Cardiodysrhythmic potassium-sensitive periodic paralysis
General Information (adopted from Orphanet):
Synonyms, Signs: |
PERIODIC PARALYSIS, POTASSIUM-SENSITIVE CARDIODYSRHYTHMIC TYPE LONG QT SYNDROME 7 LQT7 ATS Andersen syndrome QT long syndrome type 7 Long QT syndrome 7 Andersen cardiodysrhythmic periodic paralysis Andersen-tawil syndrome |
Number of Symptoms | 85 |
OrphanetNr: | 37553 |
OMIM Id: |
170390
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ICD-10: |
G72.3 |
UMLs: |
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MeSH: |
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MedDRA: |
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Snomed: |
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Prevalence, inheritance and age of onset:
Prevalence: | 0.1 of 100 000 - PMID: 24383070 [IBIS] |
Inheritance: |
Autosomal dominant - PMID: 15911703 [IBIS] |
Age of onset: |
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Disease classification (adopted from Orphanet):
Parent Diseases: |
Genetic cardiac rhythm disease
-Rare cardiac disease -Rare genetic disease Genetic muscular channelopathy -Rare genetic disease Genetic periodic paralysis -Rare genetic disease -Rare neurologic disease Muscular channelopathy -Rare neurologic disease Periodic paralysis -Rare genetic disease -Rare neurologic disease |
Comment:
Cardiodysrhythmic potassium-sensitive periodic paralysis (Andersen-Tawil syndrome) is a sub-type of familial long QT syndrome. Patients with mutations in the KCNJ2 gene are designated as ATS type 1 (LQT7), whereas patients with unknown mutations are designated as ATS type 2 (PMID:24383070). Recently, a mutation in KCNJ5 has been described (PMID:24574546). It is characterized by cardiac arrhythima, muscle weakness (periodic paralysis) and craniofacial and skeletal anomalies (PMID:20301308). |
Symptom Information:
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(HPO:0000316) | Hypertelorism | Frequent [IBIS] | 36% (n=36) | 12163457 | IBIS | 644 / 7739 |
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(HPO:0004322) | Short stature | 8080508 | IBIS | 1232 / 7739 | ||
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(HPO:0001644) | Dilated cardiomyopathy | 24383070 | IBIS | 141 / 7739 | ||
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(HPO:0005135) | EKG: T-wave abnormalities | Occasional [IBIS] | 15911703 | IBIS | 19 / 7739 | |
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(HPO:0010872) | EKG: T-wave inversion | Rare [IBIS] | 7% (n=96) | 15911703 | IBIS | 19 / 7739 |
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(HPO:0001657) | Prolonged QT interval | Very frequent [IBIS] | 93% (n=15) | 12163457 | IBIS | 33 / 7739 |
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(HPO:0011675) | Arrhythmia | Very frequent [IBIS] | 15911703 | IBIS | 226 / 7739 | |
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(HPO:0005150) | Abnormal atrioventricular conduction | Occasional [IBIS] | 23% (n=96) | 15911703 | IBIS | 16 / 7739 |
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(HPO:0011705) | First degree atrioventricular block | Rare [IBIS] | 7% (n=96) | 15911703 | IBIS | 13 / 7739 |
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(HPO:0011712) | Right bundle branch block | Occasional [IBIS] | 9% (n=96) | 15911703 | IBIS | 34 / 7739 |
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(HPO:0001962) | Palpitations | Rare [IBIS] | 5% (n=96) | 15911703 | IBIS | 62 / 7739 |
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(HPO:0004756) | Ventricular tachycardia | 26448239 | IBIS | 55 / 7739 | ||
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(HPO:0004758) | Effort-induced polymorphic ventricular tachycardias | Frequent [IBIS] | 24827800 | IBIS | 3 / 7739 | |
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(HPO:0004308) | Ventricular arrhythmia | Frequent [IBIS] | 88% (n=17) | 12163457 | IBIS | 46 / 7739 |
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(HPO:0005147) | Bidirectional ventricular ectopy | 16419128 | IBIS | 2 / 7739 | ||
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(HPO:0001664) | Torsade de pointes | Rare [IBIS] | 3% (n=96) | 15911703 | IBIS | 15 / 7739 |
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(HPO:0006682) | Ventricular extrasystoles | Frequent [IBIS] | 41% (n=96) | 15911703 | IBIS | 25 / 7739 |
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(HPO:0011713) | Left bundle branch block | Rare [IBIS] | 2% (n=96) | 15911703 | IBIS | 30 / 7739 |
