Elements of Neurogenetics
membrane and raise its electrical resistance. The action	nism, myelinated nerve fibers conduct action potentials
potentials are therefore initiated only at the nodes,	much more rapidly than unmyelinated fibers. The nor-
“jumping over” the internodal axon segments (so-called	mal motor and sensory conduction velocity of periph-
saltatory conduction). Because of this special mecha-	eral nerves is 50−60 m/s.

Elements of Neurogenetics

Many neurological diseases are caused by genetic defects or tend to arise in the presence of a genetic predisposition. In this section, we will present the basics of both “classical” (Mendelian) inheritance and molecular genetics, as a necessary prerequisite for the understanding of these diseases and for the counseling of affected patients and their families.

General Genetics

The physical characteristics (phenotype) of an individual are determined both by the totality of that individual’s genetic information (the genotype) and by environmental influences during gestation and afterward. Genetic information is contained in DNA molecules in the cell nucleus and mitochondria. A segment of DNA containing the information necessary for the synthesis of a protein molecule is called a gene and the totality of the organism’s genes is called the genome. The nuclear genes of human beings are contained in 23 pairs of chromosomes—22 pairs of autosomes and one pair of sex chromosomes (gonosomes), which can be either XX (in females) or XY (in males).

Recombination of genetic material. The growth of the organism requires a large number of cell divisions (mitoses). In each mitosis, the nuclear genetic material doubles in amount (replicates) and is then distributed to the two daughter cells, so that each daughter cell, like the original cell, contains a complete (diploid) set of chromosomes. For the purpose of sexual reproduction, however, a reductive cell division (meiosis) occurs, producing egg or sperm cells that contain only a haploid set of chromosomes—i. e., only one of each chromosome (22 autosomes and one sex chromosome), as opposed to the 23 pairs found in all other cells. The union of an egg cell and a sperm cell restores a full (diploid) complement of chromosomes, half of which are derived from the maternal genome and half from the paternal genome.

According to the rules of Mendelian inheritance, ma- ternally-derived and paternally-derived properties (genes) are assorted randomly and independently to the germ cells, and thereby to the offspring. An important limitation of this random and independent assortment comes from the fact that genes located on the same chromosome are ordinarily transmitted together (because entire chromosomes are passed on to the germ cells). Yet, in a particular phase of meiosis, corresponding DNA segments on homologous chromatids can be exchanged with each other (crossing over), producing a

new arrangement of genes on the chromatids that take hjjhjh

part in the transaction (genetic recombination). The greater the distance between two genes on a chromosome, the more frequently recombination will occur between them.

In addition to these physiological mechanisms leading to change and reassortment of the genetic material (random assortment of maternal and paternal chromosomes in meiosis and fertilization, recombination of genes on homologous chromosomes), spontaneous changes in the genome, called mutations, can also occur. Mutations in the germ line are passed on to the individual’s offspring.

Autosomal dominant inheritance. A gene that markedly influences or completely determines the phenotype of the individual in the heterozygous state is called dominant. If the father or mother is heterozygous for a dominant allele, then their child has a 50 % chance of being heterozygous and displaying the corresponding phenotypic trait.

Autosomal recessive inheritance. An autosomal gene that has no effect in the heterozygous state and only manifests itself phenotypically in homozygotes is called recessive. If both the father and the mother are heterozygous for a recessive allele, then 75 % of their progeny will also possess at least one copy of the allele: 50 % will be heterozygous and 25 % will be homozygous. Only the homozygous offspring will display the corresponding phenotypic trait (e. g., a recessively inherited genetic disease). The heterozygous offspring (“carriers”) will not display the phenotypic trait; neither will the one-quarter of offspring who do not possess the recessive allele.

X-chromosomal inheritance. Males receive an X-chro- mosome from their mother and a Y-chromosome from their father, while females receive an X-chromosome from both parents. Mothers, therefore, will pass on an X-chromosomal gene to half of their offspring, whether male or female (as long as they are themselves heterozygous for it), while fathers will pass it on to all of their daughters, but not to their sons. Dominantly inherited X-chromosomal diseases affect both males and females; recessively inherited X-chromosomal diseases mainly affect males, striking only the rare females that are homozygous for the disease, i. e., only those who have inherited an X-chromosome with the diseased gene from each of their parents. Any affected male is certain to have received the gene from his mother; as long as his female partner is not a carrier of the disease, all of his daughters will be healthy carriers. Female carriers whose male partners do not have the disease will pass on the disease to 50 % of their sons; all of their daughters will be healthy, though half will carry the gene for the disease.

