Page 255 - Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

features such as cardiac malformations and endocrine
abnormalities. Clearly, several other genes located on the
X chromosome also are involved.
S U M M A RY
Cytogenetic Disorders Involving Sex Chromosomes
• In females, one X chromosome, maternal or paternal,
is randomly inactivated during development (Lyon
hypothesis).
• In Klinefelter syndrome, there are two or more X chromo-
somes with one Y chromosome as a result of nondisjunc-
tion of sex chromosomes. Patients have testicular atrophy,
sterility, reduced body hair, gynecomastia, and eunuchoid
body habitus. It is the most common cause of male
sterility.
• In Turner syndrome, there is partial or complete mono-
somy of genes on the short arm of the X chromosome,
most commonly due to absence of one X chromosome
(45,X) and less commonly from mosaicism, or from dele-
tions involving the short arm of the X chromosome.
Short stature, webbing of the neck, cubitus valgus, cardio-
vascular malformations, amenorrhea, lack of secondary
sex characteristics, and fibrotic ovaries are typical clinical
features.
SINGLE-GENE DISORDERS WITH
ATYPICAL PATTERNS OF
INHERITANCE
Three groups of diseases resulting from mutations affect-
ing single genes do not follow the mendelian rules of
inheritance:
• Diseases caused by triplet repeat mutations
• Diseases caused by mutations in mitochondrial genes
• Diseases associated with alteration of imprinted regions
of the genome
Triplet Repeat Mutations: Fragile X Syndrome
Fragile X syndrome is the prototype of diseases in which
the causative mutation occurs in a long repeating sequence
of three nucleotides. Other examples of diseases associated
with trinucleotide repeat mutations are Huntington disease
and myotonic dystrophy. About 40 diseases are now
known to be caused by this type of mutation, and all dis-
orders discovered so far are associated with neurodegen-
erative changes. In each of these conditions, amplification of
specific sets of three nucleotides within the gene disrupts its func- which can then be transmitted to both the sons and the
tion. Certain unique features of trinucleotide repeat muta-
tions, described later, are responsible for the atypical
pattern of inheritance of the associated diseases.
Fragile X syndrome results from a mutation in the FMR1
gene, which maps to Xq27.3. The syndrome gets its name
from the karyotypic appearance of the X chromosome in
Single-Gene Disorders with Atypical Patterns of Inheritance 241
the original method of diagnosis: Culturing patient cells in
a folate-deficient medium typically revealed a discontinuity
of staining or constriction in the long arm of the X chromosome.
This method has now been supplanted by DNA-based
analysis of triplet repeat size as discussed later. With a
frequency of 1 in 1550 for affected males and 1 in 8000 for
affected females, fragile X syndrome is the second most common
genetic cause of mental retardation, after Down syndrome. Clini-
cally affected males have moderate to severe mental retar-
dation. The characteristic physical phenotype includes a
long face with a large mandible, large everted ears, and
large testicles (macroorchidism). Although characteristic of
fragile X syndrome, these abnormalities are not always
present or may be quite subtle. The only distinctive physi-
cal abnormality that can be detected in at least
90% of postpubertal males with fragile X syndrome is
macroorchidism.
As with all X-linked diseases, fragile X syndrome pre-
dominantly affects males. Analysis of several pedigrees,
however, reveals some patterns of transmission not typi-
cally associated with other X-linked recessive disorders
(Fig. 6–17). These include the following:
• Carrier males: Approximately 20% of males who, by ped-
igree analysis and by molecular tests, are known to
carry a fragile X mutation are clinically and cytogeneti-
cally normal. Because carrier males transmit the trait
through all their daughters (phenotypically normal) to
affected grandchildren, they are called normal transmit-
ting males.
• Affected females: From 30% to 50% of carrier females are
affected (i.e., mentally retarded), a number much higher
than that for other X-linked recessive disorders.
• Anticipation: This term refers to the phenomenon
whereby clinical features of fragile X syndrome worsen
with each successive generation, as if the mutation
becomes increasingly deleterious as it is transmitted
from a man to his grandsons and great-grandsons.
These unusual features have been related to the dynamic
nature of the mutation. In the normal population, the
number of repeats of the sequence CGG in the FMR1 gene
is small, averaging around 29, whereas affected persons
have 200 to 4000 repeats. These so-called full mutations are
believed to arise through an intermediate stage of premuta-
tions characterized by 52 to 200 CGG repeats. Carrier males
and females have premutations. During oogenesis (but not
spermatogenesis), the premutations can be converted to
full mutations by further amplification of the CGG repeats,
daughters of the carrier female. These observations provide
an explanation for why some carrier males are unaffected
(they have premutations), and certain carrier females are
affected (they inherit full mutations). Recent studies indi-
cate that premutations are not so benign after all. Approxi-
mately 30% of females carrying the premutation have premature
ovarian failure (before the age of 40 years), and about one third
of premutation-carrying males exhibit a progressive neurodegen-
erative syndrome starting in their sixth decade. This syndrome,
referred to as fragile X–associated tremor-ataxia, is charac-
terized by intention tremors and cerebellar ataxia and may
progress to parkinsonism. It is clear, however, that the
abnormalities in permutation carriers are milder and occur
later in life.