Basket | Login



Neurodegenerative diseases

by Giuliano Binetti

General outline

The word ataxia comes from the Greek word ataxis meaning without order or incoordination. The Hereditary Ataxias are a group of rare diseases characterised by degeneration of the cerebellum, brain stem and spinal cord. They vary in age of onset, mode of inheritance and severity of the symptoms.


Cerebellar Ataxia

Symptoms and course

1) Early Onset Friedreich ataxia (FRDA) is the most common of the hereditary ataxias. It accounts for at least 50% of cases of hereditary ataxia; the prevalence of the disease in Europe and US is between 1 and 2 per 100 000.

Symptoms: classically presenting with gait ataxia, but with a number of additional features including dysarthria, and pyramidal tract involvement.

Initially this latter feature may be mild, with just extensor plantar responses, but almost invariably a pyramidal pattern of weakness in the legs occurs, which sometimes leads to paralysis.

A peripheral neuropathy is seen with absent reflexes, large fibre sensory abnormalities, and occasionally distal wasting, particularly in the upper limbs. Skeletal abnormalities are also commonlyfound including scoliosis and pes cavus. Additionally optic atrophy and deafness may be found. Nystagmus is seen in only about 20%, but the extraocular movements are nearly always abnormal. Mental retardation is described.

The other autosomal recessive ataxias are individually rare and often have a metabolic abnormality underlying the pathogenesis (sphingomyelin lipidoses, metachromatic leukodystrophy, galactosylceramide lipidosis (Krabbe’s disease) and hexosaminidase deficiencies. Cholestanolosis (also called cerebrotendinous xanthomatosis (CTX)) is a rare autosomal recessive disorder caused by defective bile salt metabolism, resulting from a deficiency of mitochondrial sterol 27 hydroxylase. It gives rise to ataxia, dementia, spasticity, peripheral neuropathy, cataracts, and tendon xanthomata in the second decade of life. Treatment with chenodeoxycholic acid appears to improve neurological function.

2) Late onset inherited ataxias They are usually autosomal dominant. The dominant ataxias are a clinically and genetically complex group of neurodegenerative disorders. Autosomal dominant cerebellar ataxia (ADCA) type I is characterised by a progressive cerebellar ataxia and is variably associated with other extracerebellar neurological features such as ophthalmoplegia, optic atrophy, peripheral neuropathy and pyramidal/extrapyramidal signs.

The presence and severity of these signs is, in part, dependent on the duration of the disease. Mild or moderate dementia may occur but it is usually not a prominent early feature. ADCA type II is clinically distinguished from ADCA type I by the presence of pigmentary macular dystrophy, whereas ADCA type III is a relatively “pure” cerebellar syndrome and generally starts at a later age.

This clinical classification is still useful, despite the tremendous improvements in our understanding of the genetic basis, because it provides a framework that can be used in the clinic and helps direct the genetic evaluation.

3) Idiopathic degenerative late onset ataxias In the absence of a clear family history this is rarely genetic. There are a few reports with one or other of the SCAs (spino-cerebellar ataxia) or occasional FA but these are very infrequent. The main differential in this group of patients is whether or not it is the cerebellar presentation of multiple system atrophy. A frequent clinical problem is whether to test for the identifiable mutations.

Caregiver problems

Depression in the patient and family members is common. Although no cures exist for most of the causes of cerebellar ataxia and there are as yet no proven ways to protect neurons from premature cell death or to restore neuronal populations that have been lost, symptomatic treatment can greatly improve the quality of life of these patients and prevent complications that could hasten death. Supportive interventions should always be offered: education about the disease itself, genetic counseling, individual and family counseling, referral to support groups and advocacy groups, and guidance to online resources. Misinformation, fear, depression, hopelessness, isolation, and financial and interpersonal stress can often cause more harm to the patient and caregiver than the ataxia itself.

Causes and risk factors

Friedreich ataxia (FRDA): The gene frataxin was cloned in 1996. The predominant mutation is a trinucleotide repeat (GAA) in intron 1 of this gene. Expansion of both alleles is found in over 96% of patients. The remaining patients have point mutations in the frataxin gene. The DNA test for the repeat is relatively simple and widely available. The length of the repeat is a determinant of age of onset and therefore to some degree influences the severity in that early onset tends to progress more rapidly.

Late onset inherited ataxias The genetic loci causing the dominant ataxias are given the acronym SCA (spino-cerebellar ataxia). At the time ofpublication there are over 20 SCA loci identified. Of these genes are established for SCAs 1, 2, 3, 6, 7, 10, 12 and 17. Interestingly the “common” ones are all caused by a similar mutational mechanism, expansion of an exonic CAG repeat. The resultant proteins all possess an expanded polyglutaminetract and there are now at least eight conditions caused by these expansions. Other types of ADCA are exceedingly rare.


A simple clinical point when considering the nature of a possible inherited ataxia is the age of onset. As a general rule early onset (< 20 years) tends to be autosomal recessive, later onset (> 25 years) is usually autosomal dominant and X linked inheritance is very rare.


Friedreich ataxia (FRDA) is the most common of the hereditary ataxias. It accounts for at least 50% of cases of hereditary ataxia; the prevalence of the disease in Europe and US is between 1 and 2 per 100 000.

Care and treatment

There is nothing more discouraging than for a patient to be given a specific diagnosis, then to be told that there is nothing that can be done.

Physicians are equally disheartened to see exponential progress being made in the understanding of the pathophysiology of a complex disorder but few direct benefits resulting for their patients.

Over the past 5 years, molecular genetic research has completely revolutionised the way in which the progressive ataxias are classified and diagnosed, but it has yet to produce effective gene-based, neuroprotective, or neurorestorative therapies.

The treatment of cerebellar ataxia remains primarily a neurorehabilitation challenge, employing physical, occupational, speech, and swallowing therapy; adaptive equipment; driver safety training; and nutritional counseling. Modest additional gains are seen with the use of medications that can improve imbalance, incoordination, or dysarthria (amantadine, buspirone, acetazolamide); cerebellar tremor (clonazepam, propranolol); and cerebellar or central vestibular nystagmus (gabapentin, baclofen, clonazepam).

Ongoing research/Clinical trials

Pilot studies have shown the potential effect of antioxidant therapy based on idebenone or coenzyme Q10 plus Vitamin E administration in FRDA and provide a strong rationale for designing larger randomized clinical trials.

Available services

European Federation of Hereditary Ataxias (EURO-ATAXIA) Ms Dagmar KROEBEL Haagwindelaan 19 B – 3090 OVERIJSE Tel. : 32/2/657.15.10 Fax : 32/2/657.61.76


  • Rotig A, Sidi D, Munnich A, Rustin P. Molecular insights into Friedreich's ataxia and antioxidant-based therapies.Trends Mol Med. 2002 May;8(5):221-4.
  • Lynch DR, Farmer JM, Balcer LJ, Wilson RB. Friedreich ataxia: effects of genetic understanding on clinical evaluation and therapy.Arch Neurol. 2002 May;59(5):743-7.



Last Updated: Friday 09 October 2009


  • Acknowledgements

    This information was gathered in the framework of the European Commission financed project "Rare forms of dementia". Neither the European Commission nor any person acting on its behalf is responsible for any use that might be made of the following information.
  • European Union