C h a p t e r 6
Genetic and Congenital Disorders
113
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
TABLE 6-2
Some Disorders of Organ Systems Associated with Mitochondrial DNA Mutations
Disorder
Manifestations
Chronic progressive external ophthalmoplegia
Progressive weakness of the extraocular muscles
Deafness
Progressive sensorineural deafness, often associated with
aminoglycoside antibiotics
Kearns-Sayre syndrome
Progressive weakness of the extraocular muscles of early onset with
heart block, retinal pigmentation
Leber hereditary optic neuropathy
Painless, subacute, bilateral visual loss, with central blind spots
(scotomas) and abnormal color vision
Leigh disease
Proximal muscle weakness, sensory neuropathy, developmental delay,
ataxia, seizures, dementia, and visual impairment due to retinal
pigment degeneration
MELAS
Mitochondrial Encephalomyopathy (cerebral structural changes), Lactic
Acidosis, and Strokelike syndrome, seizures, and other clinical and
laboratory abnormalities; may manifest only as diabetes mellitus
MERRF
Myoclonic Epilepsy, Ragged Red Fibers in muscle; ataxia; sensorineural
deafness
Myoclonic epilepsy with ragged red fibers
Myoclonic seizures, cerebellar ataxia, mitochondrial myopathy (muscle
weakness, fatigue)
