Source:  ATAXIAS CEREBELOSAS    Tag:  spinocerebellar ataxia diagnosis
Review Article
Current Concepts
The Autosomal Recessive Cerebellar Ataxias
Mathieu Anheim, M.D., Ph.D., Christine Tranchant, M.D., and Michel Koenig, M.D., Ph.D.
N Engl J Med 2012; 366:636-646
February 16, 2012

The autosomal recessive cerebellar ataxias are a group of little known and often neglected diseases that are best understood by following a practical, multidisciplinary approach that focuses on clinical rather than molecular considerations. This review focuses on the main forms in which cerebellar ataxia is a prominent sign. It does not attempt to revisit all of the ataxias of this type. Cerebellar ataxia (from the Greek words “a,” meaning “not,” and “taxis,” meaning “order”) is characterized by an incoordination of movement and unsteadiness (see Video 1, available with the full text of this article at due to cerebellar dysfunction. Clinical examination reveals a gait disorder with imbalance, staggering, and difficulties with tandem walking, upper-limb and lower-limb dysmetria, dysdiadochokinesia (difficulty performing rapidly alternating movements), hypotonia, cerebellar dysarthria, and saccadic ocular pursuit (Videos 1 and 2).
The acute onset of a cerebellar ataxia does not suggest a neurodegenerative disease, with the exception of rare inherited metabolic disorders (e.g., nonketotic hyperglycinemia and pyruvate dehydrogenase deficiency). Instead, it is a diagnostic and therapeutic emergency because of related conditions such as cerebellar stroke, cerebellar abscess, meningitis, vitamin B1 deficiency, and drug intoxication (Table 1)Table 1
Acute Ataxias in Which Symptoms Appear Suddenly or in a Few Days. . Neurodegenerative disease should be considered whenever cerebellar ataxia is progressive and unremitting, once acquired subacute or chronic cerebellar ataxias such as cerebellar tumor, paraneoplastic syndrome, Creutzfeldt–Jakob disease, Whipple's disease, celiac disease, autoimmune thyroiditis, and cerebellar ataxia associated with autoantibodies to glutamic acid decarboxylase have been ruled out (see the table in the Supplementary Appendix, available at In all cases, the clinician must be able to rule out the latter causes by evaluating the patient for fever, intracranial hypertension, or autonomic dysfunction and with appropriate tests such as magnetic resonance imaging (MRI) of the brain, cerebrospinal fluid examination, or in subacute cases, blood tests to detect specific autoantibodies.
Autosomal dominant spinocerebellar ataxias are inherited neurodegenerative diseases that usually become evident at approximately 35 years of age, usually with a multigenerational pattern.1,2 X-linked inheritance suggests consideration of the fragile X–associated tremor–ataxia syndrome or adrenomyeloneuropathy. Particularly suggestive of autosomal recessive inheritance is the presence of similar cases in the sibship or those arising from parental consanguinity even though both parents are healthy. However, in countries where consanguinity and very large families are rare, sporadic cases are the most common presentation.
Autosomal recessive cerebellar ataxia must be considered in any patient younger than 30 years of age with a persistent and gradually worsening disorder of gait and balance (Video 1) or with the development over months or years of hypotonia or excessive clumsiness (Figure 1Figure 1

