Файл: Genetics [BRS].pdf

C

D

E

F

A

B

FIGURE 6-2. Mitochondrial inherited diseases. (A) mtDNA-associated Leigh syndrome. 

MRI (axial T2 weighted) shows

bilateral hyperdensity in the caudate nucleus, putamen, and globus pallidus. Prominent perivascular spaces (arrows) can
be observed scattered throughout the basal ganglia. (B) MELAS. MRI (axial T2 weighted) shows bilateral hyperdensity in
the basal ganglia and external capsule. (C-F) Mitochondrial myopathy. (C) Light micrograph shows a ragged red fiber with
a proliferation of subsarcolemmal mitochondria (arrow). (D) Light micrograph shows a ragged red fiber with normal suc-
cinate dehydrogenase staining (arrow) since succinate dehydrogenase is encoded by nuclear DNA. (E) Light micrograph
shows a ragged red fiber with absent cytochrome oxidase staining (arrow) since cytochrome oxidase is encoded by mito-
chondrial DNA. (F) Electron micrograph shows abnormal mitochondria with paracrystalline inclusions (arrow).

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61

Review Test

1.

Which of the following describes what

happens in a family where one of the parents
has a mitochondrial disease?

(A)

All of the children of an affected mother
will inherit the disease.

(B)

All of the children of an affected father
will inherit the disease.

(C)

Only males will be affected if the mother
has the disease.

(D)

Only females will be affected if the father
has the disease.

2.

In myoclonic epilepsy with ragged red

fibers syndrome (MERRF), expression of the
disease is highly variable, with some family
members being severely affected while oth-
ers are not affected at all. Which of the fol-
lowing explains the variable expression of
this disease?

(A)

variable expressivity

(B)

incomplete penetrance

(C)

heteroplasmy

(D)

allelic heterogeneity

3.

Jack has been diagnosed with a mitochon-

drial disease. His wife Sally does not have the
disease and currently is pregnant. What is
the risk that Jack and Sally’s child will have
the disease?

(A)

0%

(B)

25%

(C)

50%

(D)

100%

4.

Which one of the following is a character-

istic of the mitochondrial genome?

(A)

It has a very low mutation rate.

(B)

The DNA is bound to histones.

(C)

Replication of the DNA occurs in the
nucleus.

(D)

There are no introns present.

5.

Which of the following is a characteristic

of mitochondrial disorders?

(A)

They are inherited in a Mendelian fash-
ion. 

(B)

There is a threshold level of mutated
mitochondria that must be reached
before clinical symptoms appear.

(C)

All cell types in the body are equally
affected by mitochondrial disorders.

(D)

The degree of severity is the same for
most affected individuals.

6.

Which one of the following mitochondrial

diseases shows the typical mitochondrial
inheritance pattern?

(A)

MELAS

(B)

MERRF

(C)

LHON

(D)

KS

7.

A mitochondrial disorder characterized by

myoclonus, seizures, cerebellar ataxia,
dementia, and mitochondrial myopathy in
which the skeletal muscle cells have an irreg-
ular shape and blotchy red appearance is
which one of the following?

(A)

MELAS

(B)

MERRF

(C)

LHON

(D)

KS

8.

Which of the following is characteristic of

the mitochondrial genome?

(A)

There are 37 genes, which make up
93% of the genome.

(B)

DNA replication is the same as in the
nuclear genome.

(C)

The DNA in the genome is found on 23
chromosomes.

(D)

Every exon has an intron.

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62

Answers and Explanations

1. The answer is (A).

Because all of the mitochondria in a conceptus comes from the ovum,

with none coming from the sperm, all mitochondria in an individual are maternally inher-
ited. Therefore, all of the children of a mother with a mitochondrial disease will be affected
with the disease to some degree. 

2. The answer is (C).

In some mitochondrial diseases, like MERRF, there is a mixture of mito-

chondria, some of which carry the disease-causing mutation and some that are normal. This
is called heteroplasmy. If, by chance, an individual inherits more of the normal mitochon-
dria than abnormal, then they may exhibit a milder form of the disease or have no symp-
toms at all. 

3. The answer is (A).

Because mitochondrial diseases are maternally inherited, Jack cannot

pass on the disease.

4. The answer is (D).

The mitochondrial genome has a mutation rate 10 times that of the

nuclear DNA, is not protected by histones, consists only of exons, and replication occurs in
the mitochondrial matrix.

5. The answer is (B).

Inheritance in mitochondrial disorders in exclusively maternal and there

is a wide degree of severity among affected individuals because of heteroplasmy. Cell types
that have a high ATP requirement are more seriously affected by mitochondrial disorders. If
an individual does not a lot of mutated mitochondria, then the threshold where clinical
symptoms appear will not be reached. When a sufficient number of mutated mitochondria
are present in an individual, the threshold will be reached and the disease manifested.

6. The answer is (C).

In Leber’s hereditary optic neuropathy (LHON), heteroplasmy is rare and

disease expression is relatively uniform. Heteroplasmy is common in the other mitochondr-
ial diseases listed.

7. The answer is (B).

In myoclonic epilepsy with ragged red fibers (MERRF) syndrome, the

abnormal mitochondria in the skeletal muscle cells give them an irregular shape and a
blotchy red appearance so that the muscle fibers look ragged. 

