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Antithrombin III deficiency(AT3D)

MedGen UID:
75781
Concept ID:
C0272375
Disease or Syndrome
Synonyms: AT3D; Thrombophilia due to antithrombin III deficiency
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
Autosomal dominant inheritance (HPO, OMIM, Orphanet)
SNOMED CT: AT deficiency - Antithrombin deficiency (36351005); Antithrombin deficiency (36351005); Antithrombin 3 deficiency (36351005); Antithrombin III deficiency (36351005)
 
Gene (location): SERPINC1 (1q25.1)
OMIM®: 613118
HPO: HP:0001976
Orphanet: ORPHA82

Definition

Deficiency of antithrombin III is a major risk factor for venous thromboembolic disease. Two categories of AT-III deficiency have been defined on the basis of AT-III antigen levels in the plasma of affected individuals. The majority of AT-III deficiency families belong in the type I (classic) deficiency group and have a quantitatively abnormal phenotype in which antigen and heparin cofactor levels are both reduced to about 50% of normal. The second category of AT-III deficiency has been termed type II (functional) deficiency. Affected individuals from these kindreds produce dysfunctional AT-III molecules; they have reduced heparin cofactor activity levels (about 50% of normal) but levels of AT-III antigen are often normal or nearly normal (summary by Bock and Prochownik, 1987). The 2 categories of antithrombmin III deficiency have been classified further. Type I (low functional and immunologic antithrombin) has been subdivided into subtype Ia (reduced levels of normal antithrombin), and type Ib (reduced levels of antithrombin and the presence of low levels of a variant). Type II (low functional but normal immunologic antithrombin) has been subdivided into subtype IIa (functional abnormalities affecting both the reactive site and the heparin-binding site of AT3); subtype IIb (functional abnormalities limited to the reactive site); and subtype IIc (functional abnormalities limited to the heparin-binding site) (summary by Lane et al., 1992). [from OMIM]

Additional description

From GHR
Hereditary antithrombin deficiency is a disorder of blood clotting. People with this condition are at higher than average risk for developing abnormal blood clots, particularly a type of clot that occurs in the deep veins of the legs. This type of clot is called a deep vein thrombosis (DVT). Affected individuals also have an increased risk of developing a pulmonary embolism (PE), which is a clot that travels through the bloodstream and lodges in the lungs. In hereditary antithrombin deficiency, abnormal blood clots usually form only in veins, although they may rarely occur in arteries.About half of people with hereditary antithrombin deficiency will develop at least one abnormal blood clot during their lifetime. These clots usually develop after adolescence.Other factors can increase the risk of abnormal blood clots in people with hereditary antithrombin deficiency. These factors include increasing age, surgery, or immobility. The combination of hereditary antithrombin deficiency and other inherited disorders of blood clotting can also influence risk. Women with hereditary antithrombin deficiency are at increased risk of developing an abnormal blood clot during pregnancy or soon after delivery. They also may have an increased risk for pregnancy loss (miscarriage) or stillbirth.  https://ghr.nlm.nih.gov/condition/hereditary-antithrombin-deficiency

Clinical features

Pulmonary embolism
MedGen UID:
11027
Concept ID:
C0034065
Disease or Syndrome
An embolus (that is, an abnormal particle circulating in the blood) located in the pulmonary artery and thereby blocking blood circulation to the lung. Usually the embolus is a blood clot that has developed in an extremity (for instance, a deep venous thrombosis), detached, and traveled through the circulation before becoming trapped in the pulmonary artery.
Deep venous thrombosis
MedGen UID:
57448
Concept ID:
C0149871
Disease or Syndrome
A blood clot in a deep vein, predominantly in the lower extremity, but may include the pelvis or upper extremity.(NICHD)
Cerebral venous thrombosis
MedGen UID:
57743
Concept ID:
C0151945
Disease or Syndrome
Formation of a blood clot (thrombus) inside a cerebral vein, causing the obstruction of blood flow.
Antithrombin III deficiency
MedGen UID:
75781
Concept ID:
C0272375
Disease or Syndrome
Deficiency of antithrombin III is a major risk factor for venous thromboembolic disease. Two categories of AT-III deficiency have been defined on the basis of AT-III antigen levels in the plasma of affected individuals. The majority of AT-III deficiency families belong in the type I (classic) deficiency group and have a quantitatively abnormal phenotype in which antigen and heparin cofactor levels are both reduced to about 50% of normal. The second category of AT-III deficiency has been termed type II (functional) deficiency. Affected individuals from these kindreds produce dysfunctional AT-III molecules; they have reduced heparin cofactor activity levels (about 50% of normal) but levels of AT-III antigen are often normal or nearly normal (summary by Bock and Prochownik, 1987). The 2 categories of antithrombmin III deficiency have been classified further. Type I (low functional and immunologic antithrombin) has been subdivided into subtype Ia (reduced levels of normal antithrombin), and type Ib (reduced levels of antithrombin and the presence of low levels of a variant). Type II (low functional but normal immunologic antithrombin) has been subdivided into subtype IIa (functional abnormalities affecting both the reactive site and the heparin-binding site of AT3); subtype IIb (functional abnormalities limited to the reactive site); and subtype IIc (functional abnormalities limited to the heparin-binding site) (summary by Lane et al., 1992).
Recurrent thrombophlebitis
MedGen UID:
763064
Concept ID:
C3550150
Finding
Repeated episodes of inflammation of a vein associated with venous thrombosis (blood clot formation within the vein).

