CHROMOSOMAL BREAKAGE SYNDROMES
PRESENTOR : DR. REETIKA MENIA DNB RESIDENT MODERATOR: DR.USHA AGRAWAL
INTRODUCTION
These are a group of disorders that are characterized by a defect in DNA repair mechanism or genomic instability.
Patients with these disorders show increased predisposition to cancer.
Transmitted in autosomal recessive mode of inheritence .
Rare syndromes.
CBS are associated with increase risk of Leukemias,lymphomas, solid tumors (eg, breast cancer, skin cancer). immunodeficiencies, growth retardation, skeletal abnormalities, Hypogonadism and abnormal pigmentation.
PATHOGENESIS Loss of DNA repair.
Inter strand cross links.
Genomic instability.
Increase exchange between sister chromatids.
Change in nucleotide.
Double strand DNA breaks.
Major types of syndromes Ataxia telangiectasia (Louis bar syndrome)
Fanconi anemia.
Bloom syndrome.
Xeroderma pigmentosum.
ATAXIA TELANGIECTASIA
ATAXIA TELANGIECTASIA This syndrome was first described in 1941
by French physician Denise Louis-Bar. It is caused because of chromosomal
instability. It is a neuron degenerative disease mainly
affecting cerebellum. Patients are particularly sensitive to
ionizing radiation and radiomimetic compounds.
How is it caused?
It is caused due to genetic mutation in ATM gene on chromosome 11
Ataxia Telangiectasia Mutated gene produces a mutated ATM protein.
ATM gene
This protein is found in the cell nucleus.
Acting with other proteins, their role is to activate the cells to repair damaged DNA.
Mutations in the ATM gene lead to total loss of the ATM protein which normally recognizes DNA damage.
CLINICAL FEATURES
AGE: ataxia:1-4 years At the age of 10 children are usually confined to a
wheelchair Telangiectasias:2-8 Years Frequency:1 case per 40,000-100,000 live births Sex: Males and females affected equally
Clinical features
Cerebellar degeneration in ataxia
DIAGNOSIS
Immunoblotting for the protein for ATM is the preferred test for diagnosis of ataxia telangiectasia.
Chorionic villi sample: Detect prenatal ataxia telangiectasia
Molecular genetic testing (DNA analysis) is performed to identify the ATM mutation, if the mutation is detected, the diagnosis of ataxia telangiectasia is confirmed.
Serum alpha-fetoprotein levels are elevated above 10 ng/mL in more than 95% of patients with ataxia telangiectasia.
Serum immunoglobulin levels of IgA, IgG 2 or total IgG and IgE are decreased markedly or even absent.Brain MRI can detect cerebellar atrophy; Brain single-photon emission computed tomography (SPECT): indicates cerebellar regional cerebral blood flow hypoperfusionCytogenetic analysis for chromosome breakage in dividing cells exposed to irradiation. Karyotyping is performed on peripheral blood. Persons with ataxia telangiectasia frequently haveabnormalities involving chromosome 14, particularly a 7;14 chromosome translocation
MEDICAL CARE
Antioxidants Immunisation Systemic steroids Intravenous immunoglobulin (IVIG) replacement
therapy. Early and continuous physical therapy Supportive therapy may lessen drooling,
choreoathetosis, and ataxia.
FANCONI ANEMIA
Fanconi anemia Fanconi anemia is one of the inherited anemias that
causes bone marrow failure. It is autosomal recessive disorder. There are twelve complementation groups that have
been identified (A B C D1 D2 E F G I L and M) -- FA-A is the most common--
FA gene
It is located on chromosome 16. It is a protein coding gene.
Functions of FA genes
DNA repair
Cell cycle control
Oxygen sensitivity
Apoptosis and telomere maintenance
Haemopoiesis
FA pathway Proteins produced from these genes are involved in
a cell process known as the FA pathway. The FA pathway is activated during the process of
DNA replication The replication is blocked due to DNA damage. The FA pathway sends certain proteins to the area
of damage, which trigger DNA repair.
Continued...
The FA pathway is particularly responsive to a certain type of DNA damage known as interstrand cross-links (ICLs).
FA proteins produce FA core complex . The FA core complex activates two proteins, called
FANCD2 and FANCI these two proteins brings DNA repair proteins to
the area of the ICL.
FA PATHWAY
Mutations in FA gene
Mutations in FA gene Disrupt FA pathway. DNA damage is not repaired. Abnormal cell death or uncontrolled cell growth CANCER
Clinical Manifestations
AGE: 5-10 years Frequency:1 case per1,00,000 live births Sex: Males and females affected equally
Clinical Manifestations Fanconi Anemia is characterized by physical
abnormalities Abnormalities of the thumbs, forearms, skeletal
system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity and central nervous system.
Skin discolorations (hypo pigmented spots and hyperpgimented spots)
Pancytopenia, bone marrow hypoplasia developmental delay, increased susceptibility to leukemia and other
malignancies, Human papilloma virus (HPV) induced squamous
cell Carcinoma Solid tumors - medulloblastoma, Wilm’stumor,
and breast cancer
Diagnosis of FA
TREATMENT
Bone marrow transplantation of hematopoietic stem cells (HSC) can be curative for hematologic symptoms. Chemotherapy and radiationGene therapy
BLOOM SYNDROME
Bloom syndrome
It is an autosomal recessive disorder.
causes sun-sensitive skin changes, an increased risk of cancer, and other health problems.
It caused by mutation in BLM gene.
Life span- 24 yrs.
BLM gene
The BLM gene is located on the long (q) arm of chromosome 15 at position 2
It is known as the "caretaker of the genome.“ It maintains the structure and integrity of DNA.
Function of BLM gene The BLM gene provides instructions for making a member of a protein family called helicases.
Helicases are enzymes that bind to DNA and temporarily unwind the two spiral strands (double helix) of the DNA molecule.
Mutations in BLM gene
Mutated BLM gene
Mutated BLM protein
Frequency of sister chromatids exchange increased Causes chromosome instability with gaps and breaks in Genetic material
Uncontrolled cell growth
CANCER
Failure to thrive in infancy
Hyperpigmentation of skin
Facial telangectasias
Increased risk of malignancies
Immunodeficiency
Growth retardation
Clinical features
DIAGNOSIS
CYTOGENETIC ANALYSIS:Quadriradial configuration .The 4-armed figure consists of 2 homologous chromosomes caused by chromosome breaks and rearrangements.
Another cytogenetic abnormality observed in Bloom syndrome is a sharply increased SCE level
IMMUNOGLOBULINS:Decreased
Quadriradial arrangement
Increase sister chromatid exchange
XERODERMA PIGMENTOSUM
XERODERMA PIGMENTOSUM
It is caused by an abnormality in an individual’s genome.
Mutations in the XP genes (except XP-variant) lead to defective NER and hypersensitivity to UV
It can also be caused by environmental factors. Eight genes are involved in XP: XPA through XPG
and XPV (XP-Variant)
Autosomal recessive disorder.
Cause
severe photosensitivity abnormal pigmentation, mental retardation, develop skin cancer at very young age
DIAGNOSIS
Radiosensitivity assay Molecular genetic testing (DNA analysis)Cytogenetic analysis Karyotyping Prenatal diagnosis :can be made by demonstrating reduced UV-induced DNA repair synthesis in cultured chorionic villus cells.
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