Human cells contain hundreds of mitochondria, each with its own genome and associated replication system. Oocytes contain approximately 100,000 mitochondria. Sperm hold only about 100, and these are destroyed after fertilization. Each mitochon drion has multiple copies of a 16.5-kb circular DNA molecule that contains 37 genes. Mitochondrial DNA encodes peptides and transfer RNAs.
Mitochondria are inherited exclusively from the mother.
hus, although males and females both can be afected by a mitochondrial disorder, transmission is only through the mother. When a cell replicates, mitochondrial DNA sorts randomly into each of the daughter cells, a process termed replicative segregation. A consequence of replicative segregation is that any mitochondrial mutation will be propagated randomly into the daughter cells. Because each cell holds multiple copies of mitochondrial DNA, the mitochondrion may contain only normal or only abnormal DNA, termed homoplasmy. Alternatively, it may contain both normal and mutated DNA, namely heteroplasmy. If a heteroplasmic oocyte is fertilized, the relative proportion ofmutated DNA may afect whether the individual manifests a given mitochondrial disease. It is not possible to predict the potential degree of heteroplasmy among ofspring, and this poses challenges for genetic counseling.
As of 2016, 33 mitochondrial diseases or conditions with known molecular basis were described in Online Mendelian Inheritance in Man Qohns Hopkins University, 2017). Examples include myoclonic epilepsy with ragged red fibers (MERRF), Leber optic atrophy, Kearns-Sayre syndrome, Leigh syndrome, several forms of mitochondrial myopathy and cardiomyopathy, and susceptibility to chloramphenicol toxicity.
Mendel's irst law is that genes are passed unchanged from parent to progeny, and barring new mutations, this is true for many genes or traits. However, certain genes are unstable, and their size, and thus function, may be altered during parentto-child transmission. This is manifested clinically by anticipation-a phenomenon in which disease symptoms seem to be more severe and to appear at an earlier age in each successive generation. Examples of some DNA triplet (trinucleotide) repeat diseases are shown in Table 13-4.
his is the most common inherited form of intellectual disability and afects approximately 1 in 3600 males and 1 in 4000 to 6000 females (American College of Obstetricians and Gynecologists, 2017a). Fragile X syndrome is caused by expansion
TABLE 13-4. Some Disorders Caused by DNA Triplet Repeat Expansion of a repeated trinucleotide DNA segment-cytosine-guanineguanine (CGG)-at chromosome Xq27.3. When the CGG repeat number reaches a critical size-the full mutation-the ragile X mental retardation 1 (FMR1) gene becomes methyl ated. Methylation inactivates the gene, which halts expression of FMR1 protein. his protein is most abundant in nerve cells and is essential for normal cognitive development.
Although transmission of the syndrome is X-linked, both the sex of the afected individual and the number of CGG repeats determine the degree of clinical normalcy or impair ment. Intellectual disability is generally more severe in males, in whom average IQ scores are 35 to 45 (Nelson, 1995). Afected tion-deicit/hyperactivity disorder. Fragile X syndrome is also the most common known cause of autism or "autistic like" behavior. Associated phenotypic abnormalities become more prominent with age and include a narrow face with large jaw, prominent ears, connective tissue abnormalities, and macroor chidism in postpubertal males. Clinically, four groups have been described (American College of Obstetricians and Gyne •cologists, 2017a):
Premutation-55 to 200 repeats