Ataxia: DNA Repair Defects

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ATAXIA: DNA REPAIR DEFECTS

Ataxia Telangectasia
Ataxia Telangectasia-like
Ataxia with neuropathy
Cockayne Syndrome A
Cockayne Syndrome B
Xeroderma Pigmentosum

From Dr. A Kornberg

Ataxia Telangectasia

l AT Mutant (ATM) gene

; Chromosome 11q22-q23; Recessive

ATM gene mutations
- Location: All over ATM gene; No hot spots
- > 270 unique mutations described
- Most are deletions or splice-related (43%) producing premature stop (> 80%)
- Some insertions & in-frame deletions
- 40% to 50% of mutations produce splicing abnormalities
- Missense mutations found in T-cell prolymphocytic leukaemia
  - In kinase domain
  - Predicted to interfere with ATP binding or substrate recognition.
- Milder phenotype: 5762ins137nt; 8494C>T
- Most patients are compound heterozygotes
- External link: Database
ATM protein
- High molecular weight
- Expression: Constitutive; High in fibroblasats
- Cell location: Predominantly in nuclei
- Homologous to phosphatidylinositol-3'-kinases
- ATM contains intrinsic protein kinase activity
  - Phosphorylation of
    - p53 on serine 15 in a manganese-dependent manner
    - BRCA protein in response to γ-irradiation
  - Activity
    - Increased by radiomimetic drug or exposure to ionizing radiation
    - No effect of ultraviolet radiation
- Roles: Mitogenic signal transduction; Meiotic recombination; Cell cycle control
  - Senses DNA double strand breaks
  - Regulates physiological responses via TP53, CHK1 & CHK2 pathways
  - ? Tumor suppressor
    - Variable evidence that heterozygotes more prone to neoplasm
    - ATM knockout mice: Develop T-cell lymphomas
    - ATM & p53 knockout mice
      - Marked acceleration of tumor formation
      - Resistant to radiation induced apoptosis
- Ataxia telangectasia
  - Severe (typical) disease: ATM protein absent
  - Mild variant disease: ATM protein 1% to 17% of the normal level
Epidemiology
- Incidence: 1 in 40,000-300,000 live births: Differences in various ethnic groups
- Present in many populations world-wide
- Heterozygotes²
  - Frequency in populations: 0.35% to 1%
  - Disease-causing mutants: Breast cancer risk increased 2.3-fold
  - Other mutations (missense): No clear breast cancer risk
  - ? Also prone to Cancer, Diabetes, Cardiovascular diseases
Phenotypic variations
- Ataxia: Age of onset
- Level of immunodeficiency
- Level of cellular radiosensitivity
- Presence or absence of neoplasms
Neurological Features
- Onset
  - Age
    - Typical syndrome: 1 - 2 years
    - Some mutations produce mild syndrome: Later onset; Slower neurologic deterioration
  - Cerebellar signs: Staggering gait
- Oculomotor Apraxia
- Ataxia
  - Truncal > Appendicular
  - Dysarthria
- Extrapyramidal
  - Dystonia
  - Masked facies
  - Choreoathetosis
  - Other movements: Myoclonus or Tremors in 25%
  - Drooling
- Sensory Neuropathy: Large Fiber
- Spinal Muscular Atrophy: Distal
  - Onset
    - Late: 2nd decade
    - Distal weakness or resting tremor
  - Clinical
    - Weakness: Legs > Arms
    - Tendon reflexes: Reduced at ankles
    - Sensation: Normal
    - Tremor: Resting
  - Laboratory
    - EMG: Denervation
    - NCV: Reduced CMAP amplitudes
  - Disease variant: Distal SMA with little ataxia³
    - Onset age: 3rd to 4th decade
    - Resting tremor
    - Weakness: Distal
    - Ataxia: Mild
    - Immunodeficiency: Mild
    - DNA repair defect: Mild
    - Cerebellar atrophy: Mild or none
    - ATM protein: Reduced but detectable levels
- Cortical: Normal or Memory Loss
- Reflexes
  - Tendon: Reduced or absent, especially with increasing age
  - Toes: Upgoing or Absent
- Progression: Wheelchair confined by age 10
Systemic Features
- Predisposition to Neoplasia
  - Risk: 38%
  - Leukemia: 14q+ (T-CLL)
  - Lymphoma: B-cell
  - May develop before A-T is diagnosed
  - Heterozygotes: 4x increased cancer (e.g. breast) risk; ? More heart disease
- Telangectasias: Dilated small blood vessels; Skin & Ocular; Onset 4 to 6 years
- Immune
  - Skin Anergy
  - Recurrent respiratory infections
  - T-cell function: Reduced
- Endocrine: Hirsute; Testicular & Ovary hypoplasia; glucose intolerance
- Hematologic: Lymphopenia; Anemia
- Lifespan: 20 to 50 years
Differential diagnosis
- Ataxia Telangectasia-like syndrome
- Ataxia with Oculomotor apraxia
Management
- Physical therapy: Prevent contractures; Wheelchair & mobility issues
- Monitor for neoplasm
- Avoid radiation exposure
- ? Anti-oxidant treatments
Laboratory
- High serum α-fetoprotein
  - Above 10 ng/ml in more than 90% of patients with A-T
  - Serum AFP concentration may be high in unaffected children less than 24 months of age
- Serum Immunoglobulins
  - Reduced or absent IgA, IgE & IgG₂
  - IgM: Increased (23%)
  - Oligo-/monoclonal gammopathy (10%)
- Other immunodeficiency
  - T-cell deficiencies: 30%
  - Thymus: Small embryonic-like
- Chromosome breakage
  - 7;14 chromosomal translocation in 5% to 15% of peripheral cells
  - Break points: 14q11; 14q32; 7p13-p15; 7q32-q35; 2p11; 2q11
- Sensitivity to ionizing radiation
- Telomeres: Accelerated shortening with age or in cell culture
- MRI: Small cerebellum
Pathology
- Cell pathology: Nucleomegaly & Variable nuclear size
- CNS
  - Cerebellum: Paucity of Purkinje & granule cells
  - Posterior column: Progressive loss of axons
  - Other cell loss: Olive; Dentate; Substantia nigra
- Thymus: Small, embryonic-like
External links
- Information: A-T Children's Project
- Review: GeneReviews

