Clinical Features of Friedreich Ataxia

7/29/2019 Clinical Features of Friedreich Ataxia

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Clinical features of Friedreich

Ataxia

Professor Martin DelatyckiMurdoch Childrens Research Institute

Victoria, Australia


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Nikolaus Friedreich- 1825-1882


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Friedreich Ataxia- History

Described in 5 papers by Nikolous Friedreich 1863-

1877

Wrzburg, Germany

Did not describe absent reflexes initially as reflexes

were described by his student Erb 1875!


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Friedreich Ataxia

Autosomal Recessive (not that Friedreich knew this!)

98% homozygous GAA expansion intron 1 FXN, 2%compound heterozygous GAA/point mutation

Commonest Hereditary Ataxia

Prevalence 1:30 000 based on molecular data

Carrier Frequency 1:85


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Friedreich ataxia- clinical features

progressive ataxia of limbs

absent lower limb reflexes vibration, proprioception

extensor plantar responses

scoliosis

foot deformity

cardiomyopathy

diabetes mellitus

visual disturbance

dysarthria

dysphagia

eye movement

abnormalities hearing deficits

cognitive deficits

sexual problems sleep apnoea

urological disturbance

psychological issues


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Diagnostic Criteria (Geoffroy et al 1976)

Primary (must be present)

onset before the end of puberty (never after 20 years)

progressive ataxia of gait

dysarthria

loss of joint position or vibration sense absent tendon reflexes in the legs

muscle weakness

Secondary extensor plantar responses

pes cavus

Scoliosis

cardiomyopathy


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Diagnostic Criteria (Harding 1981)

Primary (must be present)

onset before 25 years

progressive ataxia of limbs and gait absence of knee and ankle jerks

Secondary

dysarthria extensor plantar responses

If secondary criteria absent must have affected sib

or +ve electrical studies.


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Atypical FRDA

Friedreich ataxia with retained reflexes (FARR) (9%)

Late onset FRDA (LOFA)- onset > 25 years (14%)

Very late onset FRDA (VLOFA)- onset > 40 years


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Frequency of symptoms/signs

Symptom Harding Durr Delatycki

Ataxia 99 100 100

Dysarthria 97 91 95

Absent lower limb reflexes 99 87 74

Scoliosis 79 60 78

Pes cavus 55 55 74

Swallowing disturbance - 27 -

Sphincter disturbance - 23 41

Reduced vision 18 13 -

Hearing impairment 8 13 -

Cardiomyopathy on echo - 63 65

Diabetes/ abnormal GT 10 32 8


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Disease progression

FARS score

0

20

40

60

80

100

120

140

1-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40

Time interval s ince disease onset (years)

FA

RSs

core

AOO < 14 years

AOO 14 years

Onset- 15.5 years (Durr et al), 10.5 years (Delatycki et al)Wheelchair-10.8 years (Durr et al), 10.1 years (Delatycki et al)


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0

5

10

15

20

25

30

0 500 1000 1500

GAA repeat size of smaller allele

Age

ofonset

Age of onset v GAA size smaller allele(R2=0.39)


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Mortality

Harding (1981)- 37 years mostly cardiomyopathy

De Michele et al (1996)- 36 years from onset

Tsou et al (2011)- 61 subjects

Mean- 36.5 years, Median- 30 years

Cause- cardiac dysfunction (59%), probable

cardiac dysfunction (3.3%), non-cardiac

(27.9%), unknown (9.8%)

Positive correlation b/w age at death and smaller

GAA


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Scoliosis

Labelle et al- 56/56 had a curve of10%

20/36 who were followed for10 years had a

curve of >60 and progressed (associated with

younger AO, onset scoliosis < puberty)

Milbrandt et al- 49/77 (63%) had scoliosis

16 (33%) had severe double curves

10 (20%) treated with a brace- many progressed 16 (33%) spinal fusion

? Role for botox, physical therapy


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Foot deformity

Pes cavus common (55-75%) but

not a major source of morbidity

Equinovarus deformity can causesignificant morbidity

Delatycki et al (2005)- 32 patients-

15 absent or mild, 8 moderateseverity but reducible, 9 severe

and irreducible

Reducible- physical therapy,splinting, botox

Fixed- surgery

Prevention critical!


