Porth's Essentials of Pathophysiology, 4e

113

Genetic and Congenital Disorders

C h a p t e r 6

nature of the mutation, which is sometimes maintained as a “premutation” (e.g., in carrier males) and some- times advances to a full mutation (e.g., in affected males and carrier females who are nonetheless affected). Mitochondrial Gene Disorders The mitochondria contain their own DNA, which is distinct from the DNA contained in the cell nucleus. An understanding of the role of mitochondrial DNA (mtDNA) has evolved since 1988, when the first muta- tion of mtDNA was discovered. 20–22 Since that time, more than 100 different disease-related rearrangements and point mutations have been identified. In contrast to the mendelian pattern of inheritance of nuclear DNA, disorders of mtDNA have a maternal form of inheri- tance. This reflects the fact that sperm mitochondria are generally eliminated from the embryo so that disorders of the mtDNA are almost always inherited entirely from the mother. 1 Mitochondrial DNA, which is packaged in a double- stranded circular chromosome located inside the mito- chondria, is often referred to as the “other human genome.” 20–22 It contains 37 genes: two ribosomal RNA (rRNA) genes; 22 transfer RNA (tRNA) genes; and 13 structural genes encoding subunits of the mitochon- drial respiratory chain enzymes, which participate in oxidative phosphorylation and generation of adenosine triphosphate (ATP; see Chapter 1). Another 74 polypep- tides that participate in oxidative phosphorylation are encoded by the nuclear genes. Although a rare disor- der in nuclear encoded mitochondrial proteins has been described, most inherited defects in mitochondrial func- tion result from mutations in the mitochondrial genome itself. Mitochondrial DNA mutations generally affect tis- sues and organs that are highly dependent on oxidative phosphorylation to meet their high needs for meta- bolic energy. Thus, mitochondrial diseases frequently

affect the brain and neuromuscular system and pro- duce encephalomyopathies, retinal degeneration, loss of extraocular muscle function, lactic acidosis, and deaf- ness. 21–23 The mitochondrial myopathies are often asso- ciated with the so-called ragged red fibers , a histologic phenotype resulting from degeneration of muscle fibers and massive accumulation of abnormal mitochondria. The range of mitochondrial diseases is broad, however, and may include liver dysfunction, bone marrow failure, pancreatic islet cell dysfunction, and diabetes, as well as other disorders. Table 6-2 describes representative examples of disorders due to mutations in mtDNA. Multifactorial Inheritance Disorders Multifactorial inheritance disorders are caused by mul- tiple genes and, in many cases, environmental factors. 1–4 The exact number of genes contributing to multifactorial traits is not known, and these traits do not follow the same clear-cut pattern of inheritance as single-gene dis- orders. Multifactorial inheritance has been described as a threshold phenomenon in which the factors contributing to the trait can be compared with water filling a glass. 24 Using this analogy, it could be said that expression of the disorder occurs when the glass overflows. Disorders of multifactorial inheritance can be expressed during fetal life and be present at birth, or they may be expressed later in life. Congenital disorders that are thought to arise through multifactorial inheritance include cleft lip or palate, clubfoot, congenital dislocation of the hip, congenital heart disease, and urinary tract malformation. Environmental factors are thought to play a greater role in disorders of multifactorial inheritance that develop in adult life, such as coronary artery disease, diabetes mel- litus, hypertension, cancer, and common psychiatric dis- orders such as bipolar disorder and schizophrenia. Although multifactorial traits cannot be predicted with the same degree of accuracy as mendelian single-gene Progressive weakness of the extraocular muscles Progressive sensorineural deafness, often associated with aminoglycoside antibiotics Progressive weakness of the extraocular muscles of early onset with heart block, retinal pigmentation Painless, subacute, bilateral visual loss, with central blind spots (scotomas) and abnormal color vision Proximal muscle weakness, sensory neuropathy, developmental delay, ataxia, seizures, dementia, and visual impairment due to retinal pigment degeneration Mitochondrial Encephalomyopathy (cerebral structural changes), Lactic Acidosis, and Strokelike syndrome, seizures, and other clinical and laboratory abnormalities; may manifest only as diabetes mellitus Myoclonic Epilepsy, Ragged Red Fibers in muscle; ataxia; sensorineural deafness Myoclonic seizures, cerebellar ataxia, mitochondrial myopathy (muscle weakness, fatigue) Manifestations

Some Disorders of Organ Systems Associated with Mitochondrial DNA Mutations

TABLE 6-2

Disorder

Chronic progressive external ophthalmoplegia

Deafness

Kearns-Sayre syndrome

Leber hereditary optic neuropathy

Leigh disease

MELAS

MERRF

Myoclonic epilepsy with ragged red fibers