Ataxia

1. Ataxia focusingon “inherited ataxia” Presented by: Vidyaningtyas BA, MD Yanuarita T, MD Widagdo S, MD

2. Ataxia – at glance • Inability to make smooth, accurate and coordinated movements, usually due to a disorder of the cerebellum and / or sensory pathways in the posterior column of the spinal cord .

3. Ataxia – at glance • Inability to make smooth, accurate and coordinated movements, usually due to a disorder of the cerebellum and / or sensory pathways in the posterior column of the spinal cord . • Types: • Cerebellar ataxia • Sensory ataxia • Vestibular ataxia

4. Ataxia – at glance • Inability to make smooth, accurate and coordinated movements, usually due to a disorder of the cerebellum and / or sensory pathways in the posterior column of the spinal cord . • Due to dysfunction of the cerebellum. • Accompanied by hypotonia, asynergy, dysmetria, dyschronometria, and dysdiadochokinesia. • Classified as vestibulocerebellum, spinocerebellum, cerebrocerebellum. • Types: • Cerebellar ataxia • Sensory ataxia • Vestibular ataxia

5. Ataxia – at glance • Inability to make smooth, accurate and coordinated movements, usually due to a disorder of the cerebellum and / or sensory pathways in the posterior column of the spinal cord . • Due to dysfunction of the cerebellum. • Accompanied by hypotonia, asynergy, dysmetria, dyschronometria, and dysdiadochokinesia. • Classified as vestibulocerebellum, spinocerebellum, cerebrocerebellum. • Types: • Cerebellar ataxia • Sensory ataxia • Vestibular ataxia

6. Ataxia – at glance • Inability to make smooth, accurate and coordinated movements, usually due to a disorder of the cerebellum and / or sensory pathways in the posterior column of the spinal cord . • Types: • Cerebellar ataxia • Sensory ataxia • Vestibular ataxia • due to loss of proprioception - the loss of sensitivity to the positions of joint and body parts • Romberg’s test positive, ataxic hand

7. Ataxia – at glance • Inability to make smooth, accurate and coordinated movements, usually due to a disorder of the cerebellum and / or sensory pathways in the posterior column of the spinal cord . • Types: • Cerebellar ataxia • Sensory ataxia • Vestibular ataxia • due to dysfunction of vestibular system, • may be associated with prominent vertigo, nausea, vomiting

8. Ataxia – at glance

9. Ataxia – at glance • As one of the members of chronic symmetrical ataxia which is genetically based

10. Inherited ataxia Harding A (1984) • Congenital • Metabolic • Defective DNA repair • Degenerative Michelle G et al (2004) • Mitochondrial • Metabolic • Defective DNA repair • Abnormal protein folding and degradation • Channelopathies • Others J Neurol 2004;251:913-22

11. Inherited ataxia

12. Inherited ataxia Harding A (1984) • Congenital • Metabolic • Defective DNA repair • Degenerative Michelle G et al (2004) • Mitochondrial • Metabolic • Defective DNA repair • Abnormal protein folding and degradation • Channelopathies • Others J Neurol 2004;251:913-22 Mendelian: Autosomal dominant, Autosomal recessive, X-linked NeuroSci 2001;21:219-28

13. Autosomal recessive

14. Friedreich ataxia • Commonest form among early onset autosomal recessive ataxia in Europe • Defect at 9q13-q21.1 98% abnormally expanded GAA in 1stintron  decreased frataxin expression J Neurol 2004;251:913-22

15. Friedreich ataxia

16. Friedreich ataxia • Commonest form among early onset autosomal recessive ataxia in Europe • Defect at 9q13-q21.1 98% abnormally expanded GAA in 1stintron  decreased frataxin expression • Paternal transmission shows contraction • Clinical manifestation: progressive gait and limb ataxia, dysarthria, absent tendon reflexes, babinski signs, decreased vibration sense, sensory axonal peripheral neuropathy, cardiac hypertrophy, diabetes. J Neurol 2004;251:913-22

17. Friedreich ataxia

18. Friedreich ataxia

19. Autosomal dominant • SCA is the main example. • After SCA1 was found in 1993, others named based on number

20. Spinocerebellar ataxia

21. Spinocerebellar ataxia

22. Spinocerebellar ataxia

23. Spinocerebellar ataxia

24. Spinocerebellar ataxia

25. X-linked (metabolic example) • Deficiency of urea cycle enzyme  deficiency of ornithinetranscarbamylase as the most common  hyperammonemia. • Lethal in male • Female: no symptoms – profound neurological impairment • Clinical manifestation: irritability, episodic vomiting, ataxia, dysarthria, lethargy, coma, developmental delay, mental retardation, seizure. • Treatment: low protein diet, arginine.

26. X-linked (FXTAS) • Fragile X-associated tremor/ataxia syndrome (FXTAS) is characterized by tremor and cerebellar gait ataxia. • caused by moderate expansions of a CGG trinucleotide in FMR1 gene • The pathogenic mechanism is related to overexpression and toxicity of the FMR1 mRNA • Clinical manifestation: intention tremor, cerebellar gait and limb ataxia, parkinsonism,decreasedreflexes, orthostatic hypotension, impotence, progressive loss of bowel and bladder control. • The pathological hallmark of FXTAS is the presence of intranuclear inclusions in neurons and astrocytes throughout the brain increased T2 signal intensity in white matter of the MCP • Treatment: low protei n diet, arginine.

27. FXTAS

29. TESTING GUIDELINES

31. The Diagnosis inheritance pattern Genetic counselling Molecular test,Prenatal Diagnosis Recurrence risk

32. Thank You