Medical Genetics - V. M. Zaporozhan 2005

Monogenic Disorders
Clinical Features and Genetics of Certain Monogenic Disorders
Mitochondrial Diseases

These are disorders caused by genetic and structural-biochemical defects in Cell/35.html">Mitochondria, accompanied by impaired tissue Respiration. Mitochondrial diseases can be associated with Mutations in both the nuclear and Mitochondrial Genomes (see Fig. 1.8).

The primary function of mitochondria is the oxygen-dependent stage of METABOLISM/26.html">Energy Metabolism and ATP synthesis. Although most mitochondrial Proteins are encoded by the nuclear genome, the mitochondria of animal and plant Cells possess their own circular DNA. In humans, Mitochondrial DNA contains 16,569 bp. The number of mtDNA molecules per cell can reach tens of thousands, with each mitochondrion containing between 2 and 10 copies of mtDNA. The absence of histone association, an imperfect DNA Repair mechanism, and the high level of free radicals generated during aerobic oxidation within mitochondria lead to a relatively high mutation rate in mitochondrial DNA. The Emergence of mutant mtDNA causes heteroplasmy, a state where two populations of mtDNA coexist within a cell. Because mtDNA Replication occurs autonomously and the distribution of mitochondria to daughter cells is stochastic, the level of heteroplasmy can vary across the same tissue at different stages of life.

The Clinical presentation of mitochondrial disorders depends on the energy demands of specific Tissues. The most highly energy-dependent Organs are affected first: the Central Nervous system, skeletal musculature, myocardium, eyes, Endocrine glands, and Kidneys. Furthermore, severity correlates with the percentage of mutant DNA. For instance, in CNS cells, the threshold level of mutant DNA required to trigger clinical manifestations exceeds 60%.

Mitochondrial disorders are characterized by a combination of diverse multisystem and multiorgan manifestations, including Muscle weakness, neuropathies, ataxia, dementia, cardiomyopathy, and diabetes. This multiplicity of symptoms is explained by a narrow threshold of sensitivity to energy deprivation in target organs. Myopathies and encephalopathies are considered the hallmark Clinical Features of mitochondrial diseases.

Table 6.10. Examples of mitochondrial disorders associated with mtDNA mutations

The severity of mitochondrial diseases progressively increases. In childhood, this is associated with the rising energy demands of developing tissues, whereas in adulthood, it is driven by a decline in Oxidative Phosphorylation efficiency and the accumulation of mtDNA mutations.

Mitochondrial disorders can exhibit various inheritance patterns depending on The Nature of the genetic defect in each specific case. When a mutation occurs in a nuclear gene encoding a mitochondrial protein, the disorder is inherited in an autosomal dominant or autosomal recessive manner. Conversely, mitochondrial DNA mutations are characterized by cytoplasmic (maternal) inheritance. Mitochondria are transmitted to the zygote exclusively through the oocyte Cytoplasm. Consequently, all mitochondria in an individual's cells are of maternal origin and are inherited by all offspring from the mother. Pedigree analysis is discussed in Section 4.2.4.

Examples of mitochondrial disorders in humans include Leigh encephalomyelopathy, Leber hereditary optic neuropathy, and various myopathies and cardiomyopathies (Tab.

6.10).

Direct biochemical Diagnosis of this group of disorders is challenging. In practice, these conditions are diagnosed using tissue biopsies, detailed histological examination, molecular genetic techniques, and cytochemical Methods.