Ataxia-telangiectasia

Ataxia-telangiectasia, also known as Louis-Bar syndrome, is a neurocutaneous syndrome, which involves multiple systems but mainly affects the neurological system. Ataxia-telangiectasia is an autosomal recessive genetic disorder caused by a mutation in the ATM gene (ATM serine/threonine kinase or the ataxia-telangiectasia mutated gene). Ataxia-telangiectasia presents with progressive ataxia, telangiectasias, extrapyramidal symptoms, dermatological manifestations, immune dysfunction, and progressive pulmonary disease. Diagnosis is based on clinical presentation and confirmed with neuroimaging and genetic testing. Management is supportive with symptom management. Prognosis is poor secondary to numerous complications.

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Overview

Definition

Ataxia-telangiectasia is a rare, autosomal recessive neurodegenerative disorder characterized by progressive ataxia and multisystem dysfunction due to a defect in the ATM gene (ATM serine/threonine kinase or the ataxia-telangiectasia mutated gene).

Epidemiology

  • Incidence: 1 per 20,000–100,000 births
  • Men = women
  • 1%–2% of Caucasians in the United States carry 1 defective ataxia-telangiectasia gene.
  • 2nd most common autosomal recessive ataxia in children

Inheritance

  • Autosomal recessive inheritance
  • The defective ATM gene is located on chromosome 11 (11q22.3).
  • Inheritance occurs when 2 parents with a recessive ATM gene (carriers) produce progeny:
    • 1 in 4 chance of giving birth to an affected child
    • 2 in 4 chance of giving birth to carriers
    • 1 in 4 chance of giving birth to an unaffected child
Inheritance pattern of autosomal recessive conditions

Diagram of the inheritance pattern of autosomal recessive conditions

Image by Lecturio.

Etiology

  • ATM gene:
    • The protein product has a region functioning similar to phosphatidylinositol-3 kinase (PI3K):
      • Stalls the cell cycle in the presence of DNA damage to allow for repair
      • Initiates cell cycle arrest or apoptosis if DNA repair attempts are inadequate
    • Protein product has a region involved in DNA repair:
      • Repairs somatic mutations to prevent passage of mutant DNA to daughter cells
      • Protects cells from damage to environmental insults (e.g., ionizing radiation)
    • Constitutively expressed in all body tissues 
  • ATM gene mutation:
    • Dysfunctional kinase fails to stall the cell cycle in the presence of damaged DNA:
      • Cells with somatic mutations are allowed to divide unchecked.
      • Mutated cell lines devoid of normal checkpoints may become tumorigenic. 
    • Inability to repair DNA makes cells susceptible to the effect of pathogenic triggers:
      • Normal cells and cells already carrying mutations may acquire new mutations furthering tumorigenicity.
      • Somatic mutation of lymphocytes impairs the monitoring function of the immune system to detect and remove the mutated cell lines.

Pathophysiology

Ataxia-telangiectasia is caused by mutations in the ATM gene. Mutations may appear in a variety of ways:

Mutation types

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

Pathogenesis

Mutations in the ATM gene increase the risk of cancer and radiosensitivity. The mutations lead to a dysfunctional protein, which causes: 

  • Defective cellular DNA repair 
  • Defective cell cycle control 
  • Defective cellular response to external triggers:
    • Oxidative damage
    • Ionizing radiation
    • Alkylating agents

Mechanism

  • The ATM gene encodes protein kinase ATM, which is a key regulator of cellular response to breaks in double-stranded DNA. 
  • Clinical presentation observed in ataxia is the direct consequence of response to DNA damage. 
  • In the presence of DNA damage, ATM kinase phosphorylates the p53 tumor suppressor protein, which arrests the cell cycle or initiates apoptosis. 
  • Defect in the ATM gene prevents cell repair and promotes the cell cycle progression of damaged DNA.

Manifestations

  • CNS abnormalities:
    • Loss of Purkinje cells → cerebellar atrophy
    • Presents with ataxia and abnormal eye movements
  • Peripheral nervous system (PNS) abnormalities:
    • Schwann cell dysfunction → defective myelination
    • Ataxia worsens as gross and fine motor skills deteriorate.
  • Immune system abnormalities:
    • Thymus gland hypoplasia → decreased numbers of and dysfunction of T cells
    • 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 fails to develop
    • Posture instability
  • Narrow-based gait (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
      • 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

Cognitive impairment

  • Presents at an early age
  • Progresses with age
  • Mild to moderate in severity
  • Speech delays are common. 
  • Chewing and swallowing difficulties often accompany speech difficulties.

