Friedreich Ataxia

Slide 1 · Friedreich Ataxia

Genetics • mitochondrial pathology • neuroanatomy • clinical correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain how an intronic FXN GAA repeat expansion reduces frataxin expression.

Relate frataxin deficiency to mitochondrial iron–sulfur proteins and cellular injury.

Localize the neurological findings to affected tracts and sensory neurons.

Construct a molecularly informed diagnostic and surveillance approach.

Slide 3 · Friedreich ataxia: Defining phenotype

Autosomal recessive, progressive multisystem neurodegenerative disease.

Progressive gait ataxia coexists with large-fiber sensory dysfunction and pyramidal signs.

Cardiomyopathy, skeletal deformity and disturbed glucose homeostasis may accompany neurologic decline.

A pathogenic FXN genotype establishes the molecular diagnosis.

Slide 4 · Where Friedreich ataxia fits among inherited ataxias

Group

Inheritance

Mechanism / defining distinction

Friedreich ataxia

Autosomal recessive

Intronic GAA expansion reduces frataxin

Many spinocerebellar ataxias

Autosomal dominant

Often coding CAG/polyglutamine or other variants

Ataxia-telangiectasia

Autosomal recessive

ATM-related DNA-damage response defect

Slide 5 · A disorder of more than one organ

Somatosensory system

Loss of proprioception; Absent reflexes

Motor pathways

Spasticity; Extensor plantar responses

Cardiac muscle

Cardiomyopathy; Rhythm disturbances

Metabolic / skeletal

Diabetes risk; Scoliosis; Pes cavus

Slide 6 · Typical and atypical age at presentation

Typical disease begins in childhood or adolescence; Early gait imbalance is common.

Later-onset disease can occur, including presentations after early adulthood.

Retained tendon reflexes do not exclude genetically confirmed disease.

Age and rate of progression vary; A single stereotyped time course is misleading.

Slide 7 · Clinical evolution: A characteristic sequence

Gait imbalance

Limb incoordination

Speech / sensory signs

Mobility limitations

The sequence illustrates a common pattern rather than a mandatory timetable.

Cardiac abnormalities may emerge before or independently of neurological disability.

Slide 8 · Inheritance is autosomal recessive

Disease ordinarily requires pathogenic variants affecting both FXN alleles.

Both sexes may be affected; Carrier parents can be clinically unaffected.

Recurrence risk in a carrier–carrier pregnancy follows Mendelian inheritance.

Family history may be negative because affected siblings are uncommon in small families.

Slide 9 · Carrier × carrier: Recurrence probabilities

Parents: Both carriers (Ff × Ff)

25% unaffected

50% carriers

25% affected

F

f

F

FF

Unaffected

Ff

Carrier

f

Ff

Carrier

ff

Affected

Slide 10 · FXN: The molecular locus

FXN is a nuclear gene encoding mitochondrial frataxin.

The characteristic pathogenic repeat lies within intron 1, not the coding sequence.

A noncoding expansion can reduce gene expression without altering the protein sequence.

Gene-based testing must interrogate repeat expansions, not coding variants alone.

Slide 11 · A GAA expansion in intron 1

Simplified FXN transcription unit

Exon 1

Exon 2

Intron 1

GAA

GAA

GAA

GAA

GAA

GAA

GAA

GAA

Expanded GAA repeat → reduced FXN transcription

Slide 12 · Common molecular genotypes

Two expanded alleles

Intronic GAA expansion on each copy of FXN

The commonest disease-causing genotype

Lowered transcription from both alleles

Expansion plus other variant

GAA expansion on one allele

Pathogenic FXN sequence variant or deletion on the other

Still produces a biallelic loss-of-function state

Slide 13 · Why a repeat expansion can be pathogenic

Pathogenicity need not involve a translated repeat or abnormal amino-acid tract.

Expanded intronic GAA sequence favors altered local chromatin and transcriptional repression.

Reduced transcription means less functional frataxin is produced.

This differs from polyglutamine toxicity in several dominant spinocerebellar ataxias.

Slide 14 · Gene silencing: A mechanistic chain

Intronic GAA expansion

Repressive chromatin

Reduced FXN transcription

Frataxin deficiency

The clinical disease is chiefly a quantitative deficiency of a mitochondrial protein.

Native schematic summarizes the gene-expression mechanism.

Slide 15 · The distinction: Gene expression versus protein aggregation

Friedreich ataxia: A noncoding expansion reduces production of frataxin.

Several dominant SCAs: Expanded coding CAG tracts create polyglutamine-bearing proteins.

