• Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
888
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
13
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide
  • Reduced expression of frataxin, not completely abolished as knockout of frataxin is embryonic lethal
  • The expanded GAA repeat in the frataxin gene ( FXN ) results in reduced levels of the frataxin protein, which probably has a role in mitochondrial iron transport ( A ), iron–sulphur cluster assembly ( B ), and protection from free radicals ( C ), by increasing SOD activity. Consequently, therapeutic targets include enhancement of FXN transcription ( 1 ), selective mitochondrial iron chelation ( 2 ), enhancement of ATP generation to compensate for the lack of iron–sulphur proteins in the respiratory chain ( 3 ) and free-radical neutralization ( 4 ). Ac, acetylation; CI–CIV, class I–IV respiratory chain proteins; HDAC, histone deacetylase; SOD, superoxide dismutase.
  • Model of SCA1 pathogenesis. ( a ) ATXN1 has stable (CIC) and transient interactions (RORα and Gfi-1). ( b ) The mutant protein interacts with its stable and transient interactors to cause neuropathology. The expression patterns of Gfi-1 and RORα suggest that their decreased levels, due to interactions with mutant ATXN1, contribute to the selective vulnerability of Purkinje cells. The stable interactions with CIC contribute both to Purkinje cell pathology as well as to other neuronal pathology given the overlapping and broad expression patterns of CIC and ATXN1. ( c ) Increasing the levels of ATXN1L, ATXN1 paralog suppresses some of ATXN1-induced toxicity by displacing ATXN1 from its native complex, leading to increased sequestration of the mutant protein in nuclear inclusions.

Transcript

  • 1. Clinical Features and Molecular Genetics of Hereditary Cerebellar Ataxia Franca Cambi, MD, PhD Professor Neurology University of Kentucky
  • 2. Outlines
    • Clinical manifestations
    • Differential Diagnosis
    • Genotypes and Molecular Diagnosis
    • Molecular mechanisms
    • Current treatments
    • Future treatments
  • 3.
    • SPORADIC ATAXIA
    • AUTOSOMAL DOMINANT ATAXIA
    • AUTOSOMAL RECESSIVE ATAXIA
    • X-LINKED ATAXIA
    Presentation
  • 4. Clinical Manifestations Ataxia of gait Dysarthria Sensory deficits Spasticity Retinopathy and optic atrophy Parkinsonian features Epilepsy
  • 5. PATIENT 1
    • 47 year-old gentleman with 7-8 year-history of progressive problems with balance
    • Normal development, was very athletic
    • First symptom was slurring of speech
    • Followed by ataxia of gait
    • No sensory, memory, visual, sphincter deficits
    • Family History : negative, parents still alive, mother may have mild dementia. No history of consanguinity.
    • Blood tests prior to his visit : gliadin and tissue trans-glutaminase antibodies were negative. Transaminase, vitamin E, sed rate, ANA, Lyme titer, TSH, SSA, SSB, methylmalonic acid, homocysteine within normal limits.
  • 6. MRI Patient 1
  • 7. PATIENT 2
    • 53 year-old gentleman with 10 year-history of progressive problems with balance
    • Normal development, was very athletic
    • First symptom was ataxia of gait
    • Followed by slurring of speech
    • Urinary urgency and cramps
    • Family History : Positive for cerebellar ataxia in 5 of his 7 siblings and in his mother deceased at 72. Earlier onset of disease in sibs (~35) and different severity of disease.
