Hereditary Ataxia

1. Approach to Ataxia
Dr ANAND

2. Ataxia refers to disturbance in fine control of posture and movement or
inability to perform a smooth,coordinated, and voluntary motor acts.
Ataxia could be due to lesions in following structures-
1. Cerebellum and its connections
2. Posterior Column
3. Vestibular System

3. Cerebellar Lesions
Cerebellar Hemispheric(Neocerebellum) lesions cause ipsilateral
appendicular ataxia.
Vermal(Paleocerebellum)lesions cause truncal ataxia, titubation,
disorders of stance and gait.
Flocculonodular lobe(archicerebellum) lesions cause nystagmus and
extraocular movement abnormalities

4. Age of onset:
Cerebellar malformations present as developmental delay with
hypotonia in early infancy. Ataxia telangiectasia may manifest in early
childhood. Friedreich ataxia becomes symptomatic by adolescence.
Spinocerebellar ataxias present after 25 years of age, though SCA 2, 3,
and 7 may manifest in infancy.
Onset and progression: Acute, recurrent, static, or progressive
Associated symptoms: Fever, vesicular rashes (varicella), early morning
headache, and projectile vomiting.
Features of raised intracranial tension may be seen in tumors,
cerebellar infarct, and cerebellitis.
History and Examination

5. History of drug or toxin intake: Anticonvulsants, antipsychotics,
benzodiazepines, alcohol, mercury.
History of trauma: Intracranial bleed, trauma to the craniovertebral
junction can cause vertebral artery dissection causing cerebellar
infarction
Birth history: History of hypoxic ischemic encephalopathy (HIE), TORCH
(toxoplasma, other viruses, rubella, cytomegalovirus, herpesvirus)
infections.
Family history: History of consanguinity and death or similar illness in
siblings. Presence of disease in parents and grandparents.

6. Examination
Look for clinical features of cerebellar dysfunction
Ataxia
Intention Tremor
Dysmetria – Overshoot/Undershoot
Dysdiadochokinesia
Asynergia
Titubation
Dysarthria
Slow,staccato and scanning speech
Hypotonia
Nystagmus
Pendular knee jerk or hyporeflexia

7. Features of posterior column dysfunction
Positive Romberg Sign
High Steppage gait
Impaired position and vibration sense
Loss of DTR
Features of Vestibular Dysfunction
Vertigo maximal at onset progressing to ataxia
Associated Nystagmus
Episodic

8. Large head: Hydrocephalus may be associated with lower limb spasticity and
ataxia (involvement of pyramidal and frontopontocerebellar fibers to the
lower limb are close to the ventricles); macrocephaly is seen in Alexander
disease and vanishing white matter disease.
Alopecia: Biotinidase deficiency.
Eye:
• Nystagmus: Gaze-evoked nystagmus in cerebellar lesions, pendular
nystagmus in Pelizaeus-Merzbacher disease, opsoclonus myoclonus in
neuroblastoma
• Slow saccades in SCA type 2 and 3
• Cataract in TORCH infections,Cerebrotendinous xanthomatosis,Marinesco-
Sjogren Syndroem
• Aniridia in Gillespie syndrome

9. • Keyser-Fleischer ring in Wilson disease
• Cherry-red spot: Tay-Sachs disease, Niemann-Pick disease
• Supranuclear gaze palsy: Niemann-Pick disease type C
• Conjunctival telangiectasia in ataxia-telangiectasia (A-T)
• Bitot spots in fat malabsorption syndromes, abetalipoproteinemia
• Papilledema in raised ICT [intracranial space occupying lesions (ICSOL)]
• Retinitis pigmentosa: Refsum disease, mitochondrial disorders [neuropathy,
ataxia,and retinitis pigmentosa (NARP) syndrome],Abetalipoproteinemia
• Ptosis and ophthalmoplegia: Mitochondrial disorders

10. Skin:
• Seborrheic dermatitis: Biotinidase deficiency
• Hypopigmented skin and hair: Menkes syndrome, phenylketonuria
syndrome
• Telangiectasia: Ataxia telangiectasia
• Photosensitive rash in exposed areas: Pellagra in Hartnup disease
• Tendon xanthomas in cerebrotendinous xanthomatosis
• Vesicular rash: Varicella
• Ichthyosis: Refsum disease.

