Alzheimer's and Genetics Quiz

Nondisjunction can occur in both meiosis and mitosis, and refers to a
failure of paired chromosomes to separate and go to different daughter cells. When this happens,
one daughter cell gets an extra chromosome and the other daughter cell is "short" one
chromosome.

A balanced translocation (choice A) is an exchange of genetic material between non-homologous
chromosomes that preserves all critical genetic material.

Chromosomal breakage (choice B) produces fragmented chromosomes and can contribute to
tumorigenesis.

Fertilization by two sperm (choice C) produces triploidy and is seen in many spontaneously
aborted fetuses.

An unbalanced translocation (choice E) occurs when non-homologous chromosomes exchange genetic
material with a net loss or gain of critical genetic material.

This patient has Huntington's disease, which has autosomal dominant
inheritance. It is characterized by severe degeneration of the caudate nucleus along with
degenerative changes in the putamen and cortex. In addition to chorea, these patients frequently
suffer from athetoid (writhing) movements, progressive dementia, and behavioral disorders.

Genotype Enzyme Activity Phenotype G/G 100 Normal G/D 75 Normal G/LA 120 Normal G/g 50 Normal
D/D 50 Normal D/LA 95 Normal LA/LA 140 Normal LA/g 70 Normal g/g

The correct answer is C. The boy probably has Klinefelter's syndrome (47, XXY), which has the
typical presentation described in the question. The condition arises as a result of failure of
separation (nondisjunction) of the sex chromosomes, and can be related to either paternal
nondisjunction (slightly more common) or maternal nondisjunction.

Deletions (choice A) are a common form of genetic disease and contribute to many genetic
recessive diseases.

Examples of nondisjunction of autosomes (choice B) include trisomies such as most cases of
Down's syndrome (trisomy 21), Edwards' syndrome (trisomy 18), and Patau syndrome (trisomy 13).

There are two types of translocations: non-Robertsonian (choice D) and Robertsonian (choice E).
Non-Robertsonian (reciprocal) translocations result when two non-homologous chromosomes exchange
genetic material. Robertsonian translocations are a special type of translocation that involve
exchange of genetic material from the long arms of one acrocentric chromosome to the long arms
of another acrocentric chromosome, with fusion of the centromeres. Four percent of cases of
Down's syndrome are caused by this mechanism.

The correct answer is C. The Barr body, or X chromatin body, is an inactivated X chromosome seen
as a small, perinuclear, dark-staining dot in somatic cells with two or more X chromosomes. Barr
bodies are seen in any individual born with at least two X chromosomes, including normal
females. (47, XXY), the classic karyotype of Klinefelter's syndrome, is defined as male
hypogonadism due to the presence of a Y chromosome and two or more X's. As in normal females,
one of the X chromosomes becomes a Barr body in Klinefelter's syndrome.

Classic Turner syndrome females (choice A) and genotypically normal males (choice D) have only
one X chromosome. Thus, no X chromosome is inactivated, and somatic cells do not show any Barr
bodies.

(47, XY+18) is the karyotype of an Edward's syndrome (choice B) fetus. Although this trisomic
phenotype is associated with a characteristic syndrome of physical abnormalities, there is no
programmed inactivation of the extra chromosome 18. Thus, no Barr body is produced.

XYY syndrome (choice E) is not associated with inactivation of any X chromosomes, so Barr bodies
are not present. Like a trisomy involving any of the non-sex-linked chromosomes, the duplicated
chromosome is expressed in its entirety.

The correct answer is C. Duchenne-type muscular dystrophy is the only disease listed that is X-
linked; the other diseases are autosomal recessive. Remembering the genetics of myriads of
diseases is very problematic, but here are some imperfect rules of thumb that can help you out
if you encounter an unfamiliar disease on an examination. Deficiencies of most enzymes are
recessive (either autosomal or X-linked), since each person has at least two copies (from each
of the parents) of each enzyme, and one working gene is usually enough (although careful
evaluation of heterozygotes often shows mildly altered physiology). In contrast, alterations in
structural proteins are often autosomal dominant, since having any amount of abnormal protein in
structures such as basement membranes or in collagen tends to disturb their function. The number
of common X-linked diseases (almost all recessive) is small, and can be memorized: Duchenne
muscular dystrophy, hemophilia A and B, chronic granulomatous disease, glucose-6- phosphate
dehydrogenase deficiency, agammaglobulinemia, Wiskott-Aldrich syndrome, diabetes insipidus,
Lesch-Nyhan syndrome, fragile-X syndrome, and color blindness.

Alpha1-antitrypsin deficiency (choice A) is a deficiency of an enzyme (alpha1-antitrypsin) that
inhibits the action of various proteolytic enzymes. The two autosomal alleles for alpha1-
antitrypsin are codominantly expressed such that they both contribute to the levels of
circulating alpha1-antitrypsin.

Cystic fibrosis (choice B) is an autosomal recessive disorder. The gene for cystic fibrosis has
been localized to chromosome 7.

Phenylketonuria (choice D), in its classical form, is an autosomal recessive deficiency of
phenylalanine hydroxylase.

