Friedreich's Ataxia (FRDA)

Friedreich's Ataxia (FRDA)

Epidemiology:

First described in 1863

The most common early-onset hereditary ataxia

- prevalence in North America estimated at 2 per 100,000

- carrier frequency of 1:120

Genetics:

Autosomal recessive inheritance

- high risk if consanguinous unions

- risk for sibling is 25%

Gene for FRDA (X25) maps to 9q

- codes for highly conserved protein, frataxin

- most FRDA due to homozygous alleles with GAA triplet repeat expansions in first intron of X25

- rarely may have compound heterozygotes, with one allele bearing the intronic expansion and the other allele having a truncation or missense mutation (usually atypical or milder disease)

- normal alleles have < 42 repeats while diseased alleles have 66 or more

- expanded repeats are unstable in transmission, esp paternal (anticipation)

FRDA is due to deficiency of frataxin protein

- GAA expansion interferes with transcription of protein

- larger repeats more profoundly inhibit frataxin production - lead to earlier more severe form while small pathological expansions may allow small amount of residual production

- frataxin is expressed mostly in heart, liver, skeletal muscle and spinal cord

- protein localized on inner mitochondrial membrane

- possibly leads to iron accumulation when deficient making mitochondria more susceptible to oxidative stress (free radical toxicity)

Pathology:

Degeneration of spinocerebellar, dorsal column and corticospinal tracts, as well as dorsal root ganglia & Clarke's column (with thinner spinal cord than normal)

- minimal involvement of brainstem, cerebellum and cerebrum (ie. not a cerebellar disease!)

- dentate nucleus may be involved

History:

NB: there is a correlation between the GAA repeat size and clinical features (esp age at onset and rate of progression), but corresponds with shorter of two alleles

Core features:

Early onset, with symptoms beginning between ages 8-15 yrs (rarely in infancy and adulthood)

Progressive gait and limb ataxia (as well as sensory ataxia from proprioceptive loss)

- children are slow in learning to walk, clumsy and less agile than other kids, subsequent involvement of arms leads to jerky incoordinated movements

- titubation and intention tremor may emerge as can pseudoathetosis

Dysarthria

- speech often scanning and explosive, eventually unintelligible

Common features:

Clumsiness (corticospinal involvement also) progressing to true weakness / spasticity

Diabetes mellitus (10-25%)

Examination:

Core features:

Ataxia with dysmetria and wide-based gait

Areflexia

Extensor plantar responses

Lower limb proprioceptive loss

Associated features:

Scoliosis

Cardiomyopathy

Spasticity and weakness +/- amyotrophy

Nystagmus and Fixation abnormalities (incl. square-wave jerks)

Pes Cavus or equinovarus deformity of foot

Optic atrophy

Should not see prominent deafness, reduced visual acuity or dementia in FRDA

- however, wider phenotype variation appreciated with genetic testing including retained reflexes, no pyramidal signs, later age of onset

- FRDA variants including chorea, spastic paraparesis and sensory neuronopathy (more likely to harbour atypical genotypes with point mutations in one allele)

- mutations even found in 5% of apparently sporadic ataxias

Investigations:

- Markedly reduced or absent SSEPs and v isual evoked responses

- Absent or reduced SNAPs with preserved motor amplitudes

- Hyperglycemia / diabetes mellitus

- MRI usually normal or mild cerebellar atrophy (+/- cervical cord atrophy)

NB: test vitamin E levels to rule-out this treatable cause of ataxia

Echo shows cardiomyopathy with concentric ventricular hypertrophy

- EKG may show ST segment changes, T-wave inversions

- risk of arrhythmias, including atrial fibrillation

Spine x-rays show scoliosis

Diagnosis:

Presence of characteristic and core clinical features without parental history (suggesting recessive inheritance)

- testing for X25 mutations is available, esp GAA repeat length

- will detect 95-98% of pathological alleles including carrier status

- may miss point mutations which can, in combination with single expanded allele, still lead to FRDA (so may need more specialized testing if FRDA suspected clinically but only one expanded allele is found)

Differential Diagnosis:

Other autosomal recessive early-onset ataxias:

1. Ataxia-telangiectasia

- early onset with telangiectasias, mental retardation, short stature, sensitivity to ionizing radiation, immunoglobulin deficiency and risk of malignancies (esp ALL, lymphoma)

2. Vitamin E deficiency (incl. AVED and abetalipoproteinemia)

- AVED has identical phenotype to FRDA but is eminently treatable with vitamin E (mutations in alpha-tocopheral transfer protein gene on 8q13, impairing its incorporation into VLDL)

- abetalipoproteinemia due to impaired formation and secretion of VLDL resulting in loss of delivery of vitamin E to periphery, diagnosed by lipoprotein electrophoresis (loss of beta component)

3. ARSACS (spastic ataxia of Charlevoix-Saguenay)

- found in region of Quebec or offspring of people from this area, maps to chromosome 13

- more prominent spasticity and cerebellar atrophy

4. Marinesco-Sjogren syndrome

- ataxia with short stature, mental retardation, and cataracts

5. Ramsay-Hunt syndrome:

- myoclonus with progressive ataxia and often seizures usually due to mitochondrial mutation (eg MERRF) or recessive disorder such as Unverricht-Lundborg disease (21q, cystatin B)

6. Posterior column ataxia with retinal pigmentary changes:

- retinal changes distinguish from FRDA, maps to chromosome 1q31-32

Other herditary ataxias:

- Autosomal dominant cerebellar ataxias (if early death of parents, false paternity / adoption, new mutation or anticipation) ie. SCAs

- Mitochondrial disorders incl. MERRF, Leigh syndrome, Kearn-Sayre syndrome, and NARP (neuropathy, ataxia, retinitis pigmentosa)

Natural History:

Rate of progression loosely correlated with repeat size

- usually unable to walk over 15 years (end up in wheelchair)

Death by 40's or 50's usually due to respiratory infection or cardiac failure

Treatment:

No proven effective therapy yet found

- aggressive surveillance for cardiac complications incl. heart failure and arrhythmias

- management of scoliosis and diabetes mellitus

Trial of the coenzyme Q analogue (idebenone) showed reduction in cardiac hypertrophy

- may treat with vitamin E also (no firm evidence)

References:

Bressman SB, Lynch T, Rosenberg RN. Hereditary ataxias. In Rowland LP, ed. Merritt's Neurology, 10th ed.2000.

Lynch DR, Farmer JM, et al. Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy. Arch Neurol 2002; 59: 743-7.

Last update: May 2004

Reviewed by: pending review

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