Ataxia-telangiectasia

Overview

Definition

Ataxia-telangiectasia is a rare, autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance neurodegenerative disorder characterized by progressive ataxia and multisystem dysfunction due to a defect in the ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics (ATM serine Serine A non-essential amino acid occurring in natural form as the l-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines; pyrimidines; and other amino acids. Synthesis of Nonessential Amino Acids/threonine kinase or the ataxia-telangiectasia mutated gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics).

Epidemiology

• Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 per 20,000–100,000 births
• Men = women
• 1%–2% of Caucasians in the United States carry 1 defective ataxia-telangiectasia gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics.
• 2nd most common autosomal recessive Autosomal recessive Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal recessive diseases are only expressed when 2 copies of the recessive allele are inherited. Autosomal Recessive and Autosomal Dominant Inheritance ataxia in children

Inheritance

• Autosomal recessive inheritance Autosomal recessive inheritance Autosomal Recessive and Autosomal Dominant Inheritance
• The defective ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics is located on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 11 (11q22.3).
• Inheritance occurs when 2 parents with a recessive ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics ( carriers Carriers The Cell: Cell Membrane) produce progeny:
  • 1 in 4 chance of giving birth to an affected child
  • 2 in 4 chance of giving birth to carriers Carriers The Cell: Cell Membrane
  • 1 in 4 chance of giving birth to an unaffected child

Etiology

• ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
  • The protein product has a region functioning similar to phosphatidylinositol-3 kinase (PI3K):
    • Stalls the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle in the presence of DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms to allow for repair
    • Initiates cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest or apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage if DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair attempts are inadequate
  • Protein product has a region involved in DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair:
    • Repairs somatic mutations to prevent passage of mutant DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure to daughter cells
    • Protects cells from damage to environmental insults (e.g., ionizing radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma)
  • Constitutively expressed in all body tissues 
• ATM gene mutation Gene Mutation Myotonic Dystrophies:
  • Dysfunctional kinase fails to stall the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle in the presence of damaged DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure:
    • Cells with somatic mutations are allowed to divide unchecked.
    • Mutated cell lines devoid of normal checkpoints may become tumorigenic. 
  • Inability to repair DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure makes cells susceptible to the effect of pathogenic triggers:
    • Normal cells and cells already carrying mutations may acquire new mutations furthering tumorigenicity.
    • Somatic mutation Somatic Mutation Non-Hodgkin Lymphomas of lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology impairs the monitoring function of the immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs to detect and remove the mutated cell lines.

Pathophysiology

Ataxia-telangiectasia is caused by mutations in the ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics. Mutations may appear in a variety of ways:

Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations types

• Nonsense mutations
• Frameshift mutations
• Missense mutations
• Insertion-deletion mutations

Pathogenesis

Mutations in the ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics increase the risk of cancer and radiosensitivity. The mutations lead to a dysfunctional protein, which causes: 

• Defective cellular DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure repair 
• Defective cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle control 
• Defective cellular response to external triggers:
  • Oxidative damage
  • Ionizing radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma
  • Alkylating agents

Mechanism

• The ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics encodes protein kinase Protein kinase A family of enzymes that catalyze the conversion of ATP and a protein to adp and a phosphoprotein. Interferons ATM, which is a key regulator of cellular response to breaks in double-stranded DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure. 
• Clinical presentation observed in ataxia is the direct consequence of response to DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms. 
• In the presence of DNA damage DNA Damage Injuries to DNA that introduce deviations from its normal, intact structure and which may, if left unrepaired, result in a mutation or a block of DNA replication. These deviations may be caused by physical or chemical agents and occur by natural or unnatural, introduced circumstances. They include the introduction of illegitimate bases during replication or by deamination or other modification of bases; the loss of a base from the DNA backbone leaving an abasic site; single-strand breaks; double strand breaks; and intrastrand (pyrimidine dimers) or interstrand crosslinking. Damage can often be repaired (DNA repair). If the damage is extensive, it can induce apoptosis. DNA Repair Mechanisms, ATM kinase phosphorylates the p53 tumor Tumor Inflammation suppressor protein, which arrests the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle or initiates apoptosis Apoptosis A regulated cell death mechanism characterized by distinctive morphologic changes in the nucleus and cytoplasm, including the endonucleolytic cleavage of genomic DNA, at regularly spaced, internucleosomal sites, I.e., DNA fragmentation. It is genetically-programmed and serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. Ischemic Cell Damage. 
• Defect in the ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics prevents cell repair and promotes the cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell’s progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle progression of damaged DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure.

