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 Bloom's
syndrome

• WHAT IS?
Bloom syndrome (BS) is a rare
autosomal recessive
chromosome instability
disorder, which means both
parents must be carriers for a
child to be affected.
It was first described by
dermatologist David Bloom in
1954.
 Etiology and
affected pathways

DNA reshaping, the

structural resolution of
the replication fork

Affected protein

Present mutations in
the BLM gene, that encodes
a protein in the Family of
DNA helicase. Related to
defects in the DNA repair
mechanism.
People with Bloom syndrome
have a huge increase in
exchange between fragments of
counterpart chromosomes or
Feature
sister chromatids, and, in
addition, increases in
chromosomal ruptures and
rearrangements compared to
people who do not.
• Diagnostic
Cytogenetic test for sister chromatid exchanges
(SCEs) is used as a diagnostic marker for BS.

• Clinical manifestations
The main clinical manifestations are growth
deficiency, telangiectasic facial erythema,
immunodeficiency, and increased risk to develop
neoplasias at early age.

There is no specific treatment

• Bloom syndrome has no specific
treatment; however, avoiding sun
exposure and using sunscreens can help
prevent some of the cutaneous changes
associated with photo-sensitivity. Efforts
to minimize exposure to other known
environmental mutagens are also
advisable.
•CLINICAL CASE
Amyotrophic lateral
sclerosis
• What is?
Amyotrophic lateral sclerosis Is a disease of the cells that
control voluntary muscle activity, (motor neuron),
progressive, which causes problems with muscle control
and movement.

The most famous and longer-lived person is physicist

Stephen Hawking, who survived 55 years with ALS. The
average life expectancy of this disease from the time of
diagnosis is approximately 14 months; in his specific case,
doctors had predicted him for two years. it was an
exceptional case, not only for being the person who
survived the most years with ALS, breaking all the
statistics, but also because his illness seemed to have
"burned" and his progress slowed down, becoming
relatively stable. For all this, it has become a "fascinating
case" and disconcerting for neurologists.
• Etiology and affected pathways
Resolution of RNA-DNA hybrids, in transcription
• Affected protein
 TDP-43
 superoxide dismutase
 C9orf72
 Senataxin
• Feature
There are several types of ALS, which are distinguished by their signs, symptoms and
cause.
Most people affected have a sporadic (non-hereditary) form of ALS. These cases are
thought to be caused by an interaction between genetic and environmental factors,
meaning that there are people who are more likely to develop the disease (they are
genetically predisposed) but only develop it after coming into contact with an
environmental factor that triggers it. About 10% of people with ALS have an affected
family member (inherited or family ALS). Family ALS can be caused by variants
(mutations) in several different genes and the type of inheritance varies depending on
the gene involved. ALS can be divided into several different subtypes according to the
gene that is mutated.
• Diagnostic
There is no evidence that can give a definitive diagnosis of ELA.
Rather, it is based primarily on the symptoms and signs that the doctor observes
in the patient, based on a series of tests that rule out other diseases that may
give similar signals and/or symptoms. Doctors get the full medical history and
usually perform a neurological exam from time to time to see if symptoms are
getting progressively worse.

The World Federation of Neurology of the Motor Neurone Diseases Research

Group has several diagnostic criteria called "El Escorial". It basically includes:
Signals indicating problems with lower motor neurons, seen by clinical
examination and electrophysiological examination (electromyography)
Signs of problems with the upper motor neuron in clinical examination
Progression of signs and symptoms of the disease
Absence of imaging tests, cephaloquidial fluid (CSF) electrophysiological
examination and serological studies suggesting it is another disease
Electromyography may show wrapping of affected regions even if there are no
signs or symptoms yet.
• Clinical manifestations

The first signs and symptoms of ALS may not be noticed

because they are very mild or faint such as muscle spasms,
cramps, stiffness or weakness. Over time, affected people
may have speech disorders and, later, difficulty chewing or
swallowing (dysphagia). Many people with ALS become
malnourished because they have difficulty feeding. As time
passes and the disease progresses the muscles weaken, and
the arms and legs begin to appear thinner with fewer muscles
(atrophy). The affected person loses his or her strength and
ability to walk having to use a wheelchair. Later they cannot
use the hands and arms and breathing becomes difficult
because the muscles of the respiratory system weaken and
there may be respiratory failure. The average time between
the onset of symptoms and shortness of breath is 3 years (2
to 10 years) but there are cases in which it lasts many years.

