Review article
Current Concepts
From Assistance Publique–Hôpitaux de
Paris, Pitié–Salpêtrière Hospital, Depart-
ment of Genetics and Cytogenetics; Cen-
tre de Référence des Maladies Neurogé-
nétiques de l’Enfant et de l’Adulte; and
Université Pierre et Marie Curie, Paris 6,
Centre de Recherche de l’Institut du Cer-
veau et de la Moelle Épinière, INSERM,
Unité Mixte de Recherche Scientifique
S975, and Centre National de la Recher-
che Scientifique, Unité Mixte de Recher-
che 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 mathieu.anheim
@psl.aphp.fr.
N Engl J Med 2012;366:636-46.
Copyright © 2012 Massachusetts Medical Society.
A video showing
features of ataxias
is available at
NEJM.org
636
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
The Autosomal Recessive Cerebellar Ataxias
Mathieu Anheim, M.D., Ph.D., Christine Tranchant, M.D.,
and Michel Koenig, M.D., Ph.D.
T
he 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 mo-
lecular 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 NEJM.org) due to cerebellar
dysfunction. Clinical examination reveals a gait disorder with imbalance, stagger-
ing, and difficulties with tandem walking, upper-limb and lower-limb dysmetria,
dysdiadochokinesia (difficulty performing rapidly alternating movements), hypoto-
nia, 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).
Neurodegenerative disease should be considered whenever cerebellar ataxia is pro-
gressive 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 NEJM.org). 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 dis-
eases that usually become evident at approximately 35 years of age, usually with a
multigenerational pattern.1,2 X-linked inheritance suggests consideration of the frag-
ile 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 exces-
sive clumsiness (Fig. 1 and Table 2). A typical presentation was that of an 18-year-old
n engl j med 366;7  nejm.org  february 16, 2012
The New England Journal of Medicine
 Current Concepts

Table 1. Acute Ataxias in Which Symptoms Appear Suddenly or in a Few Days.

Diagnosis Evaluation and Findings Initial Treatment

Alcohol consumption
Vitamin B1 deficiency
Drugs (carbamazepine, phenytoin, pheno­
barbital, lithium, fluorouracil, cytarabine,
metronidazole, amiodarone)
Toxic agents (mercury, thallium, organolead,
toluene, solvents, pesticides)
Ischemic or hemorrhagic cerebellar stroke
Relapse of multiple sclerosis
Basilar meningitis (due to tuberculosis
or listeriosis)
Cerebellitis (due to varicella–zoster virus
infection, rubeola, influenza, JC virus
infection, pertussis)
Cerebellar abscess
History of alcohol abuse, increased liver- Alcohol withdrawal, vitamin B1 supplementation
enzyme levels
Serum vitamin B1 deficiency Vitamin B1 supplementation
History of treatment, abnormally elevated Drug withdrawal, vitamin B1 supplementation
serum level (if applicable) as therapy or as prevention (if fluorouracil
received)
History of intoxication Immediate cessation of exposure
Brain MRI Admission to a stroke unit
Brain MRI Glucocorticoids
Brain MRI, cerebrospinal fluid examination Antibiotics
on direct microscopy
Brain MRI and cerebrospinal fluid ­examination Acyclovir (for varicella–zoster virus)
to detect lymphocytic pleocytosis, serologic
tests for viruses
Brain MRI Antibiotics, surgical drainage

patient referred to our center because of imbal- Cl inic a l ly C om mon S y ndrome s

ance, 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 pur-
suit, and hypotonia, as well as absent tendon re-
flexes and reduced vibration sense in the ankles.
The diagnosis of Friedreich’s ataxia was confirmed
by molecular analysis.
Autosomal recessive cerebellar ataxias are het-
erogeneous, complex, disabling inherited neuro-
degenerative diseases that are manifested mostly
in children and young adults (Table 3).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 fig-
ure in the Supplementary Appendix), and the pa-
tients may first see generalists or several special-
ists (Table 2). Important neurologic signs other
than cerebellar ataxia include peripheral neuropa-
thy (decreased or absent tendon reflexes and de-
creased vibration sense in the ankles) (Video 1);
movement disorders such as chorea (Video 2), dys-
tonia (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, cog-
nitive impairment, or both4; and epilepsy (Fig. 1).
Friedreich’s Ataxia
Friedreich’s ataxia,5 the most frequent autosomal
recessive cerebellar ataxia, is characterized by both
cerebellar and proprioceptive ataxia (with worsen-
ing on eye closure), areflexia, and extensor plantar
reflexes6 (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 imbal-
ance, falls, and increasing difficulty in the activi-
ties of daily living, including writing, dressing,
washing, and feeding. Disease progression is vari-
able. Patients with Friedreich’s ataxia generally lose
independent locomotion after they have had the
disease for 10 to 15 years. Dysarthria and dyspha-
gia both contribute to severe disability.
Two features of Friedreich’s ataxia that are often
misunderstood are the absence of obvious cerebel-
lar atrophy on brain MRI during the first years of
the disease4 (Fig. 2) 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 cardio-
myopathy. Electrocardiography (ECG) frequently

n engl j med 366;7  nejm.org  february 16, 2012 637

The New England Journal of Medicine
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Cerebellar ataxia