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(HPO:0001695) | Cardiac arrest | Rare [IBIS] | 3% (n=96) | 15911703 | IBIS | 87 / 7739 |
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(HPO:0001645) | Sudden cardiac death | Rare [IBIS] | 24383070 | IBIS | 84 / 7739 | |
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(HPO:0001279) | Syncope | Frequent [IBIS] | 11% (n=96) | 15911703 | IBIS | 94 / 7739 |
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(HPO:0003236) | Elevated serum creatine phosphokinase | 8080508 | IBIS | 214 / 7739 | ||
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(HPO:0100301) | Muscle fiber tubular inclusions | 8080508 | IBIS | 1 / 7739 | ||
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(HPO:0003690) | Limb muscle weakness | 26448239 | IBIS | 41 / 7739 | ||
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(HPO:0002486) | Myotonia | 24383070 | IBIS | 29 / 7739 | ||
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(HPO:0003768) | Periodic paralysis | Frequent [IBIS] | 50% (n=96) | 15911703 | IBIS | 9 / 7739 |
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(HPO:0008153) | Periodic hypokalemic paresis | 25284084 | IBIS | 4 / 7739 | ||
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(HPO:0001328) | Specific learning disability | Rare [IBIS] | 26448239 | IBIS | 114 / 7739 | |
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(HPO:0000716) | Depression | 16419128 | IBIS | 99 / 7739 | ||
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(HPO:0100543) | Cognitive impairment | Rare [IBIS] | 24383070 | IBIS | 230 / 7739 | |
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(HPO:0001315) | Reduced tendon reflexes | 25284084 | IBIS | 160 / 7739 | ||
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(HPO:0002373) | Febrile seizures | 26448239 | IBIS | 37 / 7739 | ||
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(HPO:0009803) | Short phalanx of finger | 16419128 | IBIS | 79 / 7739 | ||
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(HPO:0004209) | Clinodactyly of the 5th finger | 16419128 | IBIS | 288 / 7739 | ||
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(HPO:0009381) | Short finger | 16419128 | IBIS | 45 / 7739 | ||
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(HPO:0001864) | Clinodactyly of the 5th toe | 16419128 | IBIS | 6 / 7739 | ||
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(HPO:0001770) | Toe syndactyly | 16419128 | IBIS | 149 / 7739 | ||
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(HPO:0004691) | 2-3 toe syndactyly | 16419128 | IBIS | 50 / 7739 | ||
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(HPO:0011927) | Short digit | 16419128 | IBIS | 17 / 7739 | ||
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(HPO:0001156) | Brachydactyly syndrome | 16419128 | IBIS | 180 / 7739 | ||
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(HPO:0001159) | Syndactyly | Occasional [IBIS] | 11% (n=36) | 12163457 | IBIS | 140 / 7739 |
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(HPO:0010743) | Short metatarsal | 16419128 | IBIS | 56 / 7739 | ||
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(HPO:0007598) | Bilateral single transverse palmar creases | 16419128 | IBIS | 13 / 7739 | ||
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(HPO:0010049) | Short metacarpal | 16419128 | IBIS | 99 / 7739 | ||
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(HPO:0004279) | Short palm | 16419128 | IBIS | 323 / 7739 | ||
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(HPO:0200055) | Small hand | 16419128 | IBIS | 71 / 7739 | ||
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(HPO:0000347) | Micrognathia | Frequent [IBIS] | 44% (n=36) | 12163457 | IBIS | 426 / 7739 |
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(HPO:0003778) | Short mandibular rami | 16419128 | IBIS | 7 / 7739 | ||
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(HPO:0003779) | Antegonial notching of mandible | 16419128 | IBIS | 2 / 7739 | ||
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(HPO:0000278) | Retrognathia | 26448239 | IBIS | 100 / 7739 | ||
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(HPO:0009117) | Aplasia/Hypoplasia of the maxilla | 16419128 | IBIS | 18 / 7739 | ||
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(HPO:0000327) | Hypoplasia of the maxilla | 16419128 | IBIS | 129 / 7739 | ||
