Friedreich’s ataxia

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68 Friedreich’s ataxia

Instruction

Perform a neurological examination of this patient’s legs.

Salient features

History

• Age of onset (usually the same in each family and ranges from 8 to 16 years of age)

• High-arched foot in childhood in the family (Friedreich’s foot) (Fig. 68.1)

• Scoliosis developing in childhood

• Cerebellar dysarthria (p. 210) and ataxia (p. 201).

Fig. 68.1 Foot deformity in Friedreich’s ataxia.

(With permission from Bradley et al. 2008.)

Examination

• Pyramidal weakness in legs

• Cerebellar signs, ataxia being a constant sign

• Impaired vibration and joint sense

• Romberg’s sign positive

• Absence of deep tendon reflexes (caused by degeneration of peripheral nerves)

• Distal muscle wasting (in 50% of cases), especially in the hands.

Proceed as follows:

• Check for nystagmus (present in 25% of the cases), scanning speech, intention tremor

• Examine the heart for hypertrophic cardiomyopathy (Fig. 68.2)

• Check the eyes for optic atrophy (present in 30% of cases)

• Check the spine for kyphoscoliosis

• Check the urine for sugar (10% of patients have diabetes)

• Check IQ, looking for intellectual deterioration

• Tell the examiner that you would like to do a 25 ft (7.5 m) walk test to determine ambulatory capacity.

Fig. 68.2 ECG in Friedreich ataxia, showing widespread ST and T changes.

Remember: Friedreich’s ataxia is the most common genetic cause of ataxia, affecting approximately 1 : 30 000 people. Symptoms that affect mobility include ataxia, spasticity and peripheral neuropathy.

Diagnosis

This patient has kyphoscoliosis, pes cavus and a combination of pyramidal, cerebellar and sensory deficits (lesions) in the lower limbs caused by Friedreich’s ataxia (aetiology); he is severely disabled by his deformity.

Advanced-level questions

What is the mode of inheritance?

Autosomal recessive or, rarely, sex linked.

Why are the deep tendon reflexes absent even though plantars are upgoing?

This is caused by a combination of pyramidal weakness with peripheral neuropathy.

In which other conditions is there a mixture of cerebellar, pyramidal and dorsal column signs?

Multiple sclerosis.

Mention a few conditions with absent knee jerks and upgoing plantars

• Peripheral neuropathy in a stroke patient

• Motor neuron disease

• Conus medullaris: cauda equina lesion

• Tabes dorsalis

• Subacute combined degeneration of the spinal cord.

What is the forme fruste of this condition?

Pes cavus or hammer toes, without any other signs, are seen in family members of such patients.

On which chromosome is the gene for this disorder localized?

The disease is caused by triplet repeat expansions on chromosome 9. The causative mutation is a GAA trinucleotide repeat expansion in the first intron of the gene FRDA (or X25), which encodes frataxin. The mitochondrial localization of frataxin and decreased oxidation activity suggest that this is a mitochondrial disease. Frataxin is involved in iron metabolism and may protect mitochondria from oxidative damage (Lancet Neurol 2002;1:370–74). Excessive free iron may damage proteins containing iron–sulfur groups, including complexes I, II and III and aconitase, a Krebs cycle enzyme.

What are the clinical criteria for diagnosis of Friedreich’s ataxia?

Harding’s criteria (Brain 1981;104:589):

• Essential criteria are onset before the age of 25 years, ataxia of limbs and gait, absent knee and ankle jerks, extensor plantars, autosomal recessive inheritance, motor conduction velocity greater than 40 m/s, small or absent sensory nerve action potentials, dysarthria within 5 years of onset.

• Additional criteria (present in two-thirds) are scoliosis, pyramidal weakness of lower limbs, absent upper limb reflexes, loss of vibration and joint position sense in the legs, abnormal ECG and pes cavus.

• Other features (present in <50%) are nystagmus, optic atrophy, deafness, distal muscle wasting and diabetes.

What is the prognosis of Friedreich’s ataxia?

Friedreich’s ataxia usually progresses slowly and few patients live longer than 20 years after the onset of symptoms. Occasionally, it may appear to be arrested, and abortive cases may be encountered in apparently healthy relatives of affected patients. Most patients will lose their ability to walk, stand or sit without support within 10 to 15 years of disease onset.

What are the pathological changes in Friedreich’s ataxia?

• Marked loss of cells in the posterior root ganglia

• Degeneration of peripheral sensory fibres

• Involvement of the posterior and lateral columns of the cord.

What is the role of idebenone in Friedreich’s ataxia?

Therapy with idebenone, an antioxidant, is associated with improvement in neurological function and activities of daily living in patients with Friedreich’s ataxia. Idebenone also functions as an electron transport carrier (like coenzyme Q) and has various other effects, including stimulation of nerve growth factor production and blockade of voltage-sensitive calcium channels. In the murine conditional-knockout model of Friedreich’s ataxia, oxidative stress is not observed, but idebenone exerts effects on cardiac measures and increases lifespan. Idebenone also enhances viability of Friedreich’s ataxia fibroblasts in vitro (Lancet Neurol 2007; 6:878–86).

Name a few syndromes with spinocerebellar degeneration

• Roussy–Lévy disease: hereditary spinocerebellar degeneration with atrophy of lower limb muscles and loss of deep tendon reflexes

• Refsum’s disease (p. 724)

• Bassen–Kornzweig syndrome (p. 724): caused by cellular deficiency of vitamin E (α-tocopherol) resulting from a defect in the α-tocopherol-transfer protein, and abetalipoproteinaemia associated with a defect of VLDL

• Olivopontocerebellar degeneration: first described in 1882. This has an autosomal dominant inheritance and has been mapped to the HLA loci on the short arm of chromosome 6 where a highly polymorphic CAG repeat sequence occurs. The CAG repeat sequence is longer than normal and unstable in affected patients

• Machado–Joseph disease: dominant inheritance, first described in families of Portuguese origin. Clinical features include progressive ataxia, ophthalmoparesis, spasticity, dystonia, amyotrophy and parkinsonism. This disorder has been linked to chromosome 14 and is caused by the expansion of unstable CAG repeat sequences

• Dentatorubral pallidoluysian atrophy is similar to Machado–Joseph disease but maps on the short arm of chromosome 12. The abnormally expanded CAG repeat sequences identified in the gene for olivopontocerebellar degeneration, Machado–Joseph disease and dentatorubral pallidoluysian atrophy each result in the expression of a specific ataxin.

Nikolaus Friedreich (1825–1882), Professor of Pathology and neurologist in Heidelberg, described this condition, in a series of papers from 1861 to 1876.

G Roussy (1874–1948), a French neuropathologist.

G Lévy (b. 1881), a French neurologist.

Sigvald Refsum (1907–1991), a Norwegian neurologist, was successively Professor of Neurology at Bergen University and at the National Hospital in Oslo (BMJ 1991;303:919).

Anita Harding (1953–1995) Professor of Neurology at the National Hospital, Queen Square, London, died at the age of 42 years from colonic cancer.

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