Basics of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary Diseases
Mitochondrial Diseases

The Organism's genetic program is encoded by a sequence of NUCLEOTIDES in DNA, which is localized not only in the Chromosomes of The Nucleus but also in the Cytoplasm of every Cell—specifically, within the mitochondrial chromosome. The mitochondrial code differs slightly from that of nuclear DNA, as described in previous chapters. Genes located in Mitochondrial DNA are inherited not according to Mendel's Laws, but through the direct distribution of Mitochondria between new Cells along with the cytoplasm during mitosis. Mitochondria are the cellular energy systems whose DNA is referred to as the M-chromosome, or the 25th chromosome. Mitochondria replicate independently of nuclear chromosomes; they⁴ are present in the cytoplasm in large numbers (amplified). An organism may be homochondrial or heterochondrial, depending on whether the mitochondria in its cytoplasm are identical or distinct.

The energy demands of cells are met through Glycolysis or oxidation-reduction processes. The latter are driven by The activity of 60 genes (comprising 5 complexes) of the mitochondrial Respiratory Chain, of which only 13 are localized in the M-chromosome, while the rest are nuclear genes. A close, highly coordinated relationship exists among all these genes. The Genetic Map of the M-chromosome is shown in Fig. 13.

Any impairment in the respiratory chain genes leads to The Development of hereditary pathologies, namely mitochondrial disorders. Mutations in genes located in nuclear chromosomes are also a cause of Mendelian-inherited Mitochondrial Diseases. When M-chromosome genes are damaged, disorders with cytoplasmic (maternal) inheritance arise, because only egg cells possess a large volume of cytoplasm containing mitochondria. Consequently, in this case, the disease is transmitted exclusively by females, though individuals of both sexes are affected. Sporadic cases of mitochondrial diseases may also occur due to new mutations in either nuclear or Mitochondrial Genes. Damage to mitochondrial genes in somatic cells can occur in specific Tissues or Organs, causing pathology with the predominant involvement of a particular organ.

The genetic Classification of mitochondrial diseases is based on their grouping according to inheritance patterns:

1. Nuclear DNA defects, including various mutations causing: a) substrate transport defects; b) substrate utilization defects; c) Krebs cycle enzyme defects; d) Oxidative Phosphorylation defects; e) respiratory chain defects; f) protein supply defects.

2. Mitochondrial DNA defects: a) sporadic large-scale rearrangements; b) point mutations in structural genes; c) point mutations in genes that interact with structural genes.

3. Intergenomic signaling defects: a) autosomal dominant multiple deletions of mitochondrial DNA; b) autosomal recessive depletion of mitochondrial DNA.

4. Acquired damage to mitochondrial DNA resulting from harmful factors: a) toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; b) medications, such as zidovudine (AZT); and c) the Aging process.

Class="center">

Fig. 13. Diagram of the mitochondrial chromosome

Sporadic cases of mitochondrial diseases caused by single deletions or insertions in certain genes include Kearns–Sayre syndrome (ophthalmoplegia, pigmentary retinal degeneration, cardiomyopathy, Pyruvate and lactate METABOLISM disorders, and possible viral insertion); chronic progressive external ophthalmoplegia (CPEO); and Pearson syndrome.

Mitochondrial diseases with a maternal inheritance pattern include the following syndromes: MERRF (myoclonic Epilepsy with ragged-red fibers, point mutation in the tRNA-Lys Gene); MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, point mutation in the tRNA-Leu gene); cardiomyopathy and ataxia-blindness (point mutation in the ATPase 6 gene); and LHON (Leber hereditary optic neuropathy, multiple point mutations in The genes of respiratory chain complex I (NADH dehydrogenase)). All of these described mutations alter genes located within the mitochondria.

Mendelian mitochondrial diseases are represented by autosomal dominant and autosomal recessive forms of chronic progressive external ophthalmoplegia, recurrent myoglobinuria (multiple deletions in genes functioning in Muscle cells), and episodes of lactic acidosis (multiple deletions in genes functioning in muscle cells and lymphocytes). Alongside these qualitative abnormalities, a tissue-specific reduction in mitochondrial copy number is also observed, leading to the development of myopathy combined with nephropathy, hepatopathy, or encephalomyopathy.

Thus, the primary clinical and biochemical hallmarks of mitochondrial diseases include myopathies (encephalomyopathy, cardiomyopathy), Vision loss due to retinitis pigmentosa or optic atrophy, disruptions in pyruvate and lactate metabolism, and defects in respiratory chain enzyme complexes.

The Diagnosis of mitochondrial diseases typically begins with a standard geneticist's evaluation, constructing and analyzing a pedigree to determine the inheritance pattern of the pathology within the family. This is followed by a Clinical examination of the patient and family members, along with laboratory assessments of the patient's metabolic status: measuring organic acids, Amino Acids, and carnitine in Blood, daily urine, and CEREBROSPINAL FLUID (depending on the clinical scenario). The results of this initial workup dictate The Need for further investigations, such as blood tests (direct analysis for mitochondrial DNA mutations) or muscle biopsy material—specifically histochemistry and Electron Microscopy (evaluating mitochondrial count, Structure, and function), biochemical assays of oxidative phosphorylation defects (using fresh biopsy samples), and mitochondrial DNA analysis.

An understanding of the etiopathogenetic mechanisms of mitochondrial diseases opens up new possibilities for their targeted Treatment. For instance, in lactic acidosis, various approaches are successfully employed depending on the primary defect:

Mitochondrial DNA analysis is also utilized to establish maternal lineages. For example, it provided conclusive evidence regarding the royal Lineage of the members of Russian Tsar Nicholas II's family, who were executed by the Bolsheviks in 1918. This was achieved by comparing the mitochondrial DNA from Cells of the exhumed remains with that of living maternal relatives of the Tsar (Fig. 14). Thus, the presence of heteroplasmy and a novel point mutation (base pair substitution) in the mitochondrial DNA of the female germline was demonstrated for the first time.