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(HPO:0005478) | Prominent frontal sinuses | 16419128 | IBIS | 1 / 7739 | ||
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(HPO:0000268) | Dolichocephaly | 24383070 | IBIS | 144 / 7739 | ||
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(HPO:0000337) | Broad forehead | 24383070 | IBIS | 116 / 7739 | ||
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(HPO:0003691) | Scapular winging | 16419128 | IBIS | 51 / 7739 | ||
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(HPO:0002650) | Scoliosis | Occasional [IBIS] | 11% (n=36) | 8080508 | IBIS | 705 / 7739 |
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(HPO:0001388) | Joint laxity | 16419128 | IBIS | 117 / 7739 | ||
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(HPO:0001999) | Abnormal facial shape | Very frequent [IBIS] | 8080508 | IBIS | 169 / 7739 | |
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(HPO:0000272) | Malar flattening | 16419128 | IBIS | 277 / 7739 | ||
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(HPO:0000325) | Triangular face | 16419128 | IBIS | 91 / 7739 | ||
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(HPO:0000174) | Abnormality of the palate | 24383070 | IBIS | 298 / 7739 | ||
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(HPO:0000175) | Cleft palate | Occasional [IBIS] | 8% (n=36) | 16419128 | IBIS | 349 / 7739 |
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(HPO:0002705) | High, narrow palate | 16419128 | IBIS | 308 / 7739 | ||
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(HPO:0006297) | Hypoplasia of dental enamel | 16419128 | IBIS | 64 / 7739 | ||
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(HPO:0000696) | Delayed eruption of permanent teeth | 16419128 | IBIS | 12 / 7739 | ||
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(HPO:0000677) | Oligodontia | 16419128 | IBIS | 41 / 7739 | ||
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(HPO:0000219) | Thin upper lip vermilion | 16419128 | IBIS | 112 / 7739 | ||
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(HPO:0000233) | Thin vermilion border | 16419128 | IBIS | 124 / 7739 | ||
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(HPO:0000455) | Broad nasal tip | 16419128 | IBIS | 67 / 7739 | ||
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(HPO:0000414) | Bulbous nose | 16419128 | IBIS | 63 / 7739 | ||
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(HPO:0000445) | Wide nose | 24383070 | IBIS | 190 / 7739 | ||
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(HPO:0000369) | Low-set ears | Frequent [IBIS] | 39% (n=36) | 12163457 | IBIS | 372 / 7739 |
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(HPO:0001507) | Growth abnormality | 16419128 | IBIS | 36 / 7739 | ||
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(HPO:0030084) | Clinodactyly | Frequent [IBIS] | 64% (n=36) | 12163457 | IBIS | 90 / 7739 |
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(MedDRA:10072883) | Brachydactyly | 16419128 | IBIS | 153 / 7739 | ||
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(MedDRA:10055032) | Electrocardiogram U-wave abnormality | Frequent [IBIS] | 76% (n=17) | 12163457 | IBIS | 2 / 7739 |
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(OMIM) | Anterior crossbite | 16419128 | IBIS | 1 / 7739 | ||
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(OMIM) | Condylar resorption | 16419128 | IBIS | 1 / 7739 | ||
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(OMIM) | Elongated roots with open apices | 16419128 | IBIS | 1 / 7739 | ||
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(OMIM) | Facial asymmetry, mild | 8080508 | IBIS | 5 / 7739 | ||
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(OMIM) | Gracile ribs | 16419128 | IBIS | 1 / 7739 | ||
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(OMIM) | Learning disabilities, mild (some patients) | 26448239 | IBIS | 1 / 7739 | ||
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(OMIM) | Prolonged QTc | 8080508 | IBIS | 1 / 7739 | ||
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(OMIM) | Prominent U wave | Frequent [IBIS] | 76% (n=17) | 12163457 | IBIS | 1 / 7739 |
Associated genes:
KCNJ2; KCNJ5; |
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
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KCNJ2 | rs104894575 | pathogenic | RCV000009473.4 |