11. Hepatosplenomegaly: Storage disorders.
Pes cavus and scoliosis: Friedreich ataxia.
Diabetes mellitus: Friedreich ataxia.
Bronchiectasis, chronic sinusitis: Ataxia telangiectasia.
Episodic hyperpnea, tongue thrusting: Joubert syndrome.
Cardiac conduction defects: Friedreich ataxia
Sensorineural Hearing Loss: Friedreich ataxia and mitochondrial
disorders

12. Ataxia may be congenital or acquired.
Congenital ataxia is usually associated with cerebellar
malformations.
Acquired ataxia can be classified as acute, episodic, or chronic
based on the rapidity of onset and progression.

13. Chronic Ataxia
Broadly classified in to Progressive ataxia and Non progressive Ataxia
1. Non-progressive Ataxia – Congenital malformations like Cerebellar
Aplasia,Chiari Malformation,Dandy Walker malformation,vermal
aplasia and Joubert syndrome
2. Progressive Ataxia includes brain tumors,hereditary disorders and
metabolic disorders

14. Brian Neoplasms
• Cerebellar Astrocytoma
• VHL (Cerebellar Hemangioblastoma)
• Ependmoma
• Medulloblastoma
• Supratentorial Tumors

15. Congenital Malformations
• Basilar Impression
• Cerebellar Aplasia
• Dandy Walker Malformation
• Vermal Aplasia
• Arnold Chiari Malformation

16. Hereditary Ataxia
Autosomal Dominant Inheritance
Dentato-rubro-pallido-luyisal atrophy
Spinocerebellar Ataxia
X-linked Heritance
Adrenoleukodystrophy
Lebers Optic Atrophy

17. Autosomal Recessive Inherited Ataxias
• Friedreich Ataxia • Pyruvate Dehydrogenase Deficiency
• Ataxia Telangiectasia • Marinesco-Sjogren syndrome
• Ataxia with oculomotor apraxia type 1 and 2 • Juvenile sulfatide lipidosis
• Juvenile GM2 gangliosidosis • Maple syrup urine disease
• Refsum Disease • Wilson Disease
• Abetalipoproteinemia
• Ataxia with selective Vitamin E Deficiency
• Hartnup Disease

18. Friedreich Ataxia
Most common autosomal recessive spinocerebellar ataxia
Mutation- trinucleotide repeat expansion (GAA repeat in Frataxin gene
in chromosome 9)
Late onset(usual onset -5-20 years) Median age of death – 35 years
Degeneration of spinocerebellar, corticospinal, and posterior columns
of spinal cord.
Degeneration of glossopharyngeal,vagus,hypoglassal and deep
cerebellar nuclei.
Loss of betz cell in precentral gyri
Peripheral nerve involvement with loff of large myelinated fibers.

19. Clinical Features
1. Neurological- Gait Ataxia,absent deep tendon reflexes,tremor and
wasting of distal muscles,facial weakness
2. Peripheral Neuropathy-Position and vibration impaired,pain and
temperature sensations lost distally
3. Irregular ocular pursuit,slow saccades,dysmetric
saccades,squaewave jerks,failure of fixation, suppression of
vestibulooccular reflex
4. Dysarthria-slurring and staccato volume

20. 5. Cardiomyopathy-progressive,exertional
dyspnea,palpitations,angina,arrythmias(AF),Congestive Heart
failure- leading cause of death
6. Diabetes Mellitus
7. Eye – Cataracts,Optic atrophy, Retinitis Pigmentosa
8. Auditory dysfunction with vertigo
9. Skeletal Deformities – Kyphoscoliosis and Pes Cavus
D/D – Ataxia with Vitamin E defieciency,Refsum disease, Taysachs
disease,cerebrotendinous xanthomatosis,infantile onset
spinocerebellar ataxia

21. Investigation- atrophy of cerebellum and spinal cord in late stages in
MRI, Raised CSF Protein, Sensorimotor Axonal Neuropathy on NCS
Treatment –
High dose Coenzyme Q10 and Vitamin E
A0001(alpha tocopheryl quinone)- antioxidant
Idebenone – improves cardiac function but not ataxia.Higher doses
provide neurological benefit
Antispasticity agent
Surgical coorection of scoliosis