Management of Cerebellar Ataxias in Clinical Practice. and Table 2Table 2
Typical Signs and Symptoms of a Cerebellar Ataxia and Mistakes to Avoid If the Diagnosis of Cerebellar Ataxia Is Uncertain.). A typical presentation was that of an 18-year-old patient referred to our center because of imbalance, especially going down stairs, and clumsiness that developed over a period of 2 years. Ataxia had been ruled out initially because of the absence of cerebellar atrophy on MRI. However, the patient had finger-to-nose dysmetria, saccadic ocular pursuit, and hypotonia, as well as absent tendon reflexes and reduced vibration sense in the ankles. The diagnosis of Friedreich's ataxia was confirmed by molecular analysis.
Autosomal recessive cerebellar ataxias are heterogeneous, complex, disabling inherited neurodegenerative diseases that are manifested mostly in children and young adults (Table 3)Table 3
Clinical Features, Laboratory and Brain MRI Findings, and Molecular Features of the Major Autosomal Recessive Cerebellar Ataxias. .3 Cerebellar ataxia may be associated with the involvement of both the central and peripheral nervous systems, as well as with many systemic signs (see the figure in the Supplementary Appendix), and the patients may first see generalists or several specialists (Table 2). Important neurologic signs other than cerebellar ataxia include peripheral neuropathy (decreased or absent tendon reflexes and decreased vibration sense in the ankles) (Video 1); movement disorders such as chorea (Video 2), dystonia (Video 2), and oculomotor abnormalities (Videos 1, 2, and 3); pyramidal tract dysfunction such as extensor plantar responses, hyperreflexia, and spasticity (Video 1); mental retardation, cognitive impairment, or both4; and epilepsy (Figure 1).

Clinically Common Syndromes
Friedreich's Ataxia

Friedreich's ataxia,5 the most frequent autosomal recessive cerebellar ataxia, is characterized by both cerebellar and proprioceptive ataxia (with worsening on eye closure), areflexia, and extensor plantar reflexes 6 (Video 1). Scoliosis is common and may be the first indication of the disease. The initial signs generally occur between 7 and 25 years of age and worsen progressively, leading to imbalance, falls, and increasing difficulty in the activities of daily living, including writing, dressing, washing, and feeding. Disease progression is variable. Patients with Friedreich's ataxia generally lose independent locomotion after they have had the disease for 10 to 15 years. Dysarthria and dysphagia both contribute to severe disability.
Two features of Friedreich's ataxia that are often misunderstood are the absence of obvious cerebellar atrophy on brain MRI during the first years of the disease4 (Figure 2Figure 2
MRI Scans Showing Four Types of Autosomal Recessive Cerebellar Ataxias.) and ocular “square-wave jerks”7 (Video 1). Nystagmus is not a prominent sign of Friedreich's ataxia, and marked cerebellar atrophy on MRI argues against the disease. Left ventricular hypertrophy, seen in approximately 60% of patients,6,8 may be accompanied by palpitations and dyspnea and can progress to end-stage cardiomyopathy. Electrocardiography (ECG) frequently shows repolarization abnormalities. Thus, close cardiac follow-up, including ECG, is indicated every 1 to 2 years. Diabetes mellitus is reported in about 15% of patients with Friedreich's ataxia, and carbohydrate intolerance is detected in 25% because of progressive insulin deficiency and peripheral insulin resistance. Because of its frequency, Friedreich's ataxia should be suspected in whites and people from the Indian subcontinent with ataxia, and the search for the diagnostic GAA triplet expansion in the FXN gene — which can be detected with a simple molecular test — should be performed whenever the phenotype is recognized (Figure 1).

Ataxia Telangiectasia
The signs of ataxia telangiectasia,9 the second most frequent autosomal recessive cerebellar ataxia, usually develop before 5 years of age, with hypotonia and clumsiness that progressively worsen, leading to the loss of independent ambulation by 10 years and death by 20 years of age. Cerebellar ataxia is usually associated with conjunctival telangiectasias (Video 3); oculocephalic dissociation (during head rotation, the head reaches the target before the eyes, which lag) (Video 4); chorea, dystonia, or both; and sensorimotor axonal neuropathy.10 Patients with ataxia telangiectasia must be monitored carefully, since they are prone to malignant conditions (especially lymphomas and leukemias) and to recurrent infections beginning at an early age (e.g., otitis media; sinusitis; and upper respiratory infections, lung infections, or both due to Haemophilus influenzae and Streptococcus pneumoniae) because of immunoglobulin deficiencies, for which intravenous immune globulin may be indicated. Heterozygous carriers of the ATM mutation also require monitoring because they have a susceptibility to breast cancer11 and myocardial infarction.12