Manifestations

• CNS abnormalities:
  • Loss of Purkinje cells Purkinje cells The output neurons of the cerebellar cortex. Cerebellum: Anatomy → cerebellar atrophy Cerebellar Atrophy Friedreich Ataxia
  • Presents with ataxia and abnormal eye movements
• Peripheral nervous system Peripheral nervous system The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. Nervous System: Anatomy, Structure, and Classification (PNS) abnormalities:
  • Schwann cell Schwann Cell Neuroglial cells of the peripheral nervous system which form the insulating myelin sheaths of peripheral axons. Nervous System: Histology dysfunction → defective myelination
  • Ataxia worsens as gross and fine motor Fine Motor Developmental Milestones and Normal Growth skills deteriorate.
• Immune system Immune system The body’s defense mechanism against foreign organisms or substances and deviant native cells. It includes the humoral immune response and the cell-mediated response and consists of a complex of interrelated cellular, molecular, and genetic components. Primary Lymphatic Organs abnormalities:
  • Thymus Thymus A single, unpaired primary lymphoid organ situated in the mediastinum, extending superiorly into the neck to the lower edge of the thyroid gland and inferiorly to the fourth costal cartilage. It is necessary for normal development of immunologic function early in life. By puberty, it begins to involute and much of the tissue is replaced by fat. Lymphatic Drainage System: Anatomy gland hypoplasia Hypoplasia Hypoplastic Left Heart Syndrome (HLHS) → decreased numbers of and dysfunction of T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions
  • Presents with immune deficiency

Clinical Presentation

Symptoms of ataxia present in the 1st 5 years of life and progress with the age of the affected individual:

Ataxia

• Often the 1st apparent clinical manifestation
• Affected individuals may have a delay in walking:
  • Fluidity of gait Gait Manner or style of walking. Neurological Examination fails to develop
  • Posture instability
• Narrow-based gait Gait Manner or style of walking. Neurological Examination (in contrast to other childhood ataxias)
• Falling is less frequent (in contrast to other childhood ataxias).
• As CNS and PNS abnormalities deteriorate with age, the ataxia worsens:
  • Often accompanied by other symptoms/signs of cerebellar dysfunction:
    • Dysarthria Dysarthria Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from cranial nerve diseases; neuromuscular diseases; cerebellar diseases; basal ganglia diseases; brain stem diseases; or diseases of the corticobulbar tracts. The cortical language centers are intact in this condition. Wilson Disease
    • Delayed or awkward complex movements
  • Affected individuals often require mobility assistance by the 2nd decade of life.

Abnormal eye movements

• Often normal at preschool age
• A later development of abnormalities in voluntary and involuntary eye movement:
  • Discoordinated movement of the head with the eyes while following a moving object
  • Delayed initiation of eye movement
  • Fluidity of eye movement is lost (i.e., eyes move in small “jumps”).
  • Inability to hold a gaze at the extremes of eye movement:
    • Difficulty reading long passages
    • Development of strabismus Strabismus Strabismus is the misalignment of the eyes while fixating the gaze on an object. Strabismus can be idiopathic, but it may also be caused by cerebral palsy, uncorrected refractive errors, and extraocular muscle or cranial nerve dysfunction. Strabismus

Cognitive impairment

• Presents at an early age
• Progresses with age
• Mild to moderate in severity
• Speech delays are common. 
• Chewing and swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility difficulties often accompany speech difficulties.

Extrapyramidal symptoms

Responsible for many of the motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology abnormalities characteristic of ataxia-telangiectasia:

• Tremor Tremor Cyclical movement of a body part that can represent either a physiologic process or a manifestation of disease. Intention or action tremor, a common manifestation of cerebellar diseases, is aggravated by movement. In contrast, resting tremor is maximal when there is no attempt at voluntary movement, and occurs as a relatively frequent manifestation of parkinson disease. Myotonic Dystrophies
• Myoclonus Myoclonus Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome. Neurological Examination
• Dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia
• Chorea Chorea Involuntary, forcible, rapid, jerky movements that may be subtle or become confluent, markedly altering normal patterns of movement. Hypotonia and pendular reflexes are often associated. Conditions which feature recurrent or persistent episodes of chorea as a primary manifestation of disease are referred to as choreatic disorders. Chorea is also a frequent manifestation of basal ganglia diseases. Huntington Disease
• Delayed reaction time

Miscellaneous neurologic dysfunction

• Peripheral neuropathy Neuropathy Leprosy is often present but plays a minor role compared to more overt neurologic dysfunction.
• Lower motor neuron Lower Motor Neuron Motor Neuron Lesions weakness is often present and contributes to the progression of ataxia.