22. Ataxia Telangiectasia
Defects in DNA repair,mutation in ATM gene
Early onset childhood ataxia
CF-
1. Progressive Cerebellar Ataxia – Early onset- when child starts to
walks
2. Occulomotor Apraxia and impaired voluntary saccades
3. Choreoathetosis and Dystonia
4. Facial Weakness ,drooling and dysarthria

23. 5. Late spinomuscular atrophy
6. Peripheral Neuropathy – diminished DTR and large fiber loss
7. Cognition is well preserved until late stage. Short term memory loss in
3rd and 4th deacade
8. Telangiectasias – Conjuctiva,auricle,nasal bridge,antecubital,popliteal
spaces,
9. Premature ageing of hair and skin
10. Recurrent Sinopulmonary Infections-chronic bronchitis,bronchiectasis.
11. Higher risk of Hodgkin disease,leukemia,lymphoma and
lymphosarcoma,brain tumors,gstric adenocarcinoma
12. Insulin resistant diabetes,hypogonadism

24. Investigations – Elevated Alpha-fetoprotein and CEA
Decreased or absent IgA,IgE,IgM.selective IgG2 deficiency
Acanthocytes in peripheral smear
Genetic testing for mutations in ATM gene
MRI Brain Cerebellar atrophy
Management
Avoid ionizing radiation
Intravenous Ig for recuurent Infections
Early and aggressive physiotherapy
L-Dopa derivatives and anticholinergics improve basal ganglia dysfunction
Amantadine,fluoxetine /Buspirone for balance and speech
Clonazepam,propranolol for tremors

25. Abetalipoproteinemia
Autosomal Recessive
Fat Malabsorption and Deficiency of Vitamin A,E and K
Molecular defect in MTTP (microsomal Triglyceride Transfer Protein)
gene
CFs-
1. Newborn-Failure to thrive,vomiting and large volume stools
2. Delayed Psychomotor development
3. Cerebellar Ataxia and dysmetria in first decade

26. 4. Tendon Reflexes lost by age of 5
5. Progressive gait disturbances,dysmetria and difficulty performing
rapid alternating movements
6. Proprioceptive sensations loss
7. Pain and temperature relatively preserved
8. Retinitis Pigmentosa is a constant feature
9. Night Blindness due loss of central vision
10. Nystagmus

27. Diagnosis –
Severe Nutritional Anaemia
Acanthocytosis
Low Plasma Cholesterol and Triglyceride
Absent Apolipoprotein-B in plasma is diagnostic
Treatment –
Large oral Vitamin E supplementation(100MG/kg/day)
Dietary fat restriction

28. Refsum Disease
• AR disorder of phytanic acid metabolism – PAHX gene mutation
• Accumulation of phytanic acid in serum and tissues
CFs –
1. Retinitis Pigmentosa
2. Peripheral Neuropathy - chronic hypertrophic neuropathy,ataxia
3. Cerebellar Ataxia,tremors and nystagmus
4. Elevated CSF protein
5. Sensorineural hearing loss, cardiac conduction abnormalities
,ichthyois and anosmia

29. NCS – reduced amplitudes ,prologed latencies and slowed conducton
velocities
Nerve Biopsy – Onion bulb formation
Treatment – avoid phytols(fish,dairy products,ruminant fats)

30. Ataxia with Oculomotor Apraxia
Onset 4-5 years for AOA1 and 12-20 years for AOA2
APTX gene mutation for AOA1 and syntaxin gene mutation AOA2
Progressive Ataxia,Nystagmus,Slow Saccades, Oculomotor Apraxia and
dysarthria with areflexia(Peripheral Neuropathy)
External Opthalmoplegia
Peripheral Neuropathy – Areflexia,Quadriplegia and atrophy of hands
and feet
Chorea and Arm Dystonia in late stage
Pyramidal Signs in few cases
Impaired cognition and absence of immunodeficiency differentiates
from AT

31. Investigations- Cerebellar Atrophy in MRI
Sensorimotor Axonal Neuropathy
Raised AFP and CPK level
Hypoalbuminaemia and raised cholesterol
Molecular Genetic Testing
Treatment – Supportive
Coenzyme Q10
High Protein

32. Ataxia with Vitamin E Deficiency(AVED)
Mutation in TTPA gene
Progressive Gait Ataxia
Dysarthria,areflexia and impaired proprioception and vibration sense
Very Low levels of Plasma Vitamin E
Treatment with High dose oral Vitamin E