Acute

Subacute or chronic

Acquired Sporadic or among siblings Dominantly inherited spinocerebellar

(consanguinity) in a young patient ataxia, episodic ataxias
X-linked (the fragile X–associated
No tremor–ataxia syndrome, adreno-
myeloneuropathy)
Mitochondrial DNA mutation

Autosomal recessive cerebellar ataxia

Natural History
Age at onset Disease progression
≤10 yr Slow
Ataxia telangiectasia, ataxia with oculo- ARSACS, ARCA1, ARCA2
motor apraxia type 1, ARSACS, abeta- Rapid
lipoproteinemia, CDG1A Ataxia telangiectasia, ataxia with oculo-
>10 yr motor apraxia type 1, Friedreich’s ataxia
SANDO, ARCA1

Associated Clinical Signs

Oculomotor impairment
Ataxia telangiectasia, ataxia with oculo-
motor apraxia type 1, ataxia with oculo-
motor apraxia type 2, Friedreich's ataxia,
SANDO, Niemann–Pick type C disease
Pyramidal signs
Cerebrotendinous xanthomatosis, ARSACS,
Friedreich’s ataxia, AVED
Movement disorders
Ataxia telangiectasia, ataxia with oculo-
motor apraxia type 1, ataxia with oculo-
motor apraxia type 2, Niemann–Pick type
C disease, AVED, SANDO
Mental retardation or cognitive decline
CDG1A, ataxia with oculomotor apraxia
type 1, Niemann–Pick type C disease,
SANDO, ARSACS, ARCA2

Tests

MRI EMG Laboratory Tests

No obvious cerebellar atrophy
Friedreich’s ataxia, AVED, Refsum’s
disease, abetalipoproteinemia
Cerebellar atrophy
Ataxia telangiectasia, ataxia with
oculomotor apraxia type 1, ataxia
with oculomotor apraxia type 2,
ARSACS, ARCA1, ARCA2, cere-
brotendinous xanthomatosis
Axonal sensorimotor neuropathy
Ataxia with oculomotor apraxia type 1,
ataxia with oculomotor apraxia
type 2, ataxia telangiectasia, cere-
brotendinous xanthomatosis,*
Refsum’s disease,* ARSACS*
Pure sensory neuronopathy
Friedreich’s ataxia, AVED, abetalipo-
proteinemia, SANDO
No neuropathy
ARCA1, ARCA2, NPC
Molecular analysis to detect Friedreich’s
ataxia
Biomarkers
Vitamin E: AVED, abetalipoproteinemia
Alpha-fetoprotein: ataxia with oculo-
motor apraxia type 2, ataxia tel-
angiectasia