About 20% of people with ALS may have a type of problem

called frontotemporal dementia (FTD), which is a progressive
brain disorder that affects personality, behavior, and
language. Changes in personality and behavior can make it
difficult for people affected to interact with others in a
socially appropriate way. Individuals who develop both
conditions are diagnosed with ALS-DFT.
• Causes
About 90% of cases are sporadic, which means there are no other cases in the family. In these cases there appear to be genetic variations that increase the chance
(susceptibility) of developing ALS and environmental factors that trigger it. Possible environmental factors include:
 Oxidative stress
 Mitochondrial dysfunction
 immune system abnormalities
 glutamate toxicity
 Exposure to toxic substances
 The remaining 10% of ALS cases are familiar. Family ALS can be caused by mutations in various genes and the inheritance pattern varies depending on the gene that is
altered

More than 20 genes have been described, of which mutations in four genes, SOD1, TARDBP, FUS and C9orf72, cause more than 50% of family cases. Mutations in the SOD1
gene cause roughly 20% of all cases of familiar ALS and about 3% of sporadic ALS. ALS can be divided into several sub-types depending on the mutated gene.
Mutations in the following genes (and others not included here) may increase susceptibility to ALS:
ANG TARDBP gene
DCTN1 SOD1 gene
NEFH Gen C9orf72
PRPH
SMN1
SMN2
Probable helicase senataxin is an enzyme that in humans is encoded by the SETX gene
 Amyotrophic lateral sclerosis
(ALS) is a neurological disorder
clinically characterized by
motor system dysfunction,
with intraneuronal
accumulation of the TAR DNA- Developed a transgenic rat RESULTS: Compared to vehicle
binding protein 43 (TDP-43) model of ALS expressing a control, intragastric
being a pathological hallmark. mutant human TDP-43 administration of Riluzole
Treatment Riluzole is a primarily transgene (TDP-43M337V) and (30mg/kg/d) did not mitigate
prescribed medicine for ALS evaluated the therapeutic the behavioral deficits nor
patients, while its effect of Riluzole on this alter the neuropathologies in
therapeutical efficacy appears model. the transgenics.
limited. TDP-43 transgenic
mice are existing animal
models for
mechanistic/translational
research into ALS.
Fanconi Anemia

What is? FA is a rare genetic disease resulting in impaired response to DNA

damage. Although it is a very rare disorder, study of this and other bone
marrow failure syndromes has improved scientific understanding of the
mechanisms of normal bone marrow function and development of cancer.

FA is the result of a genetic defect in a cluster of proteins responsible

for DNA repair via homologous recombination.

The disease is named after the Swiss pediatrician who originally described
this disorder, Guido Fanconi It should not be confused with Fanconi
Syndrome, a kidney disorder also named after Fanconi.
• Etiology and affected pathways
Heterogeneous protection in the replication fork

• Affected protein
FANCD2, BRCA2

A is primarily an autosomal recessive genetic disorder. This means that two mutated
alleles (one from each parent) are required to cause the disease. The risk is 25% that each
subsequent child will have FA. About 2% of FA cases are X-linked recessive, which means
that if the mother carries one mutated Fanconi anemia allele on one X chromosome, a
50% chance exists that male offspring will present with Fanconi anemia.

Scientists have identified 22 FA or FA-like genes: FANCA, FANCB, FANCC, FANCD1 (BRCA2),
FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BRIP1), FANCL, FANCM, FANCN (PALB2),
FANCO (RAD51C), FANCP (SLX4), FANCQ (XPF), FANCS (BRCA1), FANCT (UBE2T), FANCU
(XRCC2), FANCV (REV7), and FANCW (RFWD3). FANCB is the one exception to FA being
autosomal recessive, as this gene is on the X chromosome. These genes are involved in
DNA repair.

The carrier frequency in the Ashkenazi Jewish population is about one in 90. Genetic
counseling and genetic testing are recommended for families who may be carriers of
Fanconi anemia.

