Andersen Tawil syndrome ATS

Andersen-Tawil syndrome first fully described by Andersen et al. (1971) is characterized by a triad of periodic paralysis, ventricular arrhythmia and distinctive physical features. Many patients do not have all of these features and there can be marked intrafamilial variation and evidence of incomplete penetrance (Plaster et al., 2001). It is the rarest form of periodic paralysis and no reliable data exist on prevalence.

Mutations in KCNJ2 encoding the inward-rectifying potassium channel Kir2.1 have been identified in about two-thirds of kindreds with ATS (Plaster et al., 2001; Tristani-Firouzi et al., 2002). Up to 20% of individuals carrying pathogenic mutations may not exhibit any phenotypic features (Andelfinger et al., 2002; Tristani-Firouzi et al., 2002; Donaldson et al., 2003). De novo mutations are frequent (Donaldson et al., 2003).

The original case described by Andersen et al. (1971) had quite marked physical abnormalities with low-set ears, hypertelorism, mandibular hypoplasia, sca-phocephalic cranium, clinodactyly, single transverse palm crease, central defect of soft and hard palate and cryptorchidism. Many patients with Andersen-Tawil syndrome have only subtle skeletal or facial abnormalities which become more obvious when the patient's appearance is compared with unaffected family members. The most common features are mandibular hypo-plasia, hypertelorism, broad-based nose, low-set ears, clinodactyly and syndactyly (Fig. 4.1; Canun et al., 1999). Other possible associated features described in a small number of cases include hypoplastic kidney (Andelfinger et al., 2002), renal tubular acidosis, dys-phonia, cognitive impairment (Davies et al., 2005), valvular heart defects (Andelfinger et al., 2002) and vaginal atresia (Canun et al., 1999).

Symptomatic onset with episodic weakness is typically in the first or second decade. The periodic paralysis is most commonly hypokalemic but may also be hyper- or normokalemic (Donaldson et al., 2003).

Electrocardiography may show bidirectional or polymorphic ventricular tachycardia, prolonged corrected QT interval, bigeminy, frequent ventricular ectopy or may be normal (Fig. 4.2). A particularly frequent finding is a prominent 'U' wave even in the presence of a normal serum potassium (Tristani-Firouzi et al., 2002). Due to the cardiac abnormalities Andersen-Tawil syndrome is also classified as long-QT syndrome 7 (LQT7). In comparison to other long-QT syndromes the arrhythmias in Andersen-Tawil syndrome are less malignant (Tristani-Firouzi et al., 2002). However sudden cardiac death does occur and patients require careful cardiac evaluation (Andelfinger et al., 2002; Tristani-Firouzi et al., 2002; Donaldson et al., 2003). A more recent study of ECGs from a large cohort of ATS patients established a distinct T-U-wave pattern that reliably distinguished between KCNJ2 mutation positive ATS patients and those where no mutation could be found (Zhang et al., 2005). The authors also point out that in many ATS patients the QT interval is in fact within the normal limits and the designation of LQT7 should therefore not be used.

Andersen Tawil Syndrome
Fig. 4.1. ATS patient with distinctive physical features including hypoplastic maxilla and mandible, hypertelorism, low set ears, webbed neck, clinodectyly, shortened digits and mild syndactyly of the 2nd and 3rd toes.

4.2.4. Thyrotoxic periodic paralysis (TPP)

The occurrence of periodic paralysis in association with hyperthyroidism was reported as early as 1902 (Rosenfeld, 1902). This form of periodic paralysis is more common in Asia, particularly China, Korea and Japan, where more than 10% of male thyrotoxic patients may be affected (Chen et al., 1965; McFadzean and Yeung, 1967; Ober, 1992; Kung et al., 2004). The overall incidence in thyrotoxic patients from these populations is approximately 2% (McFadzean and Yeung, 1967) while the incidence in Caucasians has been estimated at only 0.1-0.2% (Kelley et al., 1989). Due to migration, cases of TPP are now increasingly seen in the Western world (Ober, 1992). It is also recognized in Caucasians (Linder, 1955), native American Indians (Conway et al., 1974), Blacks (Kilpatrick et al., 1994), Aborigines (Ghose et al., 1996) and Maoris (Wild, 2004). The male-to-female predominance is much more marked in TPP (between 20:1 and 76:1) (Okinaka et al.,

1957; McFadzean and Yeung, 1967) compared to hypoPP (3:1; Elbaz et al., 1995). This is even more significant given that the prevalence of thyrotoxicosis is so much higher in females.

Most cases of TPP are sporadic but a few familial cases have been described (Kufs et al., 1989; Dias da Silva et al., 2002a). The onset of symptoms is most frequently between the second and fourth decade in parallel to the highest incidence of hyperthyroidism. A significant proportion of patients have only subtle clinical signs of hyperthyroidism (McFadzean and Yeung, 1967; Kelley et al., 1989). Autoimmune thyrotoxicosis (Graves' disease) is the most common underlying disorder but TPP may be caused by any form of hyper-thyroidism in susceptible patients including excessive administration of thyroid hormone replacement.

Thyrotoxic periodic paralysis bears phenotypic resemblance to familial hypokalemic periodic paralysis. It is associated with low serum potassium during attacks, may be triggered by glucose/insulin administration and

Andersen Disease Signs And SymptomsMuscle Diseases
Fig. 4.2. ECG traces from patients with ATS. (A) Frequent polymorphic ventricular ectopy with bidirectional ventricular ectopics detectable in the lateral chest leads. QTc interval borderline prolonged. (B) Prominent U-wave.

may also be triggered by rest following exercise. Focal weakness can develop in more strenuously exercised muscles and attacks typically occur at night or on wakening in the morning (McFadzean and Yeung, 1967). Rare cases with associated normo- or hyperkalemia have been reported, although this was prior to the availability of DNA testing for familial periodic paralysis (Adachihara and Takagi, 1974; Mehta et al., 1990). The respiratory and cranial musculature tend to be spared. Morbidity and mortality is low but significant arrhythmias associated with severe hypokalemia have been reported (McFadzean and Yeung, 1967; Fisher, 1982).

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