Dermatologic manifestations

• Telangiectasias:
  • Small, widened blood vessel eruptions on the skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions or mucosal membranes
  • Appears by 5–6 years of age (after the onset of ataxia, which may lead to delayed diagnosis)
  • Areas of telangiectasis:
    • Bulbar conjunctiva Conjunctiva The mucous membrane that covers the posterior surface of the eyelids and the anterior pericorneal surface of the eyeball. Eye: Anatomy
    • Pinnae of the ears
    • Nose Nose The nose is the human body’s primary organ of smell and functions as part of the upper respiratory system. The nose may be best known for inhaling oxygen and exhaling carbon dioxide, but it also contributes to other important functions, such as tasting. The anatomy of the nose can be divided into the external nose and the nasal cavity. Nose Anatomy (External & Internal)
    • Face
    • Neck Neck The part of a human or animal body connecting the head to the rest of the body. Peritonsillar Abscess
• Café au lait macules Café au lait macules Light brown pigmented macules associated with neurofibromatosis and Albright’s syndrome. Neurofibromatosis Type 1
• Hypopigmented macules
• Melanocytic nevi Melanocytic Nevi Nevus/Nevi
• Papulosquamous rash Rash Rocky Mountain Spotted Fever on the face

Immune deficiency

• Cellular and humoral immunity are affected.
• Primarily effects sinopulmonary systems:
  • Recurrent sinus infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
  • Recurrent pulmonary infections Recurrent pulmonary infections Selective IgA Deficiency
• Susceptibility to pneumococcal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 
• Uncommon:
  • Extrarespiratory manifestations
  • Opportunistic infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease

Progressive pulmonary disease Pulmonary disease Diseases involving the respiratory system. Blastomyces/Blastomycosis

• Recurrent sinopulmonary infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease
• Bronchiectasis Bronchiectasis Bronchiectasis is a chronic disease of the airways that results from permanent bronchial distortion. This results from a continuous cycle of inflammation, bronchial damage and dilation, impaired clearance of secretions, and recurrent infections. Bronchiectasis 
• Interstitial lung disease/pulmonary fibrosis Fibrosis Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. Bronchiolitis Obliterans:
  • Nonproductive cough
  • Dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
  • Fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Tachypnea Tachypnea Increased respiratory rate. Pulmonary Examination
  • Hypoxemia Hypoxemia Neonatal Respiratory Distress Syndrome
  • Crackles 
• Respiratory muscle weakness Respiratory muscle weakness Respiratory Acidosis
• Dysphagia Dysphagia Dysphagia is the subjective sensation of difficulty swallowing. Symptoms can range from a complete inability to swallow, to the sensation of solids or liquids becoming “stuck.” Dysphagia is classified as either oropharyngeal or esophageal, with esophageal dysphagia having 2 sub-types: functional and mechanical. Dysphagia → ↑ risk of aspiration

Increased risk of malignancy Malignancy Hemothorax

• Breast
• Ovarian
• Lymphomas
• Leukemias

Miscellaneous clinical manifestations

• Growth retardation Growth Retardation Failure of a fetus to attain expected growth. Fetal Alcohol Spectrum Disorder
• Delayed puberty Delayed Puberty Delayed puberty (DP) is defined as the lack of testicular growth in boys past the age of 14 and the lack of thelarche in girls past the age of 13. Delayed puberty affects up to 5% of healthy boys and girls, and half of all cases are due to constitutional growth delay. Delayed Puberty

Diagnosis

Diagnosis of ataxia-telangiectasia is mainly based on clinical presentation. The diagnosis is confirmed with laboratory testing, genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies, and imaging studies.

Clinical presentation

• Early-onset ataxia within the 1st decade of life:
  • Classical ataxia
  • Oculomotor apraxia Apraxia A group of cognitive disorders characterized by the inability to perform previously learned skills that cannot be attributed to deficits of motor or sensory function. The two major subtypes of this condition are ideomotor and ideational apraxia, which refers to loss of the ability to mentally formulate the processes involved with performing an action. For example, dressing apraxia may result from an inability to mentally formulate the act of placing clothes on the body. Apraxias are generally associated with lesions of the dominant parietal lobe and supramarginal gyrus. Cranial Nerve Palsies 
• Involvement of multiple systems:
  • Neurologic
  • Immunological
  • Pulmonary
  • Dermatologic

