Abstract
INTRODUCTION
Andersen Syndrome is a periodic paralysis which was initially described by Andersen [1]. The disorder was renamed Andersen-Tawil Syndrome (ATS) due to additional work by Tawil [2]. ATS accounts for less than 10% of all periodic paralysis with an incidence of 1/500,000 – 1/1,000,000. Inheritance pattern is autosomal dominant, but de novo mutations can also be seen resulting in sporadic cases. ATS has been linked to mutations in the KCNJ2 gene which codes for voltage-gated inward rectifying potassium channel [3]. Periodic paralysis, ventricular dysrhythmias and dysmorphic features are the classic triad of the syndrome. In this report we present 2 cases of ATS whose first symptom was muscle weakness and who were diagnosed with myopathy. Dysmorphic features, dysrhythmia and awareness of subtle periodic paralysis led us to the diagnosis of ATS.
CASE REPORTS
A fourteen-year old male was admitted to our clinic with progressive muscle weakness and he also described attacks of periodic severe weakness starting in the last two years. Birth and family history were normal except 36 weeks prematurity. His parents and relatives had no similar complaints. Rhabdomyolysis was not described. He received general anesthesia for circumcision and malignant hyperthermia did not develop. He started falling and getting tired quickly because of severe muscle weakness at the age of four. At the age of 6, cardiac arrhythmia was detected when he was examined for short stature. At the age of 8 investigations for muscle weakness were performed. Serum creatine kinase level was 625 U/L (38–174 U/L). Ictal potassium level was normal. Electromyography showed myopathic changes, myotonia was not observed. Muscle biopsy didn’t demonstrate any specific finding. On our physical examination he had orbital hypertelorism, micrognathia, low set ears, clinodactyly, short stature and proximal muscle weakness in both upper and lower extremities (MRC3/4). There was no ophthalmoplegia. Deep tendon reflexes were hypoactive, Gowers sign was positive. On his electrocardiography ventricular extrasystoles and U waves were seen. Andersen – Tawil Syndrome was suspected because of episodes of worsening limb weakness, his dysmorphic features and presence of cardiac arrhythmia (Fig. 1). Genetic testing confirmed a heterozygous mutation (
The second patient was an 8-year-old male, who had been suffering from muscle weakness in the limbs since early childhood especially increasing with infection. He reported increasing difficulty with walking. Birth history was unremarkable. There was no family history of sudden death, weakness or dysmorphic features. There was no attack of rhabdomyolysis, like the first case he had received general anesthesia for circumcision, however malignant hyperthermia did not develop. His muscle weakness became more evident two weeks before admission, which was prominent in the proximal upper extremities. He could not stand up and raise his arms. After 3 days he returned to his baseline status with subtle weakness.
Physical examination revealed orbital hypertelorism, micrognathia, high arched palate, low-set ears, micromelia, clinodactyly, lombar lordosis, lordotic gait, pes equinovarus deformity on left side, Gowers sign, and proximal muscle weakness in both upper and lower extremities (MRC4) (Fig. 2). There was no ophthalmoplegia. Hemogram and blood biochemistry including potassium measured after improvement of the weakness episode were normal. Serum creatine kinase level was slightly elevated 398 U/L (38–174). On Holter examination frequent multimorphic ventricular extrasystoles were detected. Motor and sensory nerve studies showed normal conduction velocities but needle EMG suggested chronic myopathy. There was no clinical or electrophysiological evidence of myotonia. KCNJ2 mutation analysis identified the same heterozygous mutation (R218W) as in our first case, confirming the diagnosis of ATS. Treatment with acetazolamide resulted in mild clinical improvement in a few months follow-up period. The frequency of paralysis attacks reduced.
DISCUSSION
Andersen-Tawil Syndrome is one of the first detected channelopathies. KCNJ2 is the first gene related with ATS, and KCNJ2 mutation was found in 60% of patients [3]. Episodes of periodic paralysis typically last several hours or days. Although dysmorphic features are usually subtle, when characteristic facial and skeletal abnormalities are noticed, they can be diagnostic. Periodic paralysis may develop with hypokalemia, hyperkalemia or normokalemia. Cardiac findings range from symptomatic ventricular dysrhythmias to sudden death. Periodic paralysis first occurs during childhood or adolescence. These episodes are generally precipitated by stress, long exercise, resting post exercise, prolonged rest, heat or cold [4].
Clinical heterogeneity is also remarkable in ATS. For these reasons it takes time for definite diagnosis. Our first patient had a diagnosis of unclassified myopathy for over 10 years in various medical centers. He experienced an invasive muscle biopsy procedure, although it was unnecessary.
Differential diagnosis of Andersen-Tawil Syndrome includes hyper- and hypokalemic periodic paralysis. Additionally, cases with RYR1 mutation may apply with periodic paralysis attacks [5]. However, our patients had normal ictal and interictal potassium values, had not rhabdomyolysis attacks, history of malignant hyperthermia with general anesthesia or ophthalmoplegia and the non-specific changes observed on muscle biopsy of our first case distanced us from other diagnoses while the dysmorphic findings and dysrhythmias primarilyindicated ATS.
Mild weakness is common, and has an important impact on the quality of life of patients [6]. Early fixed myopathy is a well known manifestation of hypo and hyperkalemic periodic paralysis but it is an unexpected finding in ATS [7]. These cases had proximal extremity weakness on different sides with chronic myopathy findings beginning at an early age; however the classic finding of periodic paralysis attacks were added later. In the literature there are two other patients with fixed myopathy and ATS with periodic weakness [8, 9]. All these patients and our cases have the same heterozygous mutation (
Treatment with acetazolamide resulted in improvement in these cases in the literature discussed above but examination revealed no changes in proximal muscle weakness. Interestingly, muscle strength improved in our first case during the course of treatment. This situation may be due to late onset and short duration of periodic paralysis or the longer follow-up time of our first case. The mechanisms of action are uncertain but carbonic anhydrase inhibitors like acetazolamide are effective, as in the other types of periodic paralysis. On the other hand, acetazolamide-induced worsening in ATS has also been reported [10]. Oral potassium supplementation may also prevent paralytic attacks if accompanied by hypokalemia.
CONCLUSIONS
Because of the life-threatening cardiac arrhythmias, ATS must be kept in mind in the differential diagnosis of periodic paralysis and myopathy. No obvious phenotype–genotype correlations are observed but in addition to the well-known triad of clinical signs, our cases suggest that ATS could be associated with fixed myopathy in mutation
CONFLICT OF INTEREST
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.