[MIM 601 005] [618 447]

(congenital long-QT type 8 syndrome)

Very rare. Mostly caused by de novo mutations of the CACNA1C gene (12p13.33), coding the a1C subunit of the L-type voltage-gated calcium channel Cav1.2, the heart's main voltage-gated calcium channel. 

From a genetic point of view, a distinction is made between the following mutations:

-        Gly406Arg (exon 8), which can lead to type 1 or type 2,

-        Gly402Ser and Ser405Arg (exon 8A), which can lead to type 2 or COTS syndrome,

-        mutations outside exons 8 and 8A, which can lead to type 2, COTS syndrome or isolated type 8 congenital long QT syndrome.

Clinically, a distinction is made between :

-            type 1: congenital long QT 8 with syndactyly due to a mutation in exon 8

-        bradycardia in utero, atrioventricular block at birth

-        associated cardiac malformation (37 %): persistent ductus arteriosus, VSD, hypertrophic cardiomyopathy, tetralogy of Fallot

-        typical facies (95 %): round face, with a high large forehead, thin upper lip, depressed nasal bridge, low-set ears, premaxillary hypoplasia. Hair is generally sparse.

-        risk of severe hypoglycemia

-        muscular hypotonia is rare

-        anesthetic problems (rhythm disorders)

-        type 2: congenital long QT 8 without syndactyly due to a mutation in exon 8 or 8A

-        bradycardia in utero, atrioventricular block at birth

-        associated cardiac malformation (20 %): persistent ductus arteriosus, VSD, left ventricular hypertrophy (COTS)

-        typical facies (72 %): round face with a high large forehead and thin upper lip

-        muscular hypotonia is frequent

-        risk of severe hypoglycemia

-        anesthetic problems (rhythm disorders)

-        other variants linked to mutations outside exons 8 and 8A :

-        no in utero bradycardia or atrioventricular block at birth: the first sign is cardiac arrest

-        no associated cardiac malformation: LQT8

-        if an heart defect is associated: COTS syndrome, acronym for Cardiac Only Timothy Syndrome

-        typical facies (50 %): round face, with high large forehead and thin upper lip

-        lower risk of hypoglycemia.

-        anesthetic problems (rhythm disorders)

Common problems: epilepsy, small and often decayed teeth, frequent lung infections, autism or autism spectrum disorders, language delay.

Anesthetic implications:

risk of hypoglycemia, see long congenital QT

References:

-         Reynolds AMJ, Auden SM, Sobczyzk WL. 
Perioperative considerations in a newly described subtype of congenital long QT syndrome.
Paediatr Anaesth 1997; 7: 237-41

-        Yates D, Yates A, Collyer T. 
A life-threatening complication of the arterial tourniquet in Timothy syndrome. 
Pediatr Anesth 2007; 17: 492-5.

-        Nathan AT, Antzelevitch C, Montenegro LM, Vetter VL. 
Case scenario: anesthesia-related caardiac arrest in a child with Timothy syndrome. 
Anesthesiology 2012; 117:1117-26

-        Isserman RS, Simpao AF, Schwartz AJ, Pearsall MF.
T-wave alternans and long QT syndrome.
Anesthesiology 2017; 127: 567.

-        Timothy KW, Bauer R, Larkin KA, Walsh EP, Abrams DJ, Gonzalez Corcia C, Valsamakis A et al.
A natural history study of Timothy syndrome.
Orphanet Journal of Rare Diseases 2024; 19:433.doi.org/10.1186/s13023-024-03445-x

Updated: March 2025