Because of the failure of hematologic components—white blood cells, red blood cells,
and platelets—to develop, the body's capabilities to fight infection, deliver oxygen, and
form clots are all diminished.
Feature

Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2,
BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary
cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development,
especially breast cancer.
The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE,
FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with
local cancer-free controls as well as GnomAD. 
Diagnostic

Common tests for Fanconi anemia include:

• Bone marrow biopsy
• Complete blood count (CSC)
• Developmental testing
• Drugs added to a blood sample to check for chromosome damage
• Hand X-ray and other imaging studies (computed tomography, MRI)
• Audiometry
• Tissue typification for HLA (to find compatible bone marrow donors)
• Ultrasound of the kidneys

Pregnant women may have amniocentesis or chorionic villus samples to diagnose the
condition in the fetus.
• Clinical manifestations

FA is characterized by bone marrow failure,

AML, solid tumors, and developmental
abnormalities. Classic features include
abnormal thumbs, absent radii, short stature,
skin hyperpigmentation, including café au lait
spots, abnormal facial features (triangular face,
microcephaly), abnormal kidneys, and
decreased fertility. Many FA patients (about
30%) do not have any of the classic physical
findings, but Diepoxybutane chromosome
fragility assay showing increased chromosomal
breaks can make the diagnosis. About 80% of
FA will develop bone marrow failure by age 20.

The first sign of a hematologic problem is

usually petechiae and bruises, with later onset
of pale appearance, feeling tired, and
infections. Because macrocytosis usually
precedes a low platelet count, patients with
typical congenital anomalies associated with FA
should be evaluated for an elevated red blood
cell mean corpuscular volume.
• Molecular basis
There are 19 genes responsible for FA,
one of them being the breast-cancer
susceptibility gene BRCA2. They are
involved in the recognition and repair
of damaged DNA; genetic defects leave
them unable to repair DNA. The FA
core complex of 8 proteins is normally
activated when DNA stops replicating
because of damage. The core complex
adds ubiquitin, a small protein that
combines with BRCA2 in another
cluster to repair DNA (see
Figure Recombinational repair of DNA
double-strand damage). At the end of
the process, ubiquitin is removed.
• Treatment
The first line of therapy is androgens and
hematopoietic growth factors, but only 50–
75% of patients respond. A more permanent
cure is hematopoietic stem cell
transplantation. If no potential donors exist, a
savior sibling can be conceived by
preimplantation genetic diagnosis (PGD) to
match the recipient's HLA type
 • What is ? Schimke immuno-osseous
Schimke dysplasia (SIOD) is a rare inherited disease
Immuno- characterized by steroid resistant nephrotic
syndrome, spondyloepiphyseal dysplasia,
Osseous and T-cell immunodeficiency.  A multisystem
Dysplasia disorder that is inherited in an autosomal
recessive pattern.
 • Etiology and affected pathways
Replication and investment fork stabilization
• Affected protein
SMARCAL1 
SIOD is inherited in an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits an abnormal gene from each parent.  
SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1 is a protein that in humans is encoded by the SMARCAL1 gene.
The mutations identified in
SMARCAL1 suggest that SIOD arises
from loss of function in the encoded
protein. These mutations include
gene deletions as well as nonsense,
frame shift, splicing and missense
mutations. Mutations in SMARCAL1
have not been found to cause any
other disease.
The SMARCAL1 gene encodes the SMARCAL1 enzyme which
has a role in DNA repair and the DNA stress response,
participates in activating stalled DNA replication forks and
reannealing single stranded DNA to double stranded DNA.
SMARCAL1 deficiency in tissue culture cells also impairs
normal replication of telomere DNA at the ends of the
chromosomes.
With the exception of the sibling of
an affected patient, all identified
patients with two mutations in
SMARCAL1 have had SIOD and none
of the tested unaffected siblings
have had two mutations.
 The protein encoded by this gene is a
member of the SWI/SNF family of proteins.
Members of this family have helicase and
ATPase activities and are thought to regulate
transcription of certain genes by altering the
chromatin structure around those genes. The
SMARCAL1 protein convert RPA-bound, single
stranded DNA into double-stranded DNA, an
enzyme activity termed "annealing helicase".

