Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple lentigines (LEOPARD) syndrome has been delineated as an autosomal dominant disorder with lentigines, cardiac abnormalities, variable mental retardation, and typical craniofacial features as the most characteristic findings. LEOPARD syndrome shows a great clinical overlap with neurofibromatosis type 1 (NF1). In this report we describe a de novo missense mutation (M 1035R) in exon 18 of the NF1 gene in a young woman with a prior diagnosis of LEOPARD syndrome. We hypothesize that some patients now diagnosed with LEOPARD syndrome have in fact a mutation in the NF1 gene, whereas in other patients with LEOPARD syndrome, a different gene might be involved.
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PMID:Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. 880 36

This review summarizes PTPN11 (protein-tyrosine phosphatase, nonreceptor type 11) mutations and genotype-phenotype correlations in Noonan syndrome (NS) and LEOPARD syndrome (LS). PTPN11 mutations have been identified in approximately 40% of NS patients and in >80% of LS patients. Since the vast majority of mutations reside in and around the broad intramolecular interaction surface between the N-SH2 and PTP domains of the PTPN11 protein, they have been suggested to affect the intramolecular N-SH2/PTP binding in the absence of a phosphopeptide, leading to excessive phosphatase activities. The type of mutations is diverse in NS and limited in LS, and is almost mutually exclusive between NS and LS. Clinical assessment in NS patients implies that cardiovascular anomalies and hematologic abnormalities are predominant in mutation positive patients, hypertrophic cardiomyopathy is predominant in mutation negative patients, and growth deficiency, mental retardation, and minor somatic anomalies are similar between the two groups of patients. Phenotypic evaluation in LS patients suggests that a hypertrophic cardiomyopathy rather than an electrocardiographic conduction abnormality is characteristic of PTPN11 mutation positive patients.
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PMID:PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. 1620 80

We report severe brain calcification in a case of LEOPARD syndrome that has not been reported in the literature. A 53-year-old Japanese man presented with generalized lentigines, arrhythmia, gonadal hypoplasia, endocrine abnormality, mental retardation and skeletal abnormalities, and was consequently diagnosed as LEOPARD syndrome. Brain computed tomography demonstrated surprisingly dense and symmetric calcifications in the cerebellar dentate nuclei, cerebral basal ganglia, thalamus, and cerebral white matter. It may be an incidental idiopathic calcification. Alternatively it may be a rare clinical manifestation of LEOPARD syndrome.
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PMID:Severe cerebral calcification in a case of LEOPARD syndrome. 1898 39

Noonan syndrome (NS) and related disorders are caused by mutations in various genes encoding molecules involved in the RAS-MAPK signalling cascade. There are strong genotype-phenotype correlations. BRAF is the major gene for cardio-facio-cutaneous syndrome (CFCS), and usually patients with a BRAF mutation have significant cognitive impairment. We report on a patient with LEOPARD syndrome and normal intelligence who was found to carry a novel sequence change in BRAF. The mutation p.L245F was demonstrated to be de novo with no evidence of somatic mosaicism. This observation illustrates that the phenotypic spectrum caused by BRAF mutations is broader than previously assumed and that mental retardation is not necessarily associated. We speculate that the impact of p.L245F on BRAF protein function differs either qualitatively or quantitatively from those mutations associated with CFCS.
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PMID:Novel BRAF mutation in a patient with LEOPARD syndrome and normal intelligence. 1941 62

