I.

Disorders with trinucleotide

expansion:
Huntington’s chorea
Fragile X syndrome
Myotonic dystrophy

II. Congenital defects of the connective

tissue:
Osteogenesis imperfecta
Marfan syndrome
Ehlers – Danlos syndrome
I. Disorders with
trinucleotide expansion
 Why Know About
Trinucleotide Repeat Disorders?
• Over 15 different genetic disorders that cause a
significant proportion of the inherited neurological
diseases in adults and the most common cause for
inherited mental retardation in males (Fragile X
syndrome).
• Molecular DNA diagnosis is available for diagnosis
confirmation, predictive testing, prenatal testing,
preconception testing, and preimplantation diagnosis.
• Genetic counseling issues are complex and important
to understand as there raise ethical issues.
 Repetitive DNA and disease
• Expansion of trinucleotide repeats (multiple
copies of a 3-nucleotide sequence).

• The longer the tract length is (i.e. number of

repeats) the more likely the repeat is going to
continue to mutate.
 Dynamic Mutations
• Unlike classic mutations dynamic mutations
change - they continue to mutate between
different tissues and across the generations.

• Genetic anticipation
 Anticipation

•Earlier onset of the symptoms with each next

generation;
•Increase of the severity of symptoms;
•Anticipation is common in trinucleotide repeat
disorders, such as Huntington's disease,
myotonic dystrophy and rare in Fragile X
syndrome.
 Major Features of Most
Trinucleotide Repeat Disorders
• Neurological/cognitive symptoms;

• Many are autosomal dominant with variable expression;

(exceptions: Friedreich ataxia (recessive); Spinobulbar muscular
atrophy, Fragile X syndrome - X-linked recessive)

• Later age of onset;

(exceptions: congenital myotonic dystrophy, Fragile X syndrome,
FRAXE);

• Meiotic and mitotic instability with some degree of anticipation

in many disorders;
 Where are the expansions located?

5’ UTR exon intron exon intron exon 3’ UTR

CGG CAG GAA CTG

**FRAXA **HD FA MD
FRAXE SCAs
SMBA
DRLPA

Trinucleotide repeat disorders can involve expansions

of various repeats in coding and non-coding regions of
the gene.
 Trinucleotide repeat mutation in
coding region

• If the expansion occurs in a coding region the

result is usually gain of function.

• The protein has an altered function.

 Trinucleotide repeat mutation in non-coding
region

5’UTR 3’UTR

5’UTR 3’UTR

If the expansion occurs in a non-coding region it often leads to loss of function or

gene silencing.
The mutation prevents the expression of the gene.
 Huntington’s Disease
CAG
repeat, >28
copies

5’UTR 3’UTR

(CAG)n
5’UTR 3’UTR

O O O
H
N CH C HN CH C NH CH C

CH2 CH2 CH2

CH2 CH2 CH2 A chain of glutamines in

C O C O C O the protein Huntingtin
NH2 NH2 NH2

QQQQ PolyGlutamine or PolyQ

 Huntington’s chorea
Progressive degenerative
disorder of
•motor,
•cognitive and
•psychiatric disturbances.

Mean age of onset - 35 to 44

years;
Median survival time - 15 to
18 years after onset;

“Chorea"
Chorea comes from the Greek word for "dance" and refers to the incessant quick,
jerky, involuntary movements that are characteristic for the disease.
• Type of inheritance: autosomal dominant
• Prevalence:
- 3 to 7 per 100,000 in people of European ancestry;
- The disorder appears to be less common in some
other populations - Japanese, Chinese, and African descent.
- Highest prevalence in Maracaibo, Venezuela;

• Anticipation
- The symptoms in the offspring are more severe when is
inherited from the father due to the instability of the
repeats in the male gametogenesis.
 Genetics of Huntington’s chorea
Gene: HTT - 67 exons and spans more than 200 kb.
The gene contains up to 26 trinucleotide repeats
(CAG) in the first exon.