Conditions with this feature

Antithrombin III deficiency
MedGen UID:
75781
Concept ID:
C0272375
Disease or Syndrome
Deficiency of antithrombin III is a major risk factor for venous thromboembolic disease. Two categories of AT-III deficiency have been defined on the basis of AT-III antigen levels in the plasma of affected individuals. The majority of AT-III deficiency families belong in the type I (classic) deficiency group and have a quantitatively abnormal phenotype in which antigen and heparin cofactor levels are both reduced to about 50% of normal. The second category of AT-III deficiency has been termed type II (functional) deficiency. Affected individuals from these kindreds produce dysfunctional AT-III molecules; they have reduced heparin cofactor activity levels (about 50% of normal) but levels of AT-III antigen are often normal or nearly normal (summary by Bock and Prochownik, 1987). The 2 categories of antithrombmin III deficiency have been classified further. Type I (low functional and immunologic antithrombin) has been subdivided into subtype Ia (reduced levels of normal antithrombin), and type Ib (reduced levels of antithrombin and the presence of low levels of a variant). Type II (low functional but normal immunologic antithrombin) has been subdivided into subtype IIa (functional abnormalities affecting both the reactive site and the heparin-binding site of AT3); subtype IIb (functional abnormalities limited to the reactive site); and subtype IIc (functional abnormalities limited to the heparin-binding site) (summary by Lane et al., 1992).
Carbohydrate-deficient glycoprotein syndrome type I
MedGen UID:
138111
Concept ID:
C0349653
Disease or Syndrome
PMM2-CDG (CDG-Ia) (previously known as congenital disorder of glycosylation type 1a), the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three types: infantile multisystem, late-infantile and childhood ataxia-intellectual disability, and adult stable disability. The three types notwithstanding, clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. Clinical presentations tend to be similar in sibs. In the infantile multisystem type, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, failure to thrive, and impaired growth are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical presentations are observed: (1) a non-fatal neurologic form with strabismus, psychomotor retardation, and cerebellar hypoplasia in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade and (2) a neurologic-multivisceral form with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia-intellectual disability type, with onset between age three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability type, intellectual ability is stable; peripheral neuropathy is variable, thoracic and spinal deformities progress, and premature aging is observed; females lack secondary sexual development and males may exhibit decreased testicular volume. Hyperglycemia-induced growth hormone release, hyperprolactinemia, insulin resistance, and coagulopathy may occur. An increased risk for deep venous thrombosis is present.
Congenital disorder of glycosylation type 1E
MedGen UID:
324784
Concept ID:
C1837396
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin. For a general discussion of CDGs, see CDG Ia (212065) and CDG Ib (602579).
Congenital disorder of glycosylation type 1B
MedGen UID:
400692
Concept ID:
C1865145
Disease or Syndrome
Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the synthesis and processing of asparagine (N)-linked glycans or oligosaccharides on glycoproteins. Type I CDGs comprise defects in the assembly of the dolichol lipid-linked oligosaccharide (LLO) chain and its transfer to the nascent protein. These disorders can be identified by a characteristic abnormal isoelectric focusing profile of plasma transferrin (Leroy, 2006). For a discussion of the classification of CDGs, see CDG1A (212065). CDG Ib is clinically distinct from most other CDGs by the lack of significant central nervous system involvement. The predominant symptoms are chronic diarrhea with failure to thrive and protein-losing enteropathy with coagulopathy. Some patients develop hepatic fibrosis. CDG Ib is also different from other CDGs in that it can be treated effectively with oral mannose supplementation, but can be fatal if untreated (Marquardt and Denecke, 2003). Thus, CDG Ib should be considered in the differential diagnosis of patients with unexplained hypoglycemia, chronic diarrhea, liver disease, or coagulopathy in order to allow early diagnosis and effective therapy (Vuillaumier-Barrot et al., 2002) Freeze and Aebi (1999) reviewed CDG Ib and CDG Ic (603147). Marques-da-Silva et al. (2017) systematically reviewed the literature concerning liver involvement in CDG.
Congenital disorder of glycosylation type 1C
MedGen UID:
443952
Concept ID:
C2930997
Disease or Syndrome
Congenital disorders of glycosylation, previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are caused by defects in mannose addition during N-linked oligosaccharide assembly. CDGs can be divided into 2 types, depending on whether they impair lipid-linked oligosaccharide (LLO) assembly and transfer (CDG I), or affect trimming of the protein-bound oligosaccharide or the addition of sugars to it (CDG II) (Orlean, 2000). CDG Ic is characterized by psychomotor retardation with delayed walking and speech, hypotonia, seizures, and sometimes protein-losing enteropathy. It is the second largest subtype of CDG (summary by Sun et al., 2005). For a discussion of the classification of CDGs, see CDG1A (212065). Freeze and Aebi (1999) reviewed CDG Ib (602579) and CDG Ic.
Congenital disorder of glycosylation type 1Q
MedGen UID:
461541
Concept ID:
C3150191
Disease or Syndrome