Gene sequencing or diagnosis

638 n engl j med 366;7  nejm.org  february 16, 2012

The New England Journal of Medicine

Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
 Current Concepts
Figure 1 (facing page). Management of Cerebellar
Ataxias in Clinical Practice.
ARCA1 denotes autosomal recessive cerebellar ataxia
type 1, ARCA2 autosomal recessive cerebellar ataxia
type 2, ARSACS autosomal recessive spastic ataxia of
Charlevoix–Saguenay, AVED ataxia with vitamin E defi-
ciency, CDG1A congenital disorder of glycosylation
type 1A, EMG electroneuromyography, MRI magnetic
resonance imaging, NPC Niemann–Pick type C disease,
and SANDO sensory axonal neuropathy with dysarthria
and ophthalmoplegia. Asterisks indicate autosomal re-
cessive cerebellar ataxias that are characterized by a
demyelinating component of the sensorimotor neurop-
athy, rather than axonal neuropathy.
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% be-
cause of progressive insulin deficiency and periph-
eral 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 trip-
let expansion in the FXN gene — which can be
detected with a simple molecular test — should be
performed whenever the phenotype is recognized
(Fig. 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 hypo-
tonia 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 tel-
angiectasias (Video 3); oculocephalic dissociation
(during head rotation, the head reaches the target
before the eyes, which lag) (Video 4); chorea, dys-
tonia, or both; and sensorimotor axonal neurop-
athy.10 Patients with ataxia telangiectasia must be
monitored carefully, since they are prone to malig-
nant conditions (especially lymphomas and leuke-
mias) 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 pneumoni-
ae) because of immunoglobulin deficiencies, for
which intravenous immune globulin may be indi-
n engl j med 366;7  nejm.org  february 16, 2012
The New England Journal of Medicine
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
Table 2. Typical Signs and Symptoms of a Cerebellar Ataxia and Mistakes
to Avoid If the Diagnosis of Cerebellar Ataxia Is Uncertain.
Typical signs and symptoms of cerebellar ataxia
Clumsiness, swerving
Difficulty in walking
Balance problems, swaying, falling (leading to or manifested as trauma)
Difficulty in dressing, handling utensils, and writing
Slurred speech
Hypotonia, slowness
Delayed motor development (onset of walking after 18 mo)
Intentional hand tremor
Dizziness (patient is sometimes referred to otorhinolaryngologist)
Visual disturbances (patient is sometimes referred to ophthalmologist)
Incidental finding of cerebellar atrophy on magnetic resonance imaging
Mistakes to avoid if diagnosis of cerebellar ataxia is uncertain
Neglecting the disorder
Considering a psychiatric origin
Suspecting an otorhinolaryngologic, ophthalmologic, orthopedic,
or a rheumatologic cause
Not requesting a second examination several weeks or months later
Not referring patient to a neurologist or a pediatrician who specializes in
neurology
Not urgently investigating an acute cerebellar ataxia
cated. Heterozygous carriers of the ATM mutation
also require monitoring because they have a sus-
ceptibility to breast cancer11 and myocardial in-
farction.12
Phenotypic and Genotypic Heterogeneity
of Autosomal Recessive Cerebellar Ataxias
Most autosomal recessive cerebellar ataxias are het-
erogeneous with respect to the age at onset, the
severity of the disease progression, and the fre-
quency 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., Fried-
reich’s ataxia or ataxia with vitamin E deficiency).
Conversely, mutations in the same autosomal re-
cessive 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
639
 640
Table 3. Clinical Features, Laboratory and Brain MRI Findings, and Molecular Features of the Major Autosomal Recessive Cerebellar Ataxias.*
Disease
Cerebellar ataxia with pure
sensory neuronopathy
Friedreich’s ataxia
Sensory axonal neuropathy
with ­dysarthria and oph-
thalmoplegia
Ataxia with vitamin E
deficiency
Abetalipoproteinemia
The New England Journal of Medicine
Cerebellar ataxia with sensori­-
motor axonal neuropathy
Ataxia telangiectasia
n engl j med 366;7  nejm.org  february 16, 2012
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
Ataxia with oculomotor
apraxia type 1
Ataxia with ocular apraxia
type 2
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Age at Onset Clinical Features
