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he Wobbly Child: An Approach to Inherited Ataxiasenevieve Bernard, MD, MSc, FRCPC,* and Michael Shevell, MD, CM, FRCPC†

Genetic causes of ataxia are numerous. These disorders often present in the pediatricpopulation, and finding a precise diagnosis can be quite challenging. Recent advances inmolecular diagnosis make it difficult for the clinician to determine what investigations toundertake and in which order. This article presents 3 cases of pediatric onset ataxia with agenetic basis that will help to formulate and show a practical approach to this importantclinical problem.Semin Pediatr Neurol 15:194–208 © 2008 Elsevier Inc. All rights reserved.

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e present 3 cases of ataxia that are recognized to pre-sumably be of genetic origin. After this, we discuss

nd elaborate a clinical stepwise approach to pediatric ataxiaseing diagnosed at a molecular level (ie., specific gene de-ect).

atient 1he first patient is a boy who presented to the neurologyutpatient clinic at the age of 21 months with motor difficul-ies. The family history was negative for neurologic diseases.he patient was an only child. The mother had two previousiscarriages. Both parents were otherwise healthy. Theyere both of Italian heritage but not consanguineous. Thereas a strong family history of neoplasms; the patient’s pater-al grandfather and paternal great uncle both died of pancre-tic cancer, the paternal great grandmother died of stomachancer, a maternal great uncle died of bladder cancer, and theaternal great grandfather died of lung cancer.His perinatal history revealed an uneventful pregnancy.

he mother was 28 years old and healthy at the time of theregnancy and birth. The patient was born at 39 weeks byesarean section because of a breech presentation. He did notequire resuscitation. His birth weight was 7 pounds, and hispgar scores were 8 and 10 at 1 and 5 minutes, respectively.is neonatal period was unremarkable, except for mild jaun-ice treated with phototherapy.When he was first seen, the parents reported a normal

rom the Departments of *Neurology/Neurosurgery, McGill University;Montreal Children’s Hospital, McGill University Health Center, Mon-treal, Quebec, Canada.

Pediatrics, McGill University; Montreal Children’s Hospital, McGill Uni-versity Health Center, Montreal, Quebec, Canada.

ddress reprint requests to Michael Shevell, MD, CM, FRPC, Room A-514,Montreal Children’s Hospital, 2300 Tupper, Montreal, Quebec, Canada

aH3H 1P3. E-mail: michael.shevell@muhc.mcgill.ca

94 1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved.doi:10.1016/j.spen.2008.10.011

evelopment without any apparent loss of milestones. Theatient’s past medical history was unremarkable, except for 2pisodes of otitis media.

On history, the parents were reporting an unsteady gait.hey were first concerned when he started to walk indepen-ently around the age of 14 or 15 months. They thought,owever, that his balance was improving steadily over time.The examination at the age of 21 months was limited be-

ause the patient was reluctant and irritable. Despite this, theatient was noticed to have a tendency to walk on his toes,ith instability while walking. His gait was narrow based,

nd he did not have any evident dysmetria of the extremitiesn reaching. The rest of the examination was unremarkable.Initially, several investigations were performed and were

ormal, including complete blood count, electrolytes, bloodrea nitrogen, creatinine, liver function tests, creatine kinaseCK), capillary blood gas, lactate, ammonia, serum aminocids, urine organic acids, very long chain fatty acids, andaryotype. Electromyogram and nerve-conduction studiesere normal. A computed tomography scan of the head andagnetic resonance imaging of the head and spine were alsoormal. Sensory-evoked potentials (4 limbs) were normal. Athe initial workup, an alpha-fetoprotein was requested be-ause of the strong family history of neoplasms and wasound to be elevated. Moreover, the immunoglobulin (Ig) Gnd IgA levels were found to be decreased, whereas the IgMevel was normal.

Based on these results, a diagnosis of ataxia telangiectasiaas suspected. Radiosensitivity testing of lymphoblastoid

ells (colony survival assay) was performed and revealed in-reased radiosensitivity. Chromosomal breakage study re-ealed an increased number of breaks and gaps. In the con-ext of these results, a Western blot for the ATM protein wasndertaken and confirmed the diagnosis of ataxia-telangiec-asia when no ATM protein was detected.

Over the following few years, the patient developed clear

taxia, dysmetria, dysdiadokokinesia, and dysarthria. He also

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Pediatric-inherited ataxias 195

eveloped characteristic signs of ataxia-telangiectasia on ex-mination, including oculomotor apraxia and conjunctivalnd skin telangiectasias.

At the age of 8 years, he is still able to walk for shortistances but needs an adapted stroller or wheelchair for

onger distances. He has pronounced dysarthria, ataxia, andysmetria. He has some drooling. Telangiectasias are presentilaterally on his conjunctiva and over his left cheek. Heeceives regular immunoglobulin injections and antibioticrophylaxis. He is carefully followed for the potential devel-pment of a neoplasm, especially leukemia or lymphoma,ith routine complete blood counts and systematic lymphodes examinations.

atient 2he second patient, also a boy, was first seen in the neurologylinic at the age of 8 years. He was referred for balance andoordination difficulties.

His family history was significant for the mother who re-orted slightly high arched feet. The maternal aunt and uncleere both healthy. The patient’s father was healthy. Thereas 1 paternal uncle who had been operated on at a young

ge for scoliosis. The patient’s 2 other paternal uncles wereealthy. A 6-year-old brother was neurodevelopmentallyormal. The parents were of Italian heritage and not consan-uineous.

The perinatal history was unremarkable. The pregnancyas uncomplicated as well as the labor, delivery, and neona-

al period. The patient reached all early motor and languageilestones appropriately. At the time of his first visit, he was

n the second grade and doing well at school. His past med-cal history was entirely unremarkable.

On history, balance difficulties and coordination problemsere reported since the age of about 5 years. Initially, thereas no report of any clear progression, and the parents

hought that their son’s difficulties had improved with phys-otherapy. His symptoms were worse when he was tired. Athe age of 8 years, he was unable to ride a bicycle. However,e never had any lost of functional motor skills.On his first visit, the neurologic examination was remark-

ble for some clumsiness in the rapid alternating movementsf both the upper and lower extremities and absent myotaticeflexes. The rest of his neurologic examination was essen-ially within normal limits. Of note, his extraocular move-ents were normal; there was no nystagmus, dysmetria, orpper motor neuron signs. His sensory examination was nor-al. Gait and tandem gait were normal both forward and

ackward. He could go up and down the stairs without hold-ng onto the handrail. He could run without difficulty.