Therefore the same clinical endpoint—ataxia—need not imply the same molecular lesion.

Molecular grouping is essential when discussing causal therapies.

Slide 16 · Frataxin: A mitochondrial protein

Frataxin participates in biogenesis of iron–sulfur (Fe–S) clusters.

Fe–S cofactors are needed for multiple mitochondrial enzymes.

A fall in frataxin impairs mitochondrial bioenergetics.

The consequences extend beyond neurons because the protein is widely required.

Slide 17 · Iron–sulfur cluster biogenesis

Frataxin → Fe–S cluster assembly

Fe–S-dependent enzyme function

Oxidative phosphorylation

Original schematic — represents functional associations, not a biochemical structural model.

Slide 18 · Deficient frataxin compromises energy production

Less frataxin

Impaired Fe–S enzyme function

Less efficient respiration

Cellular energy stress

Robbins particularly links Fe–S proteins to respiratory-chain complexes I and II.

The diagram describes a mechanistic pathway, not a measured patient ATP value.

Slide 19 · Mitochondrial iron and redox injury

Frataxin deficiency

Iron dysregulation

Potential oxidative stress

Vulnerable tissue injury

Increased available mitochondrial iron may facilitate oxidative damage.

The relative causal contribution of oxidative stress remains incompletely resolved.

Slide 20 · What is established—and what is uncertain?

Well established

Biallelic FXN disease-associated variants

Frataxin deficiency

Fe–S biogenesis and mitochondrial consequences

Not a complete explanation

Why particular neuronal populations are vulnerable

How iron/ROS pathways rank in human injury

Why phenotype varies among affected people

Slide 21 · From DNA repeat to clinical phenotype

FXN genotype

Reduced frataxin

Mitochondrial dysfunction

Selective cell injury

Multisystem disease

The causal hierarchy connects molecular and tissue-level observations.

Selectivity of degeneration is not explained by frataxin deficiency alone.

Slide 22 · Neuropathology: Principal sites of injury

Dorsal root ganglia

Large sensory-neuron hypoplasia / atrophy

Spinal cord

Dorsal column and spinocerebellar tract loss

Motor system

Corticospinal degeneration

Cerebellar circuit

Dentate nucleus neuronal loss

Slide 23 · Dorsal root ganglia are a major lesion

Large primary sensory neurons are reduced in size and number.

Developmental undergrowth and subsequent neuronal atrophy can coexist.

The loss preferentially disrupts pathways conveying vibration and position.

Degeneration of their central and peripheral processes links central tracts to neuropathy.

Slide 24 · A dorsal-root-ganglion lesion has downstream effects

Large sensory neurons impaired

Dorsal root fibers lost

Posterior columns degenerate

Proprioception deteriorates

This is an anatomically continuous sensory pathway.

Loss of primary afferents can cause secondary degeneration in their central projections.

Slide 25 · Posterior columns: Ascending sensory pathway

The dorsal columns carry vibration and conscious joint-position information.

Loss of long myelinated fibers helps explain impaired vibration sense.

Reduced position sense produces sensory contributions to gait and limb ataxia.

An abnormal posterior column does not require primary neuronal loss in its relay nuclei.

Slide 26 · Clarke nucleus and spinocerebellar pathway

Clarke-column neurons receive proprioceptive input from lower-body primary afferents.

Loss of their afferent input accompanies neuronal and tract degeneration.

The dorsal spinocerebellar pathway conveys unconscious proprioceptive information.

Dysfunction contributes to impaired coordination during posture and gait.

Slide 27 · Sensory pathway: Where the lesions accumulate

Primary sensory neuron

Dorsal root ganglion

Central axon

Posterior column

Relay / interneuron

Clarke nucleus

Ascending projection

Cerebellar pathway

Simplified pathway map; Clarke nucleus receives sensory inputs rather than being a direct relay in the conscious dorsal-column system.

Slide 28 · Corticospinal tract involvement

Corticospinal degeneration introduces upper-motor-neuron signs into an ataxic phenotype.

The extensor plantar response may coexist with diminished tendon reflexes.

Loss of long descending tracts contributes to weakness and spasticity.

Mixed motor and sensory signs are a localization clue rather than a contradiction.

Slide 29 · Dentate nucleus: Cerebellar output is affected

Large projection neurons within the dentate nucleus show selective neuronal loss.

The cerebellar output circuit is disrupted even when superficial cortex is relatively preserved.

This injury adds a central cerebellar component to limb and gait incoordination.

Neuropathologic change may exceed what conventional imaging reveals early.