yr
Mean, 16; 7–25 in most Most frequent recessive ataxia,
cases; reported range, bilateral ­extensor plantar
2–60 reflexes, ­scoliosis, square-
wave jerks
Range, 20–60 Ophthalmoparesis, dysarthria,
ptosis, myoclonus
Mean, 17; range, 2–50 Similar to Friedreich’s ataxia,
­retinitis pigmentosa,
variable head tremor
Birth Vomiting, diarrhea, neonatal
­steatorrhea
Range, 2–3; <5 in most Telangiectasias; oculocephalic
cases dissociation; susceptibility
to infections and cancer;
chorea, dystonia, or both
Mean, 7; range, 1–20 Variable oculocephalic disso­
ciation; chorea, dystonia,
or both
Mean, 15; range, 7–25 Variable oculocephalic disso­
ciation; chorea, dystonia,
or both
Laboratory Findings
GAA triplet repeat expan- No cerebellar atrophy, spi-
sion in ­intron 1 of the
FXN gene
Variable elevation of serum Variable cerebellar atrophy,
lactic acid ­level
Significantly decreased se- No cerebellar atrophy, spi-
rum vitamin E level†
Decreased serum levels of
cholesterol, triglycer-
ides, and vitamins A, D,
E, and K; abetalipopro-
teinemia; acanthocytosis
Elevated serum alpha-feto-
protein level, immuno-
globulin deficiency,
mosaic translocations
(specific karyotype)†
Variable elevation of serum
LDL cholesterol level
and low serum albumin
level
Elevated serum alpha-feto-
protein level†
Brain MRI Findings Gene and Protein
FXN, frataxin
nal cord atrophy
The
POLG, polymerase gamma
cerebellar white-matter
changes, strokelike
­lesions
TTPA, alpha-tocopherol trans-
nal cord atrophy fer protein
No cerebellar atrophy MTP, microsomal triglyceride
transfer protein
n e w e ng l a n d j o u r na l
of
Cerebellar atrophy ATM, ataxia telangiectasia
mutated
m e dic i n e
Cerebellar atrophy APTX, aprataxin
Cerebellar atrophy SETX, senataxin
 Late-onset GM2 gangliosi-
dosis
Congenital disorder of gly-
cosylation type 1A
Autosomal recessive spastic
ataxia of Charlevoix–
Saguenay
Refsum’s disease
Cerebrotendinous xantho-
matosis
Cerebellar ataxia without
neuropathy
Autosomal recessive cere-
bellar ataxia type 1
Autosomal recessive cere-
bellar ataxia type 2
The New England Journal of Medicine
n engl j med 366;7  nejm.org  february 16, 2012
Niemann–Pick type C
disease
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
* Most congenital and inherited metabolic disorders are excluded. LDL denotes low-density lipoprotein.
† This biomarker is consistently altered (either increased or decreased) in the corresponding autosomal recessive cerebellar ataxia.
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
641
Range, 15–45 Spasticity, weakness, dystonia,
epilepsy, cognitive decline,
psychosis, anterior horn
involvement
Birth Mental retardation, retinitis pig- Serum transferrin isoelectric Cerebellar atrophy
mentosa, thoracic
deformity, epilepsy
Mean, 2; up to 12 Spastic paraparesis followed
by spastic ataxia, demyelin-
ating component of the neu-
ropathy, hypertrophy
of the myelinated fibers
(of the fundus)
Range, 10–20 Retinitis pigmentosa, sensori-
neural deafness, demyelinat-
ing neuropathy
Childhood Spastic ataxia; mental retarda-
tion, dementia, or both; ten-
don xanthomas; chronic di-
arrhea; premature cataracts
Late onset; mean, 32; Pure ataxia
range, 17–46
Mean, 4; range, 1–11 Mental retardation, myoclonus,
epilepsy, strokelike condi-
tion, exercise intolerance
Range, 2–30 Vertical supranuclear ophthal-
moplegia, splenomegaly,
dystonia, cognitive dis-
order
Hexosaminidase A deficien- Cerebellar atrophy HEXA (Tay–Sachs variant)
cy (late-onset Tay–Sachs or HEXB (Sandhoff’s
disease), hexosamini- disease variant)
dase A+B deficiency
(Sandhoff’s disease)
PMM2, phospho-manno­
­focusing mutase
Anterior superior cerebellar SACS, sacsin
atrophy, variable T2-
weighted linear hypo­
intensities in pons
Elevated serum phytanic No cerebellar atrophy PhyH, phytanoyl-CoA hydroxy-
acid level† lase and PEX7, PEX7
Elevated serum cholestanol Variable cerebellar atrophy, CYP27, sterol 27 ­hydroxylase
level† cerebellar or cerebral
leukodystrophy
Current Concepts
Not applicable Cerebellar atrophy SYNE1, spectrin
­repeats-nuclear ­envelope 1
Variable elevation of serum Cerebellar atrophy, variable ADCK3 (CABC1),
lactic acid level and de- strokelike cerebral aarf-domain containing
creased coenzyme Q10 lesions kinase 3
level
Skin-biopsy findings (filipin Variable cerebellar or brain NPC1, NPC1 and NPC2, NPC2
staining) atrophy
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