At the end of this first visit, it was difficult to consider anypecific diagnosis and a decision to observe any possible evo-ution to better target future potential investigations was

ade.During the following 6 to 12 months, the child’s symptoms

rogressed slightly. The parents reported that his gait wasore unsteady. The neurologic examination showed only

ubtle changes with absent tendon stretch reflexes. Investi- F

ations were then performed, including creatine kinase, met-bolic workup, albumin, heavy metals (lead, mercury, andhallium), vitamin E level, lipid profile, and a computed to-ography scan of the head including posterior fossa cuts. All

f these investigations were negative. An electromyogramnd nerve-conduction studies were also performed and re-ealed an axonal polyneuropathy. Genetic testing for hered-tary sensory and motor neuropathies was sent and cameack negative. In the absence of any clear signs on examina-ion, except for the peripheral neuropathy, the decision wasade to perform a skin, nerve, and muscle biopsy. The mus-

le was normal. The nerve biopsy (left sural nerve) revealed ahronic advanced sensory neuropathy. The skin biopsy wasormal.Around the age of 9 years, it became clearer that the child

as developing progressive cerebellar dysfunction. More-ver, the patient developed a positive self-induced Rombergign; the patient described instability when closing his eyeshile shampooing hair in the shower. Genetic testing was

hen sent for possible Friedreich ataxia. A homozygous GAArinucleotide expansion of the FXN (FRDA or X25) gene onhromosome 9 (approximately 858 GAA triplets per allele)as found.At the latest follow-up, the patient was 10 years old. He

as in grade 5 and still doing well at school. The parentseported some slowly progressive gross (eg., some falls whenunning, difficulty going up and down the stairs) and fineeg., deterioration of hand writing) motor difficulties as well

igure 1 Suggested approach to pediatric inherited ataxias.

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196 G. Bernard and M. Shevell

s some dysarthria when tired. He was on a waiting list to beollowed in a rehabilitation center and was about to be startedn idebenone. His most recent neurologic examination re-ealed mild dysarthria, mild atrophy of intrinsic foot mus-les, bilateral high arched feet, and mild early hammering ofhe toes. Mild distal weakness (4 to 4�/5) involving bothpper and lower extremities was present as well as a de-reased sensation in a glove and socking distribution. Deependon reflexes were absent. There was no evidence of upperotor neuron involvement. He had clear gait ataxia with

ignificant difficulty on tandem gait and very mild truncaltaxia that worsened appreciably when asked to close hisyes. Bilateral dysdiadochokinesia in the upper and lowerxtremities was noticed to be present. Both finger to nose andeel to shin testing revealed significant dysmetria.

atient 3he third patient is a girl first seen at the age of 6 years. Sheas referred for ataxia. The family history was remarkable for

onsanguinity in that the parents are first cousins (theirothers were sisters). The family was from Turkey. Thereas no family history of neurologic diseases except for 1aternal cousin with epilepsy.The mother had had 6 prior miscarriages. However, her

regnancy, labor, and delivery with this child were entirelyneventful. The parents reported slow initial motor develop-ent. It was unfortunately difficult to obtain precise details

able 1 Genetic Causes of Progressive Ataxia According to T

Autosomal Dominant Autosomal Reces

AbetalipoproteinemAOA-1AOA-2ARCA-1ARSACSAtaxia-telangiectasiATLD

RPLA AVEDpisodic ataxias Caymanypobetalipoproteinemia CDGCA Coenzyme Q deficie

CTXFreidreich ataxiaIOSCALOTSMarinesco-SjögrenMIRASRefsumSCAN1

bbreviations: AOA-1, ataxia with oculomotor apraxia type 1; AOAcerebellar ataxia type 1; ARSACS, autosomal recessive ataxia oataxia with vitamin E deficiency; CDG, congenital disorders of glypallidoluysian atrophy; FXTAS, fragile X–associated tremor ataxiSayre syndrome; LOTS, late-onset Tay-Sachs disease; MERRF,drial encephalomyopathy, lactic acidosis, and strokelike episodmuscle weakness, ataxia, retinitis pigmentosa; SCA, spinocerebe

X-linked sideroblastic anemia and ataxia.

egarding the attainment of different milestones. The pastedical history was negative.The parents reported some difficulty walking with balance

roblems since the child started to walk around the age of 3nd a half years. They did not have any other concerns.

The neurologic examination revealed an alert and cooper-tive girl. Her head circumference was at the 50th percentile.er language and comprehension were difficult to assess ac-

urately because she spoke only Turkish. The examination ofhe eyes did not reveal any conjunctival telangiectasias. Theranial nerve examination was remarkable for oculomotorpraxia, saccadic pursuits, hypometric saccades, and gaze-voked nystagmus. The motor examination revealed slightlyecreased tone, both truncal and appendicular, but was oth-rwise normal. Mild chorea and a fine tremor of the upperxtremities were noticed when the patient’s arms were ex-ended in front of her. There was bilateral dysmetria andysdiadochokinesia. The sensory examination revealed nor-al light touch but apparent decreased proprioception. Her

ait was ataxic. Her reflexes were noticed to be pendular butymmetrical. The Gower maneuver was negative. Extensorlantar responses were present bilaterally.This patient underwent numerous investigations. The fol-

owing investigations were performed and were negative: vi-amin A and E levels, vitamin B12 and folate, lipid profile,lpha-fetoprotein, immunoglobulins, carcinoembryonic an-igen (CEA), liver function tests, CK, metabolic work up,orphyrins, and karyotype. Analysis of serum transferrin iso-

heritance

X-linked Maternal

KSSFXTAS (adult onset) MERRFXLSA/A MELAS

NARP

xia with oculomotor apraxia type 2; ARCA-1, autosomal recessivelevoix-Saguenay; ATLD, ataxia-telangiectasia–like disorder; AVED,tion; CTX, cerebrotendinous xanthomatosis; DRPLA, dentatorubral-rome; IOSCA, infantile-onset spinocerebellar ataxia; KSS, Kearns-nic epilepsy associated with ragged-red fibers; MELAS, mitochon-RAS, mitochondrial recessive ataxia syndrome; NARP, neurogenicxia; SCAN1, spinocerebellar ataxia with axonal neuropathy; XLSA/A,

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Pediatric-inherited ataxias 197

orms by isoelectric focusing for a congenital disorder of gly-osylation (CDG) was performed and was negative. An oph-halmology consultation did not reveal any retinalbnormality. Sensory-evoked responses revealed abnormalentral conduction, but auditory-evoked responses wereormal. An electromyogram and nerve-conduction studiesere performed and revealed a mild axonal sensory polyneu-

opathy. A computed tomography scan and magnetic reso-ance imaging of the brain showed volume loss of the cere-ellar vermis. Magnetic resonance imaging of the spine wasormal. Genetic testing was performed and found to be neg-

able 3 Intermittent Ataxias: Episodic Ataxias

GeneticDistinctive Clinical

Features

ype 1 OMIM 160120 Onset: late childhood toearly adolescence

KCNA1 gene Brief attacks (secondsto minutes)

Chromosome 12 Interictal myokymiaResponse to

Acetazolamide,phenytoin

ype 2 OMIM 108500 Onset: childhood orearly adolescence

CACNA1A gene Long attacks (hours todays)

Chromosome 19 Interictal nystagmusSlowly progressive

cerebellar dysfunctionand atrophy

Approximately 50%have migraines

Response toAcetazolamide

ype 3 OMIM 606554 Onset: variableUnknown gene brief attacks of

vestibular ataxia,vertigo, tinnitus

Chromosome 1 Interictal myokymiaResponse to

acetazolamideype 4 OMIM 606552 Onset: early adulthood

Unknown gene Attacks of vertigo,diplopia, tinnitus,ataxia

Unknown chromosome No response toacetazolamide

ype 5 OMIM 601949 May have associatedepilepsyCACNB4 gene

Chromosome 2ype 6 OMIM 600111 1 case

SLC1A3 geneChromosome 5

ype 7 OMIM 611907 1 familyUnknown geneChromosome 19

OTE. Episodic ataxias are autosomal dominant diseases charac-terized by intermittent episodes of cerebellar dysfunction with or

able 2 Inherited Ataxias More Common in Patients Withertain Ethnic Backgrounds

Continent/Country

Ataxia

AutosomalDominant

AutosomalRecessive

North Americaanada EA-4 (Mennonite) AOA-2 (province

of Quebec)ARCA-1

(province ofQuebec)