Deregulation of signaling pathways, through mutation or other molecular changes, can ultimately result in disease. The tyrosine phosphatase Shp2 has emerged as a major regulator of receptor tyrosine kinase (RTK) and cytokine receptor signaling. In the last decade, germline mutations in the human PTPN11 gene, encoding Shp2, were linked to Noonan (NS) and LEOPARD syndromes, two multisymptomatic developmental disorders that are characterized by short stature, craniofacial defects, cardiac defects, and mental retardation. Somatic Shp2 mutations are also associated with several types of human malignancies, such as the most common juvenile leukemia, juvenile myelomonocytic leukemia (JMML). Whereas NS and JMML are caused by gain-of-function (GOF) mutations of Shp2, loss-of-function (LOF) mutations are thought to be associated with LEOPARD syndrome. Animal models that carry conditional LOF and GOF mutations have allowed a better understanding of the mechanism of Shp2 function in disease, and shed light on the role of Shp2 in signaling pathways that control decisive events during embryonic development or during cellular transformation/tumorigenesis.
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PMID:The tyrosine phosphatase Shp2 in development and cancer. 2039 56

Proteins belonging to the RAS/mitogen activated protein kinase (MAPK) pathway play key roles in cell proliferation, differentiation, survival, and death. For more than 30 years now we have known that 30% of human cancers carry somatic mutations in genes encoding proteins from this pathway. Whereas somatic mutations have a high malignant potential, germline mutations are linked to developmental abnormalities that are often poorly clinically differentiated, although each is dependent upon the specific gene affected. Thus, all patients share varying degrees of mental retardation or learning difficulties, heart disease, facial dysmorphism, skin anomalies, and, in some cases, predisposition to cancer. These syndromes, known as rasopathies, include Noonan syndrome, Costello syndrome, neurofibromatosis-1, LEOPARD syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. Recognizing the skin manifestations of rasopathies can facilitate diagnosis of these syndromes.
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PMID:[Rasopathies: developmental disorders that predispose to cancer and skin manifestations]. 2153 46

The concept of neuro-cardio-facio-cutaneous (NCFC) syndrome has recently been formulated in order to bring together a number of hereditary diseases that include a number of shared phenotypic features to differing degrees: (i) craniofacial dysmorphia; (ii) delayed growth; (iii) mental retardation or learning difficulties; (iv) cardiac malformations (most commonly pulmonary valve stenosis and hypertrophic cardiomyopathy); (v) cutaneous anomalies, and in some cases, predisposition to certain forms of malignant solid tumors and blood diseases, associated at the physiopathological level with deregulation of the Ras-MAP kinase cellular signaling pathways 1. NCFC subsumes neurofibromatosis type1, Legius syndrome, LEOPARD syndrome, Noonan syndrome, Costello syndrome and cardiofaciocutaneous (CFC) syndrome. While the majority of these diseases are readily distinguishable in clinical terms, with or without diagnostic criteria, none of them have any pathognomonic signs. Many cases attest to the strong clinical homologies and forms of overlapping between these different diseases. In recent years, the discovery of germinal mutations of these different diseases has in fact reinforced the unifying clinical and biochemical concept of NCFC syndrome.
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PMID:[Neuro-cardio-facial-cutaneous syndrome]. 2170 69

Noonan syndrome [NS; Mendelian Inheritance in Men (MIM) #163950] and related syndromes [Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome; MIM #151100), Noonan-like syndrome with loose anagen hair (MIM #607721), Costello syndrome (MIM #218040), cardio-facio-cutaneous syndrome (MIM #115150), type I neurofibromatosis (MIM #162200), and Legius syndrome (MIM #611431)] are a group of related genetic disorders associated with distinctive facial features, cardiopathies, growth and skeletal abnormalities, developmental delay/mental retardation, and tumor predisposition. NS was clinically described more than 50 years ago, and disease genes have been identified throughout the last 3 decades, providing a molecular basis to better understand their physiopathology and identify targets for therapeutic strategies. Most of these genes encode proteins belonging to or regulating the so-called RAS/MAPK signaling pathway, so these syndromes have been gathered under the name RASopathies. In this review, we provide a clinical overview of RASopathies and an update on their genetics. We then focus on the functional and pathophysiological effects of RASopathy-causing mutations and discuss therapeutic perspectives and future directions.
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PMID:The RASopathy Family: Consequences of Germline Activation of the RAS/MAPK Pathway. 2992 99