An Approach to Inherited Ataxias Genevieve Bernard, MD, Msc, FRCPC,* and Michael Shevell, MD, CM, FRCPC†

Home , Sideroblastic anemia

The Wobbly Child: An Approach to Inherited Ataxias Genevieve Bernard, MD, MSc, FRCPC,* and Michael Shevell, MD, CM, FRCPC†

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

e present 3 cases of ataxia that are recognized to pre- development without any apparent loss of milestones. The Wsumably be of genetic origin. After this, we discuss patient’s past medical history was unremarkable, except for 2 and elaborate a clinical stepwise approach to pediatric ataxias episodes of otitis media. being diagnosed at a molecular level (ie., specific gene de- On history, the parents were reporting an unsteady gait. fect). They were first concerned when he started to walk indepen- dently around the age of 14 or 15 months. They thought, Patient 1 however, that his balance was improving steadily over time. The examination at the age of 21 months was limited be- The first patient is a boy who presented to the neurology cause the patient was reluctant and irritable. Despite this, the outpatient clinic at the age of 21 months with motor difficul- patient was noticed to have a tendency to walk on his toes, ties. The family history was negative for neurologic diseases. with instability while walking. His gait was narrow based, The patient was an only child. The mother had two previous and he did not have any evident dysmetria of the extremities miscarriages. Both parents were otherwise healthy. They on reaching. The rest of the examination was unremarkable. were both of Italian heritage but not consanguineous. There Initially, several investigations were performed and were was a strong family history of neoplasms; the patient’s pater- normal, including complete blood count, electrolytes, blood nal grandfather and paternal great uncle both died of pancre- urea nitrogen, creatinine, liver function tests, creatine kinase atic cancer, the paternal great grandmother died of stomach (CK), capillary blood gas, lactate, ammonia, serum amino cancer, a maternal great uncle died of bladder cancer, and the acids, urine organic acids, very long chain fatty acids, and maternal great grandfather died of lung cancer. karyotype. Electromyogram and nerve-conduction studies His perinatal history revealed an uneventful pregnancy. were normal. A computed tomography scan of the head and The mother was 28 years old and healthy at the time of the magnetic resonance imaging of the head and spine were also pregnancy and birth. The patient was born at 39 weeks by normal. Sensory-evoked potentials (4 limbs) were normal. At cesarean section because of a breech presentation. He did not the initial workup, an alpha-fetoprotein was requested be- require resuscitation. His birth weight was 7 pounds, and his cause of the strong family history of neoplasms and was Apgar scores were 8 and 10 at 1 and 5 minutes, respectively. found to be elevated. Moreover, the immunoglobulin (Ig) G His neonatal period was unremarkable, except for mild jaun- and IgA levels were found to be decreased, whereas the IgM dice treated with phototherapy. level was normal. When he was first seen, the parents reported a normal Based on these results, a diagnosis of ataxia telangiectasia was suspected. Radiosensitivity testing of lymphoblastoid cells (colony survival assay) was performed and revealed in- From the Departments of *Neurology/Neurosurgery, McGill University; creased radiosensitivity. Chromosomal breakage study re- Montreal Children’s Hospital, McGill University Health Center, Mon- vealed an increased number of breaks and gaps. In the con- treal, Quebec, Canada. text of these results, a Western blot for the ATM protein was †Pediatrics, McGill University; Montreal Children’s Hospital, McGill Uni- undertaken and confirmed the diagnosis of ataxia-telangiec- versity Health Center, Montreal, Quebec, Canada. Address reprint requests to Michael Shevell, MD, CM, FRPC, Room A-514, tasia when no ATM protein was detected. Montreal Children’s Hospital, 2300 Tupper, Montreal, Quebec, Canada Over the following few years, the patient developed clear H3H 1P3. E-mail: [email protected] ataxia, dysmetria, dysdiadokokinesia, and dysarthria. He also

