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