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5

1

Fundamentals

6 1 Fundamentals

Maternal inheritance of the mitochondrial genome.	contains a large number of repetitive sequences of trinu-
Mitochondrial DNA is passed on exclusively in the ma-	cleotides, whose presence affects the function and ex-
ternal line: mitochondrial genetic diseases are trans-	pression of genes. An important group of neurodegenera-
mitted only by mothers to their children (both male and	tive diseases is caused by mutations involving abnor-
female), but never by fathers. Mitochondria with mu-	mally long (expanded) triplet repeat sequences. These
tated DNA can coexist in the same cell with other mito-	diseases are called trinucleotide or triplet repeat dis-
chondria whose DNA is normal. This phenomenon,	eases. Where the normal repeat sequence might contain
called heteroplasmia, has no counterpart in the nuclear	only a few triplets, the diseased sequence contains
genome, which is the same in every cell of the body. In	dozens or hundreds. The longer the expansion, the earlier
mitochondrial genetic diseases, the phenotype, i. e., the	the age of onset of disease, and the more severe its
extent of damage to the involved cells and tissues, de-	manifestations. The repeat sequences tend to lengthen
pends on the ratio of mutated to normal mitochondrial	from one generation to the next, so that the disease tends
DNA and on the number of defective mitochondria that	to appear earlier and earlier (“anticipation”) and to be-
are present.	come increasingly severe.
Mutations are necessary for evolution; without them,	Mutations of mitochondrial DNA impair oxidative me-
the human species would not exist. Yet, adverse muta-	tabolism in the mitochondria, causing a number of differ-
tions can also cause genetic defects and diseases. Muta-	ent types of disease, including mitochondrial encephalo-
tions can be classified into genomic and intragenic types.	myopathies (p. 272).
Genomic mutations are of two types, designated as	Neurogenetics
numerical and structural chromosomal aberrations. In
the former type of mutation, the number of chromo-
somes is abnormal (e. g., monosomy, trisomy); in the	The triplet diseases are of special relevance to neurology.
latter type, the structure of a chromosome is abnormal.	The neurodegenerative diseases caused by expanded
Structural aberrations include deletions, transloca-	triplet repeats are listed in Table 1.1; their common fea-
tions,and inversions of chromosomal segments.	tures are summarized in Table 1.2. Some of the more
Intragenic mutations involve alterations of the DNA.	common inherited mitochondrial diseases are listed in
	Table 1.3 (for their clinical manifestations, cf. p. 272).
Within each chromosome, DNA is arranged linearly.	Ever more genetic defects are being identified as the
DNA segments (genes) that code for amino acid	cause of neurological and other diseases. Large tables and
sequences (proteins) are called exons and are found in	books are available for those seeking up-to-date infor-
alternation with noncoding sequences called introns.	mation. Rapid access to the current state of knowledge is
Exons account for only about 5 % of human chromo-	best obtained via the Internet. Two useful sites are
somal DNA. When the DNA is transcribed into RNA, the	“Online	Mendelian	Inheritance	in	Man”
primary RNA transcript contains a copy of the introns.	(http://www3.ncbi.nlm.nih.gov/OMIM/)			and	Medline
These are then spliced out in a second stage of pro-	(http://www4.ncbi.nlm.nih.gov/entrez/query.fcgi).
cessing, which yields the mature transcript, messenger
RNA (mRNA).	Genetic Counseling
Each group of three consecutive nucleotides in the
mRNA molecule (called a triplet or codon) codes for an
amino in the protein undergoing biosynthesis. “Stop co-	Many genetic mutations can be detected directly by
dons” between the exons signal the beginning and end	DNA analysis. The results are highly specific. Thus, many
of the gene and thereby determine the length of the pro-	diseases can be diagnosed even before they become
tein that is to be synthesized.	symptomatic, so that a long-term prognosis can be
Mutations involving the replacement of a DNA nu-	given. Sadly, these diseases are generally untreatable
cleotide by a different nucleotide often alter the sense of	and inexorably progressive.
the codon to which it belongs (missense mutations): the	Before any DNA analysis is performed, the treating
wrong amino acid is inserted into the gene product at this	physician should:
point in protein biosynthesis. The ultimate effect this has	perform a meticulous clinical examination,
on protein function is highly variable. If, however, a nu-	obtain a detailed family history and personally ex-
cleotide replacement happens to result in the generation	amine the patient’s relatives, if possible,
or destruction of a stop codon, an incomplete or exces-	inform the patient and his or her relatives in detail
sively long protein will be produced (nonsense muta-	about the suspected disease, and
tions). Other mutations involving the insertion of an extra	explain the consequences of the proposed DNA analy-
nucleotide into the DNA, or the deletion of a nucleotide,	sis to them in a readily understandable manner.
alter the rhythm of nucleotide triplets and are therefore
called frame-shift mutations. These usually cause severe	A negative DNA analysis can provide relief and free the
abnormalities of protein structure and function (e. g.,	patient from anxiety. A positive result, on the other
Duchenne muscular dystrophy, p. 265).	hand, may propel the patient into a severe depression,
Expanded repetitive DNA sequences. A further type of	as he or she will then face the certainty of developing an
	inherited disease, mostly with a grim prognosis, and
mutation of special importance in neurology affects the	may not be able to cope with this knowledge. The
number of trinucleotides (triplets). Normal human DNA	knowledge of a genetic abnormality may also put a