  • 8. Patient 2
  • 9. Differential Diagnosis
    • Tumors in the posterior fossa
    • Paraneoplastic syndrome (Yo antibody)
    • Vitamin B12 deficiency
    • Multiple Sclerosis
    • Ataxia associated with gliadin and tissue transglutaminase antibodies (Sprue)
    • Vitamin E deficiency
    • Alcohol abuse
    • Late sequela of Dilantin use
    • Cerebellar variant of prion disease
    • Multisystem atrophy-C
  • 10. Autosomal Dominant Cerebellar Ataxias (Harding’s Classification)
    • ADCAI ADCAII ADCAIII
    • Cerebellar syndrome Cerebellar syndrome Pure cerebellar
    • With involvement of other with pigmentary syndrome
    • CNS systems retinopathy
    • Genotypes
    • SCA1,2,3,4,12,13**,17, 8 ,23*,25* SCA7 SCA5**,6, 8 ,10+,11*,14**,
    • 26*,27**, 28*,29* 15, 16, 22*
    • * Gene not identified
    • + Repeat (ATCCT), associated with epilepsy
    • **point mutation
  • 11. Age of Onset, Disease Duration and Rate of Progression Movement Disorders Vol 20, 11: 2005 Parameter SCA 1 SCA 2 SCA 3 SCA 4 SCA 5 SCA 6 SCA 7 SCA 8 N 13 19 20 14 16 27 7 11 Families, n (%) 5 (10) 10 (20) 17 (33) 2 (4) 1 (2) 10 (20) 2 (4) 4 (8) Age at onset     Mean ± SD (yr) 30 ± 9 29 ± 11 33 ± 11 36 ± 8 33 ± 10 47 ± 11 32 ± 8 37 ± 14     Range (yr) 18-45 15-55 14-62 25-49 17-51 24-63 25-48 25-66 Disease duration     Mean ± SD (yr) 11 ± 8 15 ± 11 9 ± 6 11 ± 10 17 ± 10 13 ± 9 8 ± 5 15 ± 11     Range (yr) 2-25 1-37 0.5-25 1-32 4-30 0.5-30 3-18 0.5-37 No walking aid/wheelchair (%) 70 63 45 57 81 44 57 55 Progression to cane (n) 0 2 4 1 0 3 0 2     Range (yr)   -  8-19 7-10 28   -  7-8   -  4-8
  • 12. SCA 1 SCA 2 SCA 3 SCA 4 SCA SCA 6 SCA 7 SCA 8 Progression to cane (n) 0 2 4 1 0 3 0 2     Range (yr)   -  8-19 7-10 28   -  7-8   -  4-8 Progression to walker (n) 1 3 1 1 0 2 0 1     Range (yr) 9 13-28 12 8 0 17-23 0 31 Progression to wheelchair ( n) 3 3 6 3 1 10 3 2     Mean ± SD (yr) 13 ± 9 27 ± 9 13 ± 6 16 ± 12 5 17 ± 6 13 ± 6 21 ± 11     Range (yr) 5-22 20-33 5-20 3-25 5 9-24 9-18 13-29
  • 13. Genetic Features of SCA
    • Disease Gene Repeat Range Range
    • product normal pathologic
    • SCA1 ataxin1 CAG 6-44 39-83
    • SCA2 ataxin2 CAG 14-31 33-64
    • SCA3 ataxin3 CAG 12-40 54-86
    • SCA5 SPTBN2 point mutation
    • (spectrin beta III)
    • SCA6 CACNA1A CAG 4-20 20-31
    • SCA7 ataxin7 CAG 4-27 37->200
    • SCA8 kelch like CTG 15-91 100-155
    • antisense
  • 14. Genetic Features of SCA
    • Disease Gene Repeat Range Range
    • product normal pathologic
    • SCA10 ataxin10 ATTCT 6-44 39-83
    • SCA12 PPP2R2B CAG <29 66-93
    • (brain specific ser-thr PP2)
    • SCA13 KCNC3 point mutations
    • (voltage-dep K channel)
    • SCA14 PRKCG point mutations
    • (protein kinase C gamma)
    • SCA17 TBP CAG 25-42 45 and 63
    • (Tata box binding protein)
    • SCA27 FGF14 point mutations
    • (fibroblast growth factor)
    • CAG repeats in coding regions result in polyQ (polyglutamine stretches) in the protein product
  • 15. Two Classes of Triplet Repeat Disorders
    • 1) Translated Triplet Repeat Diseases
    • 2) Untranslated Triplet Repeat Diseases
  • 16. Translated (polyQ) triplet repeat disorders
    • Disease Triplet repeats sequence
    • HD CAG
    • SCA 1,2,3,6,7,17 CAG
    • DRPLA CAG
    • Kennedy’s Disease (SBMA) CAG
  • 17. Features of PolyQ Disorders
    • Mode of inheritance is Autosomal Dominant except for SBMA, which is X-linked
    • Neurodegeneration of specific neurons
    • Mechanism of disease: Protein gain of function
  • 18. Untranslated triplet repeat disorders
    • Disease Triplet repeat sequence
    • FRDA GAA (intron 1)
    • SCA 8 CTG (3’ UTR)
    • SCA10 ATTCT (intron)
    • SCA12 CAG (5’ UTR)
    • Myotonic Dystrophy CTG (3’ UTR)
    • Fragile X MR/tremors-ataxia syndrome CGG (promoter)
  • 19. Features of untranslated triplet repeat disorders
    • Mode of inheritance: AD, AR and X-linked, likely reflects the mechanism of disease
    • Neurodegeneration of specific neurons
    • Systemic manifestations
    • Multiple mechanisms of disease: loss of function and RNA dominant/gain of function
  • 20. Untranslated Ataxic Disorders Friedreich’s ataxia Fragile X Tremors-Ataxia Syndrome (FXTAS) SCA8, 10 and 12
  • 21. Friedreich’s Ataxia (FRDA)
    • Most common hereditary ataxia
    • Autosomal Recessive
    • Prevalence: 1 in 50,000-29,000
