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Study Description

Andersen-Tawil syndrome (ATS) is an ion channel disorder that causes episodes of muscle weakness and potentially life-threatening heart arrhythmias. The majority of ATS cases are caused by a mutation in the KCNJ2 gene, which is linked to potassium channels in the heart, brain, and skeletal muscle; other cases are presumed to be caused by an undetermined gene lesion. To date, the treatment for ATS has been largely anecdotal, and no treatments have been formally assessed in a controlled clinical trial. This study will determine whether potassium supplements and/or acetazolamide, which is a diuretic medication, affect the duration of muscle weakness and heart rhythm abnormalities in people with ATS.

Participation in this study will last about 11 months. Participants will first attend a 3-day inpatient visit that will include a medical history, physical examination, blood work, heart rhythm testing by an electrocardiogram (ECG) and Holter monitor, strength testing, a health questionnaire, and daily potassium supplementation. Participants will also track the number and length of weakness episodes that they experience while in the hospital. On the last day of the inpatient visit, participants will be provided with multiple bottles containing either potassium or placebo. Participants will then return home for an 18-week treatment period that will consist of six 3-week-long treatments of either potassium or placebo, with the treatment schedule being randomly determined. Upon completing the first 18-week treatment period, participants will attend a second 3-day inpatient visit that will include the same tests and procedures as the first. The only difference will be that participants will receive acetazolamide along with potassium. This will be followed by a second 18-week treatment period that will consist of six 3-week-long treatments of either acetazolamide or placebo. At the end of the second treatment period, participants will fill out another health questionnaire. Throughout both 18-week treatment periods, participants will phone in daily to track any muscle or heart problems. They will also provide blood samples on a weekly basis. At Weeks 2, 5, 8, 11, 14, and 17 of both treatment periods, participants will wear a Holter monitor for 24 hours and then mail it in. A final outpatient visit will occur 8 weeks after the end of the second treatment period and will include heart rhythm testing, muscle strength testing, and blood work.

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Study Inclusion/Exclusion Criteria

Eligibility Criteria

Inclusion Criteria

I. Individuals with a clinically confirmed diagnosis of ATS as defined by at least two of the following three features:

1. Neuromuscular

  • A. Presence of clear-cut episodes of transient muscle weakness with or without a fixed deficit that is typical with rest following exertion or prolonged rest.
  • B. An atypical history with specific exam findings (absent reflexes with normal sensation ictally).
  • C. Unexplained intraictal hypokalemia.
  • D. An abnormal nerve conduction exercise test (27)

2. Cardiac

  • A. Prolonged QTc interval on 12-lead ECG according to standard criteria (28, 29).
  • B. Ventricular ectopy including uniform or multifocal PVCs, polymorphic VT or bidirectional VT

3. Physical Features

At least two of the following five features:

  • A. Low set ears
  • B. Hypertelorism
  • C. Small mandible
  • D. Clinodactyly
  • E. Syndactyly
  • F. Micromelia of hands or feet

Individuals with one of the three above criteria with at least one other family member meeting two criteria
Individuals not meeting clinical criteria but possessing the KCNJ2 mutation (these individuals will likely come to the attention of the investigator because a family member is affected)

II. Participants must have an average frequency (based on self-report) of at least one neuromuscular symptom (attack of weakness) per week to qualify for this study.

III. Male and female individuals age 10 and older meeting the criteria above who are able to comply with the study conditions.

Exclusion Criteria

  1. Weight of less than 44 pounds (20 kg)
  2. Renal impairment, serum creatinine > 1.5 mg/dl
  3. Pregnancy
  4. History of renal calculi
  5. Age under 10 years
  6. Inability to comply with study guidelines
  7. Presence of cardiac disease or other disease that would make potassium supplementation or acetazolamide treatment inadvisable (e.g. Coronary heart disease)
  8. Diabetes mellitus
  9. Currently taking quinidine

Study History

♦ Study activation: 12/22/2008
♦ First accrual: 04/28/2009
♦ Study closed: 01/26/2011

Selected Publications
Diseases/Traits Related to Study (MeSH terms)
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Study Attribution
  • Study Chair
    • Paul Twydell, DO. University of Rochester Department of Neurology, Rochester, NY, USA.
  • Participating Site Principal Investigators
    • Paul Twydell, DO. University of Rochester Department of Neurology, Rochester, NY, USA.
    • Jeffrey Ralph, MD. University of California San Francisco Department of Neurology, San Francisco, CA, USA.
    • Michael Hanna, MD. Institute of Neurology, UCL, London, United Kingdom.
    • Martin Tristani-Firouzi, MD. University of Utah School of Medicine, Salt Lake City, UT, USA.
    • Jeffrey Krischer, PhD. Data Management and Coordinating Center, Tampa, FL, USA.
  • Current Funding Sources
    • National Institutes of Health (NIH), Muscular Dystrophy Association (MDA), Bethesda, MD, USA.