Unusual diagnostic and management problems in neuromuscular disease : Gitelman Syndrome

Case Report: A 24-year-old woman came to our attention because of episodes of fatiguability since the age of 3. First admission in a Hospital ward was at 13 when she experienced 24-hour weakness in the right upper limb after a 2 Km walk. She reported on several episodes of muscle weakness, often on awakening, involving all 4 limbs and also described episodes of focal weakness involving one or more limbs. Between episodes she complained of fatigue and occasional muscle cramps. Family history was unremarkable. Past medical history was also unremarkable. Neurologic exam: Normal. Laboratory examinations; creatinine and urea and electrolytes were within normal range. Aldosterone and renine were increased. The patient admitted having excessive dietary intake of table salt (2-3 tablespoons qd since the age of 3). A diagnosis of psychiatric secondary hyperaldosteronism was made. Dietary sodium intake was abolished. The clinical picture worsened: the patient experienced episodes of sudden weakness, often on awakening involving all 4 limbs lasting 24 hours or more which were associated with transitory reduced sensation in some occasions. Between episodes she complained of remarkable fatigability and muscle cramps, often severe enough to cause ‘locking’ of the limbs and interfere with walking. She was admitted for further work-up. She experienced 3 episodes of tachycardia and loss of consciousness with supraventricular arrhythmias on EKG recording during the episodes. The case was revisted.   Neurological examination: Normal except for: symmetrical increase of muscle bulk of posterior compartment of the legs; reduced muscle tone in all 4 limbs; remarkable fatigue; no focal weakness. Blood and urine analysis: Serum Na levels: 142 mEq/L, K 2.9 mEq/L, Ca 2.4 mEq/L, Mg 0.41 mEq/L, normal CK levels, normal renal and liver function. Urinary calcium: 40 mg/dl. Urinary calcium to creatinine ratio was 0.11 (< 0.2). Increased aldosterone and renine levels. Arterial blood gas showed mild metabolic alkalosis with respiratory compensation. EMG: reduced motor unit amplitude in proximal muscles of the upper limbs. Muscle biopsy: minimal variation in fiber size variability. Otherwise normal. Genetic testing: Genetic testing on the SLC12A3 gene confirmed the clinical diagnosis of Gitelman syndrome (compound heterozygous L542P/L845fs). Diagnosis: Hypokalemic and hypomagnesia secondary periodic paralysis associated with Gitelman syndrome Therapy: KCl 600mg tablets, 16-20 a day; Aldactone 100mg, bid; Omeprazol 20mg, bid; Enalapril 5mg, qd; Aspirin 100mg, qd; Magnesium oxide 400mg, tid; 40mEq/L iv potassium and 5g of MgS04 three times a week. (highest K value during treatment 3.5 mEq/L and highest Mg value during treatment 0.5 mEq/L). Discussion Secondary hypokalemic periodic paralysis has been described in the setting of thyrotoxicosis, diuretic ingestions, barium poisoning, GH deficiency, renal diseases associated with renal tubular acidosis. Magnesium depletion may also lead to muscle weakness and a magnesium myopathy has been described. Gitelman syndrome is an inherited hypokalemic metabolic alkalosis that usually presents during childhood but may also present in adult life. It is characterized by hypomagnesemia and hypocalciuria, muscle weakness and tetanic crisis. The disease is known to be related to mutations in the SLC12A3 gene, coding for the thiazide-sensitive Na-Cl cotransporter (NCCT) in the distal convoluted renal tubule. The presentation of Gitelman syndrome with hypokalemic periodic paralysis is rare. This case, highlights several points: (i) Gitelman syndrome should be specifically included in the causes of secondary hyokalemic periodic paralysis; (ii) hypomagnesemia should be considered in cases of transitory adynamia; (iii) blood pH measurements should always be done in the acute setting of hypokalemia. Hypokalemic metabolic alkalosis may direct towards the correct diagnosis of Gitelman syndrome, prevent misdiagnosis, and target treatment.