Laboratory evaluation

• Increased α-fetoprotein:
  • Present in infancy
  • Does not necessarily increase with age or disease progression
  • Does not correlate with severity of disease
• Ig Ig X-linked Agammaglobulinemia deficiency:
  • Decreased IgG IgG The major immunoglobulin isotype class in normal human serum. There are several isotype subclasses of igg, for example, igg1, igg2a, and igg2b. Hypersensitivity Pneumonitis
  • Decreased IgA IgA Represents 15-20% of the human serum immunoglobulins, mostly as the 4-chain polymer in humans or dimer in other mammals. Secretory iga is the main immunoglobulin in secretions. Immunoglobulins: Types and Functions 
  • Variable Variable Variables represent information about something that can change. The design of the measurement scales, or of the methods for obtaining information, will determine the data gathered and the characteristics of that data. As a result, a variable can be qualitative or quantitative, and may be further classified into subgroups. Types of Variables IgM IgM A class of immunoglobulin bearing mu chains (immunoglobulin mu-chains). Igm can fix complement. The name comes from its high molecular weight and originally being called a macroglobulin. Immunoglobulins: Types and Functions levels
• Lymphopenia:
  • The most prominent manifestation is a reduction in T cells T cells Lymphocytes responsible for cell-mediated immunity. Two types have been identified – cytotoxic (t-lymphocytes, cytotoxic) and helper T-lymphocytes (t-lymphocytes, helper-inducer). They are formed when lymphocytes circulate through the thymus gland and differentiate to thymocytes. When exposed to an antigen, they divide rapidly and produce large numbers of new T cells sensitized to that antigen. T cells: Types and Functions.
  • Other cell lines may be affected.

Neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant

• MRI is the gold standard. 
• Cerebellar atrophy Cerebellar Atrophy Friedreich Ataxia in the vermis is the cardinal feature:
  • Atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation may be absent or minimal at ataxia onset.
  • Findings become more prominent as age progresses.
• In older individuals, chronic white matter White Matter The region of central nervous system that appears lighter in color than the other type, gray matter. It mainly consists of myelinated nerve fibers and contains few neuronal cell bodies or dendrites. Brown-Séquard Syndrome changes may become evident.

Genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies

• Detection of homozygous mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics establishes diagnosis of ataxia-telangiectasia.
• Detection of compound heterozygous mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations of the ATM gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics
• Screening Screening Preoperative Care of family members and genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies are indicated.

Management

Management of ataxia-telangiectasia is supportive with symptom management:

Neurological symptoms

• The main goal is to ensure a good quality Quality Activities and programs intended to assure or improve the quality of care in either a defined medical setting or a program. The concept includes the assessment or evaluation of the quality of care; identification of problems or shortcomings in the delivery of care; designing activities to overcome these deficiencies; and follow-up monitoring to ensure effectiveness of corrective steps. Quality Measurement and Improvement of life for individuals living with ataxia-telangiectasia.
• Physical therapy Physical Therapy Becker Muscular Dystrophy and regular Regular Insulin assessment is done to prevent complications (i.e., falls).
• Amantadine Amantadine An antiviral that is used in the prophylactic or symptomatic treatment of influenza A. It is also used as an antiparkinsonian agent, to treat extrapyramidal reactions, and for postherpetic neuralgia. The mechanisms of its effects in movement disorders are not well understood but probably reflect an increase in synthesis and release of dopamine, with perhaps some inhibition of dopamine uptake. Antivirals for Influenza administration has shown improvement in neurological symptoms.

Cancer and radiosensitivity

• Routine screening Screening Preoperative Care of breast and ovarian malignancies 
• Regular Regular Insulin monitoring to detect early hematological malignancies 
• Management of malignancies is complicated as individuals with ataxia-telangiectasia are radiosensitive; radiotherapy can cause severe reactions. 
• Chemotherapeutic agents should be used carefully due to the increased cytotoxic Cytotoxic Parvovirus B19 effect:
  • Carefully monitor treatment.
  • Avoid alkylating agents and epipodophyllotoxins.