Xeroderma Pigmentosum: Clinical syndrome with multiple genotypes

l Recessive; Chromosomes 9q34 (A); 2q21 (B & CS); 3p25.1 (C); 19q13.2(D);
Unknown (E); 16p13 (F); 13q32-33 (G & CS)

Neurological Features: Variable severity
- Ataxia
- Choreoathetosis
- Spasticity
- Progressive mental deterioration
- Deafness
Systemic features
- Skin: Photosensitivity; Early-onset cancers; Atrophy; Telangectasia
- Eye: Photophobia; Conjunctivitis; Keratitis; Ect- & Entropion
Laboratory: Defective DNA repair after UV damage

Cockayne Syndrome A

l Excision-repair cross complementing rodent DNA repair deficiency Complementation group 8 (ERCC8)

; Chromosome 5q12; Recessive

Frequency: 25% of Cockayne syndrome
Genetics
- Inactivating mutations
ERCC8 protein
- WD repeat protein
- Interacts with CSB protein
- Mutations: Defect in transcription-coupled DNA repair
Neurological Features
- Clinical
  - Mental deterioration: Progressive; Progeria-like
  - Gait disturbance
  - Eye: Optic atrophy; Strabismus; Retinal degeneration; "Hollow" eyes
  - PNS
    - Tendon reflexes: Reduced
    - Muscle wasting
- Pathology
  - Peripheral nerve
    - Demyelination & Hypomyelination: Thin myelin sheaths
    - Onion bulbs
    - Axonal loss: Especially large myelinated axons
    - Inclusions: Schwann cell; Lysosomal, membrane-bound; Vacuoles with granular material
  - CNS
    - Hydrocephalus
    - Leukodystrophy
    - Intracranial Calcification
Systemic Features
- Skeletal: Dwarfism; Long limbs; Large hands & ears; Contractures; Microcephaly
- Skin: Precocious senility; Photosensitivity; Pigmentation
- Cardiac: Hypertension; Early atherosclerosis
- Sensory: Retinal degeneration & Hearing loss
- Vascular: Atherosclerosis; Hypertension
- Renal disease: Increased incidence
- Normal risk of cancer & infections
Pathology
- Microencephaly
- White-matter
  - Tigroid leukodystrophy
  - Oligodendrocyte proliferation
  - Reactive astrocytes
  - Dystrophic calcification: Multifocal; Most in basal ganglia
  - String vessels: Collagen IV +; No lumen
- Nerve: Demyelinating & axonal neuropathy
- Muscle: Neurogenic (grouped) atrophy; Nuclear atypia

