**8. Ion channel disorders**

The cell membrane transit of sodium and potassium ions is ruled by the ion channel genes which encode proteins responsible for the right transit of these ions. Mutations in these proteins lead to a group of familial disorders (Aleong, 2007). These ion channel disorders include the Romano-Ward syndrome (long QT syndromes), the short-QT syndrome (SQTS), Brugada syndrome, and the catecholaminergic polymorphic ventricular tachycardia (CPVT). 5% to 10% of the sudden deaths in children can be associated to ion channel disorders (Modell & Lehmann, 2006).

opathy have been observed. The type 2 patients that have been reported did not have syn‐

The Role of Genetics in Cardiomyopathy http://dx.doi.org/10.5772/55775 115

Children died at age of 2.5 years due to ventricular tachycardia and ventricular fibrillation, infection or hypoglycemia (Reichenbach, 1992; Marks, 1995a; Marks 1995b; Splawski 2004; Lo-

The Brugada syndrome, which is inherited in an autosomal dominant pattern, is associated with sudden death in young people as the patients have malignant ventricular tachyarrhyth‐ mias and sudden cardiac death. The heart is not affected by either a structural heart or systemic

The age of appearance ranges from a two- day- old patient to 85 years (Marks, 1995a; Marks,

The cardiac differential diagnosis must be made with Duchenne muscular dystrophy, Frie‐

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited tachyarrhyth‐ mia that is caused by acute adrenergic activation during exercise or acute emotion in young

It presents locus heterogeneity and in only approximatedly 50% of the cases the mutations in

The prevalence of CPVT in the population is not known, but it could be estimated in approx‐

There is an autosomal dominant form caused by mutations in the RYR2 gene that encodes the

The autosomal recessive form is due to mutations in the calsequestrin 2 gene on chromosome

Short-QT syndrome is a familial disease that is characterized by a high incidence of sudden death. Patients with this disease have QT intervals that are <300 ms, and increased risk of atrial

It is an autosomal dominant inherited disorder that affects patients of 30 years of age, but the

dactily (Splawski, 2005)

**8.4. Brugada syndrome**

dreich ataxia and ARVC.

1995b; Splawski, 2004; Huang, 2004; Lo-A-Njoe, 2005).

**8.5. Catecholaminergic polymorphic ventricular tachycardia**

The age of onset varies from 7-9 years to the fourth decade of life.

ryanodine receptor 2, a calcium-release channel (George, 2003).

fibrillation can even be observed in newborns and young patients.

the genes causing the disease have been identified.

A-Njoe, 2005).

disease.

adolescents.

imately 1:10,000.

1p13.1 (Wilde, 2008).

**8.6. Short–QT syndrome**

and ventricular arrhythmia.

The clinical diagnosis of the ion channelopathies can be often made by identification of alterations found on the ECG (Aleong, 2007; Kass, 2005).

#### **8.1. Romano–Ward syndrome**

RWS may be sporadic or transmitted as an autosomal-dominant trait with reduced penetrance. It is the most common form of inherited long QT syndrome. The prevalence of RWS has been estimated to be 1:3000 to 1:7000.

The Romano-Ward syndrome (RWS) is tipically identified in patients that present syncope, seizures, or sudden death due to episodic taquiarrhythmias, QT prolongation and T-wave abnormalities, interval torsade de pointes that lead to ventricular fibrillation and death.

RWS is associated with mutations in the following genes: *KCNQ1* on chromosome 11p15.5 p15.4, *KCNE1* on chromosome 21q22.12, *KCNE2* on chromosome 21q22.11, *KCNH2* on chromosome 7q36.1, *SCN5A* on chromosome *3p22.2, CAV3* on chromosome *3p25.3*, *SCN4B* on chromosome 11q23.3, *AKAP9* on chromosome 7q21.2, *SNTA1* on chromosome 20q11.21 and *KCNJ5* on chromosome *11q24.3* (Schwartz 1993; Schwartz 2001: Schwartz 2011).

#### **8.2. Jervell and Lange–Nielsen syndrome**

The Jervell and Lange-Nielsen syndrome (JLNS) is inherited as an autosomal recessive trait. The affected children present symptoms before the age of three and they died before the age of 15 if they are not treated.

The prevalence can vary considerably and it depends on the population studied.

The patients have a more severe QT prolongation (greater than 500 msec) which is associated which tachiarrhythmias including torsade de pointes, ventricular fibrillation, syncope and sudden death.

Mutations in the *KCNQ1* gene on chromosome 11p15.5-p15.4, *KCNE1* gene on chromosome 21q22.12, have been reported in the affected individuals (Schwartz 2000; Schwartz 2006).

#### **8.3. Timothy syndrome**

Timothy syndrome is a rare autosomal dominant disorder are due to either a *de novo* mutation or parent germline mosaicism Mutations in the same gene *CACNA1C* cause the two forms of the disorder: the classic, type 1, and type 2. The reported cases of the patients suffering type 1 syndrome have shown complete penetrance (Splawski, 2004).