Tay-Sachs disease (choice E) is an autosomal recessive deficiency of the enzyme hexosaminidase
A.

47, XXX is a surprisingly benign condition, the incidence of which is
unknown because most cases are never diagnosed, as a normal phenotype with normal life span is
typical. There is some increase in the incidence of mental retardation and menstrual
irregularities in the population, particularly with increasing numbers of supernumerary X
chromosomes. Presumably, the inactivation of the extra X chromosome (forming a second Barr body
that may be observed on a buccal smear examined for other reasons) limits the expression of the
extra genes.

The features described are typical of the familial form of mental
retardation known as fragile X syndrome. This disorder is the second most common heritable cause
of mental retardation, second only to Down syndrome. Striking features of this disease are that
the clinical features tend to worsen with each successive generation, and that males are usually
much more severely affected than females, although nearly 50% of carrier females are at least
slightly mentally retarded. The explanation appears to involve a region of DNA on the X
chromosome that normally contains 6-54 tandem repeats of the sequence CGG. Carrier females for
fragile X syndrome may have up to 200 CGG repeats. Clinically affected individuals have
250-4,000 repeats of the CGG sequence. The greater the number of repeats, the more severe the
retardation tends to be. Amplification of premutations to full mutations appears much more
likely to occur during oogenesis than spermatogenesis.

Genomic imprinting (choice B) is a phenomenon in which the phenotypic expression of a gene
differs if the gene is inherited from the mother, rather than the father. An example of this
effect is Angelman ("happy puppet") syndrome, caused by a deletion of band q12 in the maternal
copy of chromosome 15. A similar deletion in the paternal chromosome 15 produces a different
disease called Prader-Willi syndrome.

A Robertsonian translocation (choice C) causes about 5% of cases of Down syndrome. Generally the
mother [typically with genotype 45, XX, -14, -21, +t(14q; 21q)] has normal mentation, but some
of her children may carry the translocation in addition to the normal maternal chromosome 21 and
normal paternal chromosome 21, producing partial trisomy 21. This form of Down syndrome can
appear to be a recessive genetic disease.

Trisomy 13 (Patau syndrome; choice D) is characterized by microcephaly, mental retardation,
cleft lip and palate, polydactyly, and rocker-bottom feet. Survival is rare beyond one year.

Trisomy 18 (Edwards syndrome; choice E) is characterized by mental retardation, micrognathia,
low-set ears, cardiac defects, renal defects, and rocker-bottom feet. Survival is rare beyond
one year.

The correct answer is D. The disease is Duchenne muscular dystrophy, an X-linked recessive
muscular disease usually caused by a deletion involving the dystrophin gene. This defect
produces accelerated muscle breakdown leading initially to proximal muscle weakness, then later
to generalized weakness that typically begins before age 5. A feature of X-linked recessive
diseases is that carrier mothers pass the disease to half their sons; affected fathers can have
carrier daughters but not affected sons. Since the mother is presumably normal (because the
disease is X-linked), she must be a carrier to have an affected son, and the grandmother must
also be a carrier, therefore the mother's brother (maternal uncle) may also have the disease.

The father's (choice A) side of the family, including the father's brother (choice B), most
likely does not carry the defective gene (since they themselves would be affected, and
furthermore since the father cannot pass the gene on to a son). It would be extremely unlikely
for a carrier female to marry an affected male (and the question does not mention any similar
symptoms in the father).

The mother (choice C) and possibly the sister (choice E) are carriers of, but not affected by,
the defective gene.

The RFLP detects a region near the centromere of chromosome 21. The
region around the centromere exhibits a phenomenon called crossover suppression. Since genetic
exchange cannot happen in this area, the probe is a reliable marker for the individual
chromosomes. During meiosis II, sister chromatids, which are two identical copies of the same
chromosome, should separate. If a nondisjunction event occurs in this division, two copies of
the same chromosome are passed to the progeny. In this case, both parents are heterozygous for
the probe. The child received an A from the mother and two Cs from the father, leading us to
conclude that the problem occurred in the father during meiosis II.
Choice A (the child during the first mitotic division). If a nondisjunction event of chromosome
21 occurs early in development, a child that is a mosaic for trisomy 21 is the result. This
accounts for approximately 1% of children with trisomy 21. Since some of their cells are normal,
these individuals show only a mild expression of the trisomy 21 phenotype.

Choice B (the father during meiosis I). During meiosis I, homologues that carry similar but not
identical information separate. If a failure occurred in this division, we would expect the man
to pass CD and the woman to pass A or B, producing a child that was ACD or BCD.

Choice D (the mother during meiosis I). If an AB woman had a failure in meiosis I, an AB gamete
would be produced. When fertilized by the man's C or D sperm, a child that was ABC or ABD would
result.

Choice E (the mother during meiosis II). If an AB woman's sister chromatids failed to disjoin
during meiosis II, AA or BB gametes would result. When fertilized by the CD male's sperm, a
child that was AAC, AAD, BBC, or BBD would result.

