Andersen Cardiodysrhythmic Periodic Paralysis

A number sign (#) is used with this entry because Andersen-Tawil syndrome is caused by heterozygous mutation in the KCNJ2 gene (600681) on chromosome 17q24.

Description

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 incomplete penetrance (summary by Davies et al., 2005).

Clinical Features

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 disease (232500).) They found reports of 10 patients and added 4 new patients in 3 kindreds. All the patients had potassium-sensitive periodic paralysis without myotonia indistinguishable from other forms of hyperkalemic periodic paralysis (see 170500). In 1 family, a 45-year-old mother and her 22-year-old son were affected. The son had short stature, low-set ears, hypoplastic mandible, clinodactyly, and scoliosis. The mother was said to have the same dysmorphic features. Tawil et al. (1994) emphasized the variability of both the dysmorphic features and the cardiac manifestations. A variable prolongation of the QT interval, ventricular bigeminy, and short runs of bidirectional ventricular tachycardia were observed. Sudden death in this syndrome was reported by Levitt et al. (1972).

Andersen et al. (1971) reported the case of an 8-year-old boy who was short of stature and had hypertelorism, broad nasal root, mandibular hypoplasia, scaphocephaly, and clinodactyly V, as well as a defect of the soft and hard palate. Stubbs (1976) described a 31-year-old housewife with bidirectional ventricular tachycardia whose mother died of 'heart failure' at age 37. Kramer et al. (1979) described a 19-year-old man who had episodes of cardiac dysfunction associated with tetraparesis. A brother had died at age 16 from a heart condition and an older surviving brother suffered from a 'heart condition' similar to that in the proband. The father had experienced attacks of weakness that decreased in frequency with advancing age.

Tawil et al. (1994) showed that the Andersen syndrome is distinct from other forms of potassium-sensitive periodic paralysis by demonstrating lack of genetic linkage and concluded that it is probably distinct from the long QT syndrome (192500) on the same basis.

Sansone et al. (1997) reported 11 patients from 5 kindreds with the classic triad of potassium-sensitive periodic paralysis, ventricular arrhythmia, and an unusual facial appearance. In these patients, periodic paralysis was associated with low, normal, or high serum potassium levels. A long QTc was observed in almost every case, suggesting this as a minimal diagnostic sign.

Canun et al. (1999) suggested that recognition of the characteristic face in Andersen syndrome permits an early diagnosis and the detection of the severe systemic manifestations associated with the syndrome. They described a family in which 10 persons in 3 generations had Andersen syndrome. Facial photographs of 10 affected members of the family were presented. Severity of the facial involvement was not correlated with the severity of heart or muscle involvement of the affected members. Age of onset of periodic paralysis ranged from 4 to 18 years. All affected members with periodic paralysis were responsive to oral potassium except 1, who had normal potassium levels during an attack of paralysis. Two members of the family had no periodic paralysis but had hyperthyroidism. Canun et al. (1999) found a long QTc in only 3 of 8 affected members studied. Canun et al. (1999) did not find short stature; low weight and a slender constitution were found in several relatives.

Tristani-Firouzi et al. (2002) presented extensive clinical and in vitro electrophysiologic studies on a total of 17 kindreds with 10 different mutations. Among mutation carriers, the frequency of periodic paralysis was 64% (23 of 36 individuals). Unlike hypokalemic periodic paralysis (170400), in which attacks are precipitated by carbohydrate ingestion, no consistent trigger could be identified in Andersen syndrome. Rest following physical exertion was a common trigger, as in the classic forms of periodic paralysis. At least 2 dysmorphic features were present in 28 of 36 KCNJ2 mutation carriers (78%): 14 of 36 (39%) had low-set ears, 13 of 36 (36%) had hypertelorism, 16 of 36 (44%) had small mandibles, 23 of 36 (64%) had clinodactyly, and 4 of 36 (11%) had syndactyly. Cleft palate was identified in 3 of 36 Andersen syndrome subjects (8%) and scoliosis in 4 of 36 (11%). Dysmorphic features were most often mild and nondisfiguring, and were easily overlooked on routine physical examination. This is relevant given that in individuals with cardiac involvement, one-sixth demonstrated mild dysmorphic features as the only other clue to the diagnosis of Andersen syndrome. In this series, LQT was present in 71% of KCNJ2 mutation carriers, with ventricular arrhythmias present in 64%.