ARSACS(province ofQuebec)

Friedreich ataxiaexique SCA10nited States ofAmerica

EA-3SCA2SCA3SCA6

South Americarazil SCA3rand Cayman Island Cayman

Europeinland SCA8 IOSCArance SCA25 AOA-1taly SCA1 Friedreich ataxia

SCA2SCA28

etherlands SCA3SCA6SCA19SCA23SCA27

oland, CzechRepublic, Ukraine

ATLD

ortugal SCA3erbia SCA1

Africaorth Africa Friedreich ataxiaouth Africa SCA1

SCA7

Asiahina SCA3

ndia SCA1 Friedreich ataxiaSCA2SCA3SCA12

apan SCA3 AOA-1SCA6SCA16

iddle East Friedreich ataxiaaudi Arabia SCAN1ingapore SCA2

SCA3aiwan SCA22

bbreviations: AOA-1, ataxia with oculomotor apraxia type 1; ARCA-1,autosomal recessive cerebellar ataxia type 1; ARSACS, autosomalrecessive spastic ataxia of Charlevoix-Saguenay; ATLD, ataxia-tel-angiectasia–like disorder; EA, episodic ataxia; IOSCA, infantile-on-set spinocerebellar ataxia; SCA, spinocerebellar ataxia; SCAN1,

without interictal neurologic dysfunction.

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198 G. Bernard and M. Shevell

tive for Friedreich ataxia, fragile X, and ataxia with oculo-otor apraxia type 1. Chromosome breakage analysis (spon-

aneous and to ionizing radiation exposure) was performed,nd the results were inconsistent with ataxia-telangiectasia.o definite diagnosis has yet been determined in this patientespite a strong suspicion of a genetic etiology and detailed

nvestigations.

able 4 Intermittent Ataxias: Metabolic Diseases

Enzymatic Defect G

itochondrial PC deficiencyOMIM 266150Chromosome 11PDH deficiencyOMIM 312170X-linked

rea cycle defects(partial enzymaticdefects)

OTC deficiencyOMIM 311250X-linkedCPS deficiencyOMIM 237300Autosomal recessiveChromosome 2ASS deficiency or CitruOMIM 215700Autosomal recessiveChromosome 9AS deficiencyOMIM 207900Autosomal recessiveChromosome 7Arginase deficiencyOMIM 207800Autosomal recessiveChromosome 6

minoacidurias andOrganic acidurias

HartnupDefect in intestinal and ren

neutral amino acids

OMIM 234500Autosomal recessiveChromosome 5Intermittent MSUDBCKD component deficiencOMIM 248600Autosomal recessiveChromosomes 19, 7, 1Isovaleric academiaIVD deficiencyOMIM 243500Autosomal recessiveChromosome 15Biotinidase deficiencyOMIM 253260Autosomal recessiveChromosome 3

bbreviations: AS, argininosuccinase; ASS, arginosuccinate synthebamoylphosphate synthetase; IVD, isovaleryl CoA dehydrogena

PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase.

linical Approach

taxia is defined as imbalance and incoordination.1,2 Theerm is typically used to describe gait (gait ataxia) but maylso describe an unstable patient in the sitting position (trun-al ataxia) or dysmetria or incoordination of a limb whileerforming a task (limb ataxia). Gait ataxia is usually second-

tic Distinctive Clinical Features

Lactic acidosis

Lactic acidosis

Typically affecting femalesIntermittent encephalopathy, ataxia,

hyperammonemiaIntermittent encephalopathy, vomiting,

ataxia, hyperammonemia

ia

sport ofIntermittent ataxia, psychiatric disturbances;

pellagra-like rash

Treatment: Nicotinamide

Increased serum branched-chain aminoacids (leucine, valine, isoleucine) andalloisoleucine

Intermittent attacks of ataxia,encephalopathy and ketoacidosis

Intermittent episodes of metabolicdecompensation

CKD, branched-chain alpha-keto acid dehydrogenase; CPS, car-UD, maple syrup urine disease; OTC, ornithine transcarbamylase;

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Pediatric-inherited ataxias 199

ry to a dysfunction or lesion of the cerebellum and/or itsonnections. However, it is well recognized that patients canlso have gait ataxia from peripheral sensory impairment (ie.,ensory ataxia secondary to a peripheral neuropathy). Whenhe ataxia is of cerebellar origin, it is typically accompaniedy other signs and symptoms including abnormal eye move-ents (hypometric or hypermetric saccades, saccadic pur-

uits), nystagmus of varying types, dysarthria, dysmetria, andysdiadochokinesis. On the other hand, when the ataxia isaused by a sensory deficit, there is typically no associatedeature of cerebellar dysfunction. However, in that case, sen-ory symptoms (paresthesias and numbness) and signs areoted, including impaired vibration and position senses, re-uced or absent deep tendon reflexes, and a positive Rom-erg sign (ie., the standing position is rendered unstablehen the eyes are closed).Ataxias can be divided according to their mode of presen-

ation into acute, episodic, chronic, and progressive variants.his classification is very useful to the clinician because itestrains the number of possible etiologies to be consideredn the diagnostic workup. In this review, we do not discusshe acute causes of ataxia and concentrate on the episodic andhronic forms, with a special focus on inherited causes. Thisroup of disorders can be very challenging to the clinicianecause there are a plethora of rare genetic entities now iden-ified. These entities with a genetic basis are increasinglymportant to recognize and diagnose because some are treat-ble and all pose a risk of possible familial recurrence.

Childhood ataxia is often a difficult problem to evaluate,specially when the etiology is genetic. The main reason ishat this evaluation takes place at the beginning of what wille a progressive condition, at a time when not all clinicallues for a proper and definite diagnosis are present. The eraf molecular medicine has led to a plethora of diagnosticesting options for clinicians. We do not review all causes oftaxia because this has been very well covered in recent re-iews.3,4 We do suggest an approach by discussing the clueshat can be found from the clinical history and examination.igure 1 summarizes our suggested approach. We will thenuggest a stepwise workup according to this clinical informationhat should result in a direct and targeted approach that willopefully expeditiously yield an accurate and correct diagnosis.

ge of Onsetirst of all, the age of the patient at the onset of symptoms canometimes be helpful in restraining the number of possibleiagnoses. Only a few causes of inherited ataxia typicallyresent before the age of 3 years. These include ataxia-telan-iectasia,5 infantile-onset spinocerebellar ataxia,6,7 X-linkedideroblastic anemia with ataxia,8 congenital disorders of gly-osylation,9 and cerebellar malformations (eg., Dandy-alker malformation). Moreover, the principal causes of late

nset ataxia (ie., after the age of 25 years) are the autosomalominant spinocerebellar ataxias (SCAs). Between these 2xtremes, the age of the patient is unfortunately not very

seful to target one diagnosis or another.

amily Historyhe family history is sometimes very useful in the determi-ation of a diagnostic hypothesis. First, we are interested inny neurologic diseases that may have affected family mem-ers. But more so, we are interested in determining if someamily members have similar symptoms. When the familyistory is positive, pedigree analysis will help determine theode of inheritance (autosomal dominant, autosomal reces-

ive, X-linked, or maternal). Table 1 summarizes the mainenetic causes of ataxia according to their specific inheritanceattern (Mendelian or maternal).SCA is rare; however, a family pedigree featuring autoso-al dominant transmission should suggest this diagnosis,

ven if the patient presents at a young age. Moreover, thisiagnosis should be kept in mind in cases of nondiagnosedtaxias without a clear family history because these diseasesan present at a young age, before the affected parent be-omes symptomatic, particularly if there is a large intergen-rational amplification of a trinucleotide repeat sequence (ie.,nticipation).

