapy (n = 535). Control subjects (n = 521) had infertility from other causes or were oocyte donors. Prevalence of the FMR1 premutation and intermediate alleles was examined and allele length was compared between controls and women with occult POI. The frequency of the premutation (7/535 versus 1/521; P< 0.05) and intermediate alleles (17/535 versus 7/521; P< 0.05) was higher in women with occult POI than in controls. The allele with the greatest number of CGG repeats was longer in women with occult POI compared with controls (32.7 ± 7.1 versus 31.6 ± 4.3; P < 0.01). A receiver operating characteristic curve examining repeat length as a test for occult POI had an area of 0.56 ± 0.02 (P < 0.01). A repeat cutoff of 45 had a specificity of 98%, but a sensitivity of only 5% to identify occult POI. The positive predictive value was only 21% for a fertility population that has ∼ 22% of its patients with occult POI. The data suggest that FMR1 premutations and intermediate alleles are increased in women with occult POI. Thus, FMR1 testing should be performed in these women as some will have fragileX-associated POI. Although the FMR1 repeat lengths were longer in women with occult POI, the data do not support the use of a repeat length cutoff to predict occult POI.

Investigation of thealteration of gray matter volume in children with mental retardation with the optimalvoxel-based morphometry

：Objective To detectbrain structural difference between children with unexplained mental retardation andchildren with typically normal development. Methods The high-resolution magnetic MRimaging were obtained from 21 children with unexplained mental retardation and 30age-matched control children without intellectual disabilities. Voxel-based morphometryanalysis with an optimization of spatial segmentation and normalization procedures wereapplied to compare differences of gray matter volume between the two groups. The total andregional gray matter volume were compared between the two groups with independent t test.Meanwhile, correlation was conducted to analyze the relationship between the total graymatter volume and intelligence quotient (IQ) with partial correlation test. Results Thetotal gray matter volume was significantly increased in the mental retardation children[(1. 012 ±0. 079) × 106 mm3]in relative to the controls [(0. 956 ± 0. 059) × 106 mm3,t = - 2. 80, P ＜ 0. 05]. Compared tocontrols,children with unexplained mental retardation showed significantly increased graymatter volume in different regions, including the bilateral thalami, the bilateralsuperior frontal gyri, the bilateral gyri rectus, the bilateral temporal poles, the rightinferior frontal gyrus, right parahippocampal gyrus and the right cerebellum. Nocorrelation was detected between the total gray matter volume and IQ in children withmental retardation (r = 0. 078 ,P ＞ 0. 05). Conclusions VBM would detect the gray matterabnormalities that were not founded in routine MR scanning. The increase of gray mattervolume in the frontal-thalamus network might indicate the delayed maturation of the braindevelopment. This might be one of the causations of mental retardation in children. Key words: Mental retardation; Magnetic resonance imaging; Brain; Child

Screening for subtle chromosomal rearrangements in an Egyptian sample of children with unexplained mental retardation

Mental retardation is present in about 1–3% of individuals in the general population, but it can be explained in about half of the cases. A descriptive study was carried out to screen for subtle chromosomal rearrangements in a group of Egyptian children with idiopathic mental retardation (IMR) to estimate its frequency if detected. The study enrolled 30 patients with IMR, with the perquisite criteria of being <18 years at referral, their IQ <70, and manifesting at least one of the criteria for selection of patients with subtelomeric abnormalities. Males were 63.3% and females were 36.7%, with a mean age of 7.08 ± 4.22 years. Full history taking, thorough clinical examination, IQ, visual, and audiological assessment, brain CT scan, plasma aminogram, pelvi-abdominal ultrasonography, echocardiography, and cytogenetic evaluation using routine conventional karyotyping, high resolution banding (HRB), and fluorescent in situ hybridization (FISH) technique with appropriate probes were carried out for all studied patients. All enrolled patients had apparently normal karyotypes within 450 bands resolution, except for one patient who had 46, XY, [del (18) (p11.2)]. HRB and FISH showed subtle chromosomal rearrangement in 10% of cases that have been proven to be subtelomeric in 2 cases, i.e., 6.8%: 46, XY, dup (17) (p13.3), 46, XY, del (2) (q36.1–36.3), and non-subtelomeric in one case, 5.5%, 46, XX, ins (7;?) (q22;?). To conclude, in children with IMR and clinical phenotype indicative of a suspected chromosomal anomaly, once recognizable syndromes have been excluded, abnormalities that include the ends of chromosomes must be searched for using HRB and subtelomeric FISH even when conventional karyotyping fails to demonstrate any abnormality.

De novo mutations in mental retardation

Recent studies have indicated that humans have an exceptionally high per-generation mutation rate of 7.6 × 10–9 to 2.2 × 10–8. These spontaneous germline mutations can have serious phenotypic consequences when affecting functionally relevant bases in the genome. In fact, their occurrence may explain why cognitive disorders with a severely reduced fecundity, such as mental retardation, remain frequent in the human population, especially when the mutational target is large and comprises many genes. This would explain a major paradox in the evolutionary genetic theory of these disorders. In this presentation, I will describe our recent work on using a family-based exome sequencing approach to test this de novo mutation hypothesis in ten patients with unexplained mental retardation [1]. Unique nonsynonymous de novo mutations were identified and validated in nine genes. Six of these, identified in different patients, were likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. The clinical relevance of these novel genes, and the ultimate proof that they cause disease, lies in the identification of de novo mutations in additional patients with a similar phenotype. As such, we are currently screening approximately 1,200 patients with unexplained mental retardation for mutations in YY1, which is one of these newly identified genes. In addition, we are extending our family-based exome sequencing approach to 100 patients to establish the diagnostic yield for de novo mutations in patients with unexplained mental retardation. These findings, when replicated, provided strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population. In my presentation, I will explain this work, as well as related work on autism [2] and schizophrenia [3].

A de novo paradigm for mental retardation

The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.

Committee Opinion No. 469: Carrier Screening for Fragile X Syndrome

Fragile X syndrome is the most common inherited form of mental retardation. The syndrome occurs in approximately 1 in 3,600 males and 1 in 4,000-6,000 females. Approximately 1 in 250 females carry the premutation. DNA-based molecular analysis is the preferred method of diagnosis for fragile X syndrome and its premutations. Prenatal testing for fragile X syndrome should be offered to known carriers of the fragile X premutation or full mutation. Women with a family history of fragile X-related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency are candidates for genetic counseling and fragile X premutation carrier screening.

Creatine and Creatine Deficiency Syndromes: Biochemical and Clinical Aspects

Creatine deficiency syndromes, which have only recently been described, represent a group of inborn errors of creatine synthesis (L-arginine-glycine amidinotransferase deficiency and guanidinoacetate methyltransferase deficiency) and transport (creatine transporter deficiency). Patients with creatine deficiency syndromes present with mental retardation expressive speech and language delay, and epilepsy. Patients with guanidinoacetate methyltransferase deficiency or creatine transporter deficiency may exhibit autistic behavior. The common denominator of these disorders is the depletion of the brain creatine pool, as demonstrated by in vivo proton magnetic resonance spectroscopy. For diagnosis, laboratory investigations start with analysis of guanidinoacetate, creatine, and creatinine in plasma and urine. Based on these findings, enzyme assays or DNA mutation analysis may be performed. The creatine deficiency syndromes are underdiagnosed, so the possibility should be considered in all children affected by unexplained mental retardation, seizures, and speech delay. Guanidinoacetate methyltransferase deficiency and arginine-glycine amidinotransferase deficiency are treatable by oral creatine supplementation, but patients with creatine transporter deficiency do not respond to this type of treatment.