Extrapyramidal symptoms

Responsible for many of the motor abnormalities characteristic of ataxia-telangiectasia:

  • Tremor
  • Myoclonus
  • Dystonia
  • Chorea
  • Delayed reaction time

Miscellaneous neurologic dysfunction

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

Dermatologic manifestations

  • Telangiectasias:
    • Small, widened blood vessel eruptions on the skin 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
      • Pinnae of the ears
      • Nose
      • Face
      • Neck
  • Café au lait macules
  • Hypopigmented macules
  • Melanocytic nevi
  • Papulosquamous rash on the face
Ataxia-telangiectasia

Ocular telangiectasias observed in an individual with ataxia-telangiectasia

Image: “Ataxia-telangiectasia” by National Eye Institute. License: Public Domain
Cafe au lait spot

Café au lait macule is 1 of the dermatologic manifestations of ataxia-telangiectasia

Image: “Cafe au lait fleck” by Denise Nepraunig. License: Public Domain

Immune deficiency

  • Cellular and humoral immunity are affected.
  • Primarily effects sinopulmonary systems:
    • Recurrent sinus infections
    • Recurrent pulmonary infections
  • Susceptibility to pneumococcal infections 
  • Uncommon:
    • Extrarespiratory manifestations
    • Opportunistic infections

Progressive pulmonary disease

  • Recurrent sinopulmonary infections
  • Bronchiectasis 
  • Interstitial lung disease/pulmonary fibrosis:
    • Nonproductive cough
    • Dyspnea
    • Fever
    • Tachypnea
    • Hypoxemia
    • Crackles 
  • Respiratory muscle weakness
  • Dysphagia → ↑ risk of aspiration

Increased risk of malignancy

  • Breast
  • Ovarian
  • Lymphomas
  • Leukemias

Miscellaneous clinical manifestations

  • Growth retardation
  • Delayed puberty

Diagnosis

Diagnosis of ataxia-telangiectasia is mainly based on clinical presentation. The diagnosis is confirmed with laboratory testing, genetic testing, and imaging studies.

Clinical presentation

  • Early-onset ataxia within the 1st decade of life: 
    • Classical ataxia
    • Oculomotor apraxia 
  • 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 deficiency:
    • Decreased IgG
    • Decreased IgA 
    • Variable IgM levels
  • Lymphopenia:
    • The most prominent manifestation is a reduction in T cells.
    • Other cell lines may be affected.

Neuroimaging

  • MRI is the gold standard. 
  • Cerebellar atrophy in the vermis is the cardinal feature:
    • Atrophy may be absent or minimal at ataxia onset.
    • Findings become more prominent as age progresses.
  • In older individuals, chronic white matter changes may become evident.

Genetic testing

  • Detection of homozygous mutation of the ATM gene establishes diagnosis of ataxia-telangiectasia.
  • Detection of compound heterozygous mutation of the ATM gene
  • Screening of family members and genetic counseling are indicated.

Management

Management of ataxia-telangiectasia is supportive with symptom management:

Neurological symptoms

  • The main goal is to ensure a good quality of life for individuals living with ataxia-telangiectasia.
  • Physical therapy and regular assessment is done to prevent complications (i.e., falls).
  • Amantadine administration has shown improvement in neurological symptoms.

Cancer and radiosensitivity

  • Routine screening of breast and ovarian malignancies 
  • Regular 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 effect:
    • Carefully monitor treatment.
    • Avoid alkylating agents and epipodophyllotoxins.

Immunologic involvement

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

Pulmonary involvement

  • Antibiotic prophylaxis to prevent the occurrence of sinopulmonary infections 
  • Chest physiotherapy to prevent/treat chronic infections 
  • Chest clearance techniques and cough assist devices are prescribed to individuals with respiratory muscle weakness.
  • Glucocorticoids are a treatment option for individuals with interstitial lung disease, but are not preferred as glucocorticoids further compromise immunity. 
  • Regular monitoring of pulmonary function 
  • MRI surveillance to assess pulmonary damage 
  • Noninvasive ventilation for individuals with chronic respiratory failure

Nutrition

  • Swallowing 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 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 
  • Malignancy

Prognosis

  • Overall survival of individuals with ataxia-telangiectasia depends on regular monitoring of symptoms, attentive care to prevent infections, and early identification 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. 
  • Median age of survival: 19–25 years old
  • Atypical forms are milder and have a longer life expectancy.

Differential Diagnosis

  • Cerebral palsy: a congenital disorder affecting movement, muscle tone, and posture. Cerebral palsy 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 due to the rare occurrence of the disease and the onset of motor symptoms prior to the appearance of telangiectasia. Physical therapy and muscle relaxants are important in management. 
  • Friedreich ataxia: a rare inherited disease presenting with progressive neurological damage, unstable gait, 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, intrauterine growth retardation and short stature, recurrent sinopulmonary infections, increased risk of cancer, and premature ovarian failure. Diagnosis is based on clinical presentation and molecular genetic testing. Management includes vitamin supplementation, immunoglobulin therapy, and symptomatic treatment.

References

  1. Opal, P. (2019). Ataxia-telangiectasia. UpToDate. Retrieved August 29, 2021, from https://www.uptodate.com/contents/ataxia-telangiectasia
  2. Ataxia Telangiectasia (2007). National organization for rare disorders – Rare disease database. Retrieved August 29, 2021, from https://rarediseases.org/rare-diseases/ataxia-telangiectasia/
  3. Ataxia-telangiectasia. Medline Plus. US National Library of Medicine. Retrieved August 29, 2021, from https://medlineplus.gov/genetics/condition/ataxia-telangiectasia/
  4. Janniger, C.K., Jóźwiak, S., Kmieć, T., Bernatowska, E. (2021). Ataxia-Telangiectasia. [Updated July 6, 2021]. Medscape. Retrieved August 29, 2021, from https://emedicine.medscape.com/article/1113394-overview
  5. Riboldi G.M., Samanta D., Frucht S. Ataxia Telangiectasia. [Updated 2021 Jul 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. Retrieved August 29, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK519542/

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