The correct answer is A. Features of Down's syndrome (trisomy 21) in children include mental
retardation, epicanthal folds, dysplastic ears, hypotonia, a horizontal palmar crease (simian
crease), redundant neck skin, and a short trunk. However, most of these children eventually grow
to adulthood. At that point, the aging parents may have to deal with a physically strong and
healthy mentally retarded individual who is experiencing a deterioration in mental function.
This deterioration may be accompanied by aggressive behavior (as in the elderly with Alzheimer's
disease) arising out of the patient's diminishing ability to reason or understand his
environment.

Edwards' syndrome (choice B), or trisomy 18, causes death in infancy. Characteristics include
rocker-bottom feet, low-set ears, micrognathia, congenital heart disease, and mental
retardation.

Fragile X syndrome (choice C) is associated with enlarged testes as well as mental retardation.
The condition is unusual in that it is related to expansion of a CGG repeat sequence located on
the X chromosome.

Patau syndrome (choice D), or trisomy 13, is characterized by severe mental retardation,
microcephaly, microphthalmia, polydactyly, cleft lip and palate, renal defects, and cardiac
abnormalities. Affected infants typically die before the age of 1.

The effects of supernumerary Y chromosomes (choice E; most commonly XYY) include increased
stature, aggressive behavior, and infertility, but a supernumerary Y chromosome is sometimes
found in otherwise normal individuals.

The correct choice is D. This chromosomal aberration is also known as Edwards' syndrome, or
trisomy 18. It is characterized by mental deficiency, growth retardation, prominent occiput,
micrognathia, low-set ears, rocker-bottom feet, and ventricular septal defect.

XO (choice A) is the karyotype of Turner syndrome. It is characterized by short stature, webbed
neck, and hypogonadism.

XXY (choice B) represents Klinefelter syndrome. It is usually undetected at birth but is
characterized by tall stature, male hypogonadism, and sometimes, mental retardation.

Trisomy 13 (Patau syndrome; choice C) is characterized by mental retardation, nervous system
malformations, rocker-bottom feet, polydactyly, and cleft lip and palate.

Trisomy 21 (Down syndrome; choice E) is characterized by mental retardation, protruding tongue,
simian crease, congenital heart defects, and a flat nasal bridge.

The correct answer is C. Approximately half of all spontaneous abortions are of fetuses with
major chromosomal defects, most commonly trisomy 16, triploidy (due to fertilization of an egg
by two sperm), and 45 X,0 (Turner's syndrome). Trisomy 16 and triploidy do not produce viable
offspring, unlike 45 X,0.

Trisomy 8 (choice A) is one of the very rare causes of live birth trisomies.

Trisomy 13 (choice B) is one of the more common live birth trisomy syndromes (Patau syndrome).

Trisomy 18 (choice D) is one of the more common live birth trisomy syndromes (Edwards' syndrome)

Trisomy 21 (choice E) causes Down's syndrome.

Color blindness is an X-linked recessive trait. A male is hemizygous
for the X chromosome, and thus has only one copy of each trait. The frequency of an X-linked
recessive in males is thus equal to the frequency of the allele in the population. From this, we
know that q = 0.01 and p = 0.99. A female has two copies of each gene on the X chromosome, so
the equation for Hardy-Weinberg equilibrium is the same as for the autosomal traits. In this
case, a homozygous recessive female would occur at a frequency of q2 or 0.0001.

Choice B, 0.0005, is incorrect. If you remembered that color blindness was more frequent in
males, but did not know how to use the equations to get the true estimate, you might have
guessed this answer.

Choice C, 0.01, makes the assumption that the trait is autosomal, and so the frequencies of
affected males and affected females are equal.

Choice D, 0.02, assumes that q = 0.01, and then calculates the frequency of carrier females
(2pq).

Choice E, 0.025 is also incorrect; it is a distracter.

DiGeorge syndrome is caused by malformation of the third and fourth
pharyngeal pouches, leading to absence of the thymus and parathyroid glands, among other
abnormalities. It was originally believed that DiGeorge syndrome was an acquired abnormality,
but recent studies suggest that deletions of chromosome 22q11 are frequently involved. Infants
afflicted with this syndrome present as dysmorphic babies who develop convulsions or tetany a
short time after birth due to severe hypocalcemia caused by a lack of parathyroid hormone. These
patients are very difficult to manage, and frequently have severe associated cardiac defects
that may lead to death. Survivors often have at least small amounts of residual thymic tissue,
and have a few circulating T cells that tend to slowly increase with age. Antibody production is
usually adequate.

The disease is myotonic dystrophy, which is an autosomal dominant
disease; the affected gene has been localized to chromosome 19. Myotonic dystrophy is relatively
common and is best thought of as a systemic disease, since it causes cataracts, testicular
atrophy, heart disease, dementia, and baldness in addition to muscular weakness.

A mutation on the X chromosome (choice A) causes Duchenne muscular dystrophy.

None of the muscle diseases are known to be related to defects on the Y chromosome (choice B).
Facioscapulohumeral dystrophy is associated with a defective gene on chromosome 4 (choice C).

Infantile hypotonia has been related to defective genes on chromosome 5 (choice D).