    • Carrier rate:1 in 120-60
  • 22. Essential Clinical Features (Harding)
    • AR
    • Onset before 25 years
    • Progressive limb and gait ataxia
    • Absent DTR’s in legs
    • Axonal sensory neuropathy followed by (  5 years)
    • Dysarthria, loss of proprioception, areflexia of 4 limbs, extensor plantar response and pyramidal signs
  • 23. Systemic Manifestations
    • Cardiomyopathy
    • Diabetes
    • Hearing loss
    • Scoliosis
    • Pes cavus
    • Amyotrophy
  • 24. Other forms of FRDA
    • Late-onset FA , older than 20, more slowly progressive less frequent scoliosis and pes cavus
    • FRDA with retained reflexes , have all features except retain reflexes, less severe sensory neuropathy
  • 25. Neuropathology
    • Loss of large primary neurons in DRG early finding
    • Degeneration of dorsal columns, corticospinal (distal to proximal) and spinocerebellar tracts, loss of axons in nerves
    • MRI shows cord atrophy, normal cerebellum and brainstem
  • 26. Cord pathology in FRDA
  • 27. Early onset AR ataxias
    • Ataxia with ocular apraxia Type 1(AOA1) and Type 2 (AOA2)
      • Ocular apraxia, severe sensorimotor neuropathy, cognitive deficits, hypoalbuminemia, hypercholesterolemia, increased α -fetoprotein (AOA2)
      • Cerebellar atrophy on MRI
      • Mutations in aprataxin1 and senataxin, RNA helicase
      • Ataxia with vitamin E deficiency ( α -tocoferol transfer protein)
      • Ataxia-telangectasia (phosphatidylinositol-kinase protein)
  • 28. Molecular Genetics of FRDA
    • 96% of cases carry expansion of GAA repeats in intron1 of the frataxin gene (120-1700) in both alleles
    • 4% cases are compound heterozygotes and have 1 allele with GAA expansion and other allele with point mutations
    • Variants of FRDA are caused by shorter expansions in frataxin
  • 29. FRAX Molecular Diagnosis
    • Repeat length Interpretation
    • 6-60 Normal
    • 60-200 Premutation causing tremor-ataxia (FXTAS)
    • >200 Full mutations, completely penetrant in males and 50% penetrant in females
  • 30. MOLECULAR DIAGNOSIS
  • 31. Complete Ataxia Evaluation #690 Type of Disorder: Movement Disorders Typical Presentation: Ataxia, poor coordination of hand, speech and eye movements, uncoordinated and unsteady gait Disease(s) tested for:SCA1, SCA2, SCA3 (MJD), SCA6, SCA7, SCA8, SCA10, SCA13, SCA14 SCA17, AVED, MSS, Aprataxin, DRPLA & Friedreich's ataxias Aprataxin DNA Sequencing Test , DRPLA DNA Test , Friedreich Ataxia DNA Test , MIRAS-Specific POLG1 DNA Test , SCA1 DNA Test , SCA10 DNA Test , SCA13 Select Exon DNA Test , SCA14 DNA Test , SCA17 DNA Test , SCA2 DNA Test , SCA3 (Machado-Joseph Disease) DNA Test , SCA6 DNA Test , SCA7 DNA Test , SCA8 DNA Test , SETX DNA Sequencing Test , SIL1 (Marinesco-Sjogren Syndrome) DNA Sequencing Test , TTPA (Ataxia with Vitamin E Deficiency) DNA Sequencing Test Genetic Testing (Athena Diagnostics)
  • 32. Autosomal Dominant Ataxia Evaluation #680 Type of Disorder: Movement Disorders Typical Presentation: Ataxia, poor coordination of hand, speech and eye movements, uncoordinated and unsteady gait Disease(s) tested for:SCA1, SCA2, SCA3 (MJD), SCA5, SCA6, SCA7, SCA8, SCA10, SCA13, SCA14, SCA17 & DRPLA DRPLA DNA Test, SCA1 DNA Test, SCA10 DNA Test, SCA13 Select Exon DNA Test, SCA14 DNA Test, SCA17 DNA Test, SCA2 DNA Test, SCA3 (Machado-Joseph Disease) DNA Test, SCA5 Select Exon DNA Test, SCA6 DNA Test, SCA7 DNA Test, SCA8 DNA Test Genetic Testing (Athena Diagnostics)
  • 33. Frequency of SCA types
    • SCA3 is the most common (30-40%)
      • AKA: Machado-Joseph Disease
      • In the US most common in East Coast, NE, Rhode Island, Maryland, NC and in West Coast (CA), migration of Portuguese immigrants
      • SCA2 accounts for ~15-20%
      • SCA1 accounts for ~10%
      • Note: OPCA (MRI shows pontocerebellar atrophy) is associated with SCA1 and 2
      • SCA10 , epilepsy
  • 34. PATIENT 2
    • 53 year-old gentleman with 10 year-history of progressive problems with balance
    • Normal development, was very athletic
    • First symptom was ataxia of gait
    • Followed by slurring of speech
    • Urinary urgency and cramps
    • Family History : Positive for cerebellar ataxia in 5 of his 7 siblings and in his mother deceased at 72. Earlier onset of disease in sibs (~35) and different severity of disease.