Slide 30 · Sensory ataxia and cerebellar ataxia coexist

Sensory contribution

Large-fiber deafferentation

Impaired position / vibration

Worsens when visual compensation is removed

Cerebellar contribution

Spinocerebellar and dentate injury

Impaired movement timing and coordination

Limb dysmetria / dysarthria may appear

Slide 31 · Peripheral nerve pathology

Large myelinated sensory fibers are especially vulnerable.

Sensory nerve action potentials may be markedly reduced or absent.

A length-dependent neuropathy framework alone does not describe the entire disease.

Motor abnormalities and central nervous system lesions accompany sensory neuropathy.

Slide 32 · Correlating pathology with bedside signs

Sensory neuron / column

Reduced vibration and joint position sense

Reflex afferent limb

Depressed ankle and knee reflexes

Corticospinal tract

Babinski sign, spasticity

Dentate / cerebellar networks

Limb dysmetria and dysarthria

Slide 33 · Pathology is anatomically selective

Not every neuron is injured to the same degree despite systemic frataxin deficiency.

Dorsal-root-ganglion and dentate changes have different anatomic and temporal features.

Cerebellar cortex and cerebral hemispheres are not the only relevant structures.

This selectivity helps explain the unusual neurologic sign combination.

Slide 34 · First symptom: Progressive gait instability

Insidious gait imbalance is the typical neurologic presentation.

Combined proprioceptive and cerebellar dysfunction impairs walking.

Onset during school-age years or adolescence is characteristic but not universal.

Progression prompts reassessment for systemic and neurologic complications.

Slide 35 · Gait ataxia: Interpret the mechanism

An irregular, broad-based gait does not distinguish cerebellar from sensory causes alone.

Loss of leg position input can aggravate unsteadiness when eyes are closed.

Damage in cerebellar pathways impairs corrective movement coordination.

Both processes can be present in a single person with Friedreich ataxia.

Slide 36 · Hand clumsiness and upper-limb ataxia

Upper-limb dyscoordination often follows gait manifestations.

Imprecise limb placement reflects combined sensory and cerebellar pathway damage.

Fine-motor impairment affects writing, feeding, dressing and other tasks.

The pattern is progressive rather than episodic.

Slide 37 · Dysarthria localizes coordination impairment

Speech becomes slurred as fine control of articulation deteriorates.

Dysarthria is distinct from language aphasia or primary cognitive deterioration.

Additional bulbar dysfunction, including dysphagia, can develop.

Speech/swallowing assessment becomes relevant as disease advances.

Slide 38 · Position and vibration: High-yield examination

Impaired toe joint-position sense signals large-fiber proprioceptive dysfunction.

Reduced vibration sense is expected in a substantial proportion of cases.

Visual cues can partly compensate for loss of proprioceptive input.

Findings integrate peripheral afferent and posterior-column pathology.

Slide 39 · Areflexia with extensor plantar responses

Peripheral sensory circuit

Large primary afferents degenerate

Stretch reflex input declines

Tendon reflexes reduced / absent

Descending motor pathway

Corticospinal tract degenerates

Plantar response becomes extensor

Spasticity may develop

Slide 40 · Weakness and spasticity: Mixed motor signs

Strength may decline with disease progression.

Corticospinal involvement can increase tone and impair voluntary movement.

Peripheral neuropathy contributes to weakness and muscle wasting.

A comprehensive examination distinguishes pyramidal signs from peripheral weakness.

Slide 41 · Sensory findings are not uniform

Vibration and joint-position loss are the most characteristic modalities.

Pain, temperature and light-touch deficits occur in some individuals.

Clinical complaint severity need not mirror the degree of electrophysiologic sensory loss.

Absence of a striking sensory complaint should not eliminate FRDA from consideration.

Slide 42 · Orthopedic manifestations

Pes cavus

A high-arched foot often accompanies long-standing neuropathic disease

Kyphoscoliosis

Spinal deformity may progress during growth

Contractures

Weakness and spasticity restrict joint range

Functional effect

Walking, transfers, sitting balance and care needs may be affected

Slide 43 · Cardiomyopathy is not incidental

Cardiac muscle is a major extra-neural target of frataxin deficiency.

Hypertrophic remodeling is a characteristic phenotype, but cardiac presentations vary.

Structural disease may be present before prominent neurologic impairment.

Cardiac involvement importantly affects risk and long-term outcome.

Slide 44 · Cardiac complications: Clinical consequences

Cardiomyopathy

Electrical instability

Arrhythmias / dysfunction

Heart failure risk

The flow is conceptual: Different complications can coexist or arise independently.