Locus: 4p16​.3

Gene product: huntingtin – widely expressed

protein of 3144 amino acids;

Gene function: protein-protein interactions;

Huntington disease - a triplet repeat
disease

Number “13”

An expansion of 36 or more CAG trinucleotide repeats in  the 1-st exon of HTT.
Trinucleotide CAG repeat sizes in HD gene
(huntingtin)
   
Number of the CAG Phenotype
repeats
 
  normal
From 10 to 26
  intermediate
From 27 to 35
  HD-causing with reduced penetrance
between 36 and 39
  HD-causing with full penetrance
40 or more
How huntingtin harms – impaired
protein import?
 Pathophysiology

Destroys neurons in the brain areas involved in the

emotions, intellect, and movement.

BRAIN ATROPHY – Brain Cell Death

18
Neuroimaging
CT-scan - often shows
shrinkage of the brain
(actually loss about 30% of
brain weight).
MRI scans have revealed
significant striatal atrophy.
Neuropathology
selective degeneration of
neurons in the caudate and
putamen;
Intraneuronal inclusions
containing huntingtin;
19
 Types of Symptoms

1. Abnormalities of the movement

2. Cognitive

3. Psychiatric

Chorea can become more intense when the

patient is anxious or upset.

20
 Abnormalities of movement
• Nonrepetitive, non-periodic jerking of limbs,
face, or trunk;
• Bradykinesia, rigidity, and dystonia;
• Motor speed, fine motor control, and gait
are affected;
• Oculomotor disturbances;
• Dysarthria;
• Hyperreflexia;
 Cognitive impairment
 As Huntington's disease progresses, the ability to
concentrate becomes more difficult.

 May have difficulty in driving, making decisions,

answering questions, and may lose the ability to
recognize familiar objects.

 Over time judgment, memory, and other cognitive

functions develop in dementia.

22
 Psychiatric disturbance
 Early psychiatric symptoms of Huntington's disease are
subtle, varied, and easily overlooked or misinterpreted.
 Depression is the most common psychiatric symptom and
often develops early in the course of the disease. Signs of
depression include:
- Hostility/irritability
- Anhedonia
- Lack of energy
- Suicide risk
 Psychotic behavior:
- Delusions
- Hallucinations
- Inappropriate behavior (eg unprovoked aggression)
- Paranoia
23
 Genetic Testing

• PCR-based methods detect alleles up to about

115 CAG repeats.
• Southern blot protocols are occasionally useful
for:
Identification of large expansions (which may fail to
amplify well by PCR analysis);
Confirmation of apparent homozygous genotypes
obtained by PCR analysis;

24
 Treatment
 There is NO CURE for Huntington's disease.

 Collaborative goals focus on:

- Reducing symptoms;
- Preventing complications;
- Providing support and assistance to the patient;

25
 Medication
Antipsychotics (hallucinations, delusions, violent outbursts):
haloperidol, chlorpromazine, olanzapine (contraindicated if patient has dystonia)

Antidepressants (depression, obsessive-compulsive behavior):

fluoxetine, sertraline hydrochloride, nortriptyline

Tranquilizers (anxiety, chorea):

benzodiazepines, paroxetine, venlafaxin, beta-blockers

Mood-stabilizers (mania, bipolar disorder):

lithium, valproate, carbamazepine

Botulinum toxin (dystonia, jaw clenching)

26
 Nutrition
 Some patients need a lot of time for meals because the loss of
coordinated movement makes difficult the swallowing and
feeding;

 Minimize Risk of Choking:

- Cutting food into small pieces, softened, or pureed to make swallowing

easier;
- Swallowing therapy can help if started before there is serious difficulty;
- Avoid dairy products because they increase the secretion of mucus, which
can rise the risk for choking;

 Important is to consume enough calories to maintain

adequate body weight.

27
 Physical Activity

 Should walk as much as possible;

 Daily exercise promotes physical and mental well-being;

 Falls are always a risk, keep surroundings free of hard, sharp objects;

 Wearing special padding during walks helps protection against injury

from falls;

 Small weights worn around the ankles and sturdy, well-fitting shoes that
slip on and off easily can improve a patient's stability;

28
 Prognosis

 The patient in the final stages of Huntington's disease often

dies from complications such as heart failure or pneumonia.

