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)

Congenital myopathies and congenital myopathic dystrophies are distinct groups of inherited diseases of muscle, genetically heterogeneous, that manifest in early life or infancy. Congenital myopathic dystrophy is characterized by a dystrophic pattern, whereas no necrotic or degenerative changes are present in congenital myopathies. Much progress has been made in recent years in clarifying the classification of the congenital myopathies. This is a clinically and genetically heterogeneous group of conditions originally classified according to unique morphological changes seen in muscle. Not unlike the later-onset muscular dystrophies, the discovery of the genetic aetiology of many of the congenital myopathies has led to a revamping of how these conditions can now be diagnosed and this should enable physicians to give a more accurate prognosis to patients and their families. New mutations in the ryanodine receptor, slow tropomyosin, troponin T1, actin, and nebulin genes have been described in the last 2 years. Clinical and genetic guidelines for conditions like nemaline rod myopathy and central core disease have been suggested. The notion of minus and surplus protein myopathies has been developed. Several groups of congenital myopathic dystrophy have been identified. In the first category, without intellectual impairment or major structural brain abnormalities, half of the cases are merosin deficient due to mutations of the laminin alpha 2 chain gene. If generally the muscular phenotype is severe, mild allelic variants have been reported with early onset dystrophies and partial merosin deficiency. Among other pure congenital myopathic dystrophies unlinked to the laminin alpha 2 gene, one form has been assigned to chromosome 1q42. In the group of congenital myopathic dystrophies associated with mental retardation and structural brain abnormalities, two main entities are genetically characterized: (1) Fukuyama congenital myopathic dystrophy, affecting the Japanese population, is due to fukutin gene mutations, and (2) the muscle eye brain syndrome assigned to chromosome 1p32-34. In several cases, the gene localization remains unknown.
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PMID:Congenital myopathies and congenital muscular dystrophies. 1156 68

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders presenting in infancy with muscle weakness, contractures, and dystrophic changes on skeletal-muscle biopsy. Structural brain defects, with or without mental retardation, are additional features of several CMD syndromes. Approximately 40% of patients with CMD have a primary deficiency (MDC1A) of the laminin alpha2 chain of merosin (laminin-2) due to mutations in the LAMA2 gene. In addition, a secondary deficiency of laminin alpha2 is apparent in some CMD syndromes, including MDC1B, which is mapped to chromosome 1q42, and both muscle-eye-brain disease (MEB) and Fukuyama CMD (FCMD), two forms with severe brain involvement. The FCMD gene encodes a protein of unknown function, fukutin, though sequence analysis predicts it to be a phosphoryl-ligand transferase. Here we identify the gene for a new member of the fukutin protein family (fukutin related protein [FKRP]), mapping to human chromosome 19q13.3. We report the genomic organization of the FKRP gene and its pattern of tissue expression. Mutations in the FKRP gene have been identified in seven families with CMD characterized by disease onset in the first weeks of life and a severe phenotype with inability to walk, muscle hypertrophy, marked elevation of serum creatine kinase, and normal brain structure and function. Affected individuals had a secondary deficiency of laminin alpha2 expression. In addition, they had both a marked decrease in immunostaining of muscle alpha-dystroglycan and a reduction in its molecular weight on western blot analysis. We suggest these abnormalities of alpha-dystroglycan are caused by its defective glycosylation and are integral to the pathology seen in MDC1C.
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PMID:Mutations in the fukutin-related protein gene (FKRP) cause a form of congenital muscular dystrophy with secondary laminin alpha2 deficiency and abnormal glycosylation of alpha-dystroglycan. 1159 34

The congenital muscular dystrophies (CMD) are a heterogeneous group of autosomal recessive disorders. A new pathomechanism has recently been identified in a group of these disorders in which known or putative glycosyltransferases are defective. Common to all these conditions is the hypoglycosylation of alpha-dystroglycan. Fukuyama CMD, muscle-eye-brain disease and Walker-Warburg syndrome, each associated with eye abnormalities and neuronal migration defects, result from mutations in fukutin, POMGnT1 and POMT1, respectively, while mutations in the fukutin-related protein (FKRP) gene cause congenital muscular dystrophy 1C, typically lacking brain involvement. Another putative glycosyltransferase, Large, is mutated in the myodystrophy mouse. The human homologue of this gene is therefore a strong candidate for involvement in novel forms of muscular dystrophy. We studied 36 patients with muscular dystrophy and either mental retardation, structural brain changes or abnormal alpha-dystroglycan immunolabelling, unlinked to any reported CMD loci. Linkage analysis in seven informative families excluded involvement of LARGE but sequencing of this gene in the remaining 29 families identified one patient with a G1525A (Glu509Lys) missense mutation and a 1 bp insertion, 1999insT. This 17-year-old girl presented with congenital muscular dystrophy, profound mental retardation, white matter changes and subtle structural abnormalities on brain MRI. Her skeletal muscle biopsy showed reduced immunolabelling of alpha-dystroglycan. Immunoblotting with an antibody to a glycosylated epitope demonstrated a reduced molecular weight form of alpha-dystroglycan that retained some laminin binding activity. This is the first description of mutations in the human LARGE gene and we propose to name this new disorder MDC1D.
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PMID:Mutations in the human LARGE gene cause MDC1D, a novel form of congenital muscular dystrophy with severe mental retardation and abnormal glycosylation of alpha-dystroglycan. 1296 29

