Clinical Features and Molecular Genetics of Hereditary Cerebellar Ataxia
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Clinical Features and Molecular Genetics of Hereditary Cerebellar Ataxia
- 4. Ataxia of gait Dysarthria Sensory deficits Spasticity Retinopathy and optic atrophy Parkinsonian features Epilepsy
- 8. Patient 2
- 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
- 20. Friedreich’s ataxia Fragile X Tremors-Ataxia Syndrome (FXTAS) SCA8, 10 and 12
- 26. Cord pathology in FRDA
- 31. 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)
- 35. Nemes, J. P. et al. Hum. Mol. Genet. 2000 9:1543-1551; doi:10.1093/hmg/9.10.1543 SCA8 Gene
- 38. FUTURE TREATMENTS Based on pathogenesis and tailored to the genetic type
- 40. GAA Expansion in frataxin gene
- 41. Mechanism of decreased frataxin expression
- 42. Reduced frataxin expression leads to mitochondrial dysfunction
- 44. 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)
- 49. Gain-of-function in SCA1: alteration in transcription factors
Editor's Notes
- 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.