 Juvenile Huntington's disease (16%) develops fast - death

typically occurring after 10 years.

29
 Genetic Counseling
Risk to Family Members
Parents of a proband - the family history
may appear to be negative because:
o Failure to recognize the disorder in family
members;
o Early death of the parent;
o The presence of an intermediate allele or an HTT
allele with reduced penetrance;
o Late onset of the disease in the affected parent;
 Genetic Counseling
Risk to Family Members
Sibs of a proband - depends on the
genetic status of the proband's parent:
o If a parent is affected or has an HTT allele with CAG length of
40 or greater, the risk to the sibs is 50%.
o If the father has an intermediate HTT allele, the risk to the
sibs of inheriting a mutant allele (i.e., ≥36 CAG repeats) can
vary.
o A sib who inherits an HTT allele with reduced penetrance may
or may not develop symptoms of HD.
 Genetic Counseling
Risk to Family Members
Offspring of a proband
o Each child of an individual with HD as a result of
heterozygosity for a CAG repeat expansion in HTT has a
50% chance of inheriting the HD-causing allele.

o Each child of an affected individual who is homozygous

for CAG repeat expansion in HTT will inherit an HD-
causing allele.
 Prevention
• Preimplantation genetic diagnosis (PGD)
• Prenatal diagnosis
 George Huntington
An American physician who contributed a
classic clinical description of the disease that
bears his name – Huntington's disease.
Huntington described this condition in the
first of only two scientific papers he ever
wrote. He wrote the paper “On horea” when
he was 22.

1850 – 1916
East Hampton, Long Island
 Nancy Wexler Jim Gusella
HD gene - discoverer!

She knew that her mother is with horea, He pioneered the use of DNA sequence
her 3 uncles and grandfather, had all polymorphisms as genetic markers,
died young - before the end, each had initially demonstrating the feasibility of
developed the same strange grimace, RFLP linkage analysis for mapping the
unsteady walk, and slurred speech. Huntington's disease gene to
chromosome 4.
FMR1-related disorders are inherited
in an X-linked dominant manner.

Genetic condition that causes a

range of developmental problems
including learning disabilities and
cognitive impairment.
Usually males are more severely
affected.
 Fragile X syndrome (FRAXA)
• One of the most common inheritable forms of
mental retardation;

• The fragile X syndrome (FRAXA) is a result

from multiple copies of CGG triplet
(expansion) in the 5’ UTR of FMR1 gene.
• Mode of Inheritance:
FMR1-related disorders are inherited in an
X-linked dominant manner.
• Prevalence:
approximately 1 in 4000 males and 1 in
8000 females;
• May exhibit anticipation (rare).
“Fragile X"X comes
from the cytogenetic
image and refers to
small fragments which
appear separated
from the X
chromosome.
Genetics of Fragile X syndrome
Gene: FMR1 - occupies 38 kb and has 17 exons. A
trinucleotide repeat, composed primarily of CGG, is
contained in the untranslated portion of exon 1
near the 5' end.

Locus: Xq27​.3

Gene product: Fragile X mental retardation 1

protein – found in the cytoplasm of many cell types
but most abundant in neurons.
 Trinucleotide repeat mutation in non-coding
region
(CGG)n
>200 nt (full mutation)
methylation gene silencing Fragile X
50 – 200 nt

<50 nt

5’UTR 3’UTR

5’UTR 3’UTR

If the expansion occurs in a non-coding region it often leads to loss of function or

gene silencing.
The mutation prevents the expression of the gene.
 Gene product function

o Associates with ribosomes and seems to be involved in

translational regulation of a group of RNA targets.

o Has 3 RNA binding domains.

o Plays role in the structural and functional maturation of

synapses by serving as a translational suppressor in
postsynaptic spaces.
FMRP: the protein product of the FMR1
gene
• The protein and its mRNA are localised in dendritic
spines.
• The protein binds to certain “target” RNA species
and represses translation.
• Plays role in the structural and functional
maturation of synapses by serving as a
translational suppressor in postsynaptic spaces.
• Repress translation of proteins involved in
neuronal development, synaptic transmission and
cytoskeleton.
 Fragile X syndrome
There is genotype-phenotype correlation
between the number of the repeats and the
severity of the disease.