Feature

The encoded protein shows sequence

similarity to the E. coli RNA polymerase-
binding protein HepA. Mutations in this gene
are a cause of Schimke immunoosseous
dysplasia (SIOD), an autosomal recessive
disorder with the diagnostic features of
spondyloepiphyseal dysplasia, renal
dysfunction, and T-cell immunodeficiency.
• Diagnostic
The diagnosis of SIOD is made on clinical findings. The most
definitive diagnostic findings are skeletal dysplasia
(spondyloepiphyseal dysplasia), renal dysfunction (urinary protein
loss), T lymphocyte deficiency (particularly for naïve CD4 and CD8 T
cells), dysmorphic facial features, and hyperpigmented macules.
Anthropometry can help to distinguish SIOD from other forms of
chronic kidney disease: a sitting height: leg length ratio of < 0.83 is
consistent with a diagnosis of SIOD whereas a ratio of > 1.01 is
indicative of non-SIOD chronic kidney disease. DNA testing for
mutations in the SMARCAL1 gene is available to confirm the
diagnosis.
• Clinical manifestations
The symptoms are subsequently discussed according to the organ
system affected.
 Physical Traits
 Growth and Skeletal System
 Endocrine System
 Renal System
 Cardiovascular system
 Central nervous system (CNS)
 Pulmonary system
 Hematopoietic and Immune Systems
 Reproductive system
• Treatment
Treatments are selected to address
individual symptoms as they develop.
 Renal transplantation
 Blood thinning medications
 Treatment with acyclovir and some
antibacterial agents
Rothmund-
Thomson syndrome

• What is?
RTS is an uncommon genetic syndrome that exhibits
multisystem abnormalities, being autosomal recessive
genodermatosis.

The condition was originally described by August von

Rothmund (1830–1906) in 1868.
Matthew Sydney Thomson (1894–1969) published further
descriptions in 1936

Has an autosomal recessive pattern of inheritance.

• Etiology and affected pathways
DNA reshaping, replication fork structural resolution
• Affected protein
RecQL4
A hereditary basis, mutations in the DNA helicase
RECQL4 gene, causing problems during initiation of
DNA replication has been implicated in the syndrome.

RTS is caused by a mutation of the RECQL4 gene,

located at chromosome 8q24.3. The disorder is
inherited in an autosomal recessive manner. This
means the defective gene responsible for the disorder
is located on an autosome (chromosome 8 is an
autosome), and two copies of the defective gene (one
inherited from each parent) are required in order to be
born with the disorder. The parents of an individual
with an autosomal recessive disorder both carry one
copy of the defective gene, but usually do not
experience any signs or symptoms of the disorder.
• Feature
DNA repair
RECQL4 has a crucial role in DNA end resection that is the initial step required for homologous recombination
(HR)-dependent double-strand break repair. When RECQL4 is depleted, HR-mediated repair and 5’ end
resection are severely reduced in vivo. RECQL4 also appears to be necessary for other forms of DNA repair
including non-homologous end joining, nucleotide excision repair and base excision repair.The association of
deficient RECQL4-mediated DNA repair with accelerated aging is consistent with the DNA damage theory of
aging.

Accelerated aging
In humans, individuals with RTS, and carrying the RECQL4 germline mutation, can have several clinical features
of accelerated aging. These features include atrophic skin and pigment changes, alopecia, osteopenia, cataracts
and an increased incidence of cancer. Also in mice, RECQL4 mutants show features of accelerated aging.
Diagnostic

Rothmund-Thompson syndrome is diagnosed based on

the onset, appearance and progression of the
poikilodermatous rash. A diagnosis of RTS may be
suspected if the rash is present but atypical and other
physical characteristics associated with RTS are present.
Molecular genetic testing for the RECQL4 gene is available
to confirm the diagnosis, although in one-third of cases of
RTS this test can be negative. Thus, a negative test does
not rule out the diagnosis of RTS, but a positive test is
confirmatory.
• Clinical manifestations
Manifestations dermatologic,
orthopedic, ophthalmologic,
hematologic, and oncologic
manifestations. 
 Facial erythema, blisters, and
edema, followed by a
poikilodermatous stage.
The acute phase, which usually begins
between 3 and 6 months of age, is
marked by facial erythema that
spreads to the extensor surfaces of the
extremities and typically spares the
trunk and abdomen.
The chronic phase, which develops
over months to years, is characterized
by persistent, reticulated hyper- and
hypopigmentation, poikiloderma, and
telangiectasia.
Other dermatologic findings can
include sparse hair, madarosis,
palmoplantar hyperkeratosis, and
dysplastic nails or digits.
• Juvenile cataracts
• Saddle nose
• Congenital bone defects, including
short stature and radial ray
anomalies such as absent thumbs
• Hair growth problems (absent
eyelashes, eyebrows and/or hair)
• Hypogonadism has not been well
documented
• Hypodontia
• Calcium problems (not
documented in journals)
• Ear problems (not documented in
journals but identified by patients
in support groups)
• Produces osteosarcoma
Treatment

Suspecting a diagnosis of RTS at an early stage is challenging but important because patients may develop other systemic
manifestations, including juvenile cataracts, osteosarcoma, and hematologic abnormalities, and close clinical follow-up is
essential. It is also important to provide genetic counseling for parents, who are likely both carriers of the RECQL4 gene
mutation.

