Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rett syndrome (RTT) is a progressive neurologic disorder representing one of the most common causes of mental retardation in females. To date mutations in three genes have been associated with this condition. Classic RTT is caused by mutations in the MECP2 gene, whereas variants can be due to mutations in either MECP2 or FOXG1 or CDKL5. Mutations in CDKL5 have been identified both in females with the early onset seizure variant of RTT and in males with X-linked epileptic encephalopathy. CDKL5 is a kinase protein highly expressed in neurons, but its exact function inside the cell is unknown. To address this issue we established a human cellular model for CDKL5-related disease using the recently developed technology of induced pluripotent stem cells (iPSCs). iPSCs can be expanded indefinitely and differentiated in vitro into many different cell types, including neurons. These features make them the ideal tool to study disease mechanisms directly on the primarily affected neuronal cells. We derived iPSCs from fibroblasts of one female with p.Q347X and one male with p.T288I mutation, affected by early onset seizure variant and X-linked epileptic encephalopathy, respectively. We demonstrated that female CDKL5-mutated iPSCs maintain X-chromosome inactivation and clones express either the mutant CDKL5 allele or the wild-type allele that serve as an ideal experimental control. Array CGH indicates normal isogenic molecular karyotypes without detection of de novo CNVs in the CDKL5-mutated iPSCs. Furthermore, the iPS cells can be differentiated into neurons and are thus suitable to model disease pathogenesis in vitro.
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PMID:iPS cells to model CDKL5-related disorders. 2175 May 74

Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein2 (MeCP2), is a leading cause of mental retardation in females. Majority of cases are sporadic (99%) but some familial cases have also been observed. We describe a familial study with a brother-sister pair with symptoms of RTT and exhibiting distinct deletions in the MECP2. The non-shared de novo deletion in the two sibs provides important insights into the disease etiology, especially for male sibs showing varied phenotypes as compared to the classical ones seen in the females.
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PMID:Distinct de novo deletions in a brother-sister pair with RTT: a case report. 2181 1

Loss-of-function mutations of the MECP2 gene are the cause of most cases of Rett syndrome in females, a progressive neurodevelopmental disorder characterized by severe mental retardation, global regression, hand stereotypies, and microcephaly. On the other hand, gain of dosage of this gene causes the MECP2 duplication syndrome in males characterized by severe mental retardation, absence of speech development, infantile hypotonia, progressive spasticity, recurrent infections, and facial dysmorphism. Female carriers of a heterozygous duplication show a skewed X-inactivation pattern which is the most probable cause of the lack of clinical symptoms. In this paper, we describe a girl with a complex de novo copy number gain at Xq28 and non-skewed X-inactivation pattern that causes mental retardation and motor and language delay. This rearrangement implies triplication of the MECP2 and IRAK1 genes, but it does not span other proximal genes located in the common minimal region of patients affected by the MECP2 duplication syndrome. We conclude that the triplication leads to a severe phenotype due to random X-inactivation, while the preferential X chromosome inactivation in healthy carriers may be caused by a negative selection effect of the duplication on some proximal genes like ARD1A or HCFC1.
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PMID:De novo interstitial triplication of MECP2 in a girl with neurodevelopmental disorder and random X chromosome inactivation. 2193 80

Rett syndrome (RTT) is a neurodevelopmental disorder that is one of the most common causes of mental retardation in females. RTT diagnosis is based on distinct clinical criteria. We describe here a female patient with severe phenotype of congenital variant RTT. The patient originally presented with severe developmental delay prior to the age of 6 months and later exhibited characteristic features of RTT that included air swallowing, bruxism, and hand stereotypies. Results of an array-based comparative genomic hybridization analysis indicated there was a very small microdeletion in Xq28. Multiplex ligation-dependent probe amplification analysis further confirmed there were heterozygous deletions of intron 2, exon 3, intron 3, and part of exon 4 in MECP2. Findings in the present patient confirm the view that large MECP2 deletions are an important cause of severe congenital variant RTT. To ensure an accurate diagnosis of congenital variant RTT, a multiplex ligation-dependent probe amplification analysis of MECP2 should be performed in patients suspected of having this disorder.
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PMID:Congenital variant of Rett syndrome due to an intragenic large deletion in MECP2. 2200

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.
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PMID:Molecular diagnostic dilemmas in Rett syndrome. 2227 91

Rett syndrome (RTT) is a congenital neurological disorder associated with mutations in the gene encoding MECP2 on the X chromosome. An 18-year-old woman (150 cm in height and 29 kg in weight) had been diagnosed with RTT and showed myotonic trismus, frequent attacks of apnea, mental retardation, spastic paraplegia, scoliosis, and microcephalus with micrognathia. She was scheduled to undergo laparoscopic fundoplication and gastrostomy under general anesthesia. Nasal bronchofiberscopic intubation (BFI) was planned because difficult airway due to trismus and micrognathia was expected. Referring to the bispectral index (BIS), anesthesia was induced with intermittent intravenous thiopental (total 125 mg), resulting in successful opening of the mouth by 1.5 of a finger width and establishment of manual ventilation. Following intravenous administration of rocuronium (20 mg), oral BFI was easily accomplished despite Cormack grade III. Anesthesia was satisfactorily maintained with inhalation of sevoflurane (1.0-1.5%) and continuous infusion of remifentanil (0.1-0.2 microg x kg(-1) x min(-1)) with the BIS value ranging from 30 to 50. She recovered smoothly from anesthesia using sugammadex (50 mg). However, she immediately demonstrated trismus and an attack of apnea with shivering, which were successfully resolved by warming the body and intravenous fentanyl (50 microg bolus and subsequent infusion at a rate of 10 microg x hr(-1)). The postoperative course was uneventful. Characteristically, RTT shows an extremely wide range of neurological symptoms. Therefore, it is of great importance to respond to each of those symptoms during the perioperative management of patients with RTT.
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PMID:[Anesthetic management of a patient with Rett syndrome associated with trismus and apnea attacks]. 2233 70

