Diagnosis and Management of Cardiovascular Involvement in Friedreich Ataxia GAA 7-34 times→Normal GAA 100-1700 times→FRDA Current Research into Drug Treatments for Friedreich ataxia Best Practice in Rare Diseases Although CNS involvement dominates the clinical presentation of FRDA , CV involvement dictates its prognosis, accounting for ~ 59% of deaths among FRDA patients . The prognosis is particularly poor for those with progressive LV systolic dysfunction.

1. The Heart in Friedreich Ataxia
Magdy El-Masry
Prof. of Cardiology
Tanta University

2. Introduction

3. Friedreich’s ataxia is one type and it takes its
name from Dr Nikolaus Friedreich who was the
first person to describe this condition.
Friedreich’s ataxia
is often called FA (or FRDA)
for short.
ataxia = a (lack of) + taxia (order)
 The word ataxia means lack of co-ordination.
 There are many different causes and types of ataxia.

4. Ueber degenerative Atrophie der spinalen
Hinterstränge
(= Schluss von Bd. XXVI. S. 459).
IN:Virchows Arch. path. Anat., S. 1-26, 1863.
160 Years Ago From Today
( 1863 - 2023 )
27 Years Ago From Today ( 1996 – 2023 )
It took a staggering 120 years to
discover
the genetic defect underlying FRDA

5. Low Frataxin Protein→ Low Iron-Sulfur Clusters
Gene : Frataxin → Mutation : Repeat Expansion
Gene Function
Frataxin “FXN” Fe-S cluster biogenesis
Homozygous
Fe-S
cluster
Frataxin
protein
MOI “Mode Of Inheritance” → AR “ Autosomal Recessive”
25%
50%
25%
The mutation→↓ synthesis of
frataxin , a mitochondrial protein.

6. Epidemiology

7. Epidemiology
Epidemiological data refers to the US
 Frequently appears around the time of
puberty
 Classified as a rare disease* with a
prevalence 1 in 40,000
 It is estimated that approximately 70%
of these patients will develop FA-HCM
(Syndromic HCM)
28 February 2023 :Rare Disease
Day is an observance held on
the last day of February to
raise awareness about diseases
that most people will not know
of, as well as to improve access
to treatment.
*
* European Union
Friedreich Ataxia Subtypes
 In approximately 75% of cases, the onset of FA
begins before the age of 25 years.
 The remaining 25% of cases are classified as atypical
FA and include the subtypes of late-onset FA (LOFA),
(LOFA), very late-onset FA (VLOFA), and FA with
retained reflexes (FARR).
LOFA manifests in patients between the ages of 25
and 39 years, and VLOFA develops in individuals 40
years of age or older.
Williams CT, De Jesus O. Friedreich ataxia. StatPearls [Internet]. Updated
Updated September 5, 2022. Accessed January 25, 2023.

8. Genetics of FA

9. Friedreich's ataxia-Osmosis · www.osmosis.org · Feb 10, 2021
GAA 7-34 times→Normal
GAA 100-1700 times→FRDA

10. Multisystem Disorder
The most affected cells are NHP.
N=Neuronal cells→Ataxia
H=Heart cells→HCM
P=Pancreatic cells→DM
Friedreich's ataxia-Osmosis ·
www.osmosis.org · Feb 10, 2021

11. Clinical
Presentation

12. Onset of symptoms :
 Childhood and
adolescence
“male>female”
Life expectancy :
 Reduced
Prevalent cause of
death :
 Cardiomyopathy
Take a closer look
DTR : lost
↓Sense of vibration

13. Diagnosis

14. Friedreich's ataxia-Osmosis · www.osmosis.org · Feb 10, 2021
Diagnostic Delay Treatment Delay
Dare to think rare : diagnostic delay and rare diseases
Think FRDA