Most pediatric cases of ataxia are caused by autosomalecessive diseases (eg., Friedreich ataxia and ataxia-telangiec-asia), making it particularly important to inquire about theossibility of parental consanguinity. Consanguinity is wellnown to increase the likelihood of autosomal recessive dis-ases in offspring. In fact, if the parents are first cousins, theisk of having a child with an autosomal recessive condition ispproximately 5%, a figure that is much higher than fornrelated parents. In the context of a young child with pro-ressive ataxia, one should enquire about a family history ofeoplasia. A strong family history of neoplasia should suggestpossible diagnosis of ataxia-telangiectasia. In fact, individ-als heterozygous for the ATM mutation have approximately

able 5 Treatable Inherited Causes of Ataxia

Disease Treatment

betalipoproteinemia Vitamin EVED Vitamin Eiotinidase deficiency Biotinerebrotendinousxanthomatosis

Chenodeoxycholic acid

oenzyme Q deficiency Coenzyme Qpisodic ataxia types 1and 2

Acetazolamide

riedreich: ataxia Possibly effective forcardiomyopathy

Coenzyme Q, vitamin EIdebenone

artnup Nicotinamideypobetalipoproteinemia Vitamin ESUD Diet, thiamineyruvate dehydrogenasedeficiency

Ketogenic diet

efsum Diet (restriction in phytanic acid)rea cycle defects Diet, sodium benzoate

bbreviations: AVED, ataxia with vitamin E deficiency; MSUD, ma-

ple syrup urine disease.

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200 G. Bernard and M. Shevell

able 6 Central Nervous System and Peripheral Nervous System Involvement Other Than Cerebellar Dysfunction

Specific Sign or Symptom Associated Diseases

Central nervous system involvementxtensor plantar responses (Babinski signs) AOA-2 Friedreich ataxia

AVED MIRASARSACS SCA 1,3,4,7,8,11,12,23,28Ataxia telangiectasia

risk deep tendon reflexes ARSACS SCA 1,3,4,7,8,11,12,23,28

horea AOA-1 and AOA-2 LOTSAtaxia Telangiectasia MIRASATLD SCA 17DRPLA

ognitive impairment AOA-1, AOA-2 KSSARSACS LOTSCDG MELASCTX MERRFDRPLA MIRASFXTAS MSSIOSCA SCA 2,7,13,17,19,21,27

ystonia AOA-1 and AOA-2 CTXAtaxia Telangiectasia LOTSATLD SCA 3,17

pilepsy/seizures Biotinidase deficiency MELASCDG MERRFCTX MIRASDRPLA NARPLOTS SCA10

yoclonus AOA-2 LOTSAtaxia Telangiectasia MERRFCTX MIRASDRPLA

ystagmus Abetalipoproteinemia EA 2AOA-1 and AOA-2 Friedreich ataxiaARSACS LOTSAtaxia Telangiectasia MIRASATLD MSSCayman SCA 6,28

culomotor apraxia AOA-1 Ataxia TelangiectasiaAOA-2 ATLD

phthalmoplegia AOA-1 NARP

low saccades IOSCA SCA 1,2*,3,7,17,23,28KSS *Early slow saccadesMIRAS

arkinsonism CTX SCA 3,17FXTAS

sychiatric problems CTX MERRFDRPLA MIRASLOTS SCA 3,17,27

remor AOA-1 and 2 MIRASAVED MSSAtaxia Telangiectasia SCA 12Cayman SCA 20 (palatal tremor)LOTS

pasticity ARSACS LOTS

CTX SCA 1,3,4,7,8,11,12,23,28

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Pediatric-inherited ataxias 201

times the risk of neoplasm, primarily of breast cancer, whenompared with the general population.10,11

X-linked forms of ataxia are rare. Fragile X–associatedremor ataxia syndrome (FXTAS) is an interesting cause oftaxia in the adult population.12,13 It typically affects adultale carriers and less commonly female carriers of a premu-

ation for the FMR-1 gene (50-200 CGG repeats). There maye a positive family history of mental retardation in males.he onset of this syndrome is typically after the age of 50ears, well beyond the pediatric age group. Several possiblelinical features can be present, including tremor, ataxia, par-insonism (ie., tremor, rigidity, bradykinesia, postural insta-ility), cognitive decline, and autonomic dysfunction. Theharacteristic abnormality on magnetic resonance imaging ishat of hyperintense signal in the middle cerebellar pedunclesn T2-weighted images.Another form of ataxia that is transmitted in an X-linked

orm is X-linked sideroblastic anemia and ataxia. This form oftaxia affects males and is characterized by moderate anemiand an early childhood slowly progressive14 or static15 spino-erebellar ataxia syndrome.

Several maternally transmitted mitochondrial diseases canresent with ataxia,16 among other symptoms. These includeearns-Sayre syndrome, mitochondrial encephalomyopathy

actic acidosis and stroke-like episodes (MELAS), myoclonicpilepsy with ragged-red fibers (MERRF) and neurogenic

able 6 Continued

Specific Sign or Symptom

Peripheral nervouuscle weakness/amyotrophy

eripheral neuropathy

bbreviations: AOA-1, ataxia with oculomotor apraxia type 1; AOAataxia of Charlevoix-Saguenay; ATLD, ataxia-telangiectasia–like dof glycosylation; CTX, cerebrotendinous xanthomatosis; DRPLAX–associated tremor ataxia syndrome; IOSCA, infantile-onsetTay-Sachs disease; MERRF, myoclonic epilepsy associated wacidosis, and strokelike episodes; MIRAS, mitochondrial recessivmuscle weakness, ataxia, retinitis pigmentosa; SCA, spinocerebeX-linked sideroblastic anemia and ataxia.

uscle weakness, ataxia, and retinitis pigmentosa (NARP). s

he cerebellar symptoms and signs are typically associatedith other typical clinical features suggestive of mitochon-rial diseases including short stature, cardiac involvement,europathy, myopathy, epilepsy, and so on.

thnic Backgroundometimes, the patient’s ethnic origin may help the cliniciann diagnosing the ataxic patient. The diseases associated moreommonly with specific geographic areas are summarized inable 2.