• 5 – 44 copies – normal allele;

• 45-54 copies – intermediate allele „grey zone“;

• 55 – 200 copies - premutation allele (intermediate and

distinct syndrome, fragile X tremor/ataxia (FXTAS) ;

• >200 copies - full mutation;

 Clinical Description
• Males with full-mutation alleles (fragile X syndrome);

• Females heterozygous with full-mutation alleles

(fragile X syndrome);

• Fragile X-associated tremor/ataxia syndrome (FXTAS);

• FMR1-related primary ovarian insufficiency (POI);

 Males with full-mutation alleles (fragile X
syndrome)
• Mild to moderate
mental retardation;

• Long, narrow face;

• Large, protuberant ears;

• Macroorchidism
(enlarged testicles);

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.
 Fragile X Syndrome in Males
Prepubertal
– Delayed developmental milestones:
• sitting without support - 10 months
• walking - 20.6 months
• first clear words - 20 months
– Abnormal behavior: tantrums; hyperactivity; autism;
– Intellectual disability: IQ - 30 to 50;
– Facial dysmorphism: long face; prominent forehead; large ears;
– Prominent jaw;

Postpubertal
– Intellectual disability; facial dysmorphism; macroorchidism

Additional Features
– Strabismus; joint hyper-extensibility; mitral valve prolapse; soft smooth skin
Fragile X syndrome in females

The physical and behavioral features

seen in males with fragile X syndrome
have been reported in females
heterozygous for the full mutation, but
with lower frequency and milder
involvement.
 Is the fragile X premutation really
asymptomatic?

• Late-onset tremor-ataxia-dementia syndrome

in male premutation carriers;
• Recent reports of premature ovarian failure in
female premutation carriers;
• May be due to mRNA interference with the
expression of the normal FMR1 allele or with
other genes;
 Fragile X-associated tremor/ataxia
syndrome (FXTAS)
• Late-onset progressive cerebellar ataxia and intention tremor
in patients with FMR1 premutation;
• Short-term memory loss;
• Executive function deficits;
• Cognitive decline;
• Dementia;
• Parkinsonism;
• Peripheral neuropathy;
• Lower-limb proximal muscle weakness;
• Autonomic dysfunction;
 FMR1-related primary ovarian
insufficiency (POI)

Menopause before 40 years of age has been

observed in carriers of premutation alleles.
 Genetic Testing
Chromosome analysis - no longer used;

Protein testing - not performed routinely;

Molecular Genetic Testing:

 Targeted mutation analysis:

• Polymerase chain reaction
• Southern blot analysis
• CGG trinucleotide repeat genotyping.

 Methylation status can be assessed by PCR-based methods

 Sequence analysis

 Deletion/duplication analysis
52
 Genetic counselling
FMR1-related disorders are inherited in X-linked
dominant manner.

Sibs of a proband
The risk for the sibs depends on their gender, the gender
of the carrier parent, and the size of the expanded allele
in the carrier parent.
 Genetic counselling
Offspring

•Offspring of an individual with a full mutation

- Males with a full mutation have intellectual disability and generally do not reproduce.
- Female who inherit the full mutation is at an approximately 50% risk for intellectual
disability. Her offspring are at a 50% risk of inheriting the full mutation.

•Offspring of an individual with a premutation

- Males who are premutation carriers are considered "transmitting males."