We isolated a fragment of the fukutin gene promoter from differentiated human NT2 cells using chromatin immunoprecipitation technique with an anti-CREB antibody. This fragment contained a CRE-like sequence and here we describe its functional validation. The results showed that the element was functional in vitro and in vivo and that CREB in neurons was involved in the transcriptional regulation of the fukutin gene. Moreover, its expression in neurons was regulated by cAMP and calcium ions, known triggers of CREB phosphorylation. To our knowledge, this is the first report on the regulation of fukutin gene by transcription factor CREB in response to the signals generated by synaptic activity. The true biological function of fukutin, the gene responsible for Fukuyama-type congenital muscular dystrophy and mental retardation, is at present not known. However, it has been suggested that it might possess glycosyltransferase activity and its intracellular localization within the Golgi structures is consistent with this function. As such, fukutin might play a significant role in post-translational modification of synaptic proteins in neuronal cells.
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PMID:Identification of a functional CRE in the promoter of Fukuyama congenital muscular dystrophy gene fukutin. 1589 81

Walker-Warburg Syndrome (WWS) is a rare form of autosomal recessive congenital muscular dystrophy associated with brain and eye abnormalities. WWS has a worldwide distribution. The overall incidence is unknown but a survey in North-eastern Italy has reported an incidence rate of 1.2 per 100,000 live births. It is the most severe form of congenital muscular dystrophy with most children dying before the age of three years. WWS presents at birth with generalized hypotonia, muscle weakness, developmental delay with mental retardation and occasional seizures. It is associated with type II cobblestone lissencephaly, hydrocephalus, cerebellar malformations, eye abnormalities and congenital muscular dystrophy characterized by hypoglycosylation of alpha-dystroglycan. Several genes have been implicated in the etiology of WWS, and others are as yet unknown. Several mutations were found in the Protein O-Mannosyltransferase 1 and 2 (POMT1 and POMT2) genes, and one mutation was found in each of the fukutin and fukutin-related protein (FKRP) genes. Laboratory investigations usually show elevated creatine kinase, myopathic/dystrophic muscle pathology and altered alpha-dystroglycan. Antenatal diagnosis is possible in families with known mutations. Prenatal ultrasound may be helpful for diagnosis in families where the molecular defect is unknown. No specific treatment is available. Management is only supportive and preventive.
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PMID:Walker-Warburg syndrome. 1688 26

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder prevalent in Japan, characterized by cobblestone lissencephaly and dystrophic changes in skeletal muscle, resulting in mental retardation, epilepsy and motor impairment. FCMD patients in Japan carry at least one copy of an ancestral founder mutation, a 3 kb insertion in a 3'-untranslated region, that results in a reduction in fukutin mRNA levels. We analyzed 35 patients with FCMD and found 18 patients carried a homozygous founder mutation (homozygotes) and 17 a combined heterozygous between founder mutation and a nonsense or missense mutation (heterozygotes). During an average follow-up of over 10 years, 61% of homozygotes and 82% of heterozygotes developed febrile or afebrile seizures. The ages at onset of febrile and afebrile seizures on average were 5.4 and 4.6 years, respectively, in homozygotes and 3.6 and 3.7 years, respectively, in heterozygotes. Repeated seizures were treated with antiepileptic drugs. While all homozygotes showed good seizure control, four heterozygotes had intractable seizures. Mutations other than the 3 kb insertion were identified in seven of 12 heterozygotes examined. Five patients with a nonsense mutation in exon 3 and one with a missense mutation in exon 5 had a severe phenotype and some showed intractable seizures. On the other hand, one with a nonsense mutation in exon 8 had only one febrile seizure. It was concluded mutational analysis of the FCMD gene could predict seizure prognosis. Heterozygotes usually developed seizures earlier than homozygotes and some heterozygotes showed intractable seizures. Mutational analysis other than of the 3 kb insertion may also help to predict seizure prognosis.
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PMID:Seizure-genotype relationship in Fukuyama-type congenital muscular dystrophy. 1759 23