linical Presentationn history, several elements can be very useful in the diag-ostic process, particularly the temporal pattern (acute, sub-cute, chronic, and episodic) and any associated conditionsoted.The pattern of symptom onset and evolution is critical in

he diagnostic process. An acute onset of cerebellar dysfunc-ion in the pediatric patient should suggest an acquired causeespecially intoxications, postvaricella or postviral cerebelli-is, the Miller-Fisher variant of Guillain-Barré syndrome, pos-erior fossa tumors, cerebellar hemorrhage or ischemicvents, and so on). These acquired causes will not be furtheriscussed here. However, once these causes are ruled out and

f another acute episode of cerebellar ataxia occurs, one

Associated Diseases

tem involvementlipoproteinemia MELAS1 and AOA-2 MERRFCS MIRAStelangiectasia MSS

NARPeich ataxia RefsumA SACN1

SCA 3lipoproteinemia1 and AOA-2CS MELAS

MIRAStelangiectasia MSS

NARPRefsum

eich ataxia SCA 1,2,3,4,8,12,18,19,21,22,25,27

SCAN1A

ia with oculomotor apraxia type 2; ARSACS, autosomal recessive; AVED, ataxia with vitamin E deficiency; CDG, congenital disorderstorubral-pallidoluysian atrophy; EA: episodic ataxia; FXTAS, fragileerebellar ataxia; KSS, Kearns-Sayre syndrome; LOTS, late-onsetged-red fibers; MELAS, mitochondrial encephalomyopathy, lactic

syndrome; MSS, Marinesco-Sjögren syndrome; NARP, neurogenicxia; SCAN1, spinocerebellar ataxia with axonal neuropathy; XLSA/A,

s sysAbetaAOA-ARSAAtaxiaCTXFriedrIOSCLOTSAbetaAOA-ARSAAVEDAtaxiaATLDCTXFriedr

FXTASIOSCLOTS

-2, ataxisorder, dentaspinocith rage ataxiallar ata

hould consider genetic causes of intermittent ataxia, includ-

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202 G. Bernard and M. Shevell

ng the episodic ataxias and some metabolic disorders (Tablesand 4). When the presentation is more insidious (ie., sub-

cute or chronic) and nongenetic causes have been ruled outeg., slowly growing posterior fossa tumor), an inheritedorm of ataxia should be considered. In this context, treatableauses should be vigorously searched for to begin any possi-le therapy expeditiously (Table 5).17,18

Inquiring about the patient’s past medical history and anyssociated organ involvement can help in determining theost probable diagnosis. For example, a skin rash is oftenresent in Refsum disease (ichthyosis), Hartnup diseasepellagra-like rash) or biotinidase deficiency. The associa-

able 7 Organ Involvement in Different Inherited Ataxias

Organ Involvement Specific Sign or Symptom

ars Sensorineural hearing loss

ndocrinologic Abnormal fat distributionDiabetes mellitusShort stature

yes CataractsConjonctival telangiectasiaHypermyelinated retinal fibersOptic atrophyFriedreich ataxiaRetinitis pigmentosa

astrointestinal MalabsorptionLiver diseaseOthers

eart Arrhythmia

Cardiomyopathy

mmune system Recurrent sinopulmonaryinfections

usculoskeletal Scoliosis

enal Renal failure

kin Rash

Tendon xanthomas

bbreviations: AOA-1, ataxia with oculomotor apraxia type 1; AOAataxia of Charlevoix-Saguenay; ATLD, ataxia-telangiectasia–like dof glycosylation; CTX, cerebrotendinous xanthomatosis; DRPLA,ataxia syndrome; IOSCA, infantile-onset spinocerebellar ataxia; Kmyoclonic epilepsy associated with ragged-red fibers; MELAS, mMIRAS, mitochondrial recessive ataxia syndrome; MSS, Marinescpigmentosa; SCA, spinocerebellar ataxia; SCAN1, spinocerebellaataxia.

ions between the different inherited ataxias and central t

nd peripheral nervous system involvement as well as withystemic involvement have been well described by otheruthors3,4,19,20 and are summarized in Tables 6 and 7 re-pectively.3-8,15,19-34

hysical Examinationeveral physical features can be used to restrain the numberf possible diagnoses and target molecular genetic testing.hese features are presented in Tables 6 and 7. For example,

he presence of ichthyosis on the skin examination is stronglyuggestive of Refsum disease. On the skin and eye examina-

Associated Diseases

Friedreich ataxia MIRASIOSCA NARPKSS RefsumMELAS SCA 4MERRF

CDGAtaxia telangiectasia Friedreich ataxiaKSS MELASMERRF NARP

CTX MSSAtaxia telangiectasiaARSACSAOA-1 IOSCAMERRFAbetalipoproteinemia MERRFAVED NARPHypobetalipoproteinemia RefsumKSS SCA7

Abetalipoproteinemia HypobetalipoproteinemiaCDG MIRASMELAS (anorexia, vomiting)

KSS NARPMERRF (WPW)Abetalipoproteinemia KSSAVED RefsumFriedreich ataxia

Ataxia Telangiectasia

AOA-1 and AOA-2 MSSFriedreich ataxia

Refsum

Biotinidase deficiency Refsum (ichthyosis)Hartnup (pellagra-like)CTX

ia with oculomotor apraxia type 2; ARSACS, autosomal recessive; AVED, ataxia with vitamin E deficiency; CDG, congenital disorderstorubral-pallidoluysian atrophy; FXTAS, fragile X–associated tremorarns-Sayre syndrome; LOTS, late-onset Tay-Sachs disease; MERRF,ndrial encephalomyopathy, lactic acidosis, and strokelike episodes;ren syndrome; NARP, neurogenic muscle weakness, ataxia, retinitiswith axonal neuropathy; XLSA/A, X-linked sideroblastic anemia and

-2, ataxisorderdenta

SS, Keitochoo-Sjögr ataxia

ion, telangiectasias can be present in cases of ataxia-telangi-

estaep

fimSts

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Aery lon

Pediatric-inherited ataxias 203

ctasia. However, it is important to note that the telangiecta-ias observed in this disorder are typically not present whenhe child first presents with ataxia and often only becomepparent later in the first decade of life. On the neurologicxamination, examination of the cranial nerves may reveal a

able 8 Diagnostic Investigations

Investigation Resul

Blood wCBC and smear Acanthocytes

Anemia (sideroblastic)Anemia (megaloblastic)

Biochemistry High glucose

Vitamin E Low

Lipid profile Low cholesterol

High cholesterol

High cholestanol and bile

Alpha-fetoprotein High

Immunoglobulins Low

Albumin Low

Metabolic

Lactate, pyruvate High

Ammonia High

Serum amino acids High leucine, valine, isoleu

Urine organic acids Abnormal profile

VLCFA,plasmologens andphytanic acid

Normal VLCFA

Normal plasmalogensIncreased phytanic acid

Other

ABR ABR: sensorineural hearin

Cardiac echo Cardiomyopathy

EKG Arrhythmia

EMG/NCS MyopathyNeuropathy

Imaging (ideally MRI) Cerebellar hypoplasiaCerebellar malformation

Ophthalmology Pigmentary retinopathy, exanomalies, etc.

bbreviations: AVED, ataxia with vitamin E deficiency; CBC, completenous xanthomatosis; MSUD, maple syrup urine disease; VLCFA, v

igmentary retinopathy, optic atrophy, or hypermyelinated e

bers, the later finding being very typical, if not pathogno-onic, of autosomal recessive spastic ataxia of Charlevoix-

aguenay. The extraocular movements may show oculomo-or apraxia, slow saccades, hypermetric, or hypometricaccades as well as abnormal saccadic pursuits. The motor