Figure 2. MRI Scans Showing Four Types of Autosomal Recessive Cerebellar Ataxias.
Panel A shows marked cerebellar atrophy in a patient with ataxia telangiectasia. Panel B shows moderate periven-
tricular leukoencephalopathy (arrows) in a patient with cerebrotendinous xanthomatosis. Panel C shows no obvious
cerebellar atrophy but cervical spinal cord atrophy (arrow) in a patient with Friedreich’s ataxia, 10 years after the on-
set of the disease. Panel D shows T2 -weighted linear hypointensities in the pons (arrows) in a patient with autoso-
mal recessive spastic ataxia of Charlevoix–Saguenay.

of age, respectively). The rates of disease progres-
sion and severity4,6 are also variable, as are some
of the clinical abnormalities (Friedreich’s ataxia
with retained reflexes,16 spastic paraplegia, and op-
tic atrophy). Such heterogeneity is principally due
to the unstable nature of the major causative mu-
tation, an intronic GAA trinucleotide repeat expan-
sion of the FXN gene. Symptom severity and ex-
pression correlate with the size of the shortest
expanded allele (in the case of two expansions)
or with the FXN missense mutation (which is pres-
ent in 2% of patients in association with only one
expansion). A late-onset and slowly progressive
variant of ataxia telangiectasia has also been de-
scribed recently, with a markedly reduced suscep-
tibility 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 atax-
ia telangiectasia have been eliminated, the workup
should focus on autosomal recessive cerebellar

