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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