Associated Disease(s)

AbetalipoproteinemiaHypobetalipoproteinemiaXLSA/AVitamin B12 and folate deficiency

Ataxia TelangiectasiaFriedreich ataxia

AVEDAbetalipoproteinemiaHypobetalipoproteinemia

AbetalipoproteinemiaCTX (may also be normal)HypobetalipoproteinemiaAOA-1 and AOA-2SCAN1

ls CTX

AOA-2Ataxia Telangiectasia

Ataxia Telangiectasia(IgA, IgG2, IgG4, IgE)

AOA-1SCAN1

up

Mitochondrial diseases

Urea cycle defectsOrganic acidurias

alloisoleucine MSUD

Aminoacidemias, eg., MSUDOrganic aciduriasUrea cycle defectsRefsum

C.f. Table 7

C.f. Table 7

C.f. Table 7

C.f. Table 6C.f. Table 6

CDGChiari, Dandy-Walker, etc.

ular movement C.f. Table 6 and 7

ount; CDG, congenital disorders of glycosylation; CTX, cerebrotendi-g chain fatty acids; XLSA/A, X-linked sideroblastic anemia and ataxia.

t

ork

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work

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s

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tra-oc

blood c

xamination may reveal some spasticity with or without up-

T

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204 G. Bernard and M. Shevell

able 9 Genetic Defects and Testing of Hereditary Ataxias (see also table 4)

DiseaseOMIM

GeneComments Protein Chromosome Testing

Autosomal dominant conditions

CA1 ATXN1 Ataxin-1 6 ClinicalMIM 164400 CAG

CA2 ATXN2 Ataxin-2 12 ClinicalMIM 183090 CAG

CA3 ATXN3 Ataxin-3 14 ClinicalMIM 109150 CAG

CA4 — — 16 ResearchMIM 600223

CA5 SPTBN2 Puratrophin-1 11 ClinicalMIM 600224

CA6MIM 183086

CACNA1ACAG

Voltage-dependent P/Q-typecalcium channel alpha-1Asubunit

19 Clinical

CA7 ATXN7 Ataxin-7 3 ClinicalMIM 164500 CAG

CA8 ATXN8 andATXN80S

— 13 Clinical

MIM 608768 CTG

CA9

CA10 ATXN10 Ataxin-10 22 ClinicalMIM 603516

CA11 TTBK2 Tau-tubulin kinase 2 15 ResearchMIM 604432

CA12MIM 604326

PPP2R2B Serine/threonine proteinphosphatase 2A 55-kdregulatory subunit B betaisoform

5 Clinical

CA13MIM 605259

KCNC3 Voltage-gated potassiumsubfamily C member 3

19 Clinical

CA14MIM 605361

PRKCG Protein kinase C gammatype

19 Clinical

CA15MIM 606658

ITPR1 Inositol 1,4,5-triphosphatereceptor type 1

3 Research

CA16

CA17 TBP TATA-box binding protein 6 ClinicalMIM 607136 CAG

CA18 SCA18 — 7 —MIM 607458

CA19 SCA19 — 1 ResearchMIM 607346

CA20 SCA20 — 11 ClinicalMIM 608687

CA21 SCA21 — 7 ResearchMIM 607454

CA22 — — 1 —MIM 607346

CA23 — — 20 Research

MIM 610245

T

S

SO

SO

SO

SO

SO

DO

EO

EO

EO

EO

EO

EO

EO

AO

HO

AO

AO

AO

AO

AO

AO

Pediatric-inherited ataxias 205

able 9 Continued

DiseaseOMIM

GeneComments Protein Chromosome Testing

CA24

CA25 SCA25 — 2 —MIM 608703

CA26 — — 19 ResearchMIM 609306

CA27 FGF14 Fibroblast growth factor 14 13 ClinicalMIM 609307

CA28 — — 18 ResearchMIM 610246

CA29 — — 3 ResearchMIM 117360

RPLA ATN Atrophin-1 12 ClinicalMIM 125370 CAG

A1MIM 160120

KCNA1 Voltage-gated potassiumchannel subfamily Amember 1

12 Clinical

A2MIM 108500

CACNA1A Voltage-dependent P/Q-typecalcium channel alpha-1Asubunit

Non-repeat mutations

19 Clinical

A3 — — 1 ResearchMIM 606554

A4 — — — ResearchMIM 606552

A5 CACNB4 Voltage-dependent L-typecalcium beta-4 subunit

2 ResearchMIM 601949

A6 SLC1A3 5 ResearchMIM 600111

A7 — — 19 ResearchMIM 611907

DSA SAX1 — 12 ResearchMIM 108600

ypobetalipoproteinemia APOB Apolipoprotein B 2 ResearchMIM 107730

Autosomal recessive conditionsbetalipoproteinemiaMIM 200100

MTP Microsomal triglyceridetransfer protein

4 Research

RCA-1MIM 610743

SYNE1 Synaptic nuclear envelopeprotein 1 or Nesprin-1

6 Research

OA-1 APTX Aprataxin 9 ClinicalMIM 208920

OA-2 SETX Senataxin 9 ClinicalMIM 606002

RSACS SACS Sacsin 13 ClinicalMIM 270550

taxia Telangiectasia ATM Serin-protein kinase ATM 11 Clinical

MIM 208900

T

AO

AO

CO

C(

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O

IO

LO

MO

MO

R

O

SO

FO

XO

KO

MO

MO

NO

A

206 G. Bernard and M. Shevell

able 9 Continued

DiseaseOMIM

GeneComments Protein Chromosome Testing

TLD MRE11A Meiotic recombination 11 11 ResearchMIM 604391

VED TTPA Alpha-tocopherol transferprotein

8 ClinicalMIM 277460

ayman ATCAY Caytaxin 19 ResearchMIM 601238

DG13 types)

13 differentgenes

13 different enzymes(N-glycolysation)

Transferrin isoforms analysisby isoelectric focusing

Clinical for 9 types

TX CYP27A1 Sterol 27-hydroxylase 2 ClinicalMIM 213700riedreich ataxia FXN Frataxin 9 Clinical

MIM 229300 FRDAX25

OSCA PEO1 Twinkle protein 10 ClinicalMIM 271245

OTS HEXA �-Hexosaminidase A 15 ClinicalMIM 272800

arinesco-Sjögren SIL1 Nulceotide exchange factorSIL1

5 ResearchMIM 248800

IRAS POLG DNA polymerase gamma 15 ClinicalMIM 174763

efsum PAHX orPHYH

Phytanoyl-CoA hydroxylase 10 Clinical

MIM 266500PEX7 Peroxin-7 6

CAN1 TDP1 Tyrosyl-DNAphosphodiesterase 1

14 ResearchMIM 607250

X-Linked conditionsXTAS FMR1 Fragile X mental retardation

1X Clinical

MIM 300623

LSA/AMIM 301310

ABC7 ATP-binding cassettesubfamily B

member 7

X Clinical

Mitochondrial diseases (maternally inherited conditions)

SS Large mtDNA deletions ClinicalMIM 530000 (typically sporadic; when inherited, is transmitted maternally)