642 n engl j med 366;7 nejm.org february 16, 2012

The New England Journal of Medicine

Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
 Current Concepts
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, indi-
cating the need for an early diagnosis),18,19 Ref-
sum’s disease (treated in adults with a phytanic
acid–free diet and plasmapheresis),20,21 cerebro-
tendinous xanthomatosis (treated in adults with
750 mg of chenodeoxycholic acid per day in three
daily doses), Niemann–Pick type C disease (treat-
ed 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 vita-
min E),23 and autosomal recessive cerebellar atax-
ia 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 ther-
apy, speech and orthoptic rehabilitation, psycho-
logical support, and, if necessary, orthopedic sur-
gery (for foot deformities and scoliosis). Genetic
counseling provided by a specialist in medical ge-
netics 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
Biomarkers are rarely specific, and repeated assess-
ments 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 mod-
erately elevated in ataxia with oculomotor apraxia
type 2.25 The serum alpha-fetoprotein serum level
is consistently elevated in both ataxia telangiec-
tasia26 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 ex-
ception of vitamin E, coenzyme Q10, and the bio-
markers of specific metabolic diseases, biomark-
n engl j med 366;7  nejm.org  february 16, 2012
The New England Journal of Medicine
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
ers 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 diagno-
sis of autosomal recessive cerebellar ataxias (Fig. 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 vita-
min E deficiency),35 cerebellar white-matter chang-
es (in cerebrotendinous xanthomatosis, sensory
axonal neuropathy with dysarthria, and ophthal-
moplegia),32 and cerebral white-matter changes (in
autosomal recessive cerebellar ataxia type 2 and
cerebrotendinous xanthomatosis)32,36 (Fig. 2).
Figure 1 shows a simplified version of an algo-
rithm for clinical practice.4 In a patient with ataxia,
when autosomal recessive cerebellar ataxia is sus-
pected, 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.
Ne w De v el opmen t s
Epidemiologic Data
Previously, it was thought that Friedreich’s ataxia
and ataxia telangiectasia were by far the most com-
mon autosomal recessive cerebellar ataxias,10 al-
though 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, irre-
spective of the patient’s ethnic origin.4
643
 The n e w e ng l a n d j o u r na l
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 axo-
nal neuropathy, dystonia, or chorea, or with a com-
bination 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 tel-
angiectasia, 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 autoso-
mal 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 pig-
mentosa, 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 clas-
sified 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 affect-
ing 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 spinocerebel-
lar ataxias (including associated neuropathy)
and another of pure cerebellar spinocerebellar
ataxias.
644 n engl j med 366;7  nejm.org  february 16, 2012
The New England Journal of Medicine
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
A r e a s of C on t rov er s y
Molecular Mechanisms of Friedreich’s Ataxia
Initially, iron and oxidative stress were considered
to play a key role in the pathophysiology of Fried-
reich’s ataxia, but it appears that these are non-
specific consequences of the primary molecular
defect.49 Friedreich’s ataxia arises because of a
general deficit of mitochondrial, cytosolic, and nu-
clear 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 Fried-
reich’s ataxia,51 but whether this agent protects
from cardiomyopathy or from the neurologic
progression of Friedreich’s ataxia has been chal-
lenged.52-56 Neither a cardiac nor a neurologic ben-
efit 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 sev-
eral autosomal recessive cerebellar ataxias, such as
deficiency of DNA repair (in ataxia telangiectasia,
ataxia with oculomotor apraxia type 1, ataxia telan-
giectasia–like disorder, and spinocerebellar ataxia
plus neuropathy type 1), mitochondrial defects
(in Friedreich’s ataxia, infantile-onset spinocere-
bellar ataxia, sensory axonal neuropathy with dys-
arthria and ophthalmoplegia, and autosomal reces-
sive 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 Charle­
voix–Saguenay and the Marinesco–Sjögren syn-
drome). However, given the multiplicity of path-
ways that, when disrupted, could cause recessive
ataxia, it appears that no specific mechanism leads
to cerebellar degeneration. This conclusion is rein-
forced by the identification of autosomal recessive
cerebellar ataxia type 1; rundataxin-related ataxia;
polyneuropathy, hearing loss, ataxia, retinitis pig-
 Current Concepts

