Professor Yasser Metwally
• Clinical manifestations
• Differential Diagnosis
• Genotypes and Molecular Diagnosis
• Molecular mechanisms
• Current treatments
• Future treatments
1. SPORADIC ATAXIA
2. AUTOSOMAL DOMINANT ATAXIA
3. AUTOSOMAL RECESSIVE ATAXIA
4.X-LINKED ATAXIA
Presentation
Ataxia of gait
Dysarthria
Sensory deficits
Spasticity
Retinopathy and optic atrophy
Parkinsonian features
Epilepsy
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.
MRI Patient 1
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.
Patient 2
1. Tumors in the posterior fossa
2. Paraneoplastic syndrome (Yo antibody)
3. Vitamin B12 deficiency
4. Multiple Sclerosis
5. Ataxia associated with gliadin and tissue transglutaminase antibodies (Sprue)
6. Vitamin E deficiency
7. Alcohol abuse
8. Late sequela of Dilantin use
9. Cerebellar variant of prion disease
10. Multisystem atrophy-C
Autosomal Dominant Cerebellar Ataxias(Harding’s Classification)
ADCAI ADCAII ADCAIII
Cerebellar syndrome Cerebellar syndrome Pure cerebellarWith involvement of other with pigmentary syndromeCNS systems retinopathy
GenotypesSCA1,2,3,4,12,13**,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
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
Age of Onset, Disease Duration and Rate of Progression
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
Genetic Features of SCADisease Gene Repeat Range Range
product normalpathologic
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 15-91 100-155antisense
Genetic Features of SCADisease Gene Repeat Range Range
product normalpathologic
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
Two Classes of Triplet Repeat Disorders
1) Translated Triplet Repeat Diseases
2) Untranslated Triplet Repeat Diseases
Translated (polyQ) triplet repeat disorders
Disease Triplet repeatssequence
HD CAG
SCA 1,2,3,6,7,17 CAG
DRPLA CAG
Kennedy’s Disease (SBMA) CAG
Features of PolyQ DisordersMode of inheritance is Autosomal
Dominant except for SBMA, which is X-linked
Neurodegeneration of specific neurons
Mechanism of disease: Protein gain of function
Untranslated triplet repeat disorders
Disease Triplet repeatsequence
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)
Features of untranslated triplet repeat disordersMode 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
Friedreich’s ataxia
Fragile X Tremors-Ataxia Syndrome (FXTAS)
SCA8, 10 and 12
Friedreich’s Ataxia (FRDA)Most common hereditary ataxia
Autosomal Recessive
Prevalence: 1 in 50,000-29,000
Carrier rate:1 in 120-60
Essential Clinical Features(Harding)
AROnset before 25 yearsProgressive limb and gait ataxiaAbsent DTR’s in legsAxonal sensory neuropathy followed by ( 5
years)Dysarthria, loss of proprioception, areflexia
of 4 limbs, extensor plantar response and pyramidal signs
Systemic Manifestations Cardiomyopathy
Diabetes
Hearing loss
Scoliosis
Pes cavus
Amyotrophy
Other forms of FRDALate-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
NeuropathologyLoss 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
Cord pathology in FRDA
Early onset AR ataxiasAtaxia 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 MRIMutations in aprataxin1 and senataxin, RNA
helicaseAtaxia with vitamin E deficiency (α-tocoferol
transfer protein)Ataxia-telangectasia (phosphatidylinositol-
kinase protein)
Molecular Genetics of FRDA96% 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
FRAX Molecular DiagnosisRepeat length Interpretation
6-60 Normal
60-200 Premutation causing tremor-ataxia
(FXTAS)
>200 Full mutations, completely
penetrant in males and 50% penetrant in females
MOLECULAR DIAGNOSIS
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)
Frequency of SCA typesSCA3 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 2SCA10, epilepsy
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
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
Nemes, J. P. et al. Hum. Mol. Genet. 2000 9:1543-1551; doi:10.1093/hmg/9.10.1543
SCA8 Gene
Importance of Genetic TestingGenetic Counseling for children and siblings
Prognosis
Future Treatments
Current TreatmentsPhysical Therapy
Speech and Swallowing Evaluation
Supportive Devices:
cane, walker, wheelchair
Antioxidants
FUTURE TREATMENTS
Based on pathogenesis and tailored to the
genetic type
Two Classes of Triplet Repeat Disorders
Untranslated Triplet Repeat Diseases
Translated Triplet Repeat Diseases
GAA Expansion in frataxin gene
Mechanism of decreased frataxin expression
Reduced frataxin expression leads to mitochondrial dysfunction
Treatment for FRDAFrataxin is a mitochondrial protein that
regulates iron metabolism in mitochondria
Increased iron accumulation reacts with oxygen (H2O2-HOº,Fenton reaction) and causes oxidative stress
Treatment with Fe chelators (?) and antioxidants (idebenone, analog of CoQ10)
Pandolfo M (2008) Drug Insight: antioxidant therapy in inherited ataxiasNat 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)
Translated (polyQ) triplet repeat disorders
Disease Triplet repeatssequence
HD CAG
SCA 1,2,3,6,7,17 CAG
DRPLA CAG
Kennedy’s Disease (SBMA) CAG
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
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
Gain-of-function: SCA1 as an exampleATXN1 is widely expressed in all neurons and
it localizes in the nucleusATXN1 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
Gain-of-function in SCA1: alteration in transcription factors
Future Treatments for SCA Associated with polyQNeuroprotective 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