KCNJ2 | rs104894578 | pathogenic | RCV000009474.2 |
KCNJ2 | rs104894579 | pathogenic | RCV000009475.2 |
KCNJ2 | rs104894579 | pathogenic | RCV000194837.1 |
KCNJ2 | rs104894580 | pathogenic | RCV000009478.2 |
KCNJ2 | rs104894581 | pathogenic | RCV000009479.2 |
KCNJ2 | rs104894582 | pathogenic | RCV000009480.2 |
KCNJ2 | rs104894583 | pathogenic | RCV000009481.4 |
KCNJ2 | rs104894585 | pathogenic | RCV000009483.2 |
KCNJ2 | rs199473371 | pathogenic | RCV000157272.1 |
KCNJ2 | rs199473384 | pathogenic | RCV000157273.1 |
KCNJ2 | rs199473387 | pathogenic | RCV000023028.4 |
KCNJ2 | rs199473650 | pathogenic | RCV000023027.2 |
KCNJ2 | rs797044841 | pathogenic | RCV000192428.1 |
KCNJ2 | rs797044842 | pathogenic | RCV000193904.1 |
KCNJ5 | rs199830292 | pathogenic | RCV000193019.1 |
KCNJ5 | rs387906778 | pathogenic | RCV000194572.1 |
Additional Information:
Description: (OMIM) |
Andersen-Tawil syndrome is an autosomal dominant multisystem channelopathy characterized by periodic paralysis, ventricular arrhythmias, and distinctive dysmorphic facial or skeletal features. Hypoplastic kidney and valvular heart disease have also been reported. The disorder shows marked intrafamilial variability and ... |
Clinical Description OMIM |
Tawil et al. (1994) used the designation Andersen syndrome for a clinical triad consisting of potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. (This Andersen syndrome is not to be confused with Andersen disease, type IV glycogen storage ... |
Molecular genetics OMIM |
In a kindred with Andersen syndrome showing linkage to 17q23, Plaster et al. (2001) identified a missense mutation in the KCNJ2 gene (600681.0001). They identified 8 additional mutations in the KCNJ2 gene in unrelated patients with Andersen syndrome ... |
Diagnosis GeneReviews | The diagnosis of Andersen-Tawil syndrome (ATS) is suspected in individuals with either A or B: ... Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityKCNJ2Sequence analysis | Sequence variants 2~60% 3Clinical Mutation scanning 4UnknownDeletion / duplication analysis 5Partial- or whole-gene deletions / duplicationsUnknown, none reported1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Approximately 60% of individuals with ATS have a missense mutation or a small intragenic deletion in KCNJ2; more than 20 missense mutations have been described to date [Plaster et al 2001, Ai et al 2002, Andelfinger et al 2002, Tristani-Firouzi et al 2002, Donaldson et al 2003, Hosaka et al 2003]. The mutation p.Arg218Trp is considered a potential hotspot for disease-causing mutations [Davies et al 2005]. 4. Sequence analysis and mutation scanning of the entire gene can have similar mutation detection frequencies; however, mutation detection rates for mutation scanning may vary considerably among laboratories depending on the specific protocol used.5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead ECG, a 24-hour Holter monitor, and possibly the long exercise protocol.In approximately 60% of individuals, molecular genetic testing confirms the clinical diagnosis (see Genotype-Phenotype Correlations). To date there is no known role for routine deletion/duplication analysis. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with mutations in KCNJ2.
Clinical Description GeneReviews | Andersen-Tawil syndrome (ATS) is characterized by the triad of episodic flaccid muscle weakness, distinctive dysmorphic features, and ventricular arrhythmias and prolonged QT interval. Affected individuals present initially with either periodic paralysis or cardiac symptoms (palpitations and/or syncope) in the first or second decade [Tawil et al 1994, Tristani-Firouzi et al 2002]; however, prospective standardized natural history data are not yet available. ... |
Genotype-Phenotype Correlations GeneReviews | Individuals with clinically defined ATS are phenotypically indistinguishable, regardless of the presence of a KCNJ2 mutation (ATS1) or absence of a KCNJ2 mutation (ATS2) [Tristani-Firouzi et al 2002, Donaldson et al 2003]. ... |
Differential Diagnosis GeneReviews |
