**10. Mitochondrial disorders**

Mitochondrial disorders are a heterogeneous group of disorders that have common clinical features and are caused by the different mutations found in either the nuclear or mitochondrial DNA (mtDNA) genes which regulate the mitochondrial respiratory chain, the essential final common pathway of aerobic metabolism, tissues and organs. mtDNA is maternally inherited


**Table 4.** Genes that cause cardiomyopathy in muscular dystropies

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

Muscular dystrophies are a heterogeneous group of inherited disorders, characterized by progressive weakness and wasting of the skeletal muscles. They are generally associated with cardiomyopathy. In many cases, there is no correlation between the skeletal myopathy and the involvement of the heart. The mutations of the genes that cause muscular dystrophies affect the skeletal and/or cardiac muscles. These include proteins which are associated with the dystrophin–glycoprotein complex, the nuclear lamina or the sarcomere (Hermans, 2012).

Cardiomyopathy occurs in myofibrillar myopathy, myotonic dystrophies, myotonic myopa‐ thies, dystrophinopathies, Emery-Dreifuss muscular dystrophy, and limb girdle muscular

They are inherited in autosomal dominant, autosomal recessive and X-linked mode. (See Table

The different forms of muscular dystrophies vary in the age of onset with no male or female prevalence and have different clinical features and severity. Mutations in the genes that are involved muscular dystrophies can cause hypertrophic, dilated or restrictive cardiomyopathy, but most cardiomyopathies in patients with a muscular dystrophy are of the dilated type. The progression of the disorders and life expectancy vary widely, even among different members of the same family. Patients die of sudden death due to conduction defects, and heart failure. In dystrophinopathies, sarcoglycanopathies, and the disorders that are linked to mutations in the fukutin-related protein, the feature that stands out is the cardiomyopathy the patients suffer. In muscular dystrophies, the patients usually have a dilated cardiomyopathy. Hyper‐ trophic cardiomyopathy can be observed in Danon disease, α-B crystallinopathy, and on patients or carriers of DMD and BMD. (De Ambroggi, 1995, Vicart 1998; Nguyen, 1998; Lazarus, 1999; Melacini, 1999; Barresi, 2000; Politano, 2001; Selcen, 2003; Fanin, 2001; Jefferies, 2005; Nakanishi, 2006; Connuck, 2008; Kaspar, 2009; Goldfarb, 2009; Lilienbaum, 2012;

Mitochondrial disorders are a heterogeneous group of disorders that have common clinical features and are caused by the different mutations found in either the nuclear or mitochondrial DNA (mtDNA) genes which regulate the mitochondrial respiratory chain, the essential final common pathway of aerobic metabolism, tissues and organs. mtDNA is maternally inherited

is a genetically heterogeneous disease.

dystrophies (Hermans, 2012).

4, Table 5).

116 Cardiomyopathies

Hermans, 2012)

**10. Mitochondrial disorders**

**9. Cardiomyopathy in muscular dystrophies**

and the disorders can appear at any age. All the mitochondria have multiple copies of their own mtDNA and the mutation rate is much higher than in nuclear DNA (Walter, 2000; Carrasco, 2005; De Jonge, 2011).

Many mitochondrial disorders involve multiple organ systems such as the brain, the heart, the liver, and the skeletal muscles which are, therefore, affected due to the fact they depend on the energy and they are especially susceptible to energy metabolism impairment (Walter, 2000; Carrasco, 2005; De Jonge, 2011).

Mitochondrial dysfunction and clinical symptoms appear when the heteroplasmic levels are above 80%-90% (Walter, 2000; Carrasco, 2005; De Jonge, 2011).


The cardiac involvement is considered to be 18–100% (Hirano, 1994; Vydt, 2007; Wortmann, 2007). The first symptom the affected children have is the cardiomyopathy. The most common feature is a hypertrophic cardiomyopathy, although dilation has also been reported (Okajima,

The Role of Genetics in Cardiomyopathy http://dx.doi.org/10.5772/55775 119

Mutations in the nuclear genes that also encode mitochondrial proteins can cause cardiomyo‐ pathies. These disorders are sometimes not considered among the group of mitochondrial primary disorders. Two of the most well known disorders are Friedreich´s ataxia and Barth

Friedreich´s ataxia is an autosomal recessive disorder. Frataxin, the protein encoded by *FXN,* is involved in the mitochondrial transport and is needed for the synthesis of the enzymes of the respiratory chain complexes I – III and aconitase. When the protein is mutated in Friederich

Barth syndrome is a recessive X-linked inherited disease chacterized by cardiomyopathy and neutropenia. The cardiac disease presents a dilated cardiomyopathy, often with a degree of left myocardial thickening and, sometimes, endocardial fibroelastosis. The cardiac disease

Mutations in the tafazzin gene are to be held responsible for this disorder because of the inhibition of this pathway leads to changes in mitochondrial architecture and function

Although the diagnosis is based primarily on DNA analysis, a thorough clinical history and examination, blood tests, the ECG, echocardiography, electromyography, and muscle biopsy can also provide information that can be helpful for the diagnosis not only of the patients, but

With the expansion in number of the different disorders that have myocardial involvement in conjunction with the development of their molecular and biochemical bases, it can be stated that these will play a most important role in the understanding of the pathophysiology of the

The exact role and function each mutated protein has and the pathogenic mechanisms that lead to the different disorders still have to be elucidated, in spite of the fact that the mutations

It has also been observed that the mutations within the same gene and in the same family can give rise to distinct phenotypes in HCM, DCM and RCM. The pathogenesis of the three major types of cardiomyopathy can be linked to the the genetic mutations in the different sarcomeric proteins. These gene mutations are responsible to trigger the different pathways that lead to the remodeling of the heart. The mechanisms why this occurs are still unclear and the animal

**12. The impact of genetics in the understanding of cardiomyopathy**

1998).

syndrome (de Jonge, 2011).

´s ataxia, it does not allow the correct respiratory function.

appears at birth or in the first few months of life

(Spencer, 2006, Schamme, 2006).

also of the asymptomatic carriers.

that cause them have been found.

models are markedly distinct.

syndromes.

**Table 5.** Limb-girdle muscular dystrophies

The different mitochondrial cardiomyopathies are a result of the heart being commonly affected. Sometimes, the cardiomyopathy is diagnosed during the first year of life even before the mitochondrial disorder has been diagnosed. Both hypertrophic and dilated cardiomyopa‐ thies have been reported (Holmgren, 2003, de Jonge, 2011).