Phenotypic and Genotypic Heterogeneity of Autosomal Recessive Cerebellar Ataxias
Most autosomal recessive cerebellar ataxias are heterogeneous with respect to the age at onset, the severity of the disease progression, and the frequency of extracerebellar and systemic signs (see the figure in the Supplementary Appendix). The same phenotype of autosomal recessive cerebellar ataxia may be due to different diseases (e.g., Friedreich's ataxia or ataxia with vitamin E deficiency). Conversely, mutations in the same autosomal recessive cerebellar ataxia gene (e.g., FXN, POLG, or ATM) may lead to several distinct phenotypes. Friedreich's ataxia may be manifested as early-onset,13 late-onset,14 or very-late-onset15 disease (before 10 years, after 25 years, and after 40 years of age, respectively). The rates of disease progression and severity4,6 are also variable, as are some of the clinical abnormalities (Friedreich's ataxia with retained reflexes,16 spastic paraplegia, and optic atrophy). Such heterogeneity is principally due to the unstable nature of the major causative mutation, an intronic GAA trinucleotide repeat expansion of the FXN gene. Symptom severity and expression correlate with the size of the shortest expanded allele (in the case of two expansions) or with the FXN missense mutation (which is present in 2% of patients in association with only one expansion). A late-onset and slowly progressive variant of ataxia telangiectasia has also been described recently, with a markedly reduced susceptibility to cancer, the absence of immunoglobulin deficiency, and an increased frequency of resting tremor.17

Autosomal Recessive Cerebellar Ataxias for Which Treatment Is Available
Once the diagnoses of Friedreich's ataxia and ataxia telangiectasia have been eliminated, the workup should focus on autosomal recessive cerebellar ataxias for which treatment is available.18-24 These include ataxia with vitamin E deficiency (treated with 1500 mg of alpha-tocopherol in two daily doses, with maximal efficacy in presymptomatic patients and patients with very mild signs, indicating the need for an early diagnosis),18,19 Refsum's disease (treated in adults with a phytanic acid–free diet and plasmapheresis),20,21 cerebrotendinous xanthomatosis (treated in adults with 750 mg of chenodeoxycholic acid per day in three daily doses), Niemann–Pick type C disease (treated with 600 mg of miglustat per day in adults), abetalipoproteinemia22 (treated with 150 mg of alpha-tocopherol per kilogram of body weight in divided daily doses, according to the level of vitamin E),23 and autosomal recessive cerebellar ataxia type 2, due to coenzyme Q10 deficiency, for which treatment with coenzyme Q10 (at a dose of 6 mg per kilogram per day) may lead to transient clinical improvement.24

Nonspecific Treatments and Measures
Whatever the diagnosis, the treatment program should make use of physical and occupational therapy, speech and orthoptic rehabilitation, psychological support, and, if necessary, orthopedic surgery (for foot deformities and scoliosis). Genetic counseling provided by a specialist in medical genetics may be proposed for relatives at risk or for parents with an affected child who wish to discuss the risks with future pregnancies. Psychological support for caregivers and family members is often necessary and beneficial. Similarly, rehabilitation or respite stays that may be offered to patients can also relieve caregivers.

Biomarkers are rarely specific, and repeated assessments are sometimes required, but several tests for biomarkers may be useful during investigation.4 Biomarkers could, for instance, lead to evidence-based guidelines for molecular analyses such as for the serum alpha-fetoprotein level, which is moderately elevated in ataxia with oculomotor apraxia type 2.25 The serum alpha-fetoprotein serum level is consistently elevated in both ataxia telangiectasia26 and ataxia with oculomotor apraxia type 2,25,27 although the precise mechanism is not understood. In ataxia with vitamin E deficiency and abetalipoproteinemia, the serum vitamin E level is far below the normal range. With the exception of vitamin E, coenzyme Q10, and the biomarkers of specific metabolic diseases, biomarkers appear to be a consequence, not a cause, of the disease.28-33

