Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0026827 (hypotonia)
5,860 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have studied a male patient with significant developmental delay, growth failure, hypotonia, girdle weakness, microcephaly, and multiple congenital anomalies including atrial (ASD) and ventricular (VSD) septal defects. Detailed cytogenetic and molecular analyses revealed three de novo X chromosome aberrations and a karyotype 46,Y,der(X)inv(X) (p11.4q11.2)inv(X)(q11.2q21.32 approximately q22.2)del(X)(q22.3q22.3) was determined. The three X chromosome aberrations in the patient include: a pericentric inversion (inv 1) that disrupted the Duchenne muscular dystrophy (DMD) gene, dystrophin, at Xp11.4; an Xq11.2q21.32 approximately q22.2 paracentric inversion (inv 2) putatively affecting no genes; and an interstitial deletion at Xq22.3 that results in functional nullisomy of several known genes, including a gene previously associated with X-linked nonsyndromic mental retardation, acyl-CoA synthetase long chain family member 4 (ACSL4). These findings suggest that the disruption of DMD and the absence of ACSL4 in the patient are responsible for neuromuscular disease and cognitive impairment.
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PMID:Disruption of DMD and deletion of ACSL4 causing developmental delay, hypotonia, and multiple congenital anomalies. 1627 8

Lesch-Nyhan disease (LND) is a rare X-linked recessive genetic disorder caused by a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. The classic clinical condition is characterized by cognitive impairment, hypotonia at rest, choreoathetosis, hyperuricaemia and the hallmark symptom of severe and involuntary self-mutilation. We describe a man with LND who was initially thought to have suffered from a dyskinetic cerebral palsy after an uncomplicated inguinal herniorrhaphy under general anaesthesia at 5 1/2 months of age. In the absence of overt self-injurious behaviour, the diagnosis was not considered for nearly two decades. The diagnosis of LND was established at 20 years of age through clinical review, biochemical examinations and molecular analysis. HPRT haemolysate activity was 7.6% of the normal control, suggesting that he had a milder variant of the disease. Mutation analysis of the HPRT gene revealed a novel missense mutation, c.449T > G in exon 6 (p.V150G). Cascade testing of family members revealed that the mother was heterozygous for the mutation but two siblings (a brother and a sister) did not carry the sequence mutation. Whether the onset of neurological abnormalities in this particular case can be attributed to the general anaesthesia is discussed.
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PMID:Lesch-Nyhan disease in a 20-year- old man incorrectly described as developing 'cerebral palsy' after general anaesthesia in infancy. 1682 47

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis. We report a patient who presented at 10 months of age with hypotonia and global developmental delay. Subsequently, she developed seizures and choreoathetosis. Magnetic resonance imaging showed high signal bilaterally in the globus pallidus on T2-weighted images. Mitochondrial respiratory chain studies revealed low complex I activity (in muscle 0.052 nmol NADH oxidized per min per unit citrate synthase, controls 0.166 +/- 0.047; in fibroblasts 0.080 nmol NADH oxidized per min per unit citrate synthase, controls 0.197 +/- 0.034). The true diagnosis was suspected at 21 months of age because of persistent low plasma and urine creatinine concentrations. GAMT activity was undetectable in fibroblasts and compound heterozygous mutations were found in the GAMT gene (c.327G>A and c.522G>A). The patient was treated with creatine, dietary arginine restriction and ornithine supplements. Her movement disorder and seizures resolved but she still has severe cognitive impairment and no expressive language. The occurrence of secondary respiratory chain abnormalities in GAMT deficiency may lead to misdiagnosis, particularly as the clinical and radiological features resemble those seen in mitochondrial encephalopathies. It is important to establish the correct diagnosis because specific treatment is available.
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PMID:Guanidinoacetate methyltransferase deficiency masquerading as a mitochondrial encephalopathy. 1717 76