Immunologic involvement

• Administration of IV Ig Ig X-linked Agammaglobulinemia 
• Administration of prophylactic antibiotics 
• Live vaccines are contraindicated. 
• Monitoring of T cell count

Pulmonary involvement Pulmonary involvement Coccidioides/Coccidioidomycosis

• Antibiotic prophylaxis Prophylaxis Cephalosporins to prevent the occurrence of sinopulmonary infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 
• Chest physiotherapy Physiotherapy Spinal Stenosis to prevent/treat chronic infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease 
• Chest clearance techniques and cough assist devices are prescribed to individuals with respiratory muscle weakness Respiratory muscle weakness Respiratory Acidosis.
• Glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids are a treatment option for individuals with interstitial lung disease, but are not preferred as glucocorticoids Glucocorticoids Glucocorticoids are a class within the corticosteroid family. Glucocorticoids are chemically and functionally similar to endogenous cortisol. There are a wide array of indications, which primarily benefit from the antiinflammatory and immunosuppressive effects of this class of drugs. Glucocorticoids further compromise immunity. 
• Regular Regular Insulin monitoring of pulmonary function 
• MRI surveillance Surveillance Developmental Milestones and Normal Growth to assess pulmonary damage 
• Noninvasive ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing for individuals with chronic respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure

Nutrition

• Swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility should be formally evaluated in individuals with ataxia-telangiectasia. 
• Gastroesophageal reflux may be present and should be monitored.
• Speech and language therapy is recommended to aid with swallowing Swallowing The act of taking solids and liquids into the gastrointestinal tract through the mouth and throat. Gastrointestinal Motility and nutrition problems. 
• Drinks should be consumed with a straw.
• Finger feeding is more successful than utensil feeding.

Complications and Prognosis

Complications

• Silent aspiration
• Cognitive impairment
• Increased risk of falls 
• Neurological deficits 
• Pulmonary damage 
• Recurrent infections Recurrent infections Common Variable Immunodeficiency (CVID) 
• Malignancy Malignancy Hemothorax

Prognosis Prognosis A prediction of the probable outcome of a disease based on a individual’s condition and the usual course of the disease as seen in similar situations. Non-Hodgkin Lymphomas

• Overall survival of individuals with ataxia-telangiectasia depends on regular Regular Insulin monitoring of symptoms, attentive care to prevent infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, and early identification Identification Defense Mechanisms of tumors.
• Individuals with the classical form may or may not reach adulthood. 
• Milder forms and adult onset of the disease have a longer life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids. 
• Median age of survival: 19–25 years old
• Atypical forms are milder and have a longer life expectancy Life expectancy Based on known statistical data, the number of years which any person of a given age may reasonably expected to live. Population Pyramids.

Differential Diagnosis

• Cerebral palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies: a congenital Congenital Chorioretinitis disorder affecting movement, muscle tone Muscle tone The state of activity or tension of a muscle beyond that related to its physical properties, that is, its active resistance to stretch. In skeletal muscle, tonus is dependent upon efferent innervation. Skeletal Muscle Contraction, and posture. Cerebral palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies presents with exaggerated reflexes, floppy or rigid limbs, and involuntary movements. Diagnosis is based on clinical presentation. Many cases of ataxia-telangiectasia are initially misdiagnosed as cerebral palsy Palsy paralysis of an area of the body, thus incapable of voluntary movement Cranial Nerve Palsies due to the rare occurrence of the disease and the onset of motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology symptoms prior to the appearance of telangiectasia Telangiectasia Permanent dilation of preexisting blood vessels creating small focal red lesions, most commonly in the skin or mucous membranes. It is characterized by the prominence of skin blood vessels, such as vascular spiders. Chronic Venous Insufficiency. Physical therapy Physical Therapy Becker Muscular Dystrophy and muscle relaxants are important in management. 
• Friedreich ataxia: a rare inherited disease presenting with progressive neurological damage, unstable gait Gait Manner or style of walking. Neurological Examination, and movement disturbances. Diagnosis is based on clinical presentation and detailed history of the individual. Management is largely aimed at symptom management. 
• Nijmegen breakage syndrome: a genetic disorder characterized by progressive microcephaly Microcephaly A congenital abnormality in which the cerebrum is underdeveloped, the fontanels close prematurely, and, as a result, the head is small. (desk reference for neuroscience, 2nd ed. ). Fetal Alcohol Spectrum Disorder, intrauterine growth retardation Growth Retardation Failure of a fetus to attain expected growth. Fetal Alcohol Spectrum Disorder and short stature, recurrent sinopulmonary infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease, increased risk of cancer, and premature ovarian failure Premature ovarian failure Primary ovarian insufficiency (POI) is a condition resulting from the depletion or dysfunction of the ovarian follicles, leading to cessation of ovulation and menses before age 40. Primary ovarian insufficiency is primarily idiopathic. Patients present with signs and symptoms of menopause prior to age 40, including oligo- or amenorrhea, vaginal dryness (often leading to dyspareunia), and infertility. Primary Ovarian Insufficiency. Diagnosis is based on clinical presentation and molecular genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management includes vitamin supplementation, immunoglobulin therapy, and symptomatic treatment.