This complex multisystem disorder has a long QT syndrome associated with syndactily. Various forms of congenital heart defects such as tetralogy of Fallot, hypertrophic cardiomy‐ opathy have been observed. The type 2 patients that have been reported did not have syn‐ dactily (Splawski, 2005)

Children died at age of 2.5 years due to ventricular tachycardia and ventricular fibrillation, infection or hypoglycemia (Reichenbach, 1992; Marks, 1995a; Marks 1995b; Splawski 2004; Lo-A-Njoe, 2005).

#### **8.4. Brugada syndrome**

proteins lead to a group of familial disorders (Aleong, 2007). These ion channel disorders include the Romano-Ward syndrome (long QT syndromes), the short-QT syndrome (SQTS), Brugada syndrome, and the catecholaminergic polymorphic ventricular tachycardia (CPVT). 5% to 10% of the sudden deaths in children can be associated to ion channel disorders (Modell

The clinical diagnosis of the ion channelopathies can be often made by identification of

RWS may be sporadic or transmitted as an autosomal-dominant trait with reduced penetrance. It is the most common form of inherited long QT syndrome. The prevalence of RWS has been

The Romano-Ward syndrome (RWS) is tipically identified in patients that present syncope, seizures, or sudden death due to episodic taquiarrhythmias, QT prolongation and T-wave abnormalities, interval torsade de pointes that lead to ventricular fibrillation and death.

RWS is associated with mutations in the following genes: *KCNQ1* on chromosome 11p15.5 p15.4, *KCNE1* on chromosome 21q22.12, *KCNE2* on chromosome 21q22.11, *KCNH2* on chromosome 7q36.1, *SCN5A* on chromosome *3p22.2, CAV3* on chromosome *3p25.3*, *SCN4B* on chromosome 11q23.3, *AKAP9* on chromosome 7q21.2, *SNTA1* on chromosome 20q11.21 and

The Jervell and Lange-Nielsen syndrome (JLNS) is inherited as an autosomal recessive trait. The affected children present symptoms before the age of three and they died before the age

The patients have a more severe QT prolongation (greater than 500 msec) which is associated which tachiarrhythmias including torsade de pointes, ventricular fibrillation, syncope and

Mutations in the *KCNQ1* gene on chromosome 11p15.5-p15.4, *KCNE1* gene on chromosome 21q22.12, have been reported in the affected individuals (Schwartz 2000; Schwartz 2006).

Timothy syndrome is a rare autosomal dominant disorder are due to either a *de novo* mutation or parent germline mosaicism Mutations in the same gene *CACNA1C* cause the two forms of the disorder: the classic, type 1, and type 2. The reported cases of the patients suffering type 1

This complex multisystem disorder has a long QT syndrome associated with syndactily. Various forms of congenital heart defects such as tetralogy of Fallot, hypertrophic cardiomy‐

*KCNJ5* on chromosome *11q24.3* (Schwartz 1993; Schwartz 2001: Schwartz 2011).

The prevalence can vary considerably and it depends on the population studied.

syndrome have shown complete penetrance (Splawski, 2004).

alterations found on the ECG (Aleong, 2007; Kass, 2005).

& Lehmann, 2006).

114 Cardiomyopathies

**8.1. Romano–Ward syndrome**

estimated to be 1:3000 to 1:7000.

**8.2. Jervell and Lange–Nielsen syndrome**

of 15 if they are not treated.

sudden death.

**8.3. Timothy syndrome**

The Brugada syndrome, which is inherited in an autosomal dominant pattern, is associated with sudden death in young people as the patients have malignant ventricular tachyarrhyth‐ mias and sudden cardiac death. The heart is not affected by either a structural heart or systemic disease.

The age of appearance ranges from a two- day- old patient to 85 years (Marks, 1995a; Marks, 1995b; Splawski, 2004; Huang, 2004; Lo-A-Njoe, 2005).

The cardiac differential diagnosis must be made with Duchenne muscular dystrophy, Frie‐ dreich ataxia and ARVC.

#### **8.5. Catecholaminergic polymorphic ventricular tachycardia**

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited tachyarrhyth‐ mia that is caused by acute adrenergic activation during exercise or acute emotion in young adolescents.

The age of onset varies from 7-9 years to the fourth decade of life.

It presents locus heterogeneity and in only approximatedly 50% of the cases the mutations in the genes causing the disease have been identified.

The prevalence of CPVT in the population is not known, but it could be estimated in approx‐ imately 1:10,000.

There is an autosomal dominant form caused by mutations in the RYR2 gene that encodes the ryanodine receptor 2, a calcium-release channel (George, 2003).

The autosomal recessive form is due to mutations in the calsequestrin 2 gene on chromosome 1p13.1 (Wilde, 2008).

#### **8.6. Short–QT syndrome**

Short-QT syndrome is a familial disease that is characterized by a high incidence of sudden death. Patients with this disease have QT intervals that are <300 ms, and increased risk of atrial and ventricular arrhythmia.

It is an autosomal dominant inherited disorder that affects patients of 30 years of age, but the fibrillation can even be observed in newborns and young patients.

Missense mutations in the *KCNH2* gene on chromosome 7q36.1, in the *KCNQ1* gene on chromosome 11p15.5-p15.and the *KCNJ2* gene on chromosome 17q24.3 have shown that this is a genetically heterogeneous disease.