Andelfinger et al. (2002) identified a heterozygous missense mutation (R67W; 600681.0006) in the KCNJ2 gene in 41 members of a kindred with ventricular arrhythmias (13 of 16 female members, 81%) and periodic paralysis (10 of 25 male members, 40%) segregating as autosomal dominant traits with sex-specific variable expressivity. Some mutation carriers exhibited dysmorphic features, including hypertelorism, small mandible, syndactyly, clinodactyly, cleft palate, and scoliosis, which, together with cardiodysrhythmic periodic paralysis, constitute Andersen syndrome. However, no individual exhibited all manifestations of Andersen syndrome, and this diagnosis was not considered in the proband until other family members were examined. Other features seen in this kindred included unilateral dysplastic kidney and cardiovascular malformation (i.e., bicuspid aortic valve, bicuspid aortic valve with coarctation of the aorta, or valvular pulmonary stenosis), which had not previously been associated with Andersen syndrome. Nonspecific electrocardiographic abnormalities were identified in some individuals, but none had a prolonged QT interval.

Davies et al. (2005) reported 22 affected individuals from 11 unrelated families with ATS. Most patients showed the common clinical triad of hypokalemic periodic paralysis, ventricular arrhythmias, and dysmorphic features, such as hypertelorism, broad-based nose, hypoplastic mandible, and clinodactyly. Other unusual clinical features included poor dentition with abnormal enamel formation in 2 families, high-pitched voice in 1 family, learning disabilities in 1 family, gait ataxia in 1 patient, and renal tubular defects in 1 patient, Genetic analysis identified 9 different pathogenic mutations in the KCNJ2 gene, including 6 novel mutations. In vitro functional expression studies of 5 of the mutant proteins showed a dominant-negative effect on the wildtype allele.

In a father and 2 daughters with Andersen syndrome, Lu et al. (2006) identified heterozygosity for a missense mutation in the KCNJ2 gene (T75R; 600681.0011). The mutation was not found in the girls' unaffected mother and brother. In vitro studies revealed that the mutant channel was nonfunctional, and T75R transgenic mice had bidirectional ventricular tachycardia after induction and longer QT intervals. All 3 affected individuals had ventricular arrhythmias and dysmorphic features, but only 2 had periodic paralysis. None of the family members had a prolonged QTc interval, but prominent U waves could be observed in the 3 affected members.

Yoon et al. (2006) prospectively evaluated 10 individuals with confirmed mutations in the KCNJ2 gene and identified a characteristic pattern of craniofacial features and dental and skeletal anomalies. These included broad forehead, short palpebral fissures, relatively long nose with fullness along the bridge and bulbous tip, malar, maxillary, and mandibular hypoplasia, thin upper lip, high-arched or cleft palate, triangular facies, and mild facial asymmetry. Dental anomalies were identified in all patients and consisted of delayed eruption of permanent dentition, oligodontia, and dental root anomalies. Jaw characteristics included small maxilla and mandible, narrow upper and lower dental arches, and antegonial notching of the lower border of the mandible. Skeletal anomalies included hand and foot size at the lower limits of normal, brachydactyly, 2-3 toe syndactyly, and toe clinodactyly. Yoon et al. (2006) proposed that the diagnostic dysmorphology criteria of ATS be extended to include these features.

Bendahhou et al. (2007) reported 2 unrelated families with periodic paralysis and cardiac dysrhythmias without significant dysmorphic features. The 19-year-old male proband in 1 family had a small chin but no other noticeable dysmorphism. His first episode of periodic paralysis was triggered by corticosteroid treatment of a skin condition, with improvement after discontinuation of corticosteriods; since that time, he had several more attacks, including another one triggered by corticosteroids. Electromyography showed a typical hypokalemic periodic paralysis pattern. The other proband was a 23-year-old woman with no noticeable dysmorphic features who had difficulty playing sports in childhood, with pain in the lower extremities that made it difficult to walk for a few days afterward. On examination, she had full strength of upper limbs but a permanent motor deficit of the lower limbs. Electrocardiography showed ventricular arrhythmia, bidirectional tachycardia, and extrasystoles. Her mother, maternal aunt, and maternal grandmother all had a history of cardiac arrhythmias, and the grandmother had a pacemaker.