MRI Findings
MRI of the brain is an essential tool for the diagnosis of autosomal recessive cerebellar ataxias (Figure 1). The key point is whether obvious cerebellar atrophy is detected on the sagittal sections (Table 3).3,4,34 Other important signs include cervical spinal cord atrophy (in Friedreich's ataxia and ataxia with vitamin E deficiency),35 cerebellar white-matter changes (in cerebrotendinous xanthomatosis, sensory axonal neuropathy with dysarthria, and ophthalmoplegia),32 and cerebral white-matter changes (in autosomal recessive cerebellar ataxia type 2 and cerebrotendinous xanthomatosis)32,36 (Figure 2).
Figure 1 shows a simplified version of an algorithm for clinical practice.4 In a patient with ataxia, when autosomal recessive cerebellar ataxia is suspected, several steps are required. These steps, which include identification of the clinical signs, appropriate laboratory analyses plus brain MRI, and electroneuromyography, should establish the diagnosis in nearly half of patients,4 and they can inform a gene-sequencing strategy or identify the need for reappraisal of the case.

New Developments
Epidemiologic Data
Previously, it was thought that Friedreich's ataxia and ataxia telangiectasia were by far the most common autosomal recessive cerebellar ataxias,10 although ataxia telangiectasia appears to be between 3 to 8 times less frequent than Friedreich's ataxia in European and North African populations.4,37 Although Friedreich's ataxia is the most common autosomal recessive cerebellar ataxia in North America and Europe (1 case per 50,000 persons), it has never been described in Japan, where ataxia with oculomotor apraxia type 1 is most common. Ataxia telangiectasia is probably the second most frequent autosomal recessive cerebellar ataxia worldwide (1 case per 150,000 persons to 1 case per 200,000 persons). However, in North Africa, ataxia with vitamin E deficiency is the second most frequent diagnosis after Friedreich's ataxia.38-40 Entities such as ataxia with oculomotor apraxia type 2,25,41 autosomal recessive spastic ataxia of Charlevoix–Saguenay,38-40 ataxia with vitamin E deficiency,41 and ataxia with oculomotor apraxia type 129,30 need to be investigated extensively, irrespective of the patient's ethnic origin.4

Ataxias with Oculocephalic Dissociation
A group of autosomal recessive cerebellar ataxias due to DNA repair, transcriptional deficiencies, or both has emerged. These conditions, which include ataxia telangiectasia,9,10 ataxia telangiectasia–like disorder,42 ataxia with oculomotor apraxia type 1,29,30 and ataxia with oculomotor apraxia type 2,25,27 are characterized by cerebellar ataxia with oculocephalic dissociation, sensorimotor axonal neuropathy, dystonia, or chorea, or with a combination of these conditions (Table 3, the figure in the Supplementary Appendix, and Videos 2, 3, and 4) and lead to severe disability. Biomarkers are available for most of these entities; these include an elevated alpha-fetoprotein level (for ataxia telangiectasia, ataxia with oculomotor apraxia type 2, and, to some extent, ataxia with oculomotor apraxia type 1) and a low albumin level (for ataxia with oculomotor apraxia type 1). Although there is a marked susceptibility to cancer in patients with ataxia telangiectasia, such susceptibility has not been established in patients who have ataxia with oculomotor apraxia type 1 or 2.
New entities broaden the spectrum of autosomal recessive cerebellar ataxia. These new entities include autosomal recessive cerebellar ataxia type 143,44 and type 233,36; rundataxin-related ataxia45; polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts46; and autosomal recessive cerebellar ataxia type 3 (caused by mutations in the calcium-activated chloride channel ANO10).47
On clinical and neurophysiological grounds, autosomal recessive cerebellar ataxias can be classified into three groups (Table 3). The first group, cerebellar ataxia with pure sensory neuronopathy, is characterized by a degeneration of peripheral sensory neurons in dorsal-root ganglia, leading to a proprioceptive sensory loss that is not restricted to the lower limbs. The second group, cerebellar ataxia with sensorimotor axonal neuropathy, is characterized by a length-dependent degeneration of both sensory and motor nerves, primarily affecting the lower limbs. The third group is cerebellar ataxia without neuropathy. This classification shares some features with the current autosomal dominant spinocerebellar ataxia nosology, adapted from Harding's modified classification,48 which comprises one group of complex spinocerebellar ataxias (including associated neuropathy) and another of pure cerebellar spinocerebellar ataxias.