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Vision

13% in large study had visual loss (Durr et al 1996)

Fortuna et al (2009) found 26/26 had anterior and

posterior visual pathway abnormalities by opticalcoherence tomography (OCT) and pattern visual

evoked potentials (P-VEPs)

All had reduced retinal nerve fiber layer thickness Only 5/26 had visual symptoms

Occasional sudden visual loss similar to LHON


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Eye movements

Abnormalities

Pursuit

Square wave jerks

Vestibulo-ocular reflex

Fixation

Reduced visual QoL (Fahey 2008) and impactactivities such as reading, computer use

Near vision affected more than distance vision


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Vestibular Function


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Vestibular Dysfunction in FRDA

Mean Yaw Gain = 0.49 (normal 1.0)Mean Yaw Latency 25 ms (normal 8ms)

SinglePatient

GroupSummary


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Dysarthria

Present in > 90%

Folker, Murdoch, Rosen et al (2010 x4, 2011 x3)

Generally mild to moderate

3 subgroups- (i) mild dysarthric symptoms, (ii)

increased velopharyngeal involvement, (iii)increased laryngeal dysfunction

Severity correlates with disease duration

Singh et al (2010)- 4/5 measures different in FRDA cf

controls and all 4 correlated with FARS score


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Dysphagia

No published data

Anecdotally a problem in those with disease of longerduration

Can cause aspiration +/- pneumonia


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Hearing

8-13% have hearing loss as measured by

audiograms cf 4% in the general population Rance et al (2008, 2010)

3/10 abnormal BAER- auditory neuropathy

pattern

9/10 abnormal speech understanding when

tested with levels of background noise typical of

everyday listening conditions Successful treatment with microphone/receiver

systems


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Cognition

Montovan et al (2006)- 13 subjects; full scale IQ 92.8 v

controls 110.8 (NS) but significantly poorer performance

on a series of cognitive tasks The intelligence profile of individuals with FRDA is

characterised by concrete thinking, poor capacity in

concept formation and visuospatial reasoning withreduced speed of information processing

Corben et al (2010, 2011, 2011, 2011)- Subjects with

FRDA significantly disadvantaged accommodatingunexpected movement, initiating movement without a

direct visual cue and reacting to incongruent, compared

with congruent stimuli


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Urological issues

CCRN data 578 subjects

Incontinence 158 (27%)

Urgency 180 (31%)

Use at least one medication for bladder- 77 (13%)

Melbourne data- 133 subjects- 55 (41%) no bladder

problems, 78 (59%) reported bladder impairment

12% mild urgency, hesitance or retention (once a week)

5% reported loss of bladder function/catheterisation


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Cardiomyopathy Close to 100% have an abnormal ECG, particularly T wave

inversion, left axis deviation, and repolarization abnormalities

Hypertrophic cardiomyopathy with impaired septal and laterallong-axis LV function

Incidence and severity correlated with GAA1

Wall thickness reduces as disease progresses

Dilated cardiomyopathy may occur late and is a poor

prognostic sign

Arrhythmias common and can cause sudden death

Ejection fraction often preserved until late in course

Heart failure may occur but can be masked by lack ofphysical activity


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Sleep apnoea

Corban, Copeland, Ho et al (in preparation)

Increased frequency of OSA cf age matched

controls Not related to BMI

Presence correlates with disease duration

Low threshold for ordering sleep studies


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Diabetes mellitus

10-30% definite diabetes mellitus due to combined

insulin deficiency and insulin resistance

Many have impaired glucose tolerance and insulinresistance

Usually requires insulin therapy

Four studies have linked NIDDM to 9q13 where FXNresides


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Psychological issues

Increased rates of depression

Flood and Perlman (1987)- 35/38 had some degreeof affective disorder ranging from major depression to

grief reaction

Few reports of psychosis- not clear this is increasedin FRDA

Issues related to adolescence with chronic disability

End of life issues Psychological support- pharmacological and

counseling important


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Point mutations and phenotype

Can present with identical phenotype to FRDA due to

homozygous GAA expansions but can be:

Milder More severe

Different phenotype (eg: later onset, absent

cardiomyopathy, more spasticity, slowerprogression, absence of dysarthria [G130V])


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Differential diagnosis

Ataxia with vitamin E deficiency

Ataxia telangiectasia Mitochondrial cytopathies

Ataxia with oculomotor apraxia types I and II

Late onset Tay Sachs disease

Hereditary spastic paraplegia

HMSN

Huntington disease

ARSACS

SCA 4, 25 (sensory neuropathy prominent)


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Funding

National Health and Medical Research Council

FARA Australasia

FARA USA

MDA

MCRI

Lefroy family


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Scale development

Julie Pallant

Kinematic studies

Nellie Georgiou-Karistianis

John Bradshaw

CCRN

Dave Lynch et al

Acknowledgements

Clinical studies

Louise Corben

Cate Wilson

Geneieve Tai

Veronica Collins

Michael Fahey

AndrewChurchyard

Cardiac

Roger Peverill Lesley Donellan

fMRI

Gary Egan

Hamed Akhlaghi

Ocular Motility

Phillip Cremer

Owen White

Lynette Millist

Swee Aw

Speech Bruce Murdoch

Jo Mohr

Adam Vogel

Melanie Gow

Audiology

Gary Rance

Documents

Clinical Features of Friedreich Ataxia