- The premutation is inherited by all of their daughters and none of their sons.
- When premutations are transmitted by the father, small increases in trinucleotide repeat
number may occur but do not result in full mutations.
- All daughters of transmitting males are unaffected premutation carriers.
- Females who are premutation carriers have a 50% risk of transmitting an abnormal
(premutation or full mutation) allele in each pregnancy.
Risk of Expansion of Fragile X Premutations
Length of maternal Incidence of full mutation in
premutation offspring
56-59 13%
60-69 20%
70-79 58%
80-89 73%
90-99 94%
100-109 100%
120-129 100%
 Treatment
No specific treatment is available.
o Early educational intervention, special education, and vocational
training.
o Pharmacologic management of behavioral issues that significantly
affect social interaction is appropriate.
o From 2015 - Trofinetide is applied (synthetic analogue of a molecule
derived from IGF-1 (Insulin-Like Growth Factor), a growth factor
produced by both the major types of brain cells: glia and neurons. IGF-
1 in the brain is critical for normal brain development and for
responding to injury and disease.
o Routine medical management of strabismus, otitis media,
gastroesophageal reflux, seizures, mitral valve prolapse, and
hypertension is appropriate.
 Prevention

• Preimplantation genetic diagnosis (PGD)

• Prenatal diagnosis
Myotonic dystrophy

Myotonic dystrophy type 1

(DM1) is a multisystem disorder
that affects skeletal and smooth
muscles as well as the eyes,
heart, endocrine system, and
central nervous system.
• Mode of Inheritance:
Myotonic dystrophy is inherited in an
autosomal dominant manner.
• Prevalence:
1:20,000 worldwide
1:100,000 in some areas of Japan
1:10,000 in Iceland.
• Anticipation
 Genetics of myotonic dystrophy
Gene: DMPK has 14 exons covering approximately 13 kb. DM1 is
caused by expansion of a CTG trinucleotide repeat in the 3'-UTR
non-coding region of DMPK within the promoter - loss of
function.

Locus: 19q13​.32

Gene product: Myotonin-protein kinase

• Localized to specialized cell structures in heart and
skeletal muscle associated with intercellular conduction
and impulse transmission;
• Related to cyclic-AMP-dependent protein kinases;
• DMPK may interact with a GTP-binding protein that is a
regulatory subunit of myosin phosphatase;
 Clinical description

• Myotonia, weakness, muscular dystrophy;

• Cataracts, hypogonadism, frontal balding;
• Cardiac arrhythmia;
• Severe neonatal form due to dramatic CTG
repeat expansion inherited from affected
mother;
The CTG repeats number is related to disease severity.

Clinical forms Clinical Signs CTG Repeat Size 

Mutable None 35-49

(premutation)
Mild Cataract and mild myotonia; 50-~150
Life span is normal

Classic Weakness ~100-~1000

Myotonia
Cataracts
Balding
Cardiac arrhythmia
shortened life span
Congenital Infantile hypotonia >1000 
Respiratory insufficiency
Intellectual disability
Classic signs present in adults
Early death
A three-generation family affected
with myotonic dystrophy. The
degree of severity increases in
each generation (approximately
100 repeats).

Grandmother - slightly affected;

Mother - characteristic narrow

face and somewhat limited facial
expression (approximately 100
repeats);

Baby is more severely affected –

typical facial features of children
with neonatal-onset myotonic
dystrophy - an open, triangle-
shaped mouth (more than 1000
repeats).
 Diagnosis

• Electromyography
• Serum CK concentration
• Muscle biopsy
• Genetic testing
– Targeted analysis for an increased number (i.e.,
an expansion) of the CTG trinucleotide
repeate in DMPK;
– A multigene panel that includes DMPK and other
genes of interest;
64
 Genetic counselling
Sibs of a proband

•The risk to sibs of a proband depends on the genetic status of the parents.
•If one parent has an expanded DMPK allele, the risk to each sib is 50%.

Offspring of a proband

•All offspring of an individual with an expanded DMPK allele (>34 CTG

repeats) have a 50% chance of inheriting the expanded DMPK allele.
•An expanded DMPK allele may expand further in length during
gametogenesis, resulting in transmission of an allele with a larger CTG
repeat that may be associated with earlier onset and more severe disease
than that in the parent.
•The number of CTG repeats in a child is larger when the expanded allele is
transmitted by the mother.
Treatment
No specific treatment exists for the progressive weakness in
individuals with DM1.