Areas of Controversy
Molecular Mechanisms of Friedreich's Ataxia
Initially, iron and oxidative stress were considered to play a key role in the pathophysiology of Friedreich's ataxia, but it appears that these are nonspecific consequences of the primary molecular defect.49 Friedreich's ataxia arises because of a general deficit of mitochondrial, cytosolic, and nuclear iron-sulfur50 protein–related activities.
Idebenone in Friedreich's Ataxia
Idebenone antioxidant treatment has been shown in Friedreich's ataxia to have a beneficial effect on left ventricular hypertrophy in patients with Friedreich's ataxia,51 but whether this agent protects from cardiomyopathy or from the neurologic progression of Friedreich's ataxia has been challenged.52-56 Neither a cardiac nor a neurologic benefit could be confirmed in recent trials. Evidence-based results are needed for drugs awaiting study or currently under study in Friedreich's ataxia. These agents include deferiprone for iron chelation, pioglitazone as a mitochondrial enhancer, and inhibitors of histone deacetylases for stimulation of FXN transcription.

Pathophysiological Pathways
Autosomal recessive cerebellar ataxias result from the loss of function of a mutated protein. Some pathophysiological pathways are common to several autosomal recessive cerebellar ataxias, such as deficiency of DNA repair (in ataxia telangiectasia, ataxia with oculomotor apraxia type 1, ataxia telangiectasia–like disorder, and spinocerebellar ataxia plus neuropathy type 1), mitochondrial defects (in Friedreich's ataxia, infantile-onset spinocerebellar ataxia, sensory axonal neuropathy with dysarthria and ophthalmoplegia, and autosomal recessive cerebellar ataxia type 2), defects of lipoprotein assembly (in ataxia with vitamin E deficiency and abetalipoproteinemia), and chaperone dysfunction (in autosomal recessive spastic ataxia of Charlevoix–Saguenay and the Marinesco–Sjögren syndrome). However, given the multiplicity of pathways that, when disrupted, could cause recessive ataxia, it appears that no specific mechanism leads to cerebellar degeneration. This conclusion is reinforced by the identification of autosomal recessive cerebellar ataxia type 1; rundataxin-related ataxia; polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts; and autosomal recessive cerebellar ataxia type 3, in which the mutations alter a cytoskeleton protein, a protein involved in vesicular trafficking, a lipase, and a calcium-activated chloride channel, respectively. The multiplicity of involved cell types (sensory neurons, spinocerebellar neurons, and multiple cell types of the cerebellum) can only partly explain the multiplicity of pathophysiological pathways identified so far. A common feature may be the exquisite sensitivity of these neurons to even mild metabolic insults, as illustrated by the ataxia that results from even modest ethanol intoxication in adults.

The interplay between bedside and laboratory investigations has led to the identification of new genes responsible for autosomal recessive cerebellar ataxia and to the delineation of new entities. Nanotechnology methods and whole-exome, high-throughput sequencing, as well as bioinformatics, may lead to the identification of several new autosomal recessive cerebellar ataxias in the next few years, despite the rarity of these entities. However, the challenge in the coming decades will be to develop specific effective treatments for these disabling neurodegenerative disorders.

Source Information
From Assistance Publique–Hôpitaux de Paris, Pitié–Salpêtrière Hospital, Department of Genetics and Cytogenetics; Centre de Référence des Maladies Neurogénétiques de l'Enfant et de l'Adulte; and Université Pierre et Marie Curie, Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Épinière, INSERM, Unité Mixte de Recherche Scientifique S975, and Centre National de la Recherche Scientifique, Unité Mixte de Recherche Scientifique 7225 — all in Paris (M.A.); Département de Neurologie (C.T.) and Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil (M.K.), University Hospital of Strasbourg, Strasbourg; and Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, INSERM, University of Strasbourg, Illkirch (M.K.) — all in France.
Address reprint requests to Dr. Anheim at the Service de Génétique, Bâtiment Pinel, Groupe Hospitalier de la Pitié–Salpêtrière, 47-83, bd de l'Hôpital, 75651 Paris, France, or at [email protected].

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