The document discusses different classifications of hereditary ataxias including congenital cerebellar ataxias, metabolic ataxias, ataxias associated with defective DNA repair, and degenerative ataxias. It focuses on pathogenic classifications including mitochondrial, metabolic, associated with defective DNA repair, protein folding and degradation, channelopathies, toxic RNA, and others. Specific mitochondrial ataxias caused by nuclear and mitochondrial genes are examined in depth, including Friedreich's ataxia. Disorders associated with defective DNA repair including ataxia telangiectasia, ataxia oculomotor apraxia types 1 and 2 are also summarized.

1. Inherited Ataxias
Molecular Pathways to
Neurodegeneration
Professor Yasser Metwally
www.yassermetwally.com

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. Pathogenic Classification
 Mitochondrial
 Metabolic
 Associated with Defective DNA Repair
 Protein Folding & Degradation
 Channelopathies
 Toxic RNA
 Others

4. Pathogenic Classification
 Mitochondrial
 Metabolic
 Associated with Defective DNA Repair
 Protein Folding & Degradation
 Channelopathies
 Toxic RNA
 Others

5. Mitochondrial Ataxias
MITOCHONDRIAL
NUCLEAR GENES
GENES
• FRDA
• MIRAS • MERRF
• IOSCA • NARP
• ARCA2 • Kearns-Sayre syndrome
• SCA28

6. Mitochondrial Ataxias

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. 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. 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. Frataxin

11. FRATAXIN INTRACELLULAR LOCALIZATION

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. Frataxin reduction in FRDA patients

14. FRATAXIN FUNCTION
• Iron transport Iron Sulphur Centres
• Iron storage
• Anti-oxidant
• Ox-Phos stimulation
• Fe-S centres biosynthesis

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. 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. 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. 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. Mitochondrial Ataxias
NUCLEAR GENES
• FRDA
• MIRAS
• IOSCA
• CoQ10 deficiency/ARCA2
• SCA28

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. 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. Cerebellar atrophy in ARCA 2
Cerebellar atrophy is present in
MIRAS, IOSCA, and ARCA.
It is absent or mild in FRDA.

23. Mitochondrial Ataxias
NUCLEAR GENES
• FRDA
• MIRAS
• IOSCA
• ARCA2
• SCA28

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. Pathogenic Classification
 Mitochondrial
 Metabolic
 Associated with Defective DNA Repair
 Protein Folding & Degradation
 Channelopathies
 Toxic RNA
 Others

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. 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. Pathogenic Classification
 Mitochondrial
 Metabolic
 Associated with Defective DNA Repair
 Protein Folding & Degradation
 Channelopathies
 Toxic RNA
 Others

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. Associated with Defective DNA Repair
Double Strand
• Ataxia Telangiectasia
• AT like disorder

31. ATAXIA TELANGIECTASIA
A-T is characterized by a triad of clinical
manifestations:
 a complex, progressive neurological syndrome
 telangiectasias
 immunological deficiency

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. Disorders Associated with Defective DNA Repair
Single Strand
• AOA1
• SCAN1
• AOA2 (?)
• Xeroderma Pigmentosum
• Cockayne Syndrome

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. Imaging
[123I]FP-CIT

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. Disorders Associated with Defective DNA Repair
Single Strand
• AOA1
• SCAN1
• AOA2 (?)
• Xeroderma Pigmentosum
• Cockayne Syndrome

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. Imaging
Back

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. 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)