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Genetics of Neurological Disorders
张咸宁
[email protected]
Tel：13105819271; 88208367
Office: A705, Research Building
2012/11
Learning Objectives
1. To become familiar with the clinical phenotypes of the
major triplet repeat disorders such as fragile X syndrome,
Huntington disease, myotonic dystrophy and Friedreich
ataxia.
2. To understand the unique and unusual molecular
mechanisms and modes of inheritance underlying these
disorders.
3. To appreciate how this knowledge is translated to clinical
molecular genetic testing of these disorders for purposes of
diagnosis, predictive testing, and prenatal testing.
4. To become aware of some of the difficult ethical issues
associated with molecular testing for these disorders.
Required Reading
Thompson &Thompson Genetics in Medicine,
7th Ed （双语版，2009）
Pages 302-305, Chapter 12, The Molecular
and Biochemical Basis of Genetic Disease Diseases due to the Expansion of Unstable
Repeat Sequences: Biochemical and
Cellular Mechanisms
Case Study, 15. Fragile X Syndrome
22. Huntington Disease
• 在已发现的单基因遗传病（www.omim.org）中，
半数以上累及神经系统。国内神经系统单基因遗
传病的发病率约为109.3/10万，其中以遗传性共济
失调和进行性肌营养不良最常见，神经系统遗传
性代谢缺陷病则以种类多、发病率低为特征。
• 神经系统遗传病可在任何年龄发病。出生后：半
乳糖血症等，婴儿期：SMA1、Tay-Sachs病等，
儿童期：DMD等，少年期：肝豆状核变性、
SMA2等，青年期：腓骨肌萎缩症等，成年期：强
直性肌营养不良等，成年后期：Huntington舞蹈
症等，老年期：Alzheimer病等。多数神经系统遗
传病在30岁之前出现症状。
• 神经系统遗传病病种繁多，致残和致畸率很高，
治疗困难。
ALS is a lethal, paralyzing disorder of motor neurons in the
brain, brainstem and spinal cord. Its onset, typically in the 6th
decade of life, is age-dependent; mean onset is 55 yr, and mean
survival is 3–5 yr. About 5–10% of cases are transmitted as an
autosomal dominant trait familial ALS.
Classification of Neurogenetic Disorders
by Presentation
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Dementias
Muscular dystrophies and atrophies
Ataxias
Mental retardation/dysmorphism
Classification by Molecular Defect
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Point mutations
Large deletions
Trinucleotide repeat expansions
Mitochondrial DNA mutations
Trinucleotide repeat expansions are
dynamic mutations
• An unstable expanded repeat that
changes size between parent and
child.
Contrasting Features of Triplet
Repeat Disorders
Huntington AD
disease
CAG
Coding region
(exon 1)
Fragile X
syndrome
X-linked
CGG
Myotonic
dystrophy
AD
CTG
5’untranslated
region
3’untranslated
region
Friedreich
ataxia
AR
GAA
Intron
Unusual Aspects of Inheritance
of Trinucleotide Repeat Disorders
• Anticipation:
tendency toward earlier age of onset and/or greater
severity in each subsequent generation, due to
progressive expansion of the repeat length.
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•
•
•
•
•
Parent-of-origin effects
Skewed X-inactivation
Methylation effects
Incomplete penetrance
Variable expressivity
Premutation alleles:
asymptomatic, but unstable, with a tendency to expand
in the next generation
(A) In fragile X
syndrome, the expanded
repeat in the 5’ UTR of
the gene triggers
methylation of the
promoter and prevents
transcription.
(B) In myotonic
dystrophy, the expanded
repeat in the 3’ UTR
causes the mRNA
transcript to sequester
splicing factors in the
cell nucleus, preventing
the correct splicing of
several unrelated genes.
(C) In Huntington
disease, the gene
containing the expanded
repeat is transcribed
and translated as
normal, but the protein
product has an
expanded polyglutamine
tract that renders it
toxic.
Huntington Disease (Chorea)
• a progressive loss of motor control, dementia, and
psychiatric disorders. The brain area most
noticeably damaged is the corpus striatum. The
suicide rate among HD patients is >5~10 in the
general population.
• approximately 1 in 20,000 persons of European
descent.
• usually manifests between the ages of 30 and 50
years, although it has been observed as early as 1
year of age and as late as 80 years of age.
Woody Guthrie (1912-1967)
HD gene----Hero!
• In 1983, HD was the first genetic disease to be localized
to a chromosome location (4p16.3) with RFLP linkage
analysis. (Gusella et al.)
Robertson:“The beginning of the end of dilemma?”
(Nature)
• The HD gene, Huntingtin, was isolated in 1993 after a
decade of intense collaborative efforts among many
laboratories from various countries and officially
designated HD. (Gusella et al.)
Little:“Huntington’s disease: The end of the
beginning”(Nature)
Trinucleotide CAG repeat sizes in
HD gene (huntingtin)
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Normal ≤26
Mutable 27-35
Reduced penetrance 36-39
Fully penetrance ≥40
Clinical Case
Mary (35 y.o.), Samuel (30 y.o.), and Alice
(29 y.o.) are siblings at 50% risk to inherit
Huntington disease from their father, John,
who was found to have a mutable normal
allele when he was tested following
diagnosis of his brother, Bart. All three
siblings chose molecular genetic testing
following genetic counseling and
neurologic evaluation. All have normal
neurologic examinations.
