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Familial progressive cardiac conduction defect

Orpha number ORPHA871
Synonym(s) Familial Lenègre disease
Familial Lev disease
Familial Lev-Lenègre disease
Familial PCCD
Familial progressive heart block
Hereditary bundle branch defect
Prevalence <1 / 1 000 000
Inheritance
  • Autosomal dominant
Age of onset Adulthood
ICD-10
  • I45.8
OMIM
UMLS -
MeSH -
MedDRA -
SNOMED CT
  • 283645003
  • 93130009

Summary

Familial progressive cardiac conduction defect (PCCD) is a hereditary cardiac conduction disorder that may progress to complete atrioventricular (AV) block. The disease is either asymptomatic or manifests as dyspnea, dizziness, syncope, abdominal pain, heart failure or sudden death.

To date more than 50 familial PCCD cases have been described in the literature.

The age of disease onset is variable. Familial PCCD is either asymptomatic or manifests as dyspnea, dizziness, syncopal episodes, abdominal pain, heart failure or sudden death when complete heart block develops. Syncope during exertion has been reported and the disease can progress from a normal electrocardiography (ECG) to right bundle branch block and from the latter to complete heart block.

Familial PCCD is a degenerative process affecting the His-Purkinje pathway. Mutations in three genes have been identified as disease-causing: SCN5A, SCN1B and TRPM4. Mutations in the genes NKX2, TBX5, PRKAG2 and LMNA have been identified when familial PCCD is accompanied by congenital heart disease. Isolated PCCD has also been described in families with carriers of a mutation in one of these genes. A candidate gene, GJA5, has been associated with severe, early onset PCCD and has been described in 2 blood relatives.

Diagnosis of familial PCCD relies on family history of syncope, pacemaker implantation, and sudden death as well as on ECG findings showing a major conduction defect (complete right bundle branch block, complete left bundle branch block, left anterior fascicular block / hemiblock or left posterior hemiblock, prolonged PR interval or complete AV block with broad QRS complexes). In most cases, normal cardiac structure and contractile function are observed, but in some, complete AV block can lead to dilation of the left ventricle and heart failure. Ventricular tachycardia and torsade de pointes may be recorded during the recovery phase of an exercise stress test or during complete AV block. Potential congenital heart disease or cardiomyopathy is investigated by ECG or cardiac MRI. Screening of the genes involved in familial PCCD should be achieved even in cases of isolated PCCD at a young age.

The differential diagnosis includes Brugada syndrome, idiopathic ventricular fibrillation, long QT syndrome (see these terms), lupus neonatal, progressive familial heart block type II, and sudden infant death syndrome.

Transmission is autosomal dominant with incomplete penetrance and variable expressivity. Recessive or sporadic forms are rare.

Treatment of PCCD includes the timely implantation of a permanent pacemaker. Follow-up at 6-month intervals is recommended in patients with any degree of heart block and at least a yearly examination is recommended in members of the affected families with a normal ECG. Medications with conduction-slowing properties should be restricted, and fever, an aggravating trigger in individuals with SCN5A mutations, should be preemptively treated. When a clinical diagnosis of PCCD is established in an index case, clinical investigation of first-degree family members is necessary.

There is no genotype-based risk stratification for patients with PCCD. A high incidence of sudden death is observed in patients with either first-degree AV block in association with bifascicular block or in those with symptomatic advanced AV block. In patients who receive pacemaker implantation, the prognosis is excellent and is very close to that of the general population, except in those with LMNA mutations that can lead to ventricular tachycardia and sudden cardiac death. In this population, ICD implantation is recommended in case of severe cardiac conduction defect.

Expert reviewer(s)

  • Pr Vincent PROBST

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Detailed information

Clinical practice guidelines
  • EN (2013)
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