ERRF mtDNA gene MT-TK ClinicalMIM 545000 encoding for tRNALys

ELAS mtDNA mutations ClinicalMIM 540000 MT-TL1 gene

encoding for tRNA Leu(UUR)

ARP mtDNA gene MTATP6 ClinicalMIM 551500

bbreviations: ADSA, autosomal dominant spastic ataxia; AOA-1, ataxia with oculomotor apraxia type 1; AOA-2, ataxia with oculomotor apraxiatype 2; ARCA-1, autosomal recessive cerebellar ataxia type1; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; ATLD,ataxia-telangiectasia–like disorder; AVED, ataxia with vitamin E deficiency; CDG, congenital disorders of glycosylation; CTX, cerebroten-dinous xanthomatosis; DRPLA, dentatorubral-pallidoluysian atrophy; EA, episodic ataxia; FXTAS, fragile X–associated tremor ataxia syn-drome; IOSCA, infantile-onset spinocerebellar ataxia; KSS, Kearns-Sayre syndrome; LOTS, late-onset Tay-Sachs disease; MERRF, myo-clonic epilepsy associated with ragged-red fibers; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes;MIRAS, mitochondrial recessive ataxia syndrome; NARP, neurogenic muscle weakness, ataxia, retinitis pigmentosa; SCA, spinocerebellar

ataxia; SCAN1, spinocerebellar ataxia with axonal neuropathy; XLSA/A, X-linked sideroblastic anemia and ataxia.

pedbosap(aFtArfwspc

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Pediatric-inherited ataxias 207

er motor neuron signs, suggesting a spinocerebellar degen-ration (eg., Friedreich ataxia, SCA, ataxia with vitamin Eeficiency, and so on). On the other hand, amyotrophy maye present, as it is in the case of ARSACS or SCA3, amongther diseases. The sensory and/or motor examinations mayuggest a peripheral neuropathy, which may help in the di-gnostic process. Moreover, knowing that the patient has aeripheral neuropathy has an impact on clinical managementeg., use of plantar-foot orthoses for a foot drop). The rapidlternating movements typically show dysdiadochokinesia.inger-to-nose and heel-to-shin testing reveals limb dysme-ria. When the patient is sitting, truncal ataxia can be seen.taxia is seen on the tandem gait only in mild cases and onegular gait in more severe cases. When the Romberg is per-ormed, the patient is often noticed to be initially unstablehen standing with the eyes open. If there is a significant

ensory neuropathy or posterior column involvement, theatient will be significantly more unstable with the eyeslosed (positive Romberg).

nvestigationsultiple investigations are available to the clinician. We

uggest an initial and a more detailed subsequent workup.hese investigations can obviously be modified according

o the most probable diagnoses suggested by the clinicalareful assessment as described previously. Table 8 listshe initial and more detailed investigations, the possiblebnormalities that can be ascertained, and their associatedonditions.

The initial investigations should include blood work, im-ging, electrophysiology, and consultations to other relevantpecialists. Once acquired causes of ataxia have been ruledut (eg., malabsorption, celiac disease, vitamin B12 or folateeficiency, tabes dorsalis, and so on) and a genetic cause isonsidered, the initial blood workup should include the fol-owing: complete blood count with smear, biochemistryelectrolytes, blood urea nitrogen, creatinine, liver functionests, and glucose), thyroid function tests (hypothyroidisman rarely present with ataxia), vitamin E and lipid profile,lbumin, alpha-fetoprotein, immunoglobulins, and a meta-olic work up including a blood gas, lactate, pyruvate, am-onia, serum amino acids, urine organic acids, very long

hain fatty acids, total carnitine, and an acylcarnitine profile.ther metabolic investigations can be performed according

o the clinical context (eg., urine orotic acid if a urea cycleefect is suspected). Of note, when the ataxia seems to haven intermittent pattern, the metabolic workup should ideallye performed during an episode of decompensation because

t could well be completely normal between episodes. Mag-etic resonance imaging of the brain must be obtained in allatients. Abnormalities noted on the magnetic resonance im-ging can help tremendously in targeting further investiga-ions. One should not forget that diseases that have ataxia as

main sign or symptom are presented here, but multiplether diseases can have ataxia as one of their manifestations.or example, most patients with leukodystrophy have some

egree of ataxia. Moreover, malformations of the cerebellum

an be seen on magnetic resonance imaging with certain syn-romes (eg., Dandy-Walker, Joubert syndrome, and so on).hese diseases will not be discussed further here. To com-lete the initial investigations, an electromyogram and nerve-onduction studies should be performed to document theresence or absence of a neuropathy or myopathy. An elec-rocardiogram should also be performed because some dis-ases have associated potentially life-threatening arrhythmiasie., Kearns-Sayre). A consultation in ophthalmology (ideallyo a neuro-ophthalmologist) is also recommended becauseeveral abnormalities on the ophthalmological examinationan target specific diagnoses (eg., retinitis pigmentosa in abe-alipoproteinemia or hypermyelinated retinal fibers inRSACS). Consultations in occupational therapy, physio-

herapy, and possibly speech and language pathology may beeeded if the patient has significant fine-motor, gross-motor,nd speech difficulties (dysarthria), respectively.

For most patients, the clinical assessment and initial inves-igations help in formulating a diagnostic hypothesis. When apecific diagnosis is suspected, molecular genetic testinghould be performed if available. Table 9 summarizes theenetic information presently available for the different ataxicyndromes and relevant molecular testing. When the diagno-is is not as evident after the initial workup, a consultation toenetics or neurogenetics is suggested. If a significant neu-opathy is present on electromyography, a nerve biopsyould be performed. A muscle and skin biopsy is often per-ormed at the same time as the nerve biopsy. The muscle biopsyay show ragged-red fibers on Gomori-trichome staining in the

ase of a mitochondrial disease. Rarely, muscle weakness can beonfused with ataxia, especially in the young child. In theseases, a muscle biopsy may be useful as well. A skin biopsy cane useful to diagnose a few neurodegenerative diseases that canave ataxia among other neurological findings (eg., Lafora dis-ase and neuronal ceroid lipofuscinosis). If fibroblasts arerown from the skin biopsy, molecular genetic testing forifferent diseases can be performed as the disease evolvesnd results from different investigations become available.inally, one should not forget other classes of rare diseaseshat can present as slowly progressive ataxia such as vita-in B12 or folate deficiency (sensory ataxia), paraneoplas-

ic disorders (eg., opsoclonus myoclonus, often associatedith ataxia), celiac disease, and new variant Creutzfeldt

akob disease, among others.19

In conclusion, pediatric-onset hereditary ataxias can behallenging for the pediatric neurologist; there are a growingumber of diseases known, and the phenotypes are not al-ays typical or, more commonly, certain characteristics of aiven disease may not be present when the child is first seeny the clinician. Moreover, other neurologic diseases can beistaken for ataxia, especially in the young child. In this

eview, we have tried to provide an approach to this complexroblem and suggest a stepwise rational investigative ap-roach.

eferences1. Subramony SH: Ataxic disorders, in Bradley WG, Daroff RB, Fenichel

GM (eds): Neurology in Clinical Practice (ed 4). Philadelphia, PA,

Elsevier, 2004, pp 287-292

1

1

1

1

1

1

1

1

1

12

2

2

2

2

2

2

2

2

2

3

3

3

3

3

208 G. Bernard and M. Shevell

2. Timmann D, Diener HC: Coordination and ataxia, in Goetz: Textbookof Clinical Neurology (ed 2). Philadelphia, PA, Elsevier, 2003, pp 299-315