John
Mutable normal
Bart
Mary
38 CAG
repeats
Alice
42 CAG repeats
Samuel
35 CAG repeats
What do these results mean?
Diagnosis
Molecular Genetic Testing
Samuel (35 repeats) is told that he has a
mutable normal allele. Expansions of 27-35
CAG repeats have never been associated
with clinical symptoms of HD; however, his
children are at some risk to inherit an allele
with a larger allele size which could result in
symptomatic HD.
Mary
Alice
Samuel (30 y.o.)
35 CAG repeats
Mutable normal allele
Mary (38 repeats) is told that she has a reduced
penetrance allele. Expansions of 36-40 CAG
repeats may or may not cause symptoms of HD
during a normal life span. The onset of symptoms
may be later than typically observed. Mary's
children are at 50% risk for inheriting the abnormal
allele, which could remain in the reduced
penetrance range or expand into the full
penetrance range.
Mary (35 y.o.)
38 CAG repeats
Reduced
penetrance allele
Alice
Samuel
Alice (42 repeats) is told that she has a full
penetrance allele.. Expansions of 41 CAG repeats
or greater are always associated with symptomatic
HD if the individual lives a normal life span. Alice's
children are at 50% risk to inherit the full
penetrance allele and therefore to develop HD.
Mary
Samuel
Alice (29 y.o.)
42 CAG repeats
Full penetrance allele
Anticipation
• the phenomenon in which increasing disease
severity or decreasing age of onset is observed in
successive generations, is known to occur in HD.
• occurs more commonly in paternal transmission
of the mutated allele. The phenomenon of
anticipation arises from instability of the CAG
repeat during spermatogenesis. Large expansions
(i.e., an increase in allele size >27 CAG repeats)
occur almost exclusively through paternal
transmission.
• Most often children with juvenile-onset disease
have inherited the expanded allele from their
fathers.
Predominant Clinical Features of
Fragile X Syndrome in Males
Prepubertal
• Delayed developmental milestones: Sit alone, 10 mo; Walk,
20.6 mo; First clear words, 20 mo.
• Developmental delay
• Abnormal behavior: Tantrums; Hyperactivity; Autism
• Mental retardation: IQ 30 to 50
• Abnormal craniofacies: Long face; Prominent forehead;
Large ears; Prominent jaw
Postpubertal
• MR; Pronounced; Craniofacies; Macroorchidism
Additional Features
• Strabismus; Joint hyperextensibility; Mitral valve prolapse;
Soft, smooth skin
A: Two-yr-old male with a full mutation exhibiting a relatively
normal appearance with an elongated face and prominent ears;
also note tapering fingers, a minor anomaly.
B: At age 5 years, his head is large with large ears and a
prominent jaw.
C: At age 22 years.
CGG Repeat in Fragile X Syndrome
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Normal range: 6-54
Premutation range: 52-200
Full mutation range: 200- >1000
Alleles with >200 repeats are
hypermethylated, transcriptionally
repressed
Risk of Expansion of Fragile X Premutations
Length of maternal
premutation
Incidence of full mutation in
offspring
56-59
13%
60-69
20%
70-79
58%
80-89
73%
90-99
94%
100-109
100%
120-129
100%
Nolin et al., Am J Hum Genet 1996
Is the fragile X premutation really
asymptomatic?
• Recent reports of premature ovarian
failure in female premutation carriers
• Late-onset tremor-ataxia-dementia
syndrome in male premutation carriers
• May be due to mRNA interference with
expression of the normal FMR1 allele or
of other genes
A New Fragile X Testing Dilemma
• Genetic counselors and obstetricians are
beginning to order fragile X carrier screening
on all pregnant women, regardless of family
history
• Unexpected premutation alleles are being
identified, leading to amniocentesis
• Pregnancies in which the fetus is found to have
only the premutation are typically continued
• The resulting child is now labeled with a lateonset genetic disease for which there is no
treatment
NIH Task Force on Genetic Testing
Myotonic Dystrophy
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AD
Myotonia, muscular dystrophy
Cataracts, hypogonadism, frontal balding
Severe neonatal form due to dramatic
CTG repeat expansion from affected
mother only
A three-generation family
affected with myotonic
dystrophy. The degree of
severity increases in each
generation. The grandmother
(right) is only slightly affected,
but the mother (left) has a
characteristic narrow face and
somewhat limited facial
expression. The baby is more
severely affected and has the
facial features of children with
neonatal-onset myotonic
dystrophy, including an open,
triangle-shaped mouth. The
infant has more than 1000 copies
of the trinucleotide repeat,
whereas the mother and
grandmother each have
approximately 100 repeats.
Friedreich Ataxia
• AR
• The most common of the hereditary ataxias in
the Caucasian population.
• Gait disturbance in childhood
• Upper extremity ataxia
• Absent reflexes
• Intellectual decline
• Progressive cardiomyopathy
• Small proportion due to point mutations rather
than GAA repeat expansion
1
Friedreich
Ataxia
PCR
Normal allele size
2
3
Acknowledge（PPT特别鸣谢！）
• UCLA David Geffen School of Medicine
• www.medsch.ucla.edu/ANGEL/
• Prof. Grody WW (Divisions of Medical
Genetics and Molecular Pathology), et al.