2024.04.12 | Questions 77-78
2024.04.12 | Questions 77-78
Cardiovascular genetics (1/3) - A boy with intermittent weakness
Hello,
This is the 1st in a series of 3 posts related to cardiovascular genetics. Cardiovascular genetics can be divided into 5 sub-categories: cardiomyopathies, arrhythmias, thoracic aortic aneurysms, dyslipidemias, and congenital heart disease. Lysosomal storage disorders (e.g. Pompe, Fabry) and mitochondrial disorders (e.g. Barth syndrome) are also important to recognize as causes of cardiac failure and have been discussed in prior posts in this newsletter.
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-Daniel
Questions
Question 77
A 15-year-old boy presents with episodic weakness predominantly affecting his lower extremities. His episodes have occurred since childhood, usually happen after he wakes up in the morning, and last for 2 or 3 hours before improving on their own. He is unable to walk during the episodes, and has reported recent weakness in his legs even between episodes. Physical examination reveals low-set ears, a small jaw, and 5th digit clinodactyly. In addition to genetic testing, which of the following studies would most likely aid in diagnosis and management?
Question 78
An electrocardiogram is performed for the patient in Question 77 and shows a prolonged QT interval. Genetic testing shows a heterozygous pathogenic variant in KCNJ2 (c.913A>C, p.Thr305Pro). This result is most consistent with which of the following diagnoses?
Explanation
Question 77: Electrocardiogram
Question 78: Andersen-Tawil syndrome
Andersen-Tawil syndrome (ATS) (Question 78) classically presents with a triad of episodic muscle weakness or paralysis, craniofacial and skeletal anomalies, and a prolonged QT interval, which can be detected on an electrocardiogram (Question 77). The episodes of paralysis are triggered by periods of rest or sleep and can last for minutes to hours (as in the patient in Question 77), with the lower extremities being more commonly affected. Patients typically recover completely between episodes, though over time, progressive and more permanent muscle weakness can occur. Craniofacial (hypertelorism, micrognathia, and low-set ears) and skeletal anomalies (scoliosis, short stature, syndactyly, and 5th digit clinodactyly) are unique characteristics of ATS that distinguish it from other causes of periodic paralysis. A prolonged QT interval increases the risk for certain ventricular arrhythmias (e.g. Torsades de pointes) that can present as palpitations, dizziness, or even sudden death. Medications and interventions are available for people with long QT syndrome to reduce the risk for developing a life-threatening arrhythmia.
💡 Patients with “AnderSYN taWIL” have a triad of SYNcope (from prolonged QT interval), SYNdactyly (plus other skeletal differences), & (transient) Weakness In Legs. Some patients with ATS also have learning disabilities or mild intellectual disability, so consider referring children for a developmental assessment.
ATS is caused by variants in a potassium channel
Ion channels enable the flow of charged molecules (e.g. potassium, sodium, calcium) across cell membranes and are fundamental for processes like contracting and relaxing skeletal muscle, maintaining a normal heartbeat, and synchronizing neuronal action potentials. ATS is due to heterozygous variants in KCNJ2, which encodes a subunit of a potassium (K+) ion channel expressed in skeletal and cardiac muscle. In ATS, variants in KCNJ2 disrupt the normal flow of potassium ions across the skeletal and cardiac muscle cell membranes, which results in the symptoms observed in ATS (e.g. muscle weakness and cardiac arrhythmias).
Disease-causing missense variants (as described in Question 78) affect the potassium channel's structure and function. These variants often act in a dominant-negative manner, whereby one subunit containing a missense variant disrupts the function of the entire potassium channel. Dominant-negative variants can be associated with gain-of-function or loss-of-function, which can sometimes result in diseases with opposing physiology. For example, while loss-of-function variants in KCNJ2 decrease K+ flow through the channel and result in long QT syndrome, gain-of-function variants in KCNJ2 increase K+ flow through the channel and cause short QT syndrome.
Primary periodic paralyses (PPP)
Anderson-Tawil is part of a family of disorders known as the primary periodic paralyses (PPP), whose clinical hallmark is sudden-onset, short-term episodes of muscle weakness or paralysis. The PPP are due to variants in potassium, sodium, or calcium channels. In addition, the PPP can be classified as hypokalemic, normokalemic, or hyperkalemic, with these classifications being based on the observed serum potassium levels during episodes of weakness. For example, the episodic weakness in hyperkalemic periodic paralysis, which is due to variants in a sodium channel (SCN4A), is associated with elevated potassium levels in the blood and can be triggered by the intake of potassium in the diet. Of note, ATS does not fit neatly into this potassium-based classification, as the relationship between episodes of weakness in ATS and serum potassium levels is inconsistent and varies greatly between patients.
Incorrect answers
Question 77
A muscle biopsy (choice A) can help diagnose muscular dystrophies (e.g. Duchenne muscular dystrophy) or mitochondrial disorders, particularly if the initial molecular sequencing is non-diagnostic. In ATS, a muscle biopsy would be normal or show non-specific changes that would not help narrow the differential diagnosis. Nerve conduction studies (choice B) can be used to investigate a suspected peripheral neuropathy (e.g. Charcot-Marie-Tooth disease) and would be normal in ATS. Furthermore, the symptoms of a peripheral neuropathy would be persistent (not relapsing and remitting, as in ATS). Cardiac troponin (Choice D) is elevated in patients with a myocardial infarction (i.e., a “heart attack”), which is often due to coronary vascular disease and typically presents with acute-onset, severe chest pain. Patients with certain genetic dyslipidemias (for an overview, see Table 1 in this paper) are at an increased risk for myocardial infarction. Cardiac troponin would most likely be normal in a patient with ATS.
Question 78
Myotonic dystrophy type 1 (DM1, Choice B) can present with muscle weakness and cardiac arrhythmias but lacks the distinctive craniofacial and skeletal features seen in ATS. Periodic paralysis is also not typically seen in DM1, which is caused by CTG trinucleotide repeat expansion in the noncoding region of DMPK. Brugada syndrome (Choice C) is associated with an increased risk of sudden cardiac death and can cause characteristic EKG changes (e.g. ST segment elevation) but does not present with periodic paralysis or craniofacial differences. Brugada syndrome is due to variants in SCN5A, which encodes a sodium channel expressed in the heart. Hypokalemic periodic paralysis (HypoPP, Choice D) is the most common monogenic cause of episodic muscle weakness, though it lacks craniofacial and skeletal involvement. HypoPP is due to variants in CACNA1S or SCN4A.
Learning objective
Andersen-Tawil Syndrome (ATS) is part of a class of disorders termed the primary periodic paralyses, whose hallmark is the presence of sudden-onset, transient muscle weakness that is due to genetic variants in ion channels. The presence of a prolonged QT interval, skeletal malformations, and learning disabilities distinguishes ATS from other forms of periodic paralysis. ATS in inherited in an autosomal dominant manner. Patients with ATS should be screened with an electrocardiogram and referred to neurology and cardiology for management.
2023 ABMGG General Exam Blueprint | V. Single gene inheritance → d. Single gene disorders → iii) Cardiac disorders
2023 ABGC Exam Content Outline | Domain 1C. Genetic Conditions → 1. Clinical features, 5. Management options, and 8. Etiology
References