15. G. Limongelli et al, International Journal of Cardiology .357 (2022) 55–71
The Cardiologist’s
Perspective

16. A typical example of a 26year-old female Friedreich's ataxia patient with severe cardiomyopathy
F. Weidemann et al. / International Journal of Cardiology 194 (2015) 50–57.
Cardiac involvement in FRDA is characterized by concentric LVH occurring without LVOTO and with an end-diastolic wall thickness < 15 mm in the
majority of cases. Over time, wall thickness tends to decrease and LV dilatation ensues, and ultimately ~ 20% exhibit a reduced EF .
In advanced stages of the disease, the onset of AF can additionally deteriorate systolic function and lead to HF .
Resting ECG :
T-wave inversion
Note the abnormalities in the T waves
that are especially prominent in the
chest leads, V1-V6, indicative of
cardiomyopathy. This is not specific to
Friedreich ataxia nor is it prognostic.
cMRI:Late gadolinium
enhancement of the LV wall
M-mode echo showing
LVH with an end-diastolic
wall thickness of 13mm
(EF=66%).
M-mode echo after 5
years of follow-up shows
a ↓ of end-diastolic wall
thickness to 10 mm
(EF=60%).

17.  Cardiac involvement is very common, and is usually (but not exclusively)
characterized by concentric LVH without LVOT obstruction {FA-HCM} .
 Patients are usually asymptomatic from a cardiac viewpoint, but
progression to LV dilatation and heart failure is described .
 As many as 60% of patients with Friedreich’s ataxia die from cardiac causes
Akhtar, M.M., Kaski, J.P., Elliott, P. (2018). Inherited Cardiac Muscle Disorders: Hypertrophic and Restrictive
Cardiomyopathies. In: Kumar, D., Elliott, P. (eds) Cardiovascular Genetics and Genomics. Springer, Cham.
FA-HCM : Syndromic HCM
(with Other Systemic Involvement)
LVH / HFpEF / HFrEF

18. Management

19. * physical therapy ,occupational therapy, , and speech therapy are often
collectively referred to as the “rehabilitation therapy team.
*
SOURCE:Friedreich’s Ataxia Symposium : September 24-25,2022
Presented by Children’s Hospital of Philadelphia (CHOP)
&Friedreich's Ataxia Research Alliance (FARA)
Un-fortunately, there is no etiological treatment for FA
and the current treatment
are based on symptomatic management
*Selective serotonin reuptake inhibitor
*

20. SOURCE:Friedreich’s Ataxia Symposium : September 24-25,2022
Presented by Children’s Hospital of Philadelphia (CHOP)
&Friedreich's Ataxia Research Alliance (FARA)

21. Current Research
into Drug Treatments
for Friedreich ataxia

22. Research
Pipeline

23. The FA Treatment
Pipeline is a visual
tool for
communicating
the progress of
research and
development on
lead therapeutic
candidates.
Along the vertical
axis lead
candidates are
grouped based on
mechanism of
action or approach
to treatment.
The horizontal axis
indicates the stage
of the research

24. Heart Disease
in FRDA

25. =Fainting
SOURCE:Friedreich’s Ataxia Symposium :
September 24-25,2022.
Presented by Children’s Hospital of Philadelphia (CHOP)
&Friedreich's Ataxia Research Alliance (FARA)

31. Comprehensive Metabolic Panel (CMP): chemistry 14

33. Scoliosis surgery often involves
using rods and screws to
straighten and stabilize the spine.

34. Guidelines for
Rare Diseases!

35. Rare diseases
present a unique set of challenges in
evidence based medicine.
Best Practice in Rare Diseases
 Initially published in 2014
 Updated in 2022
Strength of recommendation Symbol Level of evidence Symbol
Strong for intervention ↑↑ High ⨁⨁⨁⨁
Conditional for intervention ↑ Moderate ⨁⨁⨁
◯
Neither intervention nor comparison – Low ⨁⨁
◯◯
Conditional against intervention ↓ Very low ⨁
◯◯◯
Strong against intervention ↓↓
Symbols used to
denote strength of
recommendation and
level of evidence