Family planning and prevention

Prenatal diagnosis
Preimplantional genetic diagnosis
Connective Tissue Disorders

Osteogenesis Imperfecta

Ehlers Danlos syndrome

Marfan syndrome

There are many others.

 Osteogenesis imperfecta
• Osteogenesis imperfecta (OI) is a group of genetic disorders
that mainly affect the bones due to collagen defects.

• The term "osteogenesis imperfecta" means imperfect bone

formation.

• People with this condition have bones that break easily,

often from mild trauma or spontaneous. Multiple fractures
are common and in severe cases can occur even before
birth. Milder cases may involve only a few fractures over
the person's lifetime.
Osteogenesis imperfecta
 Types of collagen

Type I (most common): In bones, scar tissues, tendons,

ligaments.
Type II: Hyaline cartilage.
Type III: Found in the extracellular matrix of early granulation
(wound healing) tissue; replaced by type I coll. in mature scar
tissue.
Type IV: Lens of eye; lamina basalis of the epithelium (esp. in
skin, beneath epidermis); capillaries, including glomeruli.
Type V: Interstitial tissue (loose connective tissue); placenta.
List goes up to XXXV…
 Collagen genes

• Multigene family;

• Mutations in COL1A1, COL1A2, CRTAP,
and P3H1 genes cause osteogenesis
imperfecta.
 Collagen Structure

Right handed helix of 3 subunits.

Each subunit is a LH helix (not an -helix
which is RH).
Collagen type I
Chromosome 17q22 7q22-1

Genes COL1A1 COL1A2

Chains 1(I) 2(I)

Molecule [1(I)]2 2(I)

Tissue Bones, ligaments, skin

 Collagen I

N-terminus

Pro
chains
(Gly-X-Y) Protease
Triple helix
cleavage collagen
assembly

C-terminus
Collagen type II
Chromosome 12q13

Gene COL2A1

Chains 1(II)

Molecule [1(II)]3

Tissues Cartilage, vitreous

 Collagen type III
Chromosome 2q31

Gene COL3A1

Chains 1(III)

Molecule [1(III)]3

Tissues Skin, arteries, uterus, bowels

The three-chain central region of the collagen
has a unique protein structures.

Each polypeptide chain comprises a repeat of

amino-acids:
- (Gly-X-Y)n
- X is often proline
- Y is hydroxyproline or hydroxylysine.

Mutations destabilize the triple-stranded helix.

 Osteogenesis Imperfecta

There are at least eight recognized forms of osteogenesis

imperfecta, designated type I -VIII.

Prevalence: 6 to 7 per 100,000 people worldwide. Types I and

IV are the most common forms of osteogenesis imperfecta,
affecting 4 to 5 per 100,000 people.

Inheritance: - autosomal dominant - most common;

- autosomal recessive - less common (some
cases of osteogenesis imperfecta type III
and mutations in the CRTAP or P3H1 gene);
Classification
Type: Gene:

Type 1 COL1A1, COL1A2

Type 2 COL1A1 COL1A2

CRTAP
Type 3 COL1A1, COL1A2

Type 4 COL1A1, COL1A2

Type 5 Unclear

Type 6 Unclear

Type 7 CRTAP

Type 8 LEPRE1
 Osteogenesis Imperfecta
Symptoms:
•Type I (most common, mildest): Bone fragility, blue sclerae. Multiple
fractures with minimal cause – mutation is in COL1A1 gene;
•Type II: Severe deformity and bone weakness; prenatal or neonatal
death due to respiratory insufficiency - mutation is in COL1A1 gene or
COL1A2;
•Type III: Progressive skeletal deformity of the limbs through childhood
and of the spine in the late childhood/early adolescence. Sclerae often
normal - mutation is in COL1A1 gene or COL1A2;
•Type IV: common variable OI with normal sclerae - mutation is in
COL1A1 gene or COL1A2;
 Osteogenesis Imperfecta
Cause
Mutation in collagen genes, usually in alpha subunit of type I collagen
gene.

Inheritance: autosomal dominant; occasionally de novo.