Routine and symptom-driven cardiac assessment is justified.

Slide 45 · Diabetes and impaired glucose regulation

Disrupted glucose homeostasis occurs in a subset of affected individuals.

Cardiometabolic disease adds to the burden of a neurologic disorder.

Glucose assessment is part of longitudinal surveillance.

Specific diabetes treatment requires individualized endocrine management.

Slide 46 · Neurologic and systemic feature matrix

Domain

Representative feature

Teaching implication

Sensory

Position/vibration loss

Check distal proprioception

Motor

Areflexia + Babinski

Localize two pathways

Cerebellar

Ataxia, dysarthria

Assess coordination

Systemic

Cardiac, metabolic, skeletal

Screen beyond the nervous system

Slide 47 · Typical versus later-onset FRDA

Typical pattern

Childhood / adolescent gait onset

Progressive sensory and pyramidal involvement

Cardiomyopathy is a key consideration

Atypical variants

Later onset, including after age 25

Some retain tendon reflexes

Molecular confirmation overrides classic checklists

Slide 48 · When to suspect Friedreich ataxia

Child or young adult with progressive gait ataxia and reduced tendon reflexes.

Impaired joint-position / vibration sense reinforces a large-fiber phenotype.

Extensor plantar responses suggest simultaneous long-tract disease.

Cardiomyopathy, pes cavus or scoliosis strengthens the syndromic impression.

Slide 49 · Diagnostic reasoning from phenotype to genotype

Progressive ataxia

Focused neurologic + systemic exam

FXN repeat testing

Biallelic variant confirmation

Testing must be chosen to detect the expanded GAA repeat.

In atypical or unresolved cases, broaden the genetic differential.

Slide 50 · Examination: Three localization questions

Is incoordination sensory, cerebellar, or a combination?

Are tendon reflexes reduced while plantar responses are extensor?

Are cardiac, skeletal or metabolic signs present?

Does the onset and inheritance pattern warrant targeted FXN analysis?

Slide 51 · Molecular confirmation: Choose the right assay

Targeted testing for intron-1 FXN GAA expansion is a core diagnostic step.

Most molecularly confirmed cases have expanded repeats on both alleles.

If only one expansion is detected, evaluate the other allele for sequence/CNV variants.

Interpretation requires the laboratory method and variant classification.

Slide 52 · A negative exome is not enough

Routine exome sequencing does not reliably resolve the pathogenic intronic repeat.

Repeat-aware assays are needed when the clinical suspicion is high.

Gene panels differ in whether they test short variants, copy-number changes and repeats.

A result must be interpreted in light of what the assay did—and did not—detect.

Slide 53 · Electrophysiology: An adjunct, not the genotype

Sensory nerve action potentials can be profoundly reduced or absent.

Motor nerve conduction may be comparatively preserved, particularly early.

Results support large-fiber sensory neuropathy but do not establish FXN causation.

Use studies to answer anatomical questions or evaluate possible alternatives.

Slide 54 · Neuroimaging: Interpret a normal early MRI carefully

Conventional brain MRI can be unremarkable early in disease.

Later abnormalities may include spinal cord and cerebellar volume loss.

Imaging findings are supportive and may help assess alternate etiologies.

Molecular diagnosis is more specific than visual pattern recognition on MRI.

Slide 55 · Genotype–phenotype: Trends are not predictions

Length of the shorter expanded GAA allele is associated with onset and severity at group level.

Clinical variability remains substantial, even among people with related genotypes.

Do not assign an individual prognosis from repeat number alone.

Cardiac burden, functional trajectory and other modifiers need direct assessment.

Slide 56 · Differential: Autosomal dominant SCA

Friedreich ataxia

Autosomal recessive pattern

FXN intronic GAA expansion

Large-fiber sensory loss and cardiac disease

Many dominant SCAs

Vertical family transmission may occur

Heterogeneous genes; Some coding CAG repeats

Clinical overlap; Variant-specific features

Slide 57 · Differential: Ataxia-telangiectasia

Friedreich ataxia

Frataxin deficiency

Sensory neuropathy and cardiomyopathy

No defining telangiectasia–immunodeficiency syndrome

Ataxia-telangiectasia

ATM pathway defect

Conjunctival / skin telangiectasias

Immunodeficiency and cancer predisposition

Slide 58 · Treatable mimics must not be missed

Alternative

Overlap with FRDA

Helpful distinction

Vitamin E deficiency / TTPA

Sensory ataxia, areflexia

Low vitamin E; treatable cause

Abetalipoproteinemia

Ataxia / sensory neuropathy

Fat malabsorption, lipid abnormalities

Other recessive ataxias

Early ataxia + neuropathy

Different molecular/clinical clues

Slide 59 · Longitudinal care must be multidisciplinary

Neurology / rehabilitation

Function, mobility, speech and swallowing

Cardiology

Rhythm and myocardial function

Endocrinology

Glucose metabolism and diabetes

Orthopedics / allied health

Scoliosis, feet, contractures, support devices

Slide 60 · Cardiac surveillance: Risk is actionable

An electrocardiogram and echocardiogram are recommended at diagnosis.