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Elements of Neurogenetics	7

Tabelle 1.1 Some neurodegenerative diseases caused by triplet repeat expansions

Disease	Major clinical manifestations	Triplet	Chromosomal
			localization
Fragile X-chromosome	diminished intelligence, sometimes facial dysmorphism, connec-	CGG	Xq27
	tive tissue dysplasia
Myotonic dystrophy	progressive, mainly distal muscular dystrophy and myotonia	CTG	19q13.3
Friedreich ataxia	ataxia, areflexia, pyramidal tract signs, dysarthria	GAA	9q13−q21.1
Spinobulbar muscle atrophy	muscle atrophy, dysarthria, fasciculations, gynecomastia	CAG	Xq13−q21
(Kennedy syndrome)
Huntington disease	chorea, rarely spasticity or rigidity, cognitive and behavioral dis-	CAG	4p16.3
	turbances
Spinocerebellar ataxia type 1 (SCA1)	cerebellar ataxia, sometimes chorea or dystonia, poly-	CAG	6p24
	neuropathy, often pyramidal tract signs, sometimes dementia
Spinocerebellar ataxia type 2 (SCA2)	cerebellar ataxia, sometimes chorea or dystonia, myoclonus,	CAG	12
	polyneuropathy, sometimes pyramidal tract signs and dementia
Spinocerebellar ataxia type 3 (SCA3);	cerebellar ataxia, sometimes chorea or dystonia, poly-	CAG	14
Machado−Joseph disease	neuropathy, sometimes pyramidal tract signs and dementia
Spinocerebellar ataxia type 6 (SCA6)	cerebellar ataxia, sometimes polyneuropathy and pyramidal	CAG	19p13
	tract signs
Spinocerebellar ataxia type 7 (SCA7)	cerebellar ataxia, sometimes chorea or dystonia, retinal	CAG	3p
	degeneration, polyneuropathy, sometimes pyramidal tract signs
Spinocerebellar ataxia type 8 (SCA8)	cerebellar ataxia, spasticity, impaired vibration sense	CTG	13q21
Dentato-rubro-pallido-luysian	ataxia, myoclonus, epilepsy, choreoathetosis, dementia	CAG	12p
atrophy (DRPLA)

1

Fundamentals

severe stress on a marriage or other partnership. Social problems of yet other kinds may arise, because persons with inherited diseases are, unfortunately, often treated like outcasts in our postindustrial society. They may have troubles in the workplace, not least because they are likely to be uninsurable. For all these reasons, genetic testing generally causes fewer problems if it is performed after the disease has become symptomatic. Asymptomatic children should not be subjected to genetic testing even if their parents ask for it. They should be allowed to decide for themselves whether to undergo testing once they are mature enough to do so and have attained legal majority.

Many patients and their relatives decide not to undergo testing after being fully informed about their potential genetic disease and the consequences of DNA analysis. In particular, presymptomatic and asymptomatic persons would often rather not find out whether they would develop the disease at some time in the future. A positive test result would destroy their hopes for good health in later life.

If the patient does decide to undergo DNA analysis and then tests positive, the physician should inform the patient and his or her relatives in a personal discussion, with ample time to consider all of the implications. Test results should never be imparted over the telephone or in written form. Patients who have tested positive often

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Table 1.2 Common features of triplet repeat diseases

Autosomal dominant or X-chromosomal inheritance

Onset usually between the ages of 25 and 45

Gradual progression of disease

Symmetrical neuronal loss and gliosis in the brain

Anticipation

The number of triplet repeats is correlated with the age of onset and the severity of the disease

The diagnosis can be established by DNA analysis

Table 1.3 Mitochondrial encephalomyopathies

Progressive external ophthalmopathy (PEO)

Kearns−Sayre syndrome (KSS)

Leber hereditary optic neuropathy (LHON)

Mitochondrial encephalomyopathy with lactic acidosis and stroke (MELAS)

Leigh disease

Neuropathy, ataxia, and retinitis pigmentosa syndrome (NARP)

Myoclonus epilepsy with ragged red fibers (MERRF)

need long-term psychotherapy. Nor does the physician− patient relationship end once the test results are given: many patients with hereditary neurological diseases can be greatly helped by continuing psychological support and symptomatic treatment.

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Mumenthaler / Mattle, Fundamentals of Neurology © 2006 Thieme

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