Prader-Willi syndrome is a rare genetic disorder, affecting 1 out of 25,000 births, in which a critical region of chromosome 15, the 15q11-q13 region, is affected. At birth, PWS infants exhibit severe hypotonia that partially improves, explaining in part suckling and swallowing troubles and the delay in psychomotor development. Characteristic facial features (dysmorphic syndrome) and very small hands and feet are frequently observed at this age. After this initial phase, the most striking signs appear: hyperphagia and absence of satiety often leading to severe obesity in affected children as young as two years. The situation may deteriorate quickly without adequate outside controls and explains in great part the morbidity and mortality of these patients. Other endocrine abnormalities in association with the hypothalamic-pituitary abnormalities contribute to the clinical picture of short stature due to a growth hormone deficiency and incomplete pubertal development. The degree of cognitive dysfunction varies widely from one child to another. It is associated with learning disabilities and impaired speech and language development worsened by psychological and behavioural troubles. The expert consensus is that diagnosis should be based on clinical criteria (Holm's criteria of 1993, revised in 2001) with confirmation by genetic study. Most cases are sporadic and familial cases are rare, those informations should be given as genetic counselling. It is necessary to set up a global and multidisciplinary management. Early diagnosis, early multidisciplinary care and growth hormone treatment have greatly improved the quality of life of these children. We have no long-term data on the effect of GH treatment in adults, on behavioural troubles and autonomy of the persons. In adults, complications particularly linked to obesity and problems of autonomy are still very important.
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PMID:[The Prader-Willi syndrome]. 1749 72

Thyroid hormone is essential for the proper development and function of the brain. The active form of thyroid hormone is T(3), which binds to nuclear receptors. Recently, a transporter specific for T(3), MCT8 (monocarboxylate transporter 8) was identified. MCT8 is highly expressed in liver and brain. The gene is located in Xq13 and mutations in MCT8 are responsible for an X-linked condition, Allan-Herndon-Dudley syndrome (AHDS). This syndrome is characterized by congenital hypotonia that progresses to spasticity with severe psychomotor delays. Affected males also present with muscle hypoplasia, generalized muscle weakness, and limited speech. Importantly, these patients have elevated serum levels of free T(3), low to below normal serum levels of free T(4), and levels of thyroid stimulating hormone that are within the normal range. This constellation of measurements of thyroid function enables quick screening for AHDS in males presenting with cognitive impairment, congenital hypotonia, and generalized muscle weakness.
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PMID:The MCT8 thyroid hormone transporter and Allan-Herndon-Dudley syndrome. 1757 10

Prader-Willi syndrome (PWS) is the leading genetic cause of obesity. After initial severe hypotonia, PWS children become hyperphagic and morbidly obese, if intake is not restricted. Short stature with abnormal growth hormone secretion, hypogonadism, cognitive impairment, anxiety and behavior problems are other features. PWS is caused by lack of expression of imprinted genes in a approximately 4 mb region of chromosome band 15q11.2. Our previous translocation studies predicted a major role for the C/D box small nucleolar RNA cluster SNORD116 (PWCR1/HBII-85) in PWS. To test this hypothesis, we created a approximately 150 kb deletion of the > 40 copies of Snord116 (Pwcr1/MBII-85) in C57BL/6 mice. Snord116del mice with paternally derived deletion lack expression of this snoRNA. They have early-onset postnatal growth deficiency, but normal fertility and lifespan. While pituitary structure and somatotrophs are normal, liver Igf1 mRNA is decreased. In cognitive and behavior tests, Snord116del mice are deficient in motor learning and have increased anxiety. Around three months of age, they develop hyperphagia, but stay lean on regular and high-fat diet. On reduced caloric intake, Snord116del mice maintain their weight better than wild-type littermates, excluding increased energy requirement as a cause of hyperphagia. Normal compensatory feeding after fasting, and ability to maintain body temperature in the cold indicate normal energy homeostasis regulation. Metabolic chamber studies reveal that Snord116del mice maintain energy homeostasis by altered fuel usage. Prolonged mealtime and increased circulating ghrelin indicate a defect in meal termination mechanism. Snord116del mice, the first snoRNA deletion animal model, reveal a novel role for a non-coding RNA in growth and feeding regulation.
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PMID:SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice. 1832 30

In a previous publication we observed aberrant levels of the human reduced folate carrier (hRFC) in cortex from fetal Down syndrome (DS) subjects. Immunoreactivity for hRFC was increased as the only chromosome 21 gene product studied. We, therefore, analyzed mice transgenic for hRFC (TghRFC1) and wild-type (WT) mice for cognitive functions, behavior and in an observational neurological battery (FOB). Cognitive functions were evaluated by the Morris water maze (MWM), the open field (OF) was used for exploratory behavior, locomotor activity and anxiety-related behavior. The elevated plus maze (EPM) was used to confirm findings in the OF testing anxiety-related behavior and the rota rod (RR) to evaluate motor function. In the MWM TghRFC1 mice performed significantly worse (P < 0.0003) on the probe trial than WT mice. In the FOB visual placing was significantly reduced inTghRFC1 mice. In the OF TghRFC1 mice crossed twice as often (P < 0.029) and in the EPM individuals from this group showed a reduced number of exits from the closed arm (P < 0.044) compared to WT mice. TghRFC1 mice showed impaired performance on the RR, spending one-fourth of the time of WT on the revolving rod (P < 0.0003). Cognitive impairment is an obligatory symptom of DS and this deficiency corresponds to findings in the MWM of mice transgenic for hRFC. Findings of visual placing and failure on the RR may reflect impaired motor performance including muscular hypotonia in DS subjects. Increased crossings in the OF may indicate modulated anxiety-related behavior observed in patients with DS.
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PMID:Mice transgenic for reduced folate carrier: an animal model of Down syndrome? 1841 76

