Lecture section...Inherited ataxias

2,015 views
1,777 views

Published on

Lecture section...Inherited ataxias
http://yassermetwally.com
http://yassermetwally.net

Published in: Health & Medicine, Technology
0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
2,015
On SlideShare
0
From Embeds
0
Number of Embeds
25
Actions
Shares
0
Downloads
67
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide

Lecture section...Inherited ataxias

  1. 1. Inherited Ataxias Molecular Pathways to Neurodegeneration Professor Yasser Metwally www.yassermetwally.com
  2. 2. CLASSIFICATION OF THE HEREDITARY ATAXIAS (HARDING, 1981) Congenital Cerebellar Ataxias Metabolic Ataxias Intermittent Metabolic Ataxias Progressive Metabolic Ataxias (AVED) Ataxias Associated With Defective DNA Repair (AT) Degenerative Ataxias Early Onset Inherited Ataxias Friedreich’s Ataxia EOCA (ARSACS, AOA-1, SCAN-1) Cerebellar Ataxia with Hypogonadism Progressive Myoclonic Ataxia Other Early Onset Ataxias Late Onset Inherited Ataxias ADCA Type I ADCA Type II ADCA Type III Other ADCA
  3. 3. Pathogenic Classification  Mitochondrial  Metabolic  Associated with Defective DNA Repair  Protein Folding & Degradation  Channelopathies  Toxic RNA  Others
  4. 4. Pathogenic Classification  Mitochondrial  Metabolic  Associated with Defective DNA Repair  Protein Folding & Degradation  Channelopathies  Toxic RNA  Others
  5. 5. Mitochondrial Ataxias MITOCHONDRIAL NUCLEAR GENES GENES • FRDA • MIRAS • MERRF • IOSCA • NARP • ARCA2 • Kearns-Sayre syndrome • SCA28
  6. 6. Mitochondrial Ataxias
  7. 7. Mitochondrial Ataxias NUCLEAR GENES Über degenerative Atrophie der spinalen Hinterstränge; 1863 • Friedreich’s ataxia • Onset around puberty • MIRAS • Prominent ataxia and • IOSCA dysarthria • ARCA2 • Inconstant nystagmus • Absent tendon reflexes • SCA28 • Late sensory loss and weakness • Scoliosis and pes cavus • Cardiac symptoms Prevalence 1:50,000 Carrier frequency 1:100
  8. 8. FXN gene GAA repeat Ex 1 Ex 2 Ex 3 Ex 4 Ex 5a Ex 5b Ex 6 Homozygotes = Truncation 93% = Missense 7% Compound heterozygotes
  9. 9. Frequency Distribution of GAA 40 chromosomes 30 Number of GAA1 20 GAA2 10 0 0 300 Normal alleles 600 6 36 900 1200 Expanded alleles 60 1300 GAA repeats
  10. 10. Frataxin
  11. 11. FRATAXIN INTRACELLULAR LOCALIZATION
  12. 12. GAA expansion in the FXN gene causes frataxin mRNA reduction in FRDA patients 35 16 Frataxin mRNA (Arbitrary units) 30 14 Frataxin mRNA (Arbitrary Units) 25 12 20 10 8 15 6 10 4 5 2 0 0 A B C D E F G H Q R T 400 500 600 700 800 900 1000 GAA repeat number Patients Controls
  13. 13. Frataxin reduction in FRDA patients
  14. 14. FRATAXIN FUNCTION • Iron transport Iron Sulphur Centres • Iron storage • Anti-oxidant • Ox-Phos stimulation • Fe-S centres biosynthesis
  15. 15. Frataxin deficiency Reduction of Fe-S Increased Fe-S cluster proteins cluster byosynthesis Impaired energy Fenton chemistry metabolism ROS production Oxidative stress Fenton chemistry Oxidative stress Neurodegeneration Neurodegeneration
  16. 16. GAA1 Expansion is inversely correlated with onset age 50 r= -0.71 40 R2 = 0.56 Age at onset 30 20 10 0 0 200 400 600 800 1000 1200 GAA1 repeats