The 2022 consensus guidelines advise repeating both at least annually.

Palpitations or possible arrhythmia warrant symptom-directed rhythm monitoring.

Cardiology input is indicated for cardiac symptoms or abnormal investigations.

Slide 61 · Glucose surveillance and diabetes care

At least annual fasting glucose and HbA1c screening is recommended.

Consider oral glucose tolerance testing selectively when screening is abnormal.

Review symptoms of hyperglycemia during routine clinical encounters.

Glucose-lowering therapy is individualized; No single regimen suits all FRDA patients.

Slide 62 · Preserving function through supportive care

Physical and occupational therapy address mobility, safety and daily activities.

Orthopedic assessment addresses scoliosis, foot deformity and contractures.

Speech and swallowing professionals evaluate dysarthria or dysphagia.

Supportive interventions remain important even with disease-targeted medication.

Slide 63 · Omaveloxolone: Disease-targeted treatment

Omaveloxolone is an Nrf2-pathway activator approved in the United States for FRDA.

The FDA indication covers adults and adolescents aged 16 years or older.

Its therapeutic goal is to slow functional disease progression—not replace rehabilitation.

Approval and safety labeling should be checked against the jurisdiction and current label.

Slide 64 · Treatment limitations and monitoring

Omaveloxolone is not a cure and does not reverse established neuronal loss.

The FDA label specifies monitoring of liver enzymes, bilirubin, BNP and lipid parameters.

Cardiac, diabetic, orthopedic and functional surveillance continues during treatment.

The decision to use therapy requires patient-specific assessment of benefit and safety.

Slide 65 · Clinical application 1: Identify the localization

Hypothetical teaching vignette

A 13-year-old develops progressive unsteadiness, impaired toe-position sense, absent knee reflexes and extensor plantar responses.

Which neural systems explain absent reflexes and Babinski signs occurring together?

Slide 66 · Clinical application 1: Explanation

Sensory-afferent and corticospinal lesions coexist.

Loss of large sensory fibers reduces tendon-reflex afferent input.

Corticospinal degeneration produces an extensor plantar response.

Dorsal-column and cerebellar circuit disease account for the ataxia.

Slide 67 · Clinical application 2: Select a molecular test

Hypothetical teaching vignette

A patient has childhood-onset ataxia, dysarthria, sensory neuropathy and a normal nondiagnostic exome sequencing report.

Does the normal exome exclude Friedreich ataxia? What testing is needed?

Slide 68 · Clinical application 2: Explanation

No. Test specifically for the intronic FXN GAA expansion.

Routine exome sequencing does not adequately interrogate this repeat.

Investigate a second pathogenic variant if a single expansion is found.

The molecular diagnosis needs biallelic pathogenic FXN variants.

Slide 69 · Integrated synthesis: Four linked levels

DNA

FXN intron-1 GAA expansion

Protein

Reduced mitochondrial frataxin

Tissue

Selective sensory, spinal and dentate injury

Patient

Ataxia plus neuropathy, pyramidal and cardiac signs

Slide 70 · High-yield diagnostic conclusions

Friedreich ataxia is an autosomal recessive frataxin-deficiency disorder.

The core biochemical lesion impairs mitochondrial Fe–S cluster biology.

Areflexia with extensor plantar responses is anatomically coherent.

Genetic testing confirms disease; Care must assess heart and metabolism.

Slide 71 · Principal references

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. 2026; Ch. 28, p. 1171.

Bidichandani SI, Delatycki MB, Napierala M, Duquette A. Friedreich Ataxia. GeneReviews. Rev. 2025.

Koeppen AH. Friedreich Ataxia: Neuropathology Revised. J Neuropathol Exp Neurol. 2013.

Corben LA, et al. Clinical management guidelines for Friedreich ataxia. Orphanet J Rare Dis. 2022.

US FDA. SKYCLARYS (omaveloxolone) prescribing information. Revised 2024.