Professional guidelines

PubMed

Pinette MG, Wax JR
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Recent clinical studies

Etiology

Muscianese L, Seese RR, Graham W, Williams JH
BMJ Case Rep 2015 Jan 27;2015 doi: 10.1136/bcr-2014-205729. PMID: 25628315Free PMC Article
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Diagnosis

Bhakuni T, Sharma A, Rashid Q, Kapil C, Saxena R, Mahapatra M, Jairajpuri MA
PLoS One 2015;10(3):e0121889. Epub 2015 Mar 26 doi: 10.1371/journal.pone.0121889. PMID: 25811371Free PMC Article
Muscianese L, Seese RR, Graham W, Williams JH
BMJ Case Rep 2015 Jan 27;2015 doi: 10.1136/bcr-2014-205729. PMID: 25628315Free PMC Article
Wang YQ, Chen QL, Zhu D, Dong L
J Cardiothorac Surg 2014 Apr 28;9:73. doi: 10.1186/1749-8090-9-73. PMID: 24775062Free PMC Article
Hattori T, Hata M, Sezai A, Wakui S, Shiono M
Ann Thorac Cardiovasc Surg 2013;19(4):323-5. Epub 2012 Nov 15 PMID: 23232305
Tu CM, Hsueg CH, Chu KM, Cheng SM, Tsao TP
Am J Emerg Med 2009 Nov;27(9):1169.e3-6. doi: 10.1016/j.ajem.2008.12.006. PMID: 19931780

Therapy

Kawano H, Maemura K
Intern Med 2016;55(22):3285-3289. Epub 2016 Nov 15 doi: 10.2169/internalmedicine.55.7314. PMID: 27853070Free PMC Article
Wang YQ, Chen QL, Zhu D, Dong L
J Cardiothorac Surg 2014 Apr 28;9:73. doi: 10.1186/1749-8090-9-73. PMID: 24775062Free PMC Article
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Prognosis

Wang YQ, Chen QL, Zhu D, Dong L
J Cardiothorac Surg 2014 Apr 28;9:73. doi: 10.1186/1749-8090-9-73. PMID: 24775062Free PMC Article
Binnetoğlu FK, Babaoğlu K, Sarper N, Bek K
Turk Kardiyol Dern Ars 2013 Oct;41(7):642-5. PMID: 24164998
Hattori T, Hata M, Sezai A, Wakui S, Shiono M
Ann Thorac Cardiovasc Surg 2013;19(4):323-5. Epub 2012 Nov 15 PMID: 23232305
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Am J Emerg Med 2009 Nov;27(9):1169.e3-6. doi: 10.1016/j.ajem.2008.12.006. PMID: 19931780
Anand M, Rajagopal K, Rajagopal KR
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Clinical prediction guides

Lee SY, Kim EK, Kim MS, Shin SH, Chang H, Jang SY, Kim HJ, Kim DK
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J Theor Biol 2008 Aug 21;253(4):725-38. Epub 2008 Apr 25 doi: 10.1016/j.jtbi.2008.04.015. PMID: 18539301
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Recent systematic reviews

Bauer KA, Nguyen-Cao TM, Spears JB
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