  17. 17. Friedreich Ataxia Onset around puberty • Prominent ataxia and dysarthria • Inconstant nystagmus • Absent tendon reflexes • Late sensory loss and weakness • Scoliosis and pes cavus • Cardiac symptoms FRDA may show variant phenotype and the molecular test should be considered in sporadic and autosomal recessive cases of ataxia, even with late onset and preserved tendon reflexes
  18. 18. DIAGNOSIS  DNA was extracted from EDTA-treated blood samples, and the (GAA)n repeat length in the first intron of the gene X25 was analyzed by PCR and separation on agarose gel. The size of alleles was estimated by leastsquare fit of fragment size to gel mobility.
  19. 19. Mitochondrial Ataxias NUCLEAR GENES • FRDA • MIRAS • IOSCA • CoQ10 deficiency/ARCA2 • SCA28
  20. 20. Nuclear Mitochondrial Ataxias Disease Acronym Gene Function MITOCHONDRIAL RECESSIVE MIRAS polymerase, dna, gamma; Mitochondrial DNA replication ATAXIA SYNDROME (POLG1) INFANTILE-ONSET IOSCA (mtDNA)-specific helicase Mitochondrial DNA replication SPINOCEREBELLAR (C10orf2) ATAXIA COENZYME Q10 DEFICIENCY - mitochondrial Coenzime Q Biosynthesis parahydroxybenzoid- polyprenyltransferase (COQ2) - decaprenyl diphosphate synthase subunit-1 gene (PDSS1) - decaprenyl diphosphate synthase subunit-2 gene (PDSS2) ARCA2 - aaarF-domain- containing kinase 3 (ADCK3/CABC1)
  21. 21. Mitochondrial Ataxias MIRAS IOSCA ARCA2 Onset (years) 1-30 1 2-11 Recessive ataxia + + + Epilepsy + + + Mental impairment + + + Ophthalmoplegia + + - Neuropathy + + - Myoclonus + - - Pyramidal signs - - - Optic atrophy - + - Hearing loss - + - Hypogonadism - + - Hyperlactatemia - - +
  22. 22. Cerebellar atrophy in ARCA 2 Cerebellar atrophy is present in MIRAS, IOSCA, and ARCA. It is absent or mild in FRDA.
  23. 23. Mitochondrial Ataxias NUCLEAR GENES • FRDA • MIRAS • IOSCA • ARCA2 • SCA28
  24. 24. SCA28 – A Dominant Mitochondrial Ataxia Phenotype • juvenile onset • cerebellar • slowly progressive ataxia atrophy • ophthalmoparesis Genetics • mutations in the AFG3L2 (Afg3 like 2) gene (AAA family) • two m-AAA protease isoenzymes: a homo-oligomeric AFG3L2 complex and a hetero-oligomeric complex (paraplegin/AFG3L2) • dominant negative effect of AFG3L2 mutations • impaired quality system control of mitochondrial proteins
  25. 25. Pathogenic Classification  Mitochondrial  Metabolic  Associated with Defective DNA Repair  Protein Folding & Degradation  Channelopathies  Toxic RNA  Others
  26. 26. Metabolic Ataxias INTERMITTENT ATAXIA Vitamin E Deficiency and Lipoprotein Disorders  Deficiency of Urea Cycle  Disorders of Amino Acid  AVED  Disorders of Pyruvate  Abetalipoproteinemia  Hypobetalipoproteinemia PROGRESSIVE ATAXIA Peroxysomal Diseases Storage Diseases  Adrenomyeloneuropathy  Niemann-Pick type C  Refsum  Krabbe  Hexosaminidase A deficiency  Kufs  Cholestanolosis (CTX)
  27. 27. Metabolic Ataxias • Rare disorders • Often autosomal recessive inheritance and early onset • Assay of enzymatic activities or measurement of serum or urine metabolite • Ataxia may be intermittent or progressive • Frequently associated to other neurological signs and multisystem involvement.