33. Juvenile GM2 gangliosidosis/Tay Sachs
Alpha and beta-Hexoaminodase A deficiency
Age of onset before 15 years
CFs-
1. Progressive Ataxia -Intenton tremor,Dysarthria and limb and gait
ataxia
2. Cherry red spot and blindness
3. Startle reponse,hypotonia and poor head control
4. Later Spasticity
Investigation – GM2 Ganglioside accumulation

34. Marinesco Sjogren Syndrome
Mutation in SIL1 gene
Onset – Infansy
Slowly Progressive
CFs –
1. Cerebellar Ataxia, Dysarthria,Nystagmus,
2. Congenital Cataracts
3. Intellectual Disability
4. Developmental Delay,Short Staure,Hypotonia.hypogonadism,pes valgus
and scoliosis
Diagnosis – Clinical and Genetic testing
Treatment - Supportive

35. Cerebrotendinous Xanthomatosis
Lipid Storage disorder
Mutation of CYP27A1 gene on chromosome 2 which is a part of hepatic
bile acid synthesis pathway
CFs-
Cerebellar Ataxia,Spastic Paraparesis,extrapyramidal signs,
sensorimotor peripheral Neuropathy,Seizures, Dementia,Congenital
Cataracts,Tendon and tuberous Xanthomas,Endocrinopathies
Investigations – Elevated levels of Serum Cholestanol,Genetic Testing
Treatment – Oral Chenodeoxycholic acid

36. Niemann Pick Disease Type C
Mutation in NPC1 and NPC2 genes
Deficient esterification of cholesterol
Early development is normal.Onset – 3 years
Cerebellar Ataxia or dystonia
Apraxia of vertical gaze and oculomotor Apraxia
Cognitive difficulties, Dementia,Seizures, Spasticity
Cherry Red spot in fundus
Investigation – Foam cells in Bone marrow biopsy
Management – Supportive Treatment
Bone Marrow transplantation
Liver Transplantation

37. Hartnups Disease
Abnormal gene is SLC6A19 Chromosome 5
Defect in aminoacid transport mainly tryptophan
Decreased synthesis of niacin and serotonin
Cfs –
1. Pellagra-photosensitive rash,Dementia
2. Delayed Milestones - Short Stature
3. Intermittent Ataxia
Diagnosis-
Aminoaciduria
Treatment –
Oral Nicotinamide
High Protein Diet

38. Maple Syrup Urine Disease
• Metabolic Disorder affecting branched chain amino acids
• Enzyme defect in Branch chain ketocid dehydrogenase
Sweet Smelling Urine and ketoacidosis during attack
Classic Form in Newborn presents with seizures,vomiting and poor feeding.
Intermediate form – Progressive Intellectual Disability
Intermittent form with recurrent ataxia and encephalopathy
• Investigation – TMS in Newborns,Urine for alpha ketocids and branched
chain aminoacids during attacks.
• Treatment – Protein restricted diet,specialized diet,thiamine for thiamine
responsive disease,Peritoneal dialysis during attacks

39. Ataxia with certain clinical features
Pyramidal Signs AOA2,FA and AVED
Cognitive impairment AOA1,AOA2,DRPLA
Peripehral Neuropathy FA,AT,abetalipoproteinemia,refsum
Seizures Mitochondrial,Biotinidase Deficiency
Myoclonus MERRF,AOA2
Oculomotor Apraxia AT,AOA1,AOA2
Chorea and Dystonia AT,AOA1,AOA2
Slow Saccades SCA,AT

40. Investigations
• MRI to look for cerebellar atrophy which is seen in AOA1,2,AT,SCA,FA.
Cervical SpinalCord atrophy in FA. Pontocerebellar atrophy in DRPLA
• Sensory and Motor Nerve Conduction studies. Sensory Neuropathies seen
in FA,AVED,abetalipoproteinemia. Axonal sensorimotor Neuropathy seen in
AT,AOA1,AOA2, and CTX. Refsum can have demyelinating neuropathy
• ECG and Echo changes in FA
• Blood Investigations – Albumin,cholesterol,alpha
fetoprotein,lactate,immunoglobin.
• Urine aminoacids- Hartnup and MSUP
• Genetic Studies

42. Thank You