Table 2. Long QT syndrome: OMIM Phenotypic Series... PhenotypePhenotype MIM NumberGene/LocusGene/Locus MIM Number{Acquired long QT syndrome, reduced susceptibility to} | 613688 ALG10, KCR1 603313 Cardiac arrhythmia, ankyrin-B-related 600919 ANK2, LQT4 106410 Long QT syndrome-1 192500 KCNQ1, KCNA9, LQT1, KVLQT1, ATFB3, SQT2 607542 {Long QT syndrome 1, acquired, susceptibility to} 192500 KCNQ1, KCNA9, LQT1, KVLQT1, ATFB3, SQT2 607542 Long QT syndrome-2 613688 KCNH2, LQT2, HERG, SQT1 152427 {Long QT syndrome-2, acquired, susceptibility to} 613688 KCNH2, LQT2, HERG, SQT1 152427 Long QT syndrome-3 603830 SCN5A, LQT3, VF1, HB1, SSS1, CMD1E, CDCD2 600163 Long QT syndrome-4 600919 ANK2, LQT4 106410 Long QT syndrome-5 613695 KCNE1, JLNS, LQT5, JLNS2 176261 Long QT syndrome-6 613693 KCNE2, MIRP1, LQT6, ATFB4 603796 Long QT syndrome-7 170390 KCNJ2, HHIRK1, KIR2.1, IRK1, LQT7, SQT3, ATFB9 600681 Long QT syndrome-9 611818 CAV3, LGMD1C, LQT9 601253 Long QT syndrome-10 611819 SCN4B 608256 Long QT syndrome-11 611820 AKAP9, YOTIAO, AKAP450 604001 Long QT syndrome 12 612955 SNT1, LQT12 601017 Long QT syndrome 13 613485 KCNJ5, GIRK4, KATP1, LQT13 600734 Timothy syndrome 601005 CACNA1C, CACNL1A1, CCHL1A1, TS 114205 Data from Online Mendelian Inheritance in ManAndersen-Tawil syndrome (ATS) should be considered in any individual presenting with periodic paralysis and ventricular arrhythmias or enlarged U waves. Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead ECG, a 24-hour Holter monitor, and possibly the long exercise protocol. The differential diagnosis depends on the initial presentation and includes the primary and secondary periodic paralyses and thyrotoxic periodic paralysis. Episodes of flaccid paralysis Hypokalemic periodic paralysis is the most common periodic paralysis. Affected individuals have episodes of reversible, flaccid paralysis associated with reduced serum potassium concentrations (<3.5 mmol/U) and/or slowly progressive proximal weakness. The onset, duration, and severity of attacks, with the associated triggers, are similar to those in individuals with ATS. Respiratory muscles are spared. Weakness is improved with oral potassium ingestion. The cardiac and dysmorphic features of ATS are, however, absent in hypokalemic periodic paralysis. Molecular testing identifies mutations in CACNA1S or SCN4A in approximately 80% of affected individuals after secondary causes such as thyrotoxicosis, diuretic use, and renal (e.g., hyperaldosteronism, distal tubular acidosis) or gastrointestinal (e.g., vomiting, diarrheal illness) causes have been ruled out. Inheritance is autosomal dominant. Hyperkalemic periodic paralysis is characterized by episodes of flaccid paralysis associated with normal or elevated ictal serum potassium concentrations (>5.0 mmol/U) and aggravated by potassium ingestion. Onset is in the first decade; episodes are briefer than those that occur in individuals with hypokalemic periodic paralysis. Electrical myotonia is evident in 50% of affected individuals. The cardiac and dysmorphic features of ATS are absent. Molecular testing reveals one of seven common mutations in SCN4A in approximately 50% of individuals. Secondary forms of hyperkalemic periodic paralysis to rule out include adrenal insufficiency, hypoaldosteronism, and adverse effects of certain medications (e.g., ACE inhibitors, spironolactone, nonsteroidal anti-inflammatory drugs). Inheritance is autosomal dominant. Thyrotoxic periodic paralysis is a consideration in any individual with severe weakness and marked hypokalemia. Men, particularly Asians, are affected in greater numbers; however, thyrotoxic periodic paralysis may be seen in all races. Diagnosis is established by measurement of serum TSH, T4, and T3 concentrations. A mutation in an inwardly rectifying potassium (Kir) channel (encoded by KCNJ18) has been identified in approximately one third of affected individuals in one series [Ryan et al 2010].Palpitations, syncope, or cardiac arrest. Syncopal episodes are often interpreted as a neurologic problem rather than arrhythmia. Physical examination and ECG should be part of the evaluation of syncope. Bidirectional ventricular tachycardia demonstrated on ECG may be seen with ATS, digitalis toxicity, and catecholaminergic polymorphic ventricular tachycardia (CPVT). A normal resting ECG with exercise-induced polymorphic arrhythmias is a clue to CPVT. Mutations in RYR2 and CASQ2 are causative. Inheritance is autosomal dominant [Tristani-Firouzi & Etheridge 2010].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
Management GeneReviews | To establish the extent of disease in an individual diagnosed with Andersen-Tawil syndrome (ATS), the following evaluations are recommended:... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMDKCNJ217q24 | Inward rectifier potassium channel 2Gene Connection for the Heart - KCNJ2