Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026827 (hypotonia)
 5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 13-year-old male presented with new onset seizures, sagittal sinus thrombosis with cerebral hemorrhage, and extensive venous thrombosis of the lower limbs. Laboratory investigation demonstrated combined deficiency of protein C, protein S, and antithrombin III. He and his 17-year-old sister had a mental retardation-multiple anomaly syndrome associated with microcephaly, unusual facies, and lax connective tissue. Their dysmorphology included elongated faces with narrow forehead, arched eyebrows, large mouth with down-turned corners, malformed teeth, and furrowed tongue. Both had Marfanoid habitus with lax joints, pectus excavatum, kyphoscoliosis, and flat narrow feet. The most likely diagnosis for these siblings is the autosomal recessive Cohen syndrome of mental retardation, congenital hypotonia with Marfanoid habitus, microcephaly, pleasant affect, micrognathia, and open mouth with prominent incisors. The sagittal sinus thrombosis, left frontal intracranial hemorrhage, carotid aneurysm, tortuous descending aorta, and deep venous thrombosis suffered by the male sibling adds the Cohen syndrome to genetic vasculopathies that may be associated with stroke.
 ...
PMID:Multiple coagulation defects and the Cohen syndrome. 806 42

The carbohydrate-deficient glycoprotein syndromes are a group of recently described autosomal recessive, metabolic defects affecting multiple systems. The disorder is caused by inefficient posttranslational glycosylation of glycoproteins. Patients with the syndrome present early in life with psychomotor retardation, seizures, hypotonia, and stroke-like episodes. They also have dysmorphic features including almond-shaped eyes, constant squint, inverted nipples, and buttock fat pads. One of the features of the syndrome is coagulopathy, and we report here a patient who presented with a prolonged activated partial thromboplastin time, and was subsequently diagnosed with the carbohydrate-deficient glycoprotein syndrome. We also summarize the results of five previously published studies of the coagulation system in these patients. Most of the reported patients are deficient in factor XI, protein C, antithrombin III, and protein S. Other coagulation proteins are less frequently affected. Both bleeding and thrombosis have been observed, yet the cause of the stroke-like episodes remains speculative. The carbohydrate-deficient glycoprotein syndrome is an increasingly recognized multisystem disorder affecting hemostasis, and thus will involve clinical hematologists as part of a multidisciplinary team caring for patients with the syndrome.
 ...
PMID:Coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome: case report and review of the literature. 988 8

Carbohydrate-deficient glycoprotein syndrome type 1 (CDGS-1) is an autosomal recessive hereditary metabolic disorder, the gene locus of which is chromosome 16p13. The disorder is characterised by genetic heterogeneity, and by decrease in the gene product, phosphomannomutase 2, though the heterogeneity is far less manifest in affected Swedish families. Its incidence is 1/80,000 live births, and the under-5 mortality rate over 30 per cent. The causes of death are liver failure, cardiac tamponade, haemorrhaging, and severe infection. The characteristic biochemical aberration is the occurrence of deficient carbohydrate chains in many but not all circulating glycoproteins, and the serum and blood concentrations of some glycoproteins may be above or below normal. These changes may improve over time, but never normalise. The clinical picture is generally more problematic during the first years of life when psychomotor retardation is complicated by failure to thrive, liver dysfunction, pericardial effusions, and stroke-like episodes. In addition, strabismus, lipocutaneous anomalies, and gluteal fat pads are always present, and muscular hypotonia and restricted joint mobility are common. Failure to thrive is common, with vomiting and diarrhoea and subsequent slow growth. Inflammation is a constant finding in the liver, and very common in the small bowel. Pancreatic function is also affected. Pericardial effusion has been reported in 50 per cent of the youngest children, requiring pericardectomy in 30 per cent of cases. Haemorrhaging and thromboembolic complications may occur, and the serum concentrations of several factors and inhibitors are low, particularly those of factors V and XI, protein C and antithrombin. Stroke-like episodes occur in about 30 per cent of cases, often following an infection, with coma lasting for hours to several days. Such sequelae as hemiplegia, blindness, and other focal neurological pathology have been observed transiently. Diagnosis is based on the serum carbohydrate-deficient transferrin level, verified by isoelectric focusing. Molecular genetic procedures enable point mutations to be identified and prenatal diagnosis to be performed in many families.
 ...
PMID:[CDGS-1--a recently discovered hereditary metabolic disease. Multiple organ manifestations, incidence 1/80,000, difficult to treat]. 988 93

We report on a 12-year-old female patient with mild dysmorphic signs, including bilateral epicanthal folds, low-set dysplastic ears, a short nose with anteverted nostrils, conically shaped fingers, generalised increase of subcutaneous fat, multiple fine venous teleangiectasia on her back, mild pectus carinatum, and a general muscular hypotonia. Cytogenetic analysis and fluorescence in situ hybridisation (FISH) studies using region-specific BAC and YAC clones indicated a de novo interstitial deletion of the long arm of chromosome 5, resulting in monosomy 5q21.1-q23.1. Molecular analysis of polymorphic markers helped to narrow down the breakpoints and demonstrated that the derivative chromosome 5 is of paternal origin. By using the same panel of polymorphic markers, a reinvestigation of a similar, already published, 5q deletion case [Raedle et al. (2001) Am J Gastroenterol 96:3016-3020] was performed, allowing a more detailed genotype-phenotype correlation. Phenotypic classification was also carried out. Several known genes, including APC and MCC, were found to map to the common deleted genomic segment. Genetic counselling based on the molecular analysis data was performed for the index family.
 ...
PMID:Phenotypic and molecular characterisation of a de novo 5q deletion that includes the APC gene. 1636 82