In this report we present two brothers with abnormal neurological development, hypotonia, short stature, pylorus stenosis, pectus excavatum, brachycephaly due to craniosynostosis, frontal bossing, depressed nasal bridge, high arched-wide palate, downslant palpebral fissures, low-set, large ears, thin upper lip and bilateral cryptorchidism. The brothers were born to a couple of second cousins and were the third and fourth pregnancies of the mother. The father, the mother and the eldest sibling were phenotypically and chromosomally normal. The clinical findings of the brothers were found to be similar. These clinical findings were compared with syndromes showing some of the symptoms, namely Apert, FG, Floating-Harbor, Shprintzen-Goldberg and Rett Syndromes. However, when the findings were detailed, we observed that they did not match completely any of the syndromes in a discernable way. The MECP2 gene mutation was analysed because of mental retardation, poor neurological evolution and large ears, but no mutation was found. So these cases are presented as a new syndrome with apparent autosomal recessive inheritance.
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PMID:A new syndrome: multiple congenital abnormalities and mental retardation in two brothers. 2261 37

Rett syndrome (RTT) is a postnatal, severe, disabling neurodevelopmental disorder occurring almost exclusively in females and is the second most common cause for genetic mental retardation in girls. In the majority of cases it is caused by mutations in gene (MECP2) encoding methyl-CpG-binding protein 2. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a major role in neuronal survival, neurogenesis and plasticity. Animal studies suggested that abnormalities in BDNF homeostasis may contribute to the pathogenesis in Mecp2 null mice, and BDNF administration in the Mecp2 mutant brain led to later onset/slower disease progression, suggesting that increased BDNF in the brain could be therapeutic for this disease. Mature BDNF is a 14 kDa protein that may have poor blood-brain barrier penetrability. However, recent animal studies demonstrated that peripheral administration of BDNF, either by intravenous injection or intranasal delivery, could increase BDNF levels in the brain. Thus it is proposed that peripheral administration of BDNF in the early stage could have therapeutic potential for RTT subjects. Furthermore, the combination use of mannitol may temporarily open the blood-brain barrier and facilitate the entry of BDNF into brain. The potential therapeutic effect of peripheral BDNF administration could be tested in RTT animal models such as Mecp2 KO mice, which may provide a new intervention for this devastating disease.
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PMID:Peripheral administration of brain-derived neurotrophic factor to Rett syndrome animal model: a possible approach for the treatment of Rett syndrome. 2284 7

Angelman syndrome is a neurodevelopmental disorder characterized by mental retardation, severe speech disorder, facial dysmorphism, secondary microcephaly, ataxia, seizures, and abnormal behaviors such as easily provoked laughter. It is most frequently caused by a de novo maternal deletion of chromosome 15q11-q13 (about 70-90%), but can also be caused by paternal uniparental disomy of chromosome 15q11-q13 (3-7%), an imprinting defect (2-4%) or in mutations in the ubiquitin protein ligase E3A gene UBE3A mostly leading to frame shift mutation. In addition, for patients with overlapping clinical features (Angelman-like syndrome), mutations in methyl-CpG binding protein 2 gene MECP2 and cyclin-dependent kinase-like 5 gene CDKL5 as well as a microdeletion of 2q23.1 including the methyl-CpG binding domain protein 5 gene MBD5 have been described. Here, we describe a patient who carries a de novo 5Mb-deletion of chromosome 15q11.2-q13.1 known to be associated with Angelman syndrome and a further, maternally inherited deletion 2q21.3 (~364kb) of unknown significance. In addition to classic features of Angelman syndrome, she presented with severe infections in the first year of life, a symptom that has not been described in patients with Angelman syndrome. The 15q11.2-q13.1 deletion contains genes critical for Prader-Willi syndrome, the Angelman syndrome causing genes UBE3A and ATP10A/C, and several non-imprinted genes: GABRB3 and GABRA5 (both encoding subunits of GABA A receptor), GOLGA6L2, HERC2 and OCA2 (associated with oculocutaneous albinism II). The deletion 2q21.3 includes exons of the genes RAB3GAP1 (associated with Warburg Micro syndrome) and ZRANB3 (not disease-associated). Despite the normal phenotype of the mother, the relevance of the 2q21.3 microdeletion for the phenotype of the patient cannot be excluded, and further case reports will need to address this point.
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PMID:Angelman syndrome and severe infections in a patient with de novo 15q11.2-q13.1 deletion and maternally inherited 2q21.3 microdeletion. 2312 39

Duplication of MECP2 causes a recently described X-linked mental retardation syndrome, of which the typical features are infantile hypotonia, poor speech development, recurrent infections, epilepsy, and progressive spasticity. Recently, the associated seizure semiology and interictal EEG features have been increasingly described, whereas ictal electroclinical features remain poorly defined. We report the case of a boy carrying a maternally-inherited MECP2 duplication and describe the video-EEG sequence of a cluster of eating-induced spasms, the only epileptic manifestation of the patient. This report expands our knowledge of the epileptic phenotype of MECP2 duplication syndrome and may contribute to a better definition and comprehension of the electroclinical spectrum of patients affected by this disease. It also supports the hypothesis that in some genetic epilepsies, the electro-clinical profile can correlate with the dysfunction of limited cortical regions despite the presence of a genetic mutation over the entire brain. [Published with video sequences].
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PMID:Eating-induced epileptic spasms in a boy with MECP2 duplication syndrome: insights into pathogenesis of genetic epilepsies. 2431 15


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