•Type I: Collagen is relatively normal (by some biochemical tests) but
present in reduced amounts. Due to mutations that affect post-
transcriptional- and/or post-translational processing.
•Type II: Low amount and low “quality” of collagen.
•Type III: Collagen is present in normal amounts, but of insufficient
quality. Often due to mutation in gene for alpha subunit of type I
collagen which prevents normal triple helix from forming.
 Osteogenesis Imperfecta

OI type II , type III: no normal triple chain

 Ehlers-Danlos syndrom

Genes:
ADAMTS2, COL1A1, COL1A2, COL3A1, COL5A, 
COL5A2, PLOD1, and TNXB genes;
Prevalence:
The combined prevalence of all types of this
condition may be about 1 in 5,000.
 Type of
EDS type Symptoms Affected gene
inheritance

Classic COL5A1, COL5A2 и АD

skin hyperextensibility
COL1A1
  abnormal wound healing
 
joint hypermobility 
Hypermobility COL3A1 и TNXB АD or АR
expressed hypermobility of the joints
Vascular COL3A1 АD
thin, translucent skin; easy bruising
  characteristic facial appearance (in some individuals)

arterial, intestinal, and/or uterine fragility

Vascular rupture

gastrointestinal perforation

organ rupture
Kyphoscoliotic PLOD1 АR
hyperextensible skin, thin scars, easy bruising
  generalized joint laxity
 
severe muscular hypotonia at birth

progressive scoliosis
Classical type of Ehlers-Danlos syndrome
General characteristics:

– skin hyperextensibility
– abnormal wound healing
– joint hypermobility

Cause

– Mutation to collagen gene, usually to type I or type V collagen gene.

 Genetics of classical form

Genes: COL5A1 and COL5A2

Inheritance: autosomal dominant inheritance.

 Genetic testing for classical Ehlers-
Danlos syndrome

Sequence analysis
– Approximately 50% of individuals with classic EDS
have an identifiable pathogenic variant in COL5A1
or COL5A2.
 Marfan syndrome
Marfan syndrome is a disorder that affects the connective tissue in many parts of
the body - bones, ligaments, muscles, blood vessels, and heart valves. The signs and
symptoms of Marfan syndrome vary widely in severity, timing of onset, and rate of
progression.
 Marfan syndrome
 Gene: FBN1
 Locus: 15q21.1
 Gene product: Fibrillin-1 - an extracellular
matrix protein that contributes to large structures
called microfibrils;
 Mutations: More than 1 000 FBN1 pathogenic
variants;
 Pathogenesis: Impaired synthesis and
deposit of fibrillin;
 Prevalence: 1/3 000-1/10 000;
Marfan syndrome
 Marfan syndrome

 Inheritance: autosomal dominant;

 Pleotropy:
- involvement of different systems;

 Variable expressivity:
- variable expressivity – different severity of
the clinical symptoms in different individuals;
Clinical characteristics

Involvement of one or three systems:

- Bones
- Cardio-vascular system
- Eyes
Bone system affection
 Arachnodactyly

The length of the thumb allows by

contraction to show the fingers into a
fist.

Тhe hand covers the thumb and fifth finger.

Ectopia lentis
Dislocation of the lens due to weakness of the links supporting
the lens.
The most serious complication is aortic aneurysm syndrome.

The aortic rupture is the most common cause for death

 Genetic testing should be offerd
after exact clinical diagnosis
Single gene testing.
The most common strategy for molecular diagnosis of a proband suspected of
having Marfan syndrome is sequence analysis of exons and flanking intronic
regions followed by deletion/duplication analysis if a pathogenic variant is not
identified.

Multi-gene testing.
Clinical laboratories may offer a multi-gene Marfan syndrome/Loeys-Dietz
syndrome/familial thoracic aortic aneurysms and dissections panel that includes
FBN1 as well as a number of other genes associated with disorders that include
aortic aneurysms and dissections.
Thank you for your patience!
 Questions?
• What is anticipation and its molecular basis?

• Clinical forms of myotonic dystrophy?

• Which systems are affected in Marfan

syndrome?