36. An ECG and an echo should be performed at diagnosis of FA and then at least
annually
Either 24-h Holter monitoring or Loop monitoring, or possibly both tests, are
indicated for individuals with palpitations or other symptoms suggesting the
possibility of an arrhythmia.
A Loop monitor will be an appropriate additional test when symptoms are infrequent
Evaluation by a cardiologist should take place if an individual with FA has cardiac
symptoms or abnormal results on cardiac testing
Patients with FA being considered for scoliosis surgery, or other major surgery,
are at risk of a poor outcome and require a multi-disciplinary approach to the
management of heart function during surgery and in the postoperative period
Monitoring : Best practice statements

37. Strength Level of evidence
There is not sufficient evidence to make a
recommendation for or against using advanced
imaging techniques over standard echo for
identifying at-risk individuals with FA
–
Neither
intervention
nor comparison
⨁
◯◯◯
Very low
There is not sufficient evidence to make a
recommendation about Holter monitoring for
individuals with FA who do not have symptoms
suggesting they might have an arrhythmia
Monitoring : Recommendations

38. For treatment of symptomatic arrhythmias in FA , antiarrhythmic medications
(other than ß-blockers) which are negatively inotropic or are recognized to
have a high risk for pro-arrhythmic effects cannot be assumed to be safe and
should rarely, if ever, be used
Arrythmias : Best practice statements

39. Strength Level of evidence
We conditionally recommend anticoagulation over
no anticoagulation in individuals with FA with
permanent, persistent or paroxysmal AF
↑
Conditional for
intervention
⨁
◯◯◯
Very low
We conditionally recommend attempts to
maintain a normal cardiac rhythm over rate
control in individuals with FA and atrial
tachyarrhythmias,
and also recommend consideration of ablation for
those who remain severely symptomatic due to a
persistent atrial tachyarrhythmia or frequent
paroxysms of an atrial tachyarrhythmia
↑
Conditional for
intervention
⨁
◯◯◯
Very low
Arrythmias : Recommendations

40. There is no therapy with proven cardiac benefits for asymptomatic people with
FA with echo or cMRI findings of either a normal heart or increased LV wall
thickness but normal EF
In adults with FA and a reduction in LVEF there is a case for treating according to
standard HF guidelines
In individuals with FA and symptomatic HF there is a case for treating according
to standard HF guidelines
Women with FA and a reduction in LVEF should be advised that
pregnancy
could result in cardiac decompensation and a greater maternal and fetal
risk
Treatment options such as an ICD and HTX are not contraindicated in FA ,
but the appropriateness of such therapy requires careful consideration of the
Heart failure : Best practice statements

41. Strength Level of evidence
We do not suggest using HF medication and/or
devices for individuals with FA with a preserved LVEF
↓
Conditional against
intervention
⨁
◯◯◯
Very low
We conditionally recommend treating individuals
with FA with a reduced LVEF with medications
according to current AHA/ACC heart failure guidelines
↑
Conditional for
intervention
⨁
◯◯◯
Very low
Advanced HF therapies such as a LVAD , ICD , CRT and
HTX should be considered for individuals with FA and
HF due to a reduced LVEF , based on consideration of
both their cardiac and overall health status
↑
Conditional
for
intervention
⨁
◯◯◯
Very low
Heart failure: Recommendations

42. Prognosis

43. Friedreich's ataxia-Osmosis · www.osmosis.org · Feb 10, 2021
Because there is no curative therapy available, the prognosis is poor. Progression and mortality
Patients often die of
cardiomyopathy

44. Friedreich Ataxia ( FRDA )
Payne RM,
J Am Coll Cardiol Basic Trans Science
2022;7:1267–1283
Triplet expansion in first
intron of the FRDA gene
Take home figure : FRDA
Although CNS involvement dominates the
clinical presentation of FRDA ,
CV involvement dictates its prognosis,
accounting for ~ 59% of deaths among
FRDA patients .
The prognosis is particularly poor for those
with progressive LV systolic dysfunction.

45. Supporting people with FA
until a treatment
or cure is found
Supporting
the Rare
With Hope