mentosa, 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-acti-
vated chloride channel, respectively. The multiplic-
ity of involved cell types (sensory neurons, spino-
cerebellar neurons, and multiple cell types of the
cerebellum) can only partly explain the multiplic-
ity of pathophysiological pathways identified so
far. A common feature may be the exquisite sen-
sitivity of these neurons to even mild metabolic
insults, as illustrated by the ataxia that results
from even modest ethanol intoxication in adults.
C onclusions
The interplay between bedside and laboratory in-
vestigations has led to the identification of new
genes responsible for autosomal recessive cerebel-
lar 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 auto-
somal recessive cerebellar ataxias in the next few
years, despite the rarity of these entities. However,
the challenge in the coming decades will be to de-
velop specific effective treatments for these dis-
abling neurodegenerative disorders.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Drs. Vincent Laugel and Christophe Marcel for pro-
viding MRI scans and for assistance with an earlier version
of the manuscript; and Drs. Fabienne Grunenberger, Philippe
Sevrin, Claire Sevrin, Vincent Anstett, Etienne Anheim, Steve
Brooks, and Karine Schutz for assistance with an earlier version
of the manuscript.

References
1. Durr A. Autosomal dominant cerebel-
lar ataxias: polyglutamine expansions and
beyond. Lancet Neurol 2010;9:885-94.
2. Schöls L, Bauer P, Schmidt T, Schulte
T, Riess O. Autosomal dominant cerebel-
lar ataxias: clinical features, genetics, and
pathogenesis. Lancet Neurol 2004;3:291-
304.
3. Fogel BL, Perlman S. Clinical features
and molecular genetics of autosomal re-
cessive cerebellar ataxias. Lancet Neurol
2007;6:245-57.
4. Anheim M, Fleury M, Monga B, et al.
Epidemiological, clinical, paraclinical
and molecular study of a cohort of 102
patients affected with autosomal reces-
sive progressive cerebellar ataxia from
Alsace, Eastern France: implications for
clinical management. Neurogenetics
2010;11:1-12.
5. Campuzano V, Montermini L, Moltò
MD, et al. Friedreich’s ataxia: autosomal
recessive disease caused by an intronic
GAA triplet repeat expansion. Science
1996;271:1423-7.
6. Durr A, Cossee M, Agid Y, et al. Clini-
cal and genetic abnormalities in patients
with Friedreich’s ataxia. N Engl J Med
1996;335:1169-75.
7. Spieker S, Schulz JB, Petersen D,
Fetter M, Klockgether T, Dichgans J. Fixa-
tion instability and oculomotor abnor-
malities in Friedreich’s ataxia. J Neurol
1995;242:517-21.
8. Isnard R, Kalotka H, Dürr A, et al.
Correlation between left ventricular hy-
pertrophy and GAA trinucleotide repeat
length in Friedreich’s ataxia. Circulation
1997;95:2247-9.
9. Savitsky K, Bar-Shira A, Gilad S, et al.
A single ataxia telangiectasia gene with a
product similar to PI-3 kinase. Science
1995;268:1749-53.
10. Chun HH, Gatti RA. Ataxia-telangiec-
tasia, an evolving phenotype. DNA Repair
(Amst) 2004;3:1187-96.
11. Swift M, Morrell D, Massey RB, Chase
CL. Incidence of cancer in 161 families
affected by ataxia-telangiectasia. N Engl J
Med 1991;325:1831-6.
12. Su Y, Swift M. Mortality rates among
carriers of ataxia-telangiectasia mutant
alleles. Ann Intern Med 2000;133:770-8.
13. Anheim M, Mariani LL, Calvas P, et al.
Exonic deletions of FXN cause early-onset
Friedreich’s ataxia. Arch Neurol (in
press).
14. Schöls L, Amoiridis G, Przuntek H,
Frank G, Epplen JT, Epplen C. Friedreich’s
ataxia: revision of the phenotype accord-
ing to molecular genetics. Brain
1997;120:2131-40.
15. Berciano J, Infante J, García A, Polo
JM, Volpini V, Combarros O. Very late-
onset Friedreich’s ataxia with minimal
GAA1 expansion mimicking multiple sys-
tem atrophy of cerebellar type. Mov Dis-
ord 2005;20:1643-5.
16. Montermini L, Richter A, Morgan K,
et al. Phenotypic variability in Friedreich
ataxia: role of the associated GAA triplet
repeat expansion. Ann Neurol 1997;41:
675-82.
17. Verhagen MM, Abdo WF, Willemsen
MA, et al. Clinical spectrum of ataxia-
telangiectasia in adulthood. Neurology
2009;73:430-7.
18. Amiel J, Maziere JC, Beucler I, et al.
Familial isolated vitamin E deficiency: ex-
tensive study of a large family with a
5-year therapeutic follow-up. J Inherit
Metab Dis 1995;18:333-40.
19. Kohlschütter A, Hübner C, Jansen W,
Lindner SG. A treatable familial neuromy-
opathy with vitamin E deficiency, normal
absorption, and evidence of increased
consumption of vitamin E. J Inherit
Metab Dis 1988;11:Suppl 2:149-52.
20. Hungerbühler JP, Meier C, Rousselle
L, Quadri P, Bogousslavsky J. Refsum’s
disease: management by diet and plasma-
pheresis. Eur Neurol 1985;24:153-9.
21. Jansen GA, Wanders RJ, Watkins PA,
Mihalik SJ. Phytanoyl-coenzyme A hy-
droxylase deficiency — the enzyme defect
in Refsum’s disease. N Engl J Med
1997;337:133-4.
22. Sharp D, Blinderman L, Combs KA, et
al. Cloning and gene defects in micro-
somal triglyceride transfer protein associ-
ated with abetalipoproteinaemia. Nature
1993;365:65-9.
23. Muller DP, Lloyd JK. Effect of large oral
doses of vitamin E on the neurological
sequelae of patients with abetalipoprotein-
emia. Ann N Y Acad Sci 1982;393:133-44.
24. Auré K, Benoist JF, Ogier de Baulny H,
Romero NB, Rigal O, Lombès A. Progres-
sion despite replacement of a myopathic
form of coenzyme Q10 defect. Neurology
2004;63:727-9.
25. Anheim M, Monga B, Fleury M, et al.
Ataxia with oculomotor apraxia type 2:
clinical, biological and genotype/pheno-
type correlation study of a cohort of 90
patients. Brain 2009;132:2688-98.
26. Stray-Pedersen A, Borresen-Dale AL,
Paus E, Lindman CR, Burgers T, Abraha-
msen TG. Alpha fetoprotein is increasing
with age in ataxia-telangiectasia. Eur J
Paediatr Neurol 2007;11:375-80.
27. Anheim M, Fleury MC, Franques J,
et al. Clinical and molecular findings of