194 1071-9091/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2008.10.011 Pediatric-inherited ataxias 195 developed characteristic signs of ataxia-telangiectasia on ex- gations were then performed, including creatine kinase, met- amination, including oculomotor apraxia and conjunctival abolic workup, albumin, heavy metals (lead, mercury, and and skin telangiectasias. thallium), vitamin E level, lipid profile, and a computed to- At the age of 8 years, he is still able to walk for short mography scan of the head including posterior fossa cuts. All distances but needs an adapted stroller or wheelchair for of these investigations were negative. An electromyogram longer distances. He has pronounced dysarthria, ataxia, and and nerve-conduction studies were also performed and re- dysmetria. He has some drooling. Telangiectasias are present vealed an axonal polyneuropathy. Genetic testing for hered- bilaterally on his conjunctiva and over his left cheek. He itary sensory and motor neuropathies was sent and came receives regular immunoglobulin injections and antibiotic back negative. In the absence of any clear signs on examina- prophylaxis. He is carefully followed for the potential devel- tion, except for the peripheral neuropathy, the decision was opment of a neoplasm, especially leukemia or lymphoma, made to perform a skin, nerve, and muscle biopsy. The mus- with routine complete blood counts and systematic lymph cle was normal. The nerve biopsy (left sural nerve) revealed a nodes examinations. chronic advanced sensory neuropathy. The skin biopsy was normal. Patient 2 Around the age of 9 years, it became clearer that the child was developing progressive cerebellar dysfunction. More- The second patient, also a boy, was first seen in the neurology over, the patient developed a positive self-induced Romberg clinic at the age of 8 years. He was referred for balance and sign; the patient described instability when closing his eyes coordination difficulties. while shampooing hair in the shower. Genetic testing was His family history was significant for the mother who re- then sent for possible Friedreich ataxia. A homozygous GAA ported slightly high arched feet. The maternal aunt and uncle trinucleotide expansion of the FXN (FRDA or X25) gene on were both healthy. The patient’s father was healthy. There chromosome 9 (approximately 858 GAA triplets per allele) was 1 paternal uncle who had been operated on at a young was found. age for scoliosis. The patient’s 2 other paternal uncles were At the latest follow-up, the patient was 10 years old. He healthy. A 6-year-old brother was neurodevelopmentally was in grade 5 and still doing well at school. The parents normal. The parents were of Italian heritage and not consan- reported some slowly progressive gross (eg., some falls when guineous. running, difficulty going up and down the stairs) and fine The perinatal history was unremarkable. The pregnancy (eg., deterioration of hand writing) motor difficulties as well was uncomplicated as well as the labor, delivery, and neonatal period. The patient reached all early motor and language milestones appropriately. At the time of his first visit, he was in the second grade and doing well at school. His past medical history was entirely unremarkable. On history, balance difficulties and coordination problems were reported since the age of about 5 years. Initially, there was no report of any clear progression, and the parents thought that their son’s difficulties had improved with phys- iotherapy. His symptoms were worse when he was tired. At the age of 8 years, he was unable to ride a bicycle. However, he never had any lost of functional motor skills. On his first visit, the neurologic examination was remarkable for some clumsiness in the rapid alternating movements of both the upper and lower extremities and absent myotatic reflexes. The rest of his neurologic examination was essen- tially within normal limits. Of note, his extraocular movements were normal; there was no nystagmus, dysmetria, or upper motor neuron signs. His sensory examination was normal. Gait and tandem gait were normal both forward and backward. He could go up and down the stairs without hold- ing onto the handrail. He could run without difficulty. At the end of this first visit, it was difficult to consider any specific diagnosis and a decision to observe any possible evolution to better target future potential investigations was made. During the following 6 to 12 months, the child’s symptoms progressed slightly. The parents reported that his gait was more unsteady. The neurologic examination showed only subtle changes with absent tendon stretch reflexes. Investi- Figure 1 Suggested approach to pediatric inherited ataxias. 