8. The answer is (A).

Mitochondrial DNA is arranged as a circular piece of double stranded

DNA with no introns, only exons, with 37 genes, which make up most of the genome. 
DNA replication occurs in the mitochondrial matrix and is catalyzed by a different DNA
polymerase than nuclear DNA.

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c h a p t e r

7

Multifactorial Inherited
Disorders

63

I. INTRODUCTION

Multifactorial inheritance involves many genes with an additive effect 

(Genetic Component)

interacting with the environment 

(Environmental Component).

Both the genetic and environ-

mental components contribute to a person inheriting the liability to develop a certain disor-
der. If one considers only the genetic component of a multifactorial disorder, the term

polygenic

(“many genes”) is used. Inheritance patterns in multifactorial disorders usually do

not conform to those seen with Mendelian inheritance. Recurrence risks are based on
empiric data from population studies.

II. CLASSES OF MULTIFACTORIAL TRAITS

A. Quantitative Traits (Figure 7-1A).

These traits are determined by many different genes

along with environmental factors (e.g., diet, job exposure) that determine the pheno-
typic outcome. These phenotypic traits tend to follow a normal distribution in the popu-
lation. Some examples of quantitative traits include: height, weight, blood pressure, and
intelligence.

B. Threshold Traits (Figure 7-1B).

1.

These traits are relatively common isolated congenital defects with an underlying varia-
tion in liability. 

Liability

is the person’s predisposition for a congenital defect that may be

determined by more than one gene. Liability can vary based on gender. 

2.

In threshold traits, there is a 

liability distribution

where a clinical effect is not seen until the

threshold is reached. Individuals above this threshold have the defect because they have
more of the alleles and environmental factors, which cause the defect than those below
the threshold. 

3.

Some examples of congenital defects, which follow this model, are:  isolated cleft lip
and/or cleft palate, neural tube defects (spina bifida and anencephaly), clubfoot, and
pyloric stenosis. An example of an environmental component to a threshold trait is neural
tube defects, where increased folic acid intake before and during pregnancy helps to pre-
vent spina bifida and anencephaly. 

C. Common Adult Disorders.

These are disorders of adult life in which a genetic component and

an environmental component play a role. Some examples include: Type 1 and Type 2 dia-
betes, hypertension, heart disease, cancer, alcoholism, and psychiatric disorders.

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64

BRS Genetics

III. FACTORS AFFECTING RECURRENCE RISKS IN MULTIFACTORIAL

INHERITED DISORDERS

The recurrence risk for having a multifactorial inherited disorder is the empirically derived

population risk.

However, if an individual in a family has a multifactorial inherited disorder,

there are a number of factors which influence the recurrence risk in that family which
include:

A.

Heritability.

Heritability (H) is the estimate of the contribution that the genetic component

makes to a trait and ranges from 0 

→

1.

1. If H 

0,

then the variation in a trait among individuals in a population is entirely due to

the 

environmental component.

2. If H 

1,

then the variation in a trait among individuals in a population is entirely due to

the 

genetic component.

3.

The heritability increases (i.e., H tends toward 1) as the 

concordance

(two individuals

having the same trait) increases in monozygotic (MZ) twins versus dizygotic (DZ) twins

(

c

c

heritability

 cc

concordance)

. This is indicated in the following examples: 

a.

Idiopathic seizures have a high heritability (i.e., a larger genetic component and a
smaller environmental component) because the concordance for idiopathic seizures is
85% to 90% in MZ twins versus 10% to 15% in DZ twins. 

b.

Cleft palate has a low heritability (i.e., smaller genetic component and a larger environ-
mental component) because the concordance for cleft palate is 25% in MZ twins versus
10% in DZ twins. 

B. Incidence in the Population.

The incidence of a trait in a multifactorial inherited disorder

often varies between populations. In Ireland, the incidence of neural tube defects is 1 in 200
births. In the United States, the incidence of neural tube defects is 1 in 1,000 births. The
recurrence risk in first-degree relatives is approximately the square root of the population
incidence 

(recurrence risk

√

population incidence).

C. Sex Bias.

Multifactorial inherited disorders are often more common in one sex than in the

other (i.e., sex biased). Examples of male sex biased disorders/malformations include:
pyloric stenosis, cleft lip with or without cleft palate, spina bifida, and anencephaly.
Examples of female sex biased disorders/malformations include: congenital hip dysplasia
and idiopathic scoliosis. In sex-biased disorders, the recurrence risk is higher in the follow-
ing conditions:

1.

If an affected child in the family is of the more-affected sex, then the recurrence risk to a
same-sexed sibling is higher than the recurrence risk to another-sex sibling. The recur-
rence risk to either-sex sibling is greater than the general population risk for the condi-
tion. 

2.

If an affected child in the family is of the less-affected sex, then the recurrence risk to
another-sexed sibling is higher than the recurrence risk to a same-sexed sibling. The
recurrence risk to either-sex sibling is greater than the general population risk for the
condition.

Example 7-1. Male-Biased Pyloric Stenosis

Pyloric stenosis is an obstruction of the area between the stomach and the intestines that
causes severe feeding problems and is more common in males (male-biased). 

1.

If a male child in a family was born with pyloric stenosis, then the recurrence risk to his
future brother is 3.8%, whereas the recurrence risk to his future sister is 2.7%. 

However, 

2.

If a female child in a family was born with pyloric stenosis, then the recurrence risk to her
future brother is 9.2%, whereas the recurrence risk to her future sister is 3.8%. 

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