Prader-Willi syndrome (PWS) is characterized by hypotonia, hypogonadism, obesity, and short stature. Neurobehavioral abnormalities, cognitive impairment, and sleep-related breathing disorders (SRBD) are common. In the general population associations between neurobehavioral and cognitive abnormalities and SRBD have been found. We investigated cognition, behavior, and SRBD in children with PWS. Thirty-one pre-pubertal PWS children were evaluated (5 with paternal deletion, 14 with maternal disomy, 4 with imprinting-center mutation, and in 8 the defect was not specified). Cognition was assessed by Wechsler scale subtests, and behavior by parent-questionnaires. Polysomnography was performed. Cognition, behavior, and associations with SRBD were evaluated. All cognitive subtests were significantly below O SDS, with the lowest median (interquartile range) scores for the Block design subtest (-2.7 SDS (-3.0 to -0.3)). In 60%, verbal subtests were less affected than performance subtests. Parents reported problem behavior related to "emotions/behavior not adapted to the social situation" and "insensitivity to social information." All children had SRBD, with an Apnea Hypopnea Index of 4.1/hr (2.6-7.9). One performance subtest score was significantly higher in children with better sleep efficiency, and daytime sleepiness was associated with more autistic-like social impairment. In contrast to our expectations, behavior was worse in children with better sleep-related breathing. In pre-pubertal PWS children, cognition is impaired. Neurobehavioral abnormalities are common, particularly autistic-like social impairment. Sleep efficiency was associated with better performance on one of the performance subtests, and neurobehavioral abnormalities were associated with daytime sleepiness. In contrast, we could not confirm a positive association of neurobehavioral abnormalities with SRBD in PWS.
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PMID:Cognition and behavior in pre-pubertal children with Prader-Willi syndrome and associations with sleep-related breathing disorders. 1900 9

Extra structurally abnormal chromosomes (ESACs) derived from the X chromosome are rare. We report a non-mosaic ESAC derived from the X chromosome in a 3-year-old female who presented with early hypotonia, developmental delay, hypertelorism, low set ears, and small hands and feet. The breakpoints of the ESAC were mapped by SNP microarray to Xp11.1-p11.22, a region encompassing 7.17 Mb and containing 110 known or putative genes and excluding the X-inactivation center. A review of other reported patients with karyotypes that cause functional disomy of proximal Xp allows delineation of a common phenotype comprising early hypotonia, cognitive impairment, hypertelorism, myopia, small hands and feet and abnormal external ears.
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PMID:Functional disomy of proximal Xp causes a distinct phenotype comprising early hypotonia, hypertelorism, small hands and feet, ear abnormalities, myopia and cognitive impairment. 1961 86

This report describes a 4 year-old girl with history of hypotonia, developmental delay, and failure to thrive in infancy. She has cognitive impairment and multiple congenital anomalies, including Duane anomaly, Mondini malformation with associated deafness, external ear malformations, and atrial and ventricular septal defects. Array comparative genomic hybridization demonstrated a de novo tandem 6.9 Mb duplication of at least 15 genes in chromosome 8q12, inclusive of CHD7, with breakpoints at 58,388,614 bp and 65,306,097 bp (NCBI build 36.1). Loss of CHD7 by microdeletion or intragenic mutation causes CHARGE syndrome. There is one previous report of an individual with microduplication of 8q12 involving CHD7. He also had early hypotonia, cognitive impairment, Duane anomaly, sensorineural deafness and a congenital heart defect. This rather specific recurrent pattern of congenital anomalies associated with overlapping duplications of the genomic region containing CHD7 suggests that the phenotype in these two patients may be the result of abnormal CHD7 dosage.
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PMID:A characteristic syndrome associated with microduplication of 8q12, inclusive of CHD7. 1977 54


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