The treatment is directed toward the specific symptoms that are apparent in each individual. Specific therapies for the
treatment of RTS are symptomatic and supportive. Special measures may be recommended to protect affected individuals.

Pulsed dye laser has been used for the cosmetic management of the telangiectatic component of the rash.

Genetic counseling is recommended for affected individuals and their families. Other treatment for this disorder is
symptomatic and supportive.
Werner Syndrome
What is?

Werner syndrome is a rare progressive disorder that is characterized by the appearance of unusually
accelerated aging (progeria). Although the disorder is typically recognized by the third or fourth
decades of life, certain characteristic findings are present beginning during adolescence and early
adulthood. Werner syndrome is named after the German scientist Otto Werner. He identified the
syndrome in four siblings observed with premature aging, which he explored as the subject of his
dissertation of 1904.

Etiology and affected pathways

DNA remodeling, structural resolution of the replication fork

Affected protein

WRN

Werner syndrome is caused by a genetic change (mutation) in

the WRN gene. This gene makes a protein that is involved with
repairing damage to DNA and maintaining the structure of DNA

Werner syndrome is inherited in an autosomal
recessive pattern. All individuals inherit two copies of each gene.

People with autosomal recessive conditions inherit one mutation

from each of their parents. The parents, who each have one
mutation, are known as carriers.
• Feature
The Werner protein helps maintain
the structure and integrity of a
person's DNA. This protein plays an
important role in copying
(replicating) DNA before cell division
and transferring the information in
genes to the cell machinery that
makes proteins (transcription).
Additionally, recent studies suggest
that the Werner protein may be
particularly important for
maintaining DNA at the ends of
chromosomes (telomeres).
• Diagnosis
In some cases, Werner syndrome may be recognized clinically as
early as approximately age 15, based upon a thorough clinical
evaluation, characteristic physical findings (e.g., absence of
growth spurt at puberty, short stature, low weight), and a
careful patient and family history. However, the disorder often
may not be recognized or confirmed until the third or fourth
decades of life, once certain distinctive symptoms and findings
are noted

• Clinical manifestations
The signs and symptoms of Werner syndrome do not usually
appear until the teens.  This first sign may be slower than
normal growth during puberty.  In the 20s-30s, other signs of
early aging appear. Some of the signs and symptoms of Werner
syndrome include 
 Shorter than average height as an adult
 Bilateral cataracts (clouding of the lens of both eyes )
 Premature graying and thinning of the hair on the head 
 Skin changes (thinning of skin, fragile skin)
 Loss of fat under the skin
 Thin limbs
 Characteristic facial changes (pinched nose, narrow face)
 Voice changes
 Decreased functioning of the testes and ovaries 
 Decreased fertility
 Open skin sores, especially on the ankles 
 Narrowing and hardening of the arteries (atherosclerosis)
 Type 2 diabetes mellitus
 Thinning of the bones (osteoporosis)
 Cancer

Not everyone with Werner syndrome will have all of these symptoms .
TREATMENT THERE IS NO SPECIFIC THE SKIN ULCERS THAT THERE IS EVIDENCE THAT IN 2010, VITAMIN C
TREATMENT FOR ACCOMPANY WS CAN BE SUGGESTS THAT THE SUPPLEMENTATION WAS
WERNER SYNDROME. THE TREATED IN SEVERAL WAYS, CYTOKINE-SUPPRESSIVE ANTI- FOUND TO REVERSE THE
TREATMENT IS BASED ON DEPENDING ON THE SEVERITY.  INFLAMMATORY DRUG PREMATURE AGING AND
MANAGING THE SYMPTOMS SB203580 MAY BE A POSSIBLE SEVERAL TISSUE
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MEDICATIONS CAN BE USED TO PATIENTS WITH WERNER'S GENETICALLY MODIFIED
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