Ataxia: DNA Repair Defects

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ATAXIA: DNA REPAIR DEFECTS

Ataxia Telangectasia: ATM; 11q22
Ataxia Telangectasia-like 1 (ATLD1): MRE11A; 11q21
AT-like 2 (ATLD2): PCNA; 20p12
Ataxia with neuropathy: TDP1; 14q32
CANVAS: RFC1; 4p14
Cockayne Syndrome
A: ERCC8; 5q12
B: ERCC6; 10q11
COFS4: ERCC1; 19q13
RIDDLE syndrome: RNF168; 3q29
Xeroderma Pigmentosum

From Dr. A Kornberg

Ataxia Telangectasia

● AT Mutant (ATM) gene

; Chromosome 11q22.3; Recessive

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
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
  - Missense mutations
- 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
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
  - Differential diagnosis: AOA1; AOA2; AOA4; ARV1
- Serum Immunoglobulins
  - Reduced or absent IgA, IgE & IgG₂
    - Low IgA: Reduced survival
  - 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
Variant syndrome: Adult diagnosis⁴
- Mutations: Missense in at least 1 allele
- Clinical
  - Onset age: 1 to 32 years
  - Childhood: Extrapyramidal features
    - Chorea-Athetosis
    - Resting tremor (30%)
  - Ataxia: Later onset
  - Dysarthria
  - Oculomotor ataxia
  - Peripheral nerve: Axonal sensory-motor polyneuropathy
  - Malignancy: Some patients
  - Disability: Wheelchair at 15 to 3 years
- Laboratory
  - MRI: Cerebellar atrophy in older patients
  - Rearrangements of chromosome 7 and 14
  - Serum α-fetoprotein: High
External links
- Information: A-T Children's Project
- Review: GeneReviews

Xeroderma Pigmentosum
● Multiple genotypes; Recessive

Genotypes
- XP Group A : XPA 9q22.33
- XP Group B + Cockayne : ERCC3 ; 2q14.3
- XP Group C : XPC ; 3p25.1
- XP Group D + Cockayne : ERCC2 ; 19q13.32
- XP Group E : DDB2 ; 11p11.2
- XP Group F ± Cockayne & Fanconi anemia : ERCC4 ; 16p13.12
- XP Group G + Cockayne : ERCC5 ; 13q33.1
Disease mechanisms
- Deficiencies in nucleotide excision repair (NER)
- NER removes sunlight-induced UV photolesions & bulky DNA base adducts from cellular DNA
Neurological Features: Variable severity
- Onset age: < 8 years
- Ataxia: Dysarthria; Gait disorder
- Choreoathetosis
- Spasticity: Onset 3rd decade
- Mental & cognitive deterioration: Progressive
- Deafness: Sensorineural
- Peripheral neuropathy
  - Axon loss
  - Sensory-Motor
  - Tendon reflexes: Reduced
  - Electrodiagnostic features
    - SNAP amplitudes: Reduced or Absent
    - CMAP amplitudes: May be reduced
- Course: Progressive
Systemic features
- Skin: Photosensitivity; Early-onset cancers; Atrophy; Telangectasia; Dry; Freckling
- Eye: Photophobia; Conjunctivitis; Keratitis; Ect- & Entropion
Laboratory
- Defective DNA repair after UV damage
- MRI: Brain atrophy; White matter T2-hyperintensities

Cockayne Syndrome A

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

; Chromosome 5q12.1; Recessive

Frequency: 25% of Cockayne syndrome
Genetics
- Inactivating mutations
- Allelic with
  - UV-sensitive syndrome 2
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

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

; Chromosome 10q11.23; Recessive

Frequency: 2/3 of of NER-defective Cockayne Syndrome
Genetics
- Inactivating mutations
- Allelic with
  - Cerebrooculofacioskeletal syndrome 1
  - De Sanctis-Cacchione syndrome
  - UV-sensitive syndrome 1
  - Lung cancer, susceptibility
  - Macular degeneration, age-related, susceptibility to 5
Clinical
- Severe phenotype
  - Failure to thrive
  - Mental retardation: No language skills
  - Peripheral neuropathy: Demyelinating
    - 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