A small supernumerary marker chromosome (SMC) was observed in a girl with severe developmental delay. Her dysmorphism included prominent forehead, hypertelorism, down-slanting palpebral fissures, low-set/large ears, and flat nasal bridge with anteverted nares. This case also presented hypotonia, hypermobility of joints, congenital heart defect, umbilical hernia, failure to thrive, and seizures. The SMC originated from the distal region of Xp as identified by FISH with multiple DNA probes. Staining with antibodies to Centromere Protein C (CENP-C) demonstrated a neocentromere, while FISH with an alpha-satellite DNA probe showed no hybridization to the SMC. A karyotype was described as 47,XX,+neo(X)(pter-->p22.31::p22.31-->pter), indicating a partial tetrasomy of Xp22.31-->pter. This karyotype represents a functional trisomy for Xp22.31-->pter and a functional tetrasomy for the pseudoautosomal region given that there is no X-inactivation center in the marker chromosome. The SMC was further characterized by microarray-based comparative genomic hybridization (array CGH) as a duplicated DNA fragment of approximately 13 megabase pairs containing about 100 genes. We have described here a new neocentromere with discussion of its clinical significance.
 ...
PMID:Characterization of a neocentric supernumerary marker chromosome originating from the Xp distal region by FISH, CENP-C staining, and array CGH. 1726 94

Pregnancy is a normal physiological state that predisposes to thrombosis, determined by hormonal changes in the body. These changes occur in the blood flow (venous stasis), changes in the vascular wall (hypotonia, endothelial lesion) and changes in the coagulation factors (increased levels of factor VII, factor VIII, factor X, von Willebrand factor) and decreased activity levels of natural anticoagulants (protein C, protein S). In this study, we tried to determine a possible association between thrombosis and inherited thrombophilia in pregnant women. This is a retrospective study of 151 pregnant women with a history of complicated pregnancy: maternal thrombosis and placental vascular pathology (intrauterine growth restriction, preeclampsia, recurrent pregnancy loss), who were admitted in our hospital during the period January 2010 to July 2014. We performed genetic analyses to detect the factor V Leiden mutation, the G20210A mutation in the prothrombin gene, the C677T mutation and the A1298C mutation in methylenetetrahydrofolate reductase (MTHFR) gene. The risk of thrombosis in patients with factor V Leiden is 2.66 times higher than the patients negative for this mutation (OR 2.66 95% CI 0.96-7.37 P=0.059). We did not find any statistical association with mutations in the MTHFR gene. Pregnant women with a family history of thrombosis present a 2.18-fold higher risk of thrombosis (OR 2.18 CI 0.9-5.26 P=0.085). Of 151 pregnant women, thrombotic events occurred in 24 patients: deep vein thrombosis, pulmonary embolism, cerebral venous sinus thrombosis and ischemic stroke. The occurrence of thrombotic events was identified in the last trimester of pregnancy, but especially postpartum. Thrombosis in pregnancy is a redoubtable complication requiring an excellent cooperation between the obstetrician and anesthesiologist.
...
PMID:Hereditary Thrombophilia and thrombotic events in pregnancy: single-center experience. 2571 24

The Integrator complex subunit 1 (INTS1) is a component of the integrator complex that comprises 14 subunits and associates with RPB1 to catalyze endonucleolytic cleavage of nascent snRNAs and assist RNA polymerase II in promoter-proximal pause-release on protein-coding genes. We present five patients, including two sib pairs, with biallelic sequence variants in INTS1. The patients manifested absent or severely limited speech, an abnormal gait, hypotonia and cataracts. Exome sequencing revealed biallelic variants in INTS1 in all patients. One sib pair demonstrated a missense variant, p.(Arg77Cys), and a frameshift variant, p.(Arg1800Profs*20), another sib pair had a homozygous missense variant, p.(Pro1874Leu), and the fifth patient had a frameshift variant, p.(Leu1764Cysfs*16) and a missense variant, p.(Leu2164Pro). We also report additional clinical data on three previously described individuals with a homozygous, loss of function variant, p.(Ser1784*) in INTS1 that shared cognitive delays, cataracts and dysmorphic features with these patients. Several of the variants affected the protein C-terminus and preliminary modeling showed that the p.(Pro1874Leu) and p.(Leu2164Pro) variants may interfere with INTS1 helix folding. In view of the cataracts observed, we performed in-situ hybridization and demonstrated expression of ints1 in the zebrafish eye. We used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 to make larvae with biallelic insertion/deletion (indel) variants in ints1. The mutant larvae developed typically through gastrulation, but sections of the eye showed abnormal lens development. The distinctive phenotype associated with biallelic variants in INTS1 points to dysfunction of the integrator complex as a mechanism for intellectual disability, eye defects and craniofacial anomalies.
 ...
PMID:Biallelic sequence variants in INTS1 in patients with developmental delays, cataracts, and craniofacial anomalies. 3062 26