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)

The Northwest Regional Screening Program to detect congenital hypothyroidism in infants born in Oregon, Montana, Alaska, and Idaho (combined birthrate of 69,000/ yr) was added to our ongoing screening program in 1975. The program utilizes dried blood filter paper specimens collected routinely in the first few days of life in all four states and again at about 6 weeks of age in Oregon only. The screening test consist of an initial thyroxine (T4) measurement; a thyroid-stimulating hormore (TSH) determination is performed on those specimens with T4 concentrations in the lowest 3% group. Serum samples obtained by venipuncture are requested for confirmation of the diagnosis. In the first two years of the program, 25 infants with primary hypothyroidism were detected amont 110,667 infants screened, a frequency of 1:4,430. Fourteen cases of thyroxine-binding globulin deficiency were also detected, a frequency of 1:7,900. Using the T4 followed by TSH testing approach, the frequency of request for repeat specimens was 0.4% in Oregon and 0.05% in the other states. The cost per specimen was $1.96. The majority of infants lacked clinical signs or symptoms of hypothyroidism; only one infant was clinically suspected of having hypothyroidism prior to detection. The most common neonatal symptoms were constipation, lethargy, and prolonged jaundice, while the most common physical signs were hypotonia, umbilical hernia, and large fontanels. Thyroid scans showed the most common etiology to be thyroid aplasia, followed by an ectopic gland, hypoplasia, and goiter. Serum T4 concentrations were lowest in those infants with aplasia, intermediate in infants with an ectopic gland or hypoplasia, and normal in the infant with the goiter. Neonatal hypothyroidism varies in degree and has several different causes; the capacity to secrete thyroid hormone, the duration before hypothyroidism becomes clinically manifest, and possibly the eventual prognosis for intellectual function depend on the nature of the underlying cause. While the mean age at treatment was 59 days, the goal of diagnosing congenital hypothyroidism and treating affected infants by 1 month of age seems realistic.
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PMID:Neonatal hypothyroidism detected by the Northwest Regional Screening Program. 10 59

Resistance to thyroid hormone (RTH) is a syndrome in which patients have elevated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-old female presented to the NIH with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain magnetic resonance imaging showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T3 and free T4 levels of more than 2000 pg/dl (normal, 230-420 pg/dl) and more than 64 pmol/liter (normal, 10.3-20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6-6.3 mU/liter). These are the highest TH levels reported for a heterozygous RTH patient. A T3 stimulation test confirmed the diagnosis of RTH in the pituitary and peripheral tissues. Molecular analyses of the patient's genomic DNA by PCR identified a single base deletion in exon 10 of her TRbeta gene that resulted in a frameshift and early stop codon. This, in turn, encoded a truncated receptor that lacked the last 20 amino acids. Cotransfection studies showed that the mutant TR was transcriptionally inactive even in the presence of 10(-6) M T3 and had strong dominant negative activity over the wild-type receptor. It is likely that the severely defective TRbeta mutant contributed to the extreme RTH phenotype and resistance in our patient.
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PMID:Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant. 1170 67

The occurrence of neurological symptoms and developmental delay in patients affected by congenital hypothyroidism (CH) has been attributed to the lack of thyroid hormone in the developing CNS. Accordingly, after the introduction of neonatal screening programs for CH, which allowed early and adequate treatment, an almost normal outcome for most CH patients could be achieved. However, a few patients did not reach this favorable outcome despite early and adequate treatment. Here we describe five patients with variable degrees of CH who suffered from choreoathetosis, muscular hypotonia, and pulmonary problems, an association of symptoms that had not been described before this study. Since this clinical picture matched the phenotype of mice targeted for deletion of the transcription factor gene Nkx2-1, we investigated the human NKX2-1 gene in these five patients. We found heterozygous loss of function mutations in each of these five patients, e.g., one complete gene deletion, one missense mutation (G2626T), and three nonsense mutations (2595insGG, C2519A, C1302A). Therefore, the unfavorable outcome in patients with CH, especially those with choreoathetosis and pulmonary symptoms, can be explained by mutations in the NKX2-1 gene rather than by hypothyroidism. Moreover, the association of symptoms in the patients with NKX2-1 mutations points to an important role of human NKX2-1 in the development and function of thyroid, basal ganglia, and lung, as already described for rodents.
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PMID:Choreoathetosis, hypothyroidism, and pulmonary alterations due to human NKX2-1 haploinsufficiency. 1185 16

In Japan, mass screening tests on newborns for Cretinism have been performed since 1984, Cretinism is a very rare condition. We report the clinical course and complications of longitudinal thyroid hormone replacement therapy (liothyronine sodium: T3) of two women with Cretinism and ectopic thyroid gland for the past 33 years until 2001. They were born in April 1951 (Case 1) and in January 1952 (Case 2). On admission in June 1968, they were 17 and 16 years old. They had short stature, mental retardation, macroglossia, saddle nose, retardation of bone maturation, edematous face, coexistence of permanent teeth and deciduous teeth, abdominal distention, hypotonia, anemia, hypophosphatemia and hypercholesterolemia. After admission, Case 2 had an appendectomy for appendicitis. She was found to have a right ovarian cyst, but was not operated upon. Later, the right ovarian cyst disappeared during thyroid hormone replacement therapy. The complication in this case was NIDDM. Over secretion of thyroid hormone in for example, hyperthyroidism sometimes induces NIDDM. On their admission, a levothyroxine sodium (T4: Thyradin S) was unavailable in Japan, so we had no choice but to treat them with liothyronine sodium for thyroid hormone replacement therapy. We suspect that liothyronine sodium replacement therapy probably induced NIDDM. They experienced improved bone maturation, anemia, hypophsphatemia and hypercholesterolemia, but their intellectual and mental disabilities were not improved.
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PMID:The longitudinal course of two cases with cretinism diagnosed after adolescence. 1280 80

Thyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613-amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter.
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PMID:A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. 1466 Nov 63

This paper will suggest that the Down syndrome phenotype would have been well suited, physiologically, for a deprived environment and that it may represent a predictive, adaptive response to severe maternal deprivation. A trisomy of the 21st chromosome, prior to, or at conception is responsible for Down syndrome and is known to increase in incidence with advanced maternal age. One out of 11 mothers over the age of 50 conceives a Down syndrome baby, compared to one in one thousand at age 30. This article emphasizes that an older mother is more likely to die before she is able to provide the parental investment necessary to produce an ecologically self-sufficient offspring. Prolonged maternal investment is known to be essential for hunter-gatherers to master the skill intensive food procurement techniques that they will need in order to become independent of their mothers. Because Down syndrome individuals are much more likely to be born to older mothers, they must have been routinely deprived of maternal investment in the human environment of evolutionary adaptedness. This consistent paring of maternal deprivation to trisomy 21 conceptions, over time, may have caused natural selection to favor genes responsible for the energy conserving traits seen in modern day Down syndrome. These traits include muscle hypotonia, decreased cerebral metabolism, decreased hippocampal volume, a strong propensity for obesity and growth hormone and thyroid hormone paucity. Such a "thrifty phenotype" may have allowed Down syndrome individuals to become independent of their mothers at a far earlier age and allowed them to forgo the skill intensive ecological niche that non-trisomic humans are phenotypically suited for in order to take up a less cognitively and physically rigorous one.
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PMID:Evolutionary neuropathology and Down syndrome: an analysis of the etiological and phenotypical characteristics of Down syndrome suggests that it may represent an adaptive response to severe maternal deprivation. 1673 81

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

Monocarboxylate transporter 8 acts as a specific cell membrane transporter for thyroxine and especially triiodothyronine into target cells. It is expressed in brain neurons and in many other tissues. The monocarboxylate transporter 8 gene resides on chromosome Xq13.2. An 11-month-old male infant was referred because of severe hypotonia from early life and global developmental delay. Thyroid-function tests showed normal thyrotropin levels and the characteristic for the disorder, including high serum triiodothyronine and low thyroxine concentrations. Molecular analysis of the monocarboxylate transporter 8 gene showed that the patient was hemizygous for a novel missense mutation P537L. This case highlights the importance of determining thyroid hormone levels, especially triiodothyronine, in infants with severe neonatal hypotonia.
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PMID:A novel monocarboxylate transporter 8 gene mutation as a cause of severe neonatal hypotonia and developmental delay. 1816 39

The Allan-Herndon-Dudley syndrome (AHDS;MIM 300523) of X-linked mental retardation and hypotonia is caused by mutations in a thyroid hormone transporter gene--the monocarboxylate transporter 8 (MCT8 also known as SLC16A2) gene. A 23-month-old boy with severe developmental delay, hypotonia, recurrent emesis, and irritability is described. He was diagnosed with hypothyroidism at the age of 4 months. However, T3 level was elevated. Molecular analysis of the MCT8 gene detected a single base duplication in exon 5 c.1614dupC (p.Ile539fs), consistent with a diagnosis of AHDS. While T3 is the best marker for this disorder, elevations in TSH should alert to the diagnosis.
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PMID:Elevated TSH levels in a mentally retarded boy. 1993 87

Congenital hypothyroidism (CH) occurs in approximately 1:2,000 to 1:4,000 newborns. The clinical manifestations are often subtle or not present at birth. This likely is due to trans-placental passage of some maternal thyroid hormone, while many infants have some thyroid production of their own. Common symptoms include decreased activity and increased sleep, feeding difficulty, constipation, and prolonged jaundice. On examination, common signs include myxedematous facies, large fontanels, macroglossia, a distended abdomen with umbilical hernia, and hypotonia. CH is classified into permanent and transient forms, which in turn can be divided into primary, secondary, or peripheral etiologies. Thyroid dysgenesis accounts for 85% of permanent, primary CH, while inborn errors of thyroid hormone biosynthesis (dyshormonogeneses) account for 10-15% of cases. Secondary or central CH may occur with isolated TSH deficiency, but more commonly it is associated with congenital hypopitiutarism. Transient CH most commonly occurs in preterm infants born in areas of endemic iodine deficiency. In countries with newborn screening programs in place, infants with CH are diagnosed after detection by screening tests. The diagnosis should be confirmed by finding an elevated serum TSH and low T4 or free T4 level. Other diagnostic tests, such as thyroid radionuclide uptake and scan, thyroid sonography, or serum thyroglobulin determination may help pinpoint the underlying etiology, although treatment may be started without these tests. Levothyroxine is the treatment of choice; the recommended starting dose is 10 to 15 mcg/kg/day. The immediate goals of treatment are to rapidly raise the serum T4 above 130 nmol/L (10 ug/dL) and normalize serum TSH levels. Frequent laboratory monitoring in infancy is essential to ensure optimal neurocognitive outcome. Serum TSH and free T4 should be measured every 1-2 months in the first 6 months of life and every 3-4 months thereafter. In general, the prognosis of infants detected by screening and started on treatment early is excellent, with IQs similar to sibling or classmate controls. Studies show that a lower neurocognitive outcome may occur in those infants started at a later age (> 30 days of age), on lower l-thyroxine doses than currently recommended, and in those infants with more severe hypothyroidism.
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PMID:Congenital hypothyroidism. 2053 82


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