Transcript Clinical Features and Molecular Genetics of Hereditary

Clinical Features and
Molecular Genetics of
Hereditary Cerebellar Ataxia
Franca Cambi, MD, PhD
Professor Neurology
University of Kentucky
Outlines
• Clinical manifestations
• Differential Diagnosis
• Genotypes and Molecular
Diagnosis
• Molecular mechanisms
• Current treatments
• Future treatments
Presentation
1. SPORADIC ATAXIA
2. AUTOSOMAL DOMINANT ATAXIA
3. AUTOSOMAL RECESSIVE ATAXIA
4. X-LINKED ATAXIA
Clinical Manifestations
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 transglutaminase 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
Differential Diagnosis
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
With involvement of other
CNS systems
Cerebellar syndrome
with pigmentary
retinopathy
Pure cerebellar
syndrome
Genotypes
SCA1,2,3,4,12,13**,17,8,23*,25*
26*,27**, 28*,29*
SCA7
* Gene not identified
+ Repeat (ATCCT), associated with epilepsy
**point mutation
SCA5**,6,8,10+,11*,14**,
15, 16, 22*
Age of Onset, Disease Duration and Rate of Progression
Parameter
SCA 1
SCA 2
SCA 3
SCA 4
SCA 5
SCA 6
SCA 7
SCA 8
13
19
20
14
16
27
7
11
5 (10)
10 (20)
17 (33)
2 (4)
1 (2)
10 (20)
2 (4)
4 (8)
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
11 ± 8
15 ± 11
9±6
11 ± 10
17 ± 10
13 ± 9
8±5
15 ± 11
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
-
8-19
7-10
28
-
7-8
-
4-8
N
Families, n (%)
Age at onset
Disease duration
Mean ± SD (yr)
Range (yr)
Range (yr)
Movement Disorders Vol 20, 11: 2005
Progression to cane (n)
Range (yr)
Progression to walker (n)
Range (yr)
Progression to wheelchair
(n)
Mean ± SD (yr)
Range (yr)
SCA 1
SCA 2
SCA 3
SCA 4
SCA
0
2
4
1
0
-
8-19
7-10
28
1
3
1
9
13-28
3
SCA 6
SCA 7
SCA 8
3
0
2
-
7-8
-
4-8
1
0
2
0
1
12
8
0
17-23
0
31
3
6
3
1
10
3
2
13 ± 9
27 ± 9
13 ± 6
16 ± 12
5
17 ± 6
13 ± 6
21 ± 11
5-22
20-33
5-20
3-25
5
9-24
9-18
13-29
Genetic Features of SCA
Disease
Gene
product
Repeat
Range
normal
Range
pathologic
SCA1
ataxin1
CAG
6-44
39-83
SCA2
ataxin2
CAG
14-31
33-64
SCA3
ataxin3
CAG
12-40
54-86
SCA5
SCA6
SPTBN2
point mutation
(spectrin beta III)
CACNA1A
CAG
4-20
20-31
SCA7
ataxin7
CAG
4-27
37->200
SCA8
kelch like
antisense
CTG
15-91
100-155
Genetic Features of SCA
Disease
Gene
product
Repeat
Range
normal
Range
pathologic
SCA10
ataxin10
ATTCT
6-44
39-83
SCA12
PPP2R2B
CAG
<29
(brain specific ser-thr PP2)
KCNC3
point mutations
(voltage-dep K channel)
PRKCG
point mutations
(protein kinase C gamma)
TBP
CAG
25-42
(Tata box binding protein)
FGF14
point mutations
(fibroblast growth factor)
SCA13
SCA14
SCA17
SCA27
66-93
45 and 63
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 repeats
sequence
• HD
CAG
• SCA 1,2,3,6,7,17
CAG
• DRPLA
CAG
• Kennedy’s Disease (SBMA)
CAG
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
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)
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
Untranslated Ataxic Disorders
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)
•
•
•
•
•
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
Systemic Manifestations
• Cardiomyopathy
• Diabetes
• Hearing loss
• Scoliosis
• Pes cavus
• Amyotrophy
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
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
Cord pathology in
FRDA
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 (phosphatidylinositolkinase protein)
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
FRAX Molecular Diagnosis
Repeat length
Interpretation
6-60
Normal
60-200
Premutation causing
tremor-ataxia (FXTAS)
>200
Full mutations,
completely penetrant
males and 50%
penetrant in females
in
MOLECULAR
DIAGNOSIS
Genetic Testing (Athena Diagnostics)
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)
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
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
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 transglutaminase antibodies were negative. Transaminase,
vitamin E, sed rate, ANA, Lyme titer, TSH, SSA, SSB,
methylmalonic acid, homocysteine within normal limits.
DNA testing: SCA8
SCA8 Gene
Nemes, J. P. et al. Hum. Mol. Genet. 2000 9:1543-1551; doi:10.1093/hmg/9.10.1543
Copyright restrictions may apply.
Importance of Genetic Testing
Genetic Counseling for children and
siblings
Prognosis
Future Treatments
Current Treatments
• Physical 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 FRDA
• Frataxin 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)
Table 2 Doses of idebenone used in the NIH phase II trial (placebo-controlled,
double-blinded to assess tolerability and initial efficacy determination)
Pandolfo M (2008) Drug Insight: antioxidant therapy in inherited ataxias
Nat Clin Pract Neurol 4: 86–96 10.1038/ncpneuro0704
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
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
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
Gain-of-function in SCA1: alteration in
transcription factors
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