Cerebrooculofacioskeletal syndrome-4 (COFS4)

● Excision-repair cross complementing rodent DNA repair deficiency Complementation group 1 (ERCC1)

; Chromosome 19q13.32; Recessive

Nosology: Cockayne Syndrome
Epidemiology: 2 patients
Genetics
- Mutations: Phe231Leu; Gln158X
Clinical
- Head: Microcephaly, Micrognathia, Deepset eyes
- Contractures: Knees; Elbows; Wrist
- Hypertonic: Tendon refelxes Brisk
- Nystagmus
- Skeletal: Camptodactyly, Adducted thumbs, Stiff limbs, Steeply sloping acetabulae, Slender long bones with mildly flared metaphyses, Kyphoscoliosis
- Death: 2.5 years
Laboratory
- EEG: Abnormal
- Abnormal recovery of RNA synthesis after UV irradiation

Ataxia-telangiectasia-like disorder 1 (ATLD1)

● Meiotic recombination 11, S. Cerevisiae, homolog of, A (MRE11; MRE11A)

; 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

Ataxia-telangiectasia-like disorder 2 (ATLD2)

● Proliferating cell nuclear antigen (PCNA)

; Chromosome 20p13-p12; Recessive

Epidemiology: 2 Ohio Amish families, 4 patients
Genetics
- Mutation: Ser228Ile
PCNA protein
- DNA replication accessory protein
- Mutation
  - Cells more sensitive to UV irradiation
  - Reduced interaction with Fen1 & Lig1
Clinical
- Onset age: Childhood
- CNS
  - Cognitive; Delayed development; Learning difficulties; Decline
  - Ataxia: Gait instability; Dysarthria; Dysphagia
- Hearing loss: Sensorineural
- Weakness: Progressive
- Skeletal
  - Short stature
  - Foot deformity
  - Contractures, joint
  - Microcephaly (Some patients)
- Endocrine
  - Loss of pubertal growth spurt
  - Premature aging
- Telangiectasia: Skin; Conjunctiva
- Eye: Photophobia; Photosensitivity, Sun-induced malignancy (1 patient)
- No immunodeficiency
Laboratory
- Brain MRI
  - Cerebellar atrophy, vermis & hemispheres
  - Labyrinth dysplasia: Bilateral, Mild, Dilated vestibules
Differential diagnosis
- Ataxia telangiectasia (AT)
- Xeroderma pigmentosum (XP)
- Cockayne syndrome (CS)

Spinocerebellar ataxia with axonal neuropathy (SCAN1)

¹
● Tyrosyl-DNA phosphodiesterase 1 (TDP1)

; Chromosome 14q32.11; Recessive

Epidemiology: Saudi Arabian family
Genetics
- 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
Clinical
- Onset
  - Age: 13 to 15 years
  - Gait ataxia
- 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

RIDDLE syndrome

● Ring finger protein 168 (RNF168)

; Chromosome 3q29; Recessive

Nosology: Radiosensitivity, Immunodeficiency, Dysmorphic features & Learning difficulties
Epidemiology: 2 patients
Genetics
- Mutations: Stop
RNF168 protein
- E3 ubiquitin ligase
- DNA double-strand break repair
Clinical
- Skeletal
  - Short stature
  - Microcephaly
  - Face: Dysmorphism
- Eye: Telangiectasia
- Respiratory: Pulmonary fibrosis
- CNS
  - Learning difficulties
  - Motor control, impaired
  - Ataxia
Laboratory
- Immunodeficiency
- Reduced serum IgA, IgG & IgM
- Cell sensitivity to ionizing radiation: Increased
- Double-stranded DNA repair: Defective
- α-fetoprotein: Increased

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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
4. Neurology 2009; Online July

9/6/2021