  28. 28. Pathogenic Classification  Mitochondrial  Metabolic  Associated with Defective DNA Repair  Protein Folding & Degradation  Channelopathies  Toxic RNA  Others
  29. 29. Disorders Associated with Defective DNA Repair Single Strand Double Strand • AOA1 • Ataxia Telangiectasia • AOA2 (?) • AT like disorder • SCAN1 • Xeroderma Pigmentosum • Cockayne Syndrome Neurological and Absence of non-neurological deficits non-neurological deficits
  30. 30. Associated with Defective DNA Repair Double Strand • Ataxia Telangiectasia • AT like disorder
  31. 31. ATAXIA TELANGIECTASIA A-T is characterized by a triad of clinical manifestations:  a complex, progressive neurological syndrome  telangiectasias  immunological deficiency
  32. 32. ATAXIA TELANGIECTASIA AT Onset (years) 1-4 Recessive ataxia + Oculomotor apraxia + Neuropathy + Choreothetosis + Mental impairment - α-fetoprotein + Cholesterol - Albumin - Immunoglobulins + Telangiectases + Malignancies + Early menopause -
  33. 33. Disorders Associated with Defective DNA Repair Single Strand • AOA1 • SCAN1 • AOA2 (?) • Xeroderma Pigmentosum • Cockayne Syndrome
  34. 34. Ataxia oculomotor apraxia 1 Aprataxin (APTX) AOA1 presents with early onset cerebellar ataxia, oculomotor apraxia, choreoathetosis, dystonia, axonal motor neuropathy, but no extra- neurological feature. Mild cognitive impairment may occur. In later stages, decreased serum albumin and increased total cholesterol may appear.
  35. 35. Imaging [123I]FP-CIT
  36. 36. Diagnosis We analyzed the PCR products by single-strand conformation polymorphism (SSCP) on PlusOne precast acrylamide gels (Pharmacia) with a Genephor electrophoresis device (Pharmacia) at two different running temperatures (5 °C and 20 °C) and then carried out silver staining. We sequenced the electrophoretic variants from both the forward and reverse strands after purification of the PCR products with the NucleoSpin Extract 2 in 1 kit (Macherey-Nagel GmbH). [Moreira et al. Nature Genetics 29, 189 - 193 (2001)]
  37. 37. Disorders Associated with Defective DNA Repair Single Strand • AOA1 • SCAN1 • AOA2 (?) • Xeroderma Pigmentosum • Cockayne Syndrome
  38. 38. AOA2 Senataxin (SETX) 12 3 4 5 6 7 8 9 10 12131415 17 192021 22232425 26 16 18 ATG TAG AOA2 presents with early onset cerebellar ataxia, oculomotor apraxia, choreoathetosis, dystonia, axonal motor neuropathy, but no extra- neurological feature. Early menopause may occur. Increased serum alphafetoprotein is a reliable peripheral marker.
  39. 39. Imaging Back
  40. 40. DNA REPAIR ATAXIAS AT AOA1 AOA2 Onset (years) 1-4 2-30 10-22 Recessive ataxia + + + Oculomotor apraxia + + + Neuropathy + + + Choreothetosis + + + Mental impairment - +/- - α-fetoprotein + - + Cholesterol - + + Albumin - + + Immunoglobulins + - - Telangiectases + - - Malignancies + - - Early menopause - - +
  41. 41. Disorders Associated with Defective DNA Repair Single Strand Double Strand • AOA1 • Ataxia Telangiectasia • AOA2 (?) • AT like disorder • SCAN1 • Xeroderma Pigmentosum • Cockayne Syndrome Sporadic and autosomal recessive cases of ataxia with neuropathy negative for FRDA should be considered for screening of ataxia associated with defect of DNA repair (look for suggestive laboratory markers)

×