CS: Friedreich's Ataxia

Question 1

Case presentation of FA

Answer 1

Examination approach as per cerebellar syndrome
Note too many extra features suggestive of genetic syndrome - pes cavus, pyramidal weakness, areflexia, extensor plantars, dorsal column neuropatrhy

A. Inspection - young patient with deformities and syndromic
1. Pes cavus, foot inversion or hammertoes +/- foot orthoses, corrective surgery scar - chronic neuropathy
2. Kyphoscoliosis
3. High arch palate
4. Gait deformities - broad based gait, high stepping gait

B. Bilateral mixed UMNL (pyramidal) and LMNL (peripheral neuropathy) pattern
4. Normal tone or hypotonia
5. Pyramidal distal wasting and weakness (UMNL)
- UL: extensor weaker; LL: flexors weaker
- Distal wasting of feet, legs, hands
6. Hypo/areflexia (LMNL) - degenerated peripheral nerves
7. Extensor plantar response (UMNL) (or absent in 10%)

C. Dorsal column sensory loss
8. Loss of vibration, proprioception - initially over hands and feet
8A. Advanced disease spinothalamic tract affected with loss of pain and temperature sensation

D. Cerebellar (ataxia) signs
9. Bilateral limb ataxia - dysdiadochokinesia, heel shin positive, or even titubation of trunk
10. Bilateral gaze-evoked nystagmus with broken pursuit - fast towards side of lesion, or bilaterally fast
11. Hypermetric saccades
12. Dysmetria and past pointing, intentional tremor
13. Romberg’s positive (loss of proprioception)
14. Staccato speech
15. Normal pupillary reflexes (important negative TRO tabes dorsalis)

Wishlist
1. Diabetic neuropathy - finger prick, fundoscopy
2. Optic atrophy - fundoscopy for optic disc pallor
3. HOCM - jerky carotid pulse, double apical impulse, systolic murmur
4. Sensorineural deafness (10%)

Question 3

Molecular genetics of FA

Answer 3

Autosomal recessive - chromosome 9q13
- GAA trinucleotide repeat expansion (up to 200-1000 times) for protein fraxatin
- Fraxatin deficiency - iron accumulation in mitochondria of affected cells, causing free radial formation and impaired oxidative phosphorylation and cell death

(Fraxatin involves in mitochondrial iron regulation and oxidative phosphorylation)
(Normal individuals at most 50 times repeat)

Question 4

Explain the pathophysiology of clinical features in FA

Answer 4

Neurodegenerative disorder of spinal cord and spinal roots
1. Molecular genetic defect leading to fraxatin deficiency and neuronal cell death
2. Demyelination and depletion of large myelinated nerve fibres leading to fibrous gliosis
- Affects: posterior column, corticospinal, spinocerebellar tract, peripheral nerves
3. Spinal cord becomes thin, dorsal root ganglia become atrophic
(relative sparing of unmyelinated fibres)

Proprioception and vibration loss
- Degeneration of posterior columns

Hyporeflexia
- Loss of large nerve fibres in dorsal root ganglia

Cerebellar ataxia
- Degeneration lateral and ventral spinocerebellar tracts, Clarke column, dentate nucleus, superior vermis, dentatorubral pathways

Pyramidal weakness and extensor plantars
- Degeneration of corticospinal tract

Question 5

Differential diagnoses of absent deep tendon reflex (LMNL) and extensor plantars (UMNL)

Answer 5

1. Combined condition
   - Peripheral neuropathy and stroke, or cervical myelopathy
   - Cervical and lumbar spondylosis
2. Subacute combined degeneration of cord (B12)
3. Tabes dorsalis
4. Conus medullaris syndrome
5. Friedreich’s ataxia
6. Motor neuron disease

Question 6

Age of onset of FA

Attnuated FA

Answer 6

Children 10-15 years old, almost always before 20 years

Some family members may have attenuated FA - only pes cavus or hammertoes, with loss of ankle reflex

Question 7

What is the presenting complaints of patient with FA?

Answer 7

Gait ataxia

Question 8

Cardiac manifestation of FA

Answer 8

1. TWI inferolateral leads
2. LVH
3. Conduction defects
4. Arrhythmias
5. Chronic interstitial myocarditis
6. Myocardial fibrosis
7. Hypertrophic cardiomyopathy (50%)

Question 9

Management of patient with FA

Answer 9

1. Multidisciplinary team - Neurology, podiatry, PT, OT, orthopaedics, geneticist
2. Physiotherapy and occupational therapy - delay deformities and maintain function of limbs
3. Foot and ankle orthoses, walking aids
4. Orthopaedics correction of scoliosis, pes cavus
5. Management of diabetes mellitus
6. Visual aids and hearing aids
7. Symptomatic treatment of cardiomyopathy and arrhythmias

Question 10

Prognosis of FA

Answer 10

Variable rate - WC bound after 15 years onset
Death at 4-5th decade

Question 11

Other early onset recessive ataxias

Answer 11

1. Ataxia telangiectasia
2. Abetalipoproteinaemia
3. Refsum’s disease