Muscular dystrophies with reduced glycosylation of alpha-dystroglycan (alpha-DG), commonly referred to as dystroglycanopathies, are a heterogeneous group of autosomal recessive conditions which include a wide spectrum of clinical severity. Reported phenotypes range from severe congenital onset Walker-Warburg syndrome (WWS) with severe structural brain and eye involvement, to relatively mild adult onset limb girdle muscular dystrophy (LGMD). Specific clinical syndromes were originally described in association with mutations in any one of six demonstrated or putative glycosyltransferases. Work performed on patients with mutations in the FKRP gene has identified that the spectrum of phenotypes due to mutations in this gene is much wider than originally assumed. To further define the mutation frequency and phenotypes associated with mutations in the other five genes, we studied a large cohort of patients with evidence of a dystroglycanopathy. Exclusion of mutations in FKRP was a prerequisite for participation in this study. Ninety-two probands were screened for mutations in POMT1, POMT2, POMGnT1, fukutin and LARGE. Homozygous and compound heterozygous mutations were detected in a total of 31 probands (34 individuals from 31 families); 37 different mutations were identified, of which 32 were novel. Mutations in POMT2 were the most prevalent in our cohort with nine cases, followed by POMT1 with eight cases, POMGnT1 with seven cases, fukutin with six cases and LARGE with only a single case. All patients with POMT1 and POMT2 mutations had evidence of either structural or functional central nervous system involvement including four patients with mental retardation and a LGMD phenotype. In contrast mutations in fukutin and POMGnT1 were detected in four patients with LGMD and no evidence of brain involvement. The majority of patients (six out of nine) with mutations in POMT2 had a Muscle-Eye-Brain (MEB)-like condition. In addition we identified a mutation in the gene LARGE in a patient with WWS. Our data expands the clinical phenotypes associated with POMT1, POMT2, POMGnT1, fukutin and LARGE mutations. Mutations in these five glycosyltransferase genes were detected in 34% of patients indicating that, after the exclusion of FKRP, the majority of patients with a dystroglycanopathy harbour mutations in novel genes.
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PMID:Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. 1787 7

Walker-Warburg Syndrome (WWS) is an alpha-dystroglycan deficient congenital muscular dystrophy that is associated with brain and eye abnormalities. Patients present with hypotonia, weakness, developmental delay, mental retardation and occasional seizures. Other abnormalities were also described including cleft lip and palate. Mutations in POMT1, POMT2, fukutin, FKRP and LARGE genes are found in 20-30% of children with WWS. We report a novel mutation in POMT1 gene and provide further evidence that WWS with cleft lip and palate is associated with POMT1 mutations. We recommend POMT1 analysis in WWS cases associated with cleft lip and palate when considering which gene to sequence first.
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PMID:Walker-Warburg Syndrome with POMT1 mutations can be associated with cleft lip and cleft palate. 1864 39

Alpha-dystroglycan (alpha-DG) is a glycoprotein that binds to laminin in the basal lamina and helps provide mechanical support. A group of muscular dystrophies are caused by glycosylation defects of alpha-DG and are hence collectively called alpha-dystroglycanopathy (alpha-DGP). Alpha-DGP is clinically characterized by a combination of muscular dystrophies, structural brain anomalies, and ocular involvement. So far, 6 causative genes have been identified: LARGE, POMGNT1, POMT1, POMT2, FKRP, and FKTN. Initially, alpha-DGP was classified under congenital muscular dystrophies; however, the clinical phenotype is now expanded to include a markedly wide spectrum ranging from the most severe, lethal congenital muscular dystrophy with severe brain deformity to the mildest limb girdle muscular dystrophy with minimal muscle weakness. This is exemplified by Fukuyama congenital muscular dystrophy (FCMD), which is the most prevalent alpha-DGP in Japan, and is caused by mutations in FKTN. FCMD is clinically characterized by a triad of mental retardation, brain deformities, and congenital muscular dystrophy, and a majority of FCMD patients have a homozygous 3-kb retrotransposal insertion in the 3'non-coding region. Typically, they are able to sit but never attain independent ambulation in their lives. Recently, a patient from Turkey harboring homozygous 1-bp insertion reportedly showed a severe brain deformity with hydrocephalus and died 10 days after birth. In contrast, the mildest FKTN phenotype, LGMD2L, was identified in 6 cases from 4 families in Japan. These patients harbored compound heterozygous mutation with 3-kb retrotransposal insertion in the 3'non-coding region and a novel missense mutation in the coding region. Clinically, these patients presented with minimal muscle weakness and dilated cardiomyopathy and had normal intelligence. These data clearly indicate that FKTN mutations can cause a broad spectrum of muscular dystrophies. Therefore, clinicians should always bear in mind the possibility of alpha-DGP when they have a patient suspected to have muscular dystrophy.
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PMID:[Fukuyama congenital muscular dystrophy and related alpha-dystroglycanopathies]. 1897 3

Fukuyama congenital muscular dystrophy (FCMD) is frequent in Japan, due to a founder mutation of the fukutin gene (FKTN). Outside Japan, FKTN mutations have only been reported in a few patients with a wide spectrum of phenotypes from Walker-Warburg syndrome to limb-girdle muscular dystrophy (LGMD2M). We studied four new Caucasian patients from three unrelated families. All showed raised serum CK initially isolated in one case and muscular dystrophy. Immunohistochemical studies and haplotype analysis led us to search for mutations in FKTN. Two patients (two sisters) presented with congenital muscular dystrophy, mental retardation, and posterior fossa malformation including cysts, and brain atrophy at Brain MRI. The other two patients had normal intelligence and brain MRI. Sequencing of the FKTN gene identified three previously described mutations and two novel missense mutations. Outside Japan, fukutinopathies are associated with a large spectrum of phenotypes from isolated hyperCKaemia to severe CMD, showing a clear overlap with that of FKRP.
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PMID:Four Caucasian patients with mutations in the fukutin gene and variable clinical phenotype. 1917 78


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