Cockayne Syndrome B

l Excision-repair cross complementing rodent DNA repair deficiency Complementation group 6 (ERCC6; CSB)

; Chromosome 10q11; Dominant

Frequency: 2/3 of of NER-defective Cockayne Syndrome
Genetics
- Inactivating mutations
Clinical
- Severe phenotype
  - Failure to thrive
  - Mental retardation: No language skills
  - Peripheral neuropathy
    - NCV: 16 to 19 M/s
  - Eye
    - Retinopathy: Pigmentary
    - Cataracts: Congenital
  - Adipose tissue: Loss
  - Joint contractures
  - Face: Small, deep-set eyes; Prominent nasal bridge; Triangular; Senile appearance
  - Skeletal: Kyphosis; Cachectic dwarfism; Microcephaly
  - Hearing loss: Sensorineural
  - Motor: No sit or walk independently
  - Death: 5 to 10 years
- Mild phenotype
  - Late-onset Cockayne syndrome
  - Survival beyond 2nd decade
Laboratory
- Defect in transcription-coupled DNA repair
- Involves nucleotide excision repair (NER) pathway
CNS Pathology
- Leukodystrophy
- Atrophy: Cortex & Cerebellum
- Calcification

Ataxia-telangiectasia-like disorder (ATLD)

l Meiotic recombination 11, S. Cerevisiae, homolog of, A (MRE11)

; Chromosome 11q21; Recessive

Protein
- Function: Repairs Double-strand DNA breaks that arise during normal DNA replication
- Mutations: Cause sensitivity to double-strand DNA break damage
- Endonuclease activity
Clinical features
- Similar to Ataxia telangectasia: Milder course
- Cerebellar degeneration
- Normal intellect
Differential diagnosis
- Ataxia telangectasia
- Ataxia with Oculomotor apraxia
Laboratory
- Increased radiosensitivity
- Increased level of spontaneous chromosome changes in peripheral blood lymphocytes

Spinocerebellar ataxia with axonal neuropathy (SCAN1)¹

l Tyrosyl-DNA phosphodiesterase 1 (TDP1)

; Chromosome 14q31�q32; Recessive

Mutation: His493Arg missense; Homozygous
TDP1 protein
- Repairs covalently bound topoisomerase I�DNA complexes
  - Prevents formation of double-strand breaks when stalled
    topoisomerase I complexes interfere with DNA replication
- Maintenance of non-dividing tissues
- Phospholipase D superfamily
- Expressed ubiquitously throughout CNS
Epidemiology: Saudi Arabian family
Onset
- Age: 13 to 15 years
- Gait ataxia
Clinical
- Cerebellar: Ataxia; Dysarthria
- Sensory loss: Vibration; Position sense; Legs > Arms
- Weakness: Distal; Mild
- Tendon reflexes: Absent
- Intelligence: Normal
- Systemic features: Few
Laboratory
- Serum albumin: Mildly reduced
- Serum cholesterol: Mildly high
- MRI: Cerebellar atrophy; Mild cerebral atrophy
Electrophysiology
- Motor conduction velocities: 26 to 58 M/s in legs
- Sensory potentials: Absent
Nerve pathology: Loss of large myelinated axons

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References
1. Nature Genet 2002; Online September 2002
2. Nature Genet 2006; Online July 2006
3. Neurology 2006;67:346�349

7/14/2008