3. Fogel BL, Perlman S: Clinical features and molecular genetics of auto-somal recessive cerebellar ataxias. Lancet Neurol 6:245-257, 2007

4. Schöls L, Bauer P, Schmidt T, et al: Autosomal dominant cerebellarataxias: clinical features, genetics, and pathogenesis. Lancet 3:291-304,2004

5. Gatti RA: Ataxia-Telangiectasia, in GeneReviews at GeneTests: MedicalGenetics Information Resource (database online). Copyright, University ofWashington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�ataxia-telangiectas. AccessedJuly 27, 2008

6. Nikali K, Suomalainen A, Saharinen J, et al: Infantile onset spinocere-bellar ataxia is caused by recessive mutations in mitochondrial proteinstwinkle and twinky. Hum Mol Genet 14:2981-2990, 2005

7. Lonnqvist T, Paetau A, Nikali K, et al: Infantile onset spinocerebellarataxia with sensory neuropathy (IOSCA): Neuropathological features.J Neurol Sci 161:57-65, 1998

8. Pagon RA, Bird TD: X-linked sideroblastic anemia and ataxia (2008), inGeneReviews at GeneTests: Medical Genetics Information Resource(database online). Copyright, University of Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�sider-anemia. Accessed July 27, 2008

9. Freeze HH: Congenital disorders of glycosylation: CDG-I, CDG-II, andbeyond. Curr Mol Med 7:389-396, 2007

0. Easton DF: Cancer risks in A-T heterozygotes. Int J Radiat Biol 66:S177-S182, 1994 (suppl)

1. Geoffroy-Perez B, Janin N, Ossian K, et al: Cancer risk in heterozygotesfor ataxia-telangiectasia. Int J Cancer 93:288-293, 2001

2. Jacquemont S, Hagerman RJ, Leehey MA, et al: Penetrance of the fragileX-associated tremor/ataxia syndrome in a premutation carrier popula-tion. JAMA 291:460-469, 2004

3. Hagerman RJ, Leavitt BR, Farzin F, et al: Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am JHum Genet 74:1051-1056, 2004

4. Hellier KD, Hatchwell E, Duncombe AS, et al: X-linked sideroblasticanaemia with ataxia: Another mitochondrial disease? J Neurol Neuro-surg Psychiatry 70:65-69, 2001

5. Pagon RA, Bird TD, Detter JC, et al: Hereditary sideroblastic anaemiaand ataxia: an X linked recessive disorder. J Med Genet 22:267-273,1985

6. DiMauro S, Schon EA: Mitochondrial respiratory-chain diseases.N Engl J Med 348:2656-2668, 2003

7. Hart PE, Lodi R, Rajagopalan B, et al: Antioxidant treatment of patientswith Friedreich ataxia: Four-year follow-up. Arch Neurol 62:621-626,2005

8. Mariotti C, Solari A, Torta D, et al: Idebenone treatment in Friedreichpatients: One-year-long randomized placebo-controlled trial. Neurol-ogy 60:1676-1679, 2003

9. Perlman SL: Ataxias. Clin Geriatr Med 22:859-877, 20060. Bird TD: Hereditary ataxia overview, in GeneReviews at GeneTests:

Medical Genetics Information Resource (database online). Copyright,University of Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�ataxias. Ac-cessed July 27, 2008

1. Coutinho P, Barbot C, Moreira da Silva MC, et al: Ataxia with oculo-motor apraxia type 1, in GeneReviews at GeneTests: Medical GeneticsInformation Resource (database online). Copyright, University ofWashington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�aoa. AccessedJuly 27, 2008

2. Moreira MC, Koenig M: Ataxia with oculomotor apraxia type 2 (2007),

in GeneReviews at GeneTests: Medical Genetics Information Resource

(database online). Copyright, University of Washington, Seattle.1997-2008. Available from: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�aoa2. Accessed July 27, 2008

3. Schuelke M: Ataxia with vitamin E deficiency, in GeneReviews atGeneTests: Medical Genetics Information Resource (database online).Copyright, University of Washington, Seattle. 1997-2008. Available at:http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�aved.Accessed July 27, 2008

4. Concannon PJ, Gatti RA: Nijmegen breakage syndrome, in GeneR-eviews at GeneTests: Medical Genetics Information Resource (databaseonline). Copyright, University of Washington, Seattle. 1997-2008.Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�nijmegen. Accessed July 27, 2008

5. Robitaille Y, Richter A, Mathieu J, et al: ARSACS [autosomal recessivespastic ataxia of Charlevoix-Saguenay], in GeneReviews at GeneTests:Medical Genetics Information Resource (database online). Copyright,University of Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�arsacs. AccessedJuly 27, 2008

6. Spacey S: Episodic ataxia type 2, in GeneReviews at GeneTests: MedicalGenetics Information Resource (database online). Copyright, Univer-sity of Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�ea2. Ac-cessed July 27, 2008

7. Saul RA, Tarleton JC: FMR1-related disorders, in GeneReviews atGeneTests: Medical Genetics Information Resource (database online).Copyright, University of Washington, Seattle. 1997-2008. Available at:http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�fragilex. Accessed July 27, 2008

8. Bidichandani SI, Delatycki MB, Ashizawa T: Friedreich ataxia, in Ge-neReviews at GeneTests: Medical Genetics Information Resource (da-tabase online). Copyright, University of Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�friedreich. Accessed July 27, 2008

9. Lin X, Ashizawa T: Spinocerebellar ataxia type 1, in GeneReviews atGeneTests: Medical Genetics Information Resource (database online).Copyright, University of Washington, Seattle. 1997-2008. Available at:http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�sca1.Accessed July 27, 2008

0. Pulst SM: Spinocerebellar ataxia type 2, in GeneReviews at GeneTests:Medical Genetics Information Resource (database online). Copyright,University of Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�sca2. AccessedJuly 27, 2008

1. Paulson H: Spinocerebellar ataxia type 3 (2007), in GeneReviews atGeneTests: Medical Genetics Information Resource (database online).Copyright, University of Washington, Seattle. 1997-2008. Available at:http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�sca3.Accessed July 27, 2008

2. Gomez CM: Spinocerebellar ataxia type 6, in GeneReviews atGeneTests: Medical Genetics Information Resource (database online).Copyright, University of Washington, Seattle. 1997-2008. Available at:http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�sca6.Accessed July 27, 2008

3. Hirano R, Salih MAS, Takashima H, et al: Spinocerebellar ataxia withaxonal neuropathy, autosomal recessive, in GeneReviews at GeneTests:Medical Genetics Information Resource (database online). Copyright,University of Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book�gene&part�scan1. AccessedJuly 27, 2008

4. Dupré N, Gros-Louis F, Bouchard JP, et al: SYNE1-related autosomal re-cessive cerebellar ataxia, in GeneReviews at GeneTests: Medical GeneticsInformation Resource (database online). Copyright, University of Wash-ington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/

bookshelf/br.fcgi?book�gene&part�syne1ca-ar. Accessed July 27, 2008