    • DNA testing: SCA2
  • 35. PATIENT 1
    • 47 year-old gentleman with 7-8 year-history of progressive problems with balance
    • Normal development, was very athletic
    • First symptom was slurring of speech
    • Followed by ataxia of gait
    • No sensory, memory, visual, sphincter deficits
    • Family History : negative, parents still alive, mother may have mild dementia. No history of consanguinity.
    • Blood tests prior to his visit : gliadin and tissue trans-glutaminase antibodies were negative. Transaminase, vitamin E, sed rate, ANA, Lyme titer, TSH, SSA, SSB, methylmalonic acid, homocysteine within normal limits.
    • DNA testing: SCA8
  • 36. Copyright restrictions may apply. Nemes, J. P. et al. Hum. Mol. Genet. 2000 9:1543-1551; doi:10.1093/hmg/9.10.1543 SCA8 Gene
  • 37. Importance of Genetic Testing
    • Genetic Counseling for children and siblings
    • Prognosis
    • Future Treatments
  • 38. Current Treatments
    • Physical Therapy
    • Speech and Swallowing Evaluation
    • Supportive Devices:
      • cane, walker, wheelchair
    • Antioxidants
  • 39. FUTURE TREATMENTS Based on pathogenesis and tailored to the genetic type
  • 40. Two Classes of Triplet Repeat Disorders
    • Untranslated Triplet Repeat Diseases
    • Translated Triplet Repeat Diseases
  • 41. GAA Expansion in frataxin gene
  • 42. Mechanism of decreased frataxin expression
  • 43. Reduced frataxin expression leads to mitochondrial dysfunction
  • 44. Treatment for FRDA
    • Frataxin is a mitochondrial protein that regulates iron metabolism in mitochondria
    • Increased iron accumulation reacts with oxygen (H 2 O 2 -HO º, Fenton reaction) and causes oxidative stress
    • Treatment with Fe chelators (?) and antioxidants (idebenone, analog of CoQ10)
  • 45. Pandolfo M (2008) Drug Insight: antioxidant therapy in inherited ataxias Nat Clin Pract Neurol 4: 86 –96 10.1038/ncpneuro0704 Table 2 Doses of idebenone used in the NIH phase II trial (placebo-controlled, double-blinded to assess tolerability and initial efficacy determination)
  • 46. Translated (polyQ) triplet repeat disorders
    • Disease Triplet repeats sequence
    • HD CAG
    • SCA 1,2,3,6,7,17 CAG
    • DRPLA CAG
    • Kennedy’s Disease (SBMA) CAG
  • 47. Gain-of-function
    • “ Although genetic evidence consistently indicates that a gain-of-function mechanism of pathogenesis is critical for each of the polyglutamine-induced diseases, the extent to which there might be a specific pathogenic pathway common among these disorders remains unresolved”.
    Annu Rev Neurosci, 2007, Orr and Zoghbi
  • 48. Gain-of-function
    • “ It is becoming increasingly apparent that each polyglutamine disorder is, to a large degree, defined by the actions of the expanded polyglutamine tract in the context of the “host” protein ( Gatchel & Zoghbi 2005, Orr 2001 ). Central to this idea is the concept that the normal function and interactions of each disease-associated polyglutamine protein are critical for defining the pathogenic pathway”.
    Annu Rev Neurosci, 2007, Orr and Zoghbi
  • 49. Gain-of-function: SCA1 as an example
    • ATXN1 is widely expressed in all neurons and it localizes in the nucleus
    • ATXN1 interacts with RNAs, shuttles between nucleus and cytoplasm and interacts with transcription factors
    • The polyQ changes the properties of ATXN1 and its interactions with transcription factors leading to neurodegeneration
  • 50. Gain-of-function in SCA1: alteration in transcription factors
  • 51. Future Treatments for SCA Associated with polyQ
    • Neuroprotective agents: high doses of CoQ10 and creatine (in testing for Huntington Disease)
    • HDAC inhibitors (corrects abnormal transcription)
    • Lithium (shown to be effective in mouse model of SCA1, affects transcription, inhibits GSK3)
    • Genetic treatment aimed at reducing the amount of mutated gene for SCA: siRNA and microRNA as potential modulators