Clinical features of Friedreich Ataxia

Professor Martin Delatycki Murdoch Childrens Research Institute Victoria, Australia

Nikolaus Friedreich- 1825-1882

Friedreich Ataxia- History

Described in 5 papers by Nikolous Friedreich 18631877 Wrzburg, Germany Did not describe absent reflexes initially as reflexes were described by his student Erb 1875!

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

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

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 extensor plantar responses pes cavus Scoliosis cardiomyopathy

Secondary

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.

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

Frequency of symptoms/signs
Symptom Ataxia Dysarthria Absent lower limb reflexes Scoliosis Pes cavus Swallowing disturbance Sphincter disturbance Reduced vision Hearing impairment Cardiomyopathy on echo Diabetes/ abnormal GT Harding 99 97 99 79 55 18 8 10 Durr 100 91 87 60 55 27 23 13 13 63 32 Delatycki 100 95 74 78 74 41 65 8

Disease progression
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)
FARS score
140 120 100 FARS score 80 60 40 20 0 1-5 6-10 11-15 16-20 21-25 26-30 31-35 36-40 Time interval since disease onset (years)
AOO < 14 years AOO 14 years

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

30 25 20 15 10 5 0 0 500 1000 1500 GAA repeat size of smaller allele Age of onset

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

Scoliosis
Labelle et al- 56/56 had a curve of 10%
20/36 who were followed for 10 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

Foot deformity
Pes cavus common (55-75%) but not a major source of morbidity Equinovarus deformity can cause significant morbidity Delatycki et al (2005)- 32 patients15 absent or mild, 8 moderate severity but reducible, 9 severe and irreducible Reducible- physical therapy, splinting, botox Fixed- surgery Prevention critical!

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 optical coherence 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

Eye movements
Abnormalities Pursuit Square wave jerks Vestibulo-ocular reflex Fixation Reduced visual QoL (Fahey 2008) and impact activities such as reading, computer use Near vision affected more than distance vision

Vestibular Function

Vestibular Dysfunction in FRDA

Single Patient

Group Summary

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

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

Dysphagia
No published data Anecdotally a problem in those with disease of longer duration Can cause aspiration +/- pneumonia

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

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 with reduced speed of information processing Corben et al (2010, 2011, 2011, 2011)- Subjects with FRDA significantly disadvantaged accommodating unexpected movement, initiating movement without a direct visual cue and reacting to incongruent, compared with congruent stimuli

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 month), 21% moderate urgency, hesitance or retention (once a week to once a month), 20% frequent urinary incontinence (>once a week) 5% reported loss of bladder function/catheterisation

Cardiomyopathy
Close to 100% have an abnormal ECG, particularly T wave inversion, left axis deviation, and repolarization abnormalities Hypertrophic cardiomyopathy with impaired septal and lateral long-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 of physical activity

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

Diabetes mellitus
10-30% definite diabetes mellitus due to combined insulin deficiency and insulin resistance Many have impaired glucose tolerance and insulin resistance Usually requires insulin therapy Four studies have linked NIDDM to 9q13 where FXN resides

Psychological issues
Increased rates of depression Flood and Perlman (1987)- 35/38 had some degree of affective disorder ranging from major depression to grief reaction Few reports of psychosis- not clear this is increased in FRDA Issues related to adolescence with chronic disability End of life issues Psychological support- pharmacological and counseling important

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, slower progression, absence of dysarthria [G130V])

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)

Funding
National Health and Medical Research Council FARA Australasia FARA USA MDA MCRI Lefroy family

Acknowledgements
Clinical studies Louise Corben Cate Wilson Geneieve Tai Veronica Collins Michael Fahey Andrew Churchyard 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 Scale development Julie Pallant Kinematic studies Nellie GeorgiouKaristianis John Bradshaw

CCRN Dave Lynch et al