Other Features

In a prospective evaluation of neurocognition in 10 individuals with Andersen-Tawil syndrome aged 8 to 45 years, Yoon et al. (2006) found evidence for neurocognitive deficits compared to unaffected sibs. There was no difference between the 2 groups on tests of verbal or visual memory, and no patients had an abnormal EEG. Although patients and sibs had similar IQ scores in the normal range, patients reported more school difficulties. Detailed neurocognitive testing showed that patients with ATS had decreased scores on tests of executive functioning, matrix reasoning, mathematics, and reading. Six of the 7 adult patients completed high school, 4 of whom completed 1 or more years of post-secondary or technical education. Five of the 7 adults held full-time jobs at the time of the study.

Chan et al. (2010) reported a 3-generation Taiwanese family with ATS confirmed by genetic analysis. The 35-year-old female proband had periodic paralysis, characteristic facial features, and long QT syndrome and also had major depression with suicide ideation, hyperreflexia with extensor plantar responses, and evidence of demyelination with periventicular and subcortical white matter lesions on brain MRI. Her 8-year-old affected son had borderline decreased executive function and learning disability. Chan et al. (2010) suggested that neuropsychiatric involvement in ATS may be underestimated, and postulated a role for the KCNJ2 gene in proper myelination and neuronal function.

Clinical Management

In a young woman with Andersen syndrome and an R218W mutation in the KCNJ2 gene (600681.0002), Junker et al. (2002) observed that amiodarone and acetazolamide treatment resulted in marked and long-lasting improvement of cardiac and muscular symptoms.

Mapping

Using 400 polymorphic markers across the entire genome in 15 individuals of a kindred with Andersen syndrome, Plaster et al. (2001) mapped the disease locus to chromosome 17q23 (maximum lod of 3.23 at theta = 0.0 for D17S949) near the KCNJ2 gene.

Molecular Genetics

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 (see, e.g., 600681.0002-600681.0005).

Using targeted mutation, Lopes et al. (2002) established that mutations in KCNJ2 residues decreased the strength of channel interactions with phosphatidylinositol 4,5-bisphosphate (PIP2). They concluded that a decrease in channel-PIP2 interactions underlies the molecular mechanism of Andersen syndrome when these mutations are present in patients.

Among 17 unrelated probands with clinical symptoms of ATS, Donaldson et al. (2003) identified 8 different mutations, including 6 novel mutations, in the KCNJ2 gene in 9 probands. Six probands possessed mutations of residues implicated in binding membrane-associated PIP2. Including previous reports, the authors determined that mutations in PIP2-related residues accounted for disease in 18 of 29 (62%) reported families with KCNJ2-related ATS. Donaldson et al. (2003) found no phenotypic differences between patients with mutations in the PIP2-related residues and those with mutations elsewhere in the gene. The authors suggested that genetic heterogeneity likely exists for this disorder.

Choi et al. (2007) identified 2 different heterozygous missense mutations in the KCNJ2 gene in affected members of 2 Korean families with Andersen-Tawil syndrome. The authors stated that this was the first report of causative mutations in KCNJ2 in Korean ATS patients.

In 2 unrelated probands with periodic paralysis and cardiac dysrhythmias, who were known to be negative for common CACNA1S and SCN4A mutations causing hypokalemic periodic paralysis, Bendahhou et al. (2007) identified heterozygosity for 2 different missense mutations in the KCNJ2 gene (600681.0012 and 600681.0013, respectively). Bendahhou et al. (2007) noted that except for a small chin in 1 proband, there were no dysmorphic features in these families, and suggested that KCNJ2 should be screened in patients with periodic paralysis even when the classic dysmorphic features of Andersen syndrome are not present.