n engl j med 366;7  nejm.org  february 16, 2012 645

The New England Journal of Medicine
Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.
 Current Concepts

ataxia with oculomotor apraxia type 2
in 4 families. Arch Neurol 2008;65:958-
62.
28. Moreira MC, Barbot C, Tachi N, et al.
The gene mutated in ataxia-ocular aprax-
ia 1 encodes the new HIT/Zn-finger pro-
tein aprataxin. Nat Genet 2001;29:189-93.
29. Le Ber I, Moreira MC, Rivaud-Péchoux
S, et al. Cerebellar ataxia with oculomotor
apraxia type 1: clinical and genetic stud-
ies. Brain 2003;126:2761-72.
30. Tranchant C, Fleury M, Moreira MC,
Koenig M, Warter JM. Phenotypic vari-
ability of aprataxin gene mutations. Neu-
rology 2003;60:868-70.
31. Takashima H, Boerkoel CF, John J, et
al. Mutation of TDP1, encoding a topo­
isomerase I-dependent DNA damage re-
pair enzyme, in spinocerebellar ataxia
with axonal neuropathy. Nat Genet
2002;32:267-72.
32. Tzoulis C, Engelsen BA, Telstad W, et
al. The spectrum of clinical disease
caused by the A467T and W748S POLG
mutations: a study of 26 cases. Brain
2006;129:1685-92.
33. Lagier-Tourenne C, Tazir M, López
LC, et al. ADCK3, an ancestral kinase, is
mutated in a form of recessive ataxia as-
sociated with coenzyme Q10 deficiency.
Am J Hum Genet 2008;82:661-72.
34. Schulz JB, Boesch S, Bürk K, et al. Di-
agnosis and treatment of Friedreich atax-
ia: a European perspective. Nat Rev Neu-
rol 2009;5:222-34.
35. Mascalchi M, Salvi F, Piacentini S,
Bartolozzi C. Friedreich’s ataxia: MR
findings involving the cervical portion of
the spinal cord. AJR Am J Roentgenol
1994;163:187-91.
36. Mollet J, Delahodde A, Serre V, et al.
CABC1 gene mutations cause ubiquinone
deficiency with cerebellar ataxia and sei-
zures. Am J Hum Genet 2008;82:623-30.
37. Cossée M, Schmitt M, Campuzano V,
et al. Evolution of the Friedreich’s ataxia
trinucleotide repeat expansion: founder
effect and premutations. Proc Natl Acad
Sci U S A 1997;94:7452-7.
38. Anheim M, Chaigne D, Fleury M, et al.
Autosomal recessive spastic ataxia of
Charlevoix-Saguenay: study of a family
and review of the literature. Rev Neurol
(Paris) 2008;164:363-8. (In French.)
39. Vermeer S, Meijer RP, Pijl BJ, et al.
ARSACS in the Dutch population: a fre-
quent cause of early-onset cerebellar ataxia.
Neurogenetics 2008;9:207-14. [Erratum,
Neurogenetics 2009;10:87.]
40. Engert JC, Bérubé P, Mercier J, et al.
ARSACS, a spastic ataxia common in
northeastern Québec, is caused by muta-
tions in a new gene encoding an 11.5-kb
ORF. Nat Genet 2000;24:120-5.
41. Tazir M, Ali-Pacha L, M’Zahem A, et
al. Ataxia with oculomotor apraxia type 2:
a clinical and genetic study of 19 patients.
J Neurol Sci 2009;278:77-81.
42. Stewart GS, Maser RS, Stankovic T, et
al. The DNA double-strand break repair
gene hMRE11 is mutated in individuals
with an ataxia-telangiectasia-like disor-
der. Cell 1999;99:577-87.
43. Gros-Louis F, Dupré N, Dion P, et al.
Mutations in SYNE1 lead to a newly dis-
covered form of autosomal recessive cer-
ebellar ataxia. Nat Genet 2007;39:80-5.
44. Dupré N, Gros-Louis F, Chrestian N,
et al. Clinical and genetic study of autoso-
mal recessive cerebellar ataxia type 1.
Ann Neurol 2007;62:93-8.
45. Assoum M, Salih MA, Drouot N, et al.
Rundataxin, a novel protein with RUN
and diacylglycerol binding domains, is
mutant in a new recessive ataxia. Brain
2010;133:2439-47.
46. Fiskerstrand T, H’Mida-Ben Brahim
D, Johansson S, et al. Mutations in
ABHD12 cause the neurodegenerative dis-
ease PHARC: an inborn error of endocan-
nabinoid metabolism. Am J Hum Genet
2010;87:410-7.
47. Vermeer S, Hoischen A, Meijer RP,
et al. Targeted next-generation sequencing
of a 12.5 Mb homozygous region reveals
ANO10 mutations in patients with auto-
somal-recessive cerebellar ataxia. Am J
Hum Genet 2010;87:813-9.
48. Harding AE. Classification of the he-
reditary ataxias and paraplegias. Lancet
1983;1:1151-5.
49. Seznec H, Simon D, Bouton C, et al.
Friedreich ataxia: the oxidative stress
paradox. Hum Mol Genet 2005;14:463-74.
50. Schmucker S, Martelli A, Colin F, et
al. Mammalian frataxin: an essential
function for cellular viability through an
interaction with a preformed ISCU/NFS1/
ISD11 iron-sulfur assembly complex.
PLoS ONE 2011;6(1):e16199.
51. Rustin P, von Kleist-Retzow JC,
Chantrel-Groussard K, Sidi D, Munnich
A, Rötig A. Effect of idebenone on cardio-
myopathy in Friedreich’s ataxia: a pre-
liminary study. Lancet 1999;354:477-9.
52. Di Prospero NA, Baker A, Jeffries N,
Fischbeck KH. Neurological effects of
high-dose idebenone in patients with
Friedreich’s ataxia: a randomised, place-
bo-controlled trial. Lancet Neurol 2007;
6:878-86.
53. Mariotti C, Solari A, Torta D, Marano
L, Fiorentini C, Di Donato S. Idebenone
treatment in Friedreich patients: one-
year-long randomized placebo-controlled
trial. Neurology 2003;60:1676-9.
54. Lagedrost SJ, Sutton MS, Cohen MS,
et al. Idebenone in Friedreich ataxia car-
diomyopathy-results from a 6-month
phase III study (IONIA). Am Heart J;
161(3):639.e1-645.e1.
55. Lynch DR, Perlman SL, Meier T.
A phase 3, double-blind, placebo-con-
trolled trial of idebenone in Friedreich
ataxia. Arch Neurol 2010;67:941-7.
56. Kearney M, Orrell RW, Fahey M,
Pandolfo M. Antioxidants and other phar-
macological treatments for Friedreich
ataxia. Cochrane Database Syst Rev 2009;
(4):CD007791.
Copyright © 2012 Massachusetts Medical Society.

journal archive at nejm.org

Every article published by the Journal is now available at NEJM.org, beginning
with the first article published in January 1812. The entire archive is fully searchable,
and browsing of titles and tables of contents is easy and available to all.
Individual subscribers are entitled to free 24-hour access to 50 archive articles per year.
Access to content in the archive is available on a per-article basis and is also
being provided through many institutional subscriptions.

646 n engl j med 366;7  nejm.org  february 16, 2012

The New England Journal of Medicine

Downloaded from nejm.org by DAYA KRISHNA JHA on December 3, 2013. For personal use only. No other uses without permission.
Copyright © 2012 Massachusetts Medical Society. All rights reserved.