196 G. Bernard and M. Shevell as some dysarthria when tired. He was on a waiting list to be regarding the attainment of different milestones. The past followed in a rehabilitation center and was about to be started medical history was negative. on idebenone. His most recent neurologic examination re- The parents reported some difficulty walking with balance vealed mild dysarthria, mild atrophy of intrinsic foot mus- problems since the child started to walk around the age of 3 cles, bilateral high arched feet, and mild early hammering of and a half years. They did not have any other concerns. the toes. Mild distal weakness (4 to 4ϩ/5) involving both The neurologic examination revealed an alert and cooper- upper and lower extremities was present as well as a de- ative girl. Her head circumference was at the 50th percentile. creased sensation in a glove and socking distribution. Deep Her language and comprehension were difficult to assess ac- tendon reflexes were absent. There was no evidence of upper curately because she spoke only Turkish. The examination of motor neuron involvement. He had clear gait ataxia with the eyes did not reveal any conjunctival telangiectasias. The significant difficulty on tandem gait and very mild truncal cranial nerve examination was remarkable for oculomotor ataxia that worsened appreciably when asked to close his apraxia, saccadic pursuits, hypometric saccades, and gaze- eyes. Bilateral dysdiadochokinesia in the upper and lower evoked nystagmus. The motor examination revealed slightly extremities was noticed to be present. Both finger to nose and decreased tone, both truncal and appendicular, but was oth- heel to shin testing revealed significant dysmetria. erwise normal. Mild chorea and a fine tremor of the upper extremities were noticed when the patient’s arms were ex- tended in front of her. There was bilateral dysmetria and Patient 3 dysdiadochokinesia. The sensory examination revealed nor- The third patient is a girl first seen at the age of 6 years. She mal light touch but apparent decreased proprioception. Her was referred for ataxia. The family history was remarkable for gait was ataxic. Her reflexes were noticed to be pendular but consanguinity in that the parents are first cousins (their symmetrical. The Gower maneuver was negative. Extensor mothers were sisters). The family was from Turkey. There plantar responses were present bilaterally. was no family history of neurologic diseases except for 1 This patient underwent numerous investigations. The fol- paternal cousin with epilepsy. lowing investigations were performed and were negative: vi- The mother had had 6 prior miscarriages. However, her tamin A and E levels, vitamin B12 and folate, lipid profile, pregnancy, labor, and delivery with this child were entirely alpha-fetoprotein, immunoglobulins, carcinoembryonic an- uneventful. The parents reported slow initial motor develop- tigen (CEA), liver function tests, CK, metabolic work up, ment. It was unfortunately difficult to obtain precise details porphyrins, and karyotype. Analysis of serum transferrin iso-

Table 1 Genetic Causes of Progressive Ataxia According to Their Inheritance Autosomal Dominant Autosomal Recessive X-linked Maternal Abetalipoproteinemia AOA-1 AOA-2 ARCA-1 ARSACS Ataxia-telangiectasia ATLD DRPLA AVED Episodic ataxias Cayman KSS Hypobetalipoproteinemia CDG FXTAS (adult onset) MERRF SCA Coenzyme Q deficiency XLSA/A MELAS CTX NARP Freidreich ataxia IOSCA LOTS Marinesco-Sjögren MIRAS Refsum SCAN1 Abbreviations: AOA-1, ataxia with oculomotor apraxia type 1; AOA-2, ataxia with oculomotor apraxia type 2; ARCA-1, autosomal recessive cerebellar ataxia type 1; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; ATLD, ataxia-telangiectasia–like disorder; AVED, ataxia with vitamin E deficiency; CDG, congenital disorders of glycosylation; CTX, cerebrotendinous xanthomatosis; DRPLA, dentatorubral- pallidoluysian atrophy; FXTAS, fragile X–associated tremor ataxia syndrome; IOSCA, infantile-onset spinocerebellar ataxia; KSS, Kearns- Sayre syndrome; LOTS, late-onset Tay-Sachs disease; MERRF, myoclonic 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. Pediatric-inherited ataxias 197

Table 2 Inherited Ataxias More Common in Patients With forms by isoelectric focusing for a congenital disorder of gly- Certain Ethnic Backgrounds cosylation (CDG) was performed and was negative. An oph- Ataxia thalmology consultation did not reveal any retinal abnormality. Sensory-evoked responses revealed abnormal Autosomal Autosomal Continent/Country Dominant Recessive central conduction, but auditory-evoked responses were normal. An electromyogram and nerve-conduction studies North America were performed and revealed a mild axonal sensory polyneu- Canada EA-4 (Mennonite) AOA-2 (province of Quebec) ropathy. A computed tomography scan and magnetic reso- ARCA-1 nance imaging of the brain showed volume loss of the cere- (province of bellar vermis. Magnetic resonance imaging of the spine was Quebec) normal. Genetic testing was performed and found to be neg- ARSACS (province of Quebec) Friedreich ataxia Table 3 Intermittent Ataxias: Episodic Ataxias Mexique SCA10 Distinctive Clinical United States of EA-3 America SCA2 Genetic Features SCA3 Type 1 OMIM 160120 Onset: late childhood to SCA6 early adolescence South America KCNA1 gene Brief attacks (seconds Brazil SCA3 to minutes) Grand Cayman Island Cayman Chromosome 12 Interictal myokymia Europe Response to Finland SCA8 IOSCA Acetazolamide, France SCA25 AOA-1 phenytoin Italy SCA1 Friedreich ataxia Type 2 OMIM 108500 Onset: childhood or SCA2 early adolescence SCA28 CACNA1A gene Long attacks (hours to Netherlands SCA3 SCA6 days) SCA19 Chromosome 19 Interictal nystagmus SCA23 Slowly progressive SCA27 cerebellar dysfunction Poland, Czech ATLD and atrophy Republic, Ukraine Approximately 50% Portugal SCA3 have migraines Serbia SCA1 Response to Africa Acetazolamide North Africa Friedreich ataxia Type 3 OMIM 606554 Onset: variable South Africa SCA1 Unknown gene brief attacks of SCA7 vestibular ataxia, Asia vertigo, tinnitus China SCA3 Chromosome 1 Interictal myokymia India SCA1 Friedreich ataxia Response to SCA2 acetazolamide SCA3 SCA12 Type 4 OMIM 606552 Onset: early adulthood Japan SCA3 AOA-1 Unknown gene Attacks of vertigo, SCA6 diplopia, tinnitus, SCA16 ataxia Middle East Friedreich ataxia Unknown chromosome No response to Saudi Arabia SCAN1 acetazolamide Singapore SCA2 Type 5 OMIM 601949 May have associated SCA3 CACNB4 gene epilepsy Taiwan SCA22 Chromosome 2 Abbreviations: AOA-1, ataxia with oculomotor apraxia type 1; ARCA-1, Type 6 OMIM 600111 1 case autosomal recessive cerebellar ataxia type 1; ARSACS, autosomal SLC1A3 gene recessive spastic ataxia of Charlevoix-Saguenay; ATLD, ataxia-tel- Chromosome 5 angiectasia–like disorder; EA, episodic ataxia; IOSCA, infantile-on- Type 7 OMIM 611907 1 family set spinocerebellar ataxia; SCA, spinocerebellar ataxia; SCAN1, Unknown gene spinocerebellar ataxia with axonal neuropathy. Chromosome 19 NOTE. Episodic ataxias are autosomal dominant diseases characterized by intermittent episodes of cerebellar dysfunction with or without interictal neurologic dysfunction. 198 G. Bernard and M. Shevell ative for Friedreich ataxia, fragile X, and ataxia with oculo- Clinical Approach motor apraxia type 1. Chromosome breakage analysis (spon- taneous and to ionizing radiation exposure) was performed, Ataxia is deﬁned as imbalance and incoordination.1,2 The and the results were inconsistent with ataxia-telangiectasia. term is typically used to describe gait (gait ataxia) but may No deﬁnite diagnosis has yet been determined in this patient also describe an unstable patient in the sitting position (trun- despite a strong suspicion of a genetic etiology and detailed cal ataxia) or dysmetria or incoordination of a limb while investigations. performing a task (limb ataxia). Gait ataxia is usually second-

Table 4 Intermittent Ataxias: Metabolic Diseases Enzymatic Defect Genetic Distinctive Clinical Features Mitochondrial PC deficiency Lactic acidosis OMIM 266150 Chromosome 11 PDH deficiency Lactic acidosis OMIM 312170 X-linked Urea cycle defects OTC deficiency Typically affecting females (partial enzymatic OMIM 311250 Intermittent encephalopathy, ataxia, defects) X-linked hyperammonemia CPS deficiency Intermittent encephalopathy, vomiting, OMIM 237300 ataxia, hyperammonemia Autosomal recessive Chromosome 2 ASS deficiency or Citrullinemia OMIM 215700 Autosomal recessive Chromosome 9 AS deficiency OMIM 207900 Autosomal recessive Chromosome 7 Arginase deficiency OMIM 207800 Autosomal recessive Chromosome 6 Aminoacidurias and Hartnup Intermittent ataxia, psychiatric disturbances; Organic acidurias Defect in intestinal and renal transport of pellagra-like rash neutral amino acids Treatment: Nicotinamide OMIM 234500 Autosomal recessive Chromosome 5 Intermittent MSUD Increased serum branched-chain amino BCKD component deficiency acids (leucine, valine, isoleucine) and OMIM 248600 alloisoleucine Autosomal recessive Chromosomes 19, 7, 1 Isovaleric academia Intermittent attacks of ataxia, IVD deficiency encephalopathy and ketoacidosis OMIM 243500 Autosomal recessive Chromosome 15 Biotinidase deficiency Intermittent episodes of metabolic OMIM 253260 decompensation Autosomal recessive Chromosome 3 Abbreviations: AS, argininosuccinase; ASS, arginosuccinate synthetase; BCKD, branched-chain alpha-keto acid dehydrogenase; CPS, car- bamoylphosphate synthetase; IVD, isovaleryl CoA dehydrogenase; MSUD, maple syrup urine disease; OTC, ornithine transcarbamylase; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase. Pediatric-inherited ataxias 199 ary to a dysfunction or lesion of the cerebellum and/or its Family History connections. However, it is well recognized that patients can The family history is sometimes very useful in the determi- also have gait ataxia from peripheral sensory impairment (ie., nation of a diagnostic hypothesis. First, we are interested in sensory ataxia secondary to a peripheral neuropathy). When any neurologic diseases that may have affected family mem- the ataxia is of cerebellar origin, it is typically accompanied bers. But more so, we are interested in determining if some by other signs and symptoms including abnormal eye move- family members have similar symptoms. When the family ments (hypometric or hypermetric saccades, saccadic pur- history is positive, pedigree analysis will help determine the suits), nystagmus of varying types, dysarthria, dysmetria, and mode of inheritance (autosomal dominant, autosomal reces- dysdiadochokinesis. On the other hand, when the ataxia is sive, X-linked, or maternal). Table 1 summarizes the main caused by a sensory deficit, there is typically no associated genetic causes of ataxia according to their specific inheritance feature of cerebellar dysfunction. However, in that case, sen- pattern (Mendelian or maternal). sory symptoms (paresthesias and numbness) and signs are SCA is rare; however, a family pedigree featuring autoso- noted, including impaired vibration and position senses, re- mal dominant transmission should suggest this diagnosis, duced or absent deep tendon reflexes, and a positive Rom- even if the patient presents at a young age. Moreover, this berg sign (ie., the standing position is rendered unstable diagnosis should be kept in mind in cases of nondiagnosed when the eyes are closed). ataxias without a clear family history because these diseases Ataxias can be divided according to their mode of presen- can present at a young age, before the affected parent be- tation into acute, episodic, chronic, and progressive variants. comes symptomatic, particularly if there is a large intergen- This classification is very useful to the clinician because it erational amplification of a trinucleotide repeat sequence (ie., restrains the number of possible etiologies to be considered anticipation). in the diagnostic workup. In this review, we do not discuss Most pediatric cases of ataxia are caused by autosomal the acute causes of ataxia and concentrate on the episodic and recessive diseases (eg., Friedreich ataxia and ataxia-telangiec- chronic forms, with a special focus on inherited causes. This tasia), making it particularly important to inquire about the group of disorders can be very challenging to the clinician possibility of parental consanguinity. Consanguinity is well because there are a plethora of rare genetic entities now iden- known to increase the likelihood of autosomal recessive dis- tified. These entities with a genetic basis are increasingly eases in offspring. In fact, if the parents are first cousins, the important to recognize and diagnose because some are treat- risk of having a child with an autosomal recessive condition is able and all pose a risk of possible familial recurrence. approximately 5%, a figure that is much higher than for Childhood ataxia is often a difficult problem to evaluate, unrelated parents. In the context of a young child with pro- especially when the etiology is genetic. The main reason is gressive ataxia, one should enquire about a family history of that this evaluation takes place at the beginning of what will neoplasia. A strong family history of neoplasia should suggest be a progressive condition, at a time when not all clinical a possible diagnosis of ataxia-telangiectasia. In fact, individ- uals heterozygous for the ATM mutation have approximately clues for a proper and definite diagnosis are present. The era of molecular medicine has led to a plethora of diagnostic testing options for clinicians. We do not review all causes of ataxia because this has been very well covered in recent re- Table 5 Treatable Inherited Causes of Ataxia 3,4 views. We do suggest an approach by discussing the clues Disease Treatment that can be found from the clinical history and examination. Abetalipoproteinemia Vitamin E Figure 1 summarizes our suggested approach. We will then AVED Vitamin E suggest a stepwise workup according to this clinical information Biotinidase deficiency Biotin that should result in a direct and targeted approach that will Cerebrotendinous Chenodeoxycholic acid hopefully expeditiously yield an accurate and correct diagnosis. xanthomatosis Coenzyme Q deficiency Coenzyme Q Episodic ataxia types 1 Acetazolamide Age of Onset and 2 First of all, the age of the patient at the onset of symptoms can Friedreich: ataxia Possibly effective for sometimes be helpful in restraining the number of possible cardiomyopathy diagnoses. Only a few causes of inherited ataxia typically Coenzyme Q, vitamin E present before the age of 3 years. These include ataxia-telan- Idebenone giectasia,5 infantile-onset spinocerebellar ataxia,6,7 X-linked Hartnup Nicotinamide Hypobetalipoproteinemia Vitamin E sideroblastic anemia with ataxia,8 congenital disorders of gly- MSUD Diet, thiamine 9 cosylation, and cerebellar malformations (eg., Dandy- Pyruvate dehydrogenase Ketogenic diet Walker malformation). Moreover, the principal causes of late deficiency onset ataxia (ie., after the age of 25 years) are the autosomal Refsum Diet (restriction in phytanic acid) dominant spinocerebellar ataxias (SCAs). Between these 2 Urea cycle defects Diet, sodium benzoate extremes, the age of the patient is unfortunately not very Abbreviations: AVED, ataxia with vitamin E deficiency; MSUD, ma- useful to target one diagnosis or another. ple syrup urine disease. 200 G. Bernard and M. Shevell

Table 6 Central Nervous System and Peripheral Nervous System Involvement Other Than Cerebellar Dysfunction Specific Sign or Symptom Associated Diseases Central nervous system involvement Extensor plantar responses (Babinski signs) AOA-2 Friedreich ataxia AVED MIRAS ARSACS SCA 1,3,4,7,8,11,12,23,28 Ataxia telangiectasia Brisk deep tendon reflexes ARSACS SCA 1,3,4,7,8,11,12,23,28 Chorea AOA-1 and AOA-2 LOTS Ataxia Telangiectasia MIRAS ATLD SCA 17 DRPLA Cognitive impairment AOA-1, AOA-2 KSS ARSACS LOTS CDG MELAS CTX MERRF DRPLA MIRAS FXTAS MSS IOSCA SCA 2,7,13,17,19,21,27 Dystonia AOA-1 and AOA-2 CTX Ataxia Telangiectasia LOTS ATLD SCA 3,17 Epilepsy/seizures Biotinidase deficiency MELAS CDG MERRF CTX MIRAS DRPLA NARP LOTS SCA10 Myoclonus AOA-2 LOTS Ataxia Telangiectasia MERRF CTX MIRAS DRPLA Nystagmus Abetalipoproteinemia EA 2 AOA-1 and AOA-2 Friedreich ataxia ARSACS LOTS Ataxia Telangiectasia MIRAS ATLD MSS Cayman SCA 6,28 Oculomotor apraxia AOA-1 Ataxia Telangiectasia AOA-2 ATLD Ophthalmoplegia AOA-1 NARP Slow saccades IOSCA SCA 1,2*,3,7,17,23,28 KSS *Early slow saccades MIRAS Parkinsonism CTX SCA 3,17 FXTAS Psychiatric problems CTX MERRF DRPLA MIRAS LOTS SCA 3,17,27 Tremor AOA-1 and 2 MIRAS AVED MSS Ataxia Telangiectasia SCA 12 Cayman SCA 20 (palatal tremor) LOTS Spasticity ARSACS LOTS CTX SCA 1,3,4,7,8,11,12,23,28 Pediatric-inherited ataxias 201

Table 6 Continued Specific Sign or Symptom Associated Diseases Peripheral nervous system involvement Muscle weakness/amyotrophy Abetalipoproteinemia MELAS AOA-1 and AOA-2 MERRF ARSACS MIRAS Ataxia telangiectasia MSS CTX NARP Friedreich ataxia Refsum IOSCA SACN1 LOTS SCA 3 Peripheral neuropathy Abetalipoproteinemia AOA-1 and AOA-2 ARSACS MELAS AVED MIRAS Ataxia telangiectasia MSS ATLD NARP CTX Refsum Friedreich ataxia SCA 1,2,3,4,8,12, 18,19,21,22,25,27 FXTAS SCAN1 IOSCA LOTS Abbreviations: AOA-1, ataxia with oculomotor apraxia type 1; AOA-2, ataxia with oculomotor apraxia type 2; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; ATLD, ataxia-telangiectasia–like disorder; AVED, ataxia with vitamin E deficiency; CDG, congenital disorders of glycosylation; CTX, cerebrotendinous xanthomatosis; DRPLA, dentatorubral-pallidoluysian atrophy; EA: episodic ataxia; FXTAS, fragile X–associated tremor ataxia syndrome; IOSCA, infantile-onset spinocerebellar ataxia; KSS, Kearns-Sayre syndrome; LOTS, late-onset Tay-Sachs disease; MERRF, myoclonic epilepsy associated with ragged-red fibers; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MIRAS, mitochondrial recessive ataxia syndrome; MSS, Marinesco-Sjögren 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.

4 times the risk of neoplasm, primarily of breast cancer, when The cerebellar symptoms and signs are typically associated compared with the general population.10,11 with other typical clinical features suggestive of mitochon- X-linked forms of ataxia are rare. Fragile X–associated drial diseases including short stature, cardiac involvement, tremor ataxia syndrome (FXTAS) is an interesting cause of neuropathy, myopathy, epilepsy, and so on. ataxia in the adult population.12,13 It typically affects adult male carriers and less commonly female carriers of a premu- Ethnic Background tation for the FMR-1 gene (50-200 CGG repeats). There may Sometimes, the patient’s ethnic origin may help the clinician be a positive family history of mental retardation in males. in diagnosing the ataxic patient. The diseases associated more The onset of this syndrome is typically after the age of 50 commonly with speciﬁc geographic areas are summarized in years, well beyond the pediatric age group. Several possible Table 2. clinical features can be present, including tremor, ataxia, parkinsonism (ie., tremor, rigidity, bradykinesia, postural instability), cognitive decline, and autonomic dysfunction. The Clinical Presentation characteristic abnormality on magnetic resonance imaging is On history, several elements can be very useful in the diag- that of hyperintense signal in the middle cerebellar peduncles nostic process, particularly the temporal pattern (acute, sub- on T2-weighted images. acute, chronic, and episodic) and any associated conditions Another form of ataxia that is transmitted in an X-linked noted. form is X-linked sideroblastic anemia and ataxia. This form of The pattern of symptom onset and evolution is critical in ataxia affects males and is characterized by moderate anemia the diagnostic process. An acute onset of cerebellar dysfunc- and an early childhood slowly progressive14 or static15 spino- tion in the pediatric patient should suggest an acquired cause cerebellar ataxia syndrome. (especially intoxications, postvaricella or postviral cerebelli- Several maternally transmitted mitochondrial diseases can tis, the Miller-Fisher variant of Guillain-Barré syndrome, pos- present with ataxia,16 among other symptoms. These include terior fossa tumors, cerebellar hemorrhage or ischemic Kearns-Sayre syndrome, mitochondrial encephalomyopathy events, and so on). These acquired causes will not be further lactic acidosis and stroke-like episodes (MELAS), myoclonic discussed here. However, once these causes are ruled out and epilepsy with ragged-red ﬁbers (MERRF) and neurogenic if another acute episode of cerebellar ataxia occurs, one muscle weakness, ataxia, and retinitis pigmentosa (NARP). should consider genetic causes of intermittent ataxia, includ- 202 G. Bernard and M. Shevell

Table 7 Organ Involvement in Different Inherited Ataxias Organ Involvement Specific Sign or Symptom Associated Diseases Ears Sensorineural hearing loss Friedreich ataxia MIRAS IOSCA NARP KSS Refsum MELAS SCA 4 MERRF Endocrinologic Abnormal fat distribution CDG Diabetes mellitus Ataxia telangiectasia Friedreich ataxia Short stature KSS MELAS MERRF NARP Eyes Cataracts CTX MSS Conjonctival telangiectasia Ataxia telangiectasia Hypermyelinated retinal fibers ARSACS Optic atrophy AOA-1 IOSCA Friedreich ataxia MERRF Retinitis pigmentosa Abetalipoproteinemia MERRF AVED NARP Hypobetalipoproteinemia Refsum KSS SCA7 Gastrointestinal Malabsorption Abetalipoproteinemia Hypobetalipoproteinemia Liver disease CDG MIRAS Others MELAS (anorexia, vomiting) Heart Arrhythmia KSS NARP MERRF (WPW) Cardiomyopathy Abetalipoproteinemia KSS AVED Refsum Friedreich ataxia Immune system Recurrent sinopulmonary Ataxia Telangiectasia infections Musculoskeletal Scoliosis AOA-1 and AOA-2 MSS Friedreich ataxia Renal Renal failure Refsum Skin Rash Biotinidase deficiency Refsum (ichthyosis) Hartnup (pellagra-like) Tendon xanthomas CTX Abbreviations: AOA-1, ataxia with oculomotor apraxia type 1; AOA-2, ataxia with oculomotor apraxia type 2; ARSACS, autosomal recessive ataxia of Charlevoix-Saguenay; ATLD, ataxia-telangiectasia–like disorder; AVED, ataxia with vitamin E deficiency; CDG, congenital disorders of glycosylation; CTX, cerebrotendinous xanthomatosis; DRPLA, dentatorubral-pallidoluysian atrophy; FXTAS, fragile X–associated tremor ataxia syndrome; IOSCA, infantile-onset spinocerebellar ataxia; KSS, Kearns-Sayre syndrome; LOTS, late-onset Tay-Sachs disease; MERRF, myoclonic epilepsy associated with ragged-red fibers; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes; MIRAS, mitochondrial recessive ataxia syndrome; MSS, Marinesco-Sjögren 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. ing the episodic ataxias and some metabolic disorders (Tables and peripheral nervous system involvement as well as with 3 and 4). When the presentation is more insidious (ie., sub- systemic involvement have been well described by other acute or chronic) and nongenetic causes have been ruled out authors3,4,19,20 and are summarized in Tables 6 and 7 re- (eg., slowly growing posterior fossa tumor), an inherited spectively.3-8,15,19-34 form of ataxia should be considered. In this context, treatable causes should be vigorously searched for to begin any possible therapy expeditiously (Table 5).17,18 Physical Examination Inquiring about the patient’s past medical history and any Several physical features can be used to restrain the number associated organ involvement can help in determining the of possible diagnoses and target molecular genetic testing. most probable diagnosis. For example, a skin rash is often These features are presented in Tables 6 and 7. For example, present in Refsum disease (ichthyosis), Hartnup disease the presence of ichthyosis on the skin examination is strongly (pellagra-like rash) or biotinidase deficiency. The associa- suggestive of Refsum disease. On the skin and eye examinations between the different inherited ataxias and central tion, telangiectasias can be present in cases of ataxia-telangi- Pediatric-inherited ataxias 203

Table 8 Diagnostic Investigations Investigation Result Associated Disease(s) Blood work CBC and smear Acanthocytes Abetalipoproteinemia Hypobetalipoproteinemia Anemia (sideroblastic) XLSA/A Anemia (megaloblastic) Vitamin B12 and folate deficiency Biochemistry High glucose Ataxia Telangiectasia Friedreich ataxia Vitamin E Low AVED Abetalipoproteinemia Hypobetalipoproteinemia Lipid profile Low cholesterol Abetalipoproteinemia CTX (may also be normal) Hypobetalipoproteinemia High cholesterol AOA-1 and AOA-2 SCAN1 High cholestanol and bile alcohols CTX Alpha-fetoprotein High AOA-2 Ataxia Telangiectasia Immunoglobulins Low Ataxia Telangiectasia (IgA, IgG2, IgG4, IgE) Albumin Low AOA-1 SCAN1 Metabolic work up Lactate, pyruvate High Mitochondrial diseases Ammonia High Urea cycle defects Organic acidurias Serum amino acids High leucine, valine, isoleucine, alloisoleucine MSUD Urine organic acids Abnormal profile Aminoacidemias, eg., MSUD Organic acidurias Urea cycle defects VLCFA, Normal VLCFA Refsum plasmologens and phytanic acid Normal plasmalogens Increased phytanic acid Others ABR ABR: sensorineural hearing loss C.f. Table 7 Cardiac echo Cardiomyopathy C.f. Table 7 EKG Arrhythmia C.f. Table 7 EMG/NCS Myopathy C.f. Table 6 Neuropathy C.f. Table 6 Imaging (ideally MRI) Cerebellar hypoplasia CDG Cerebellar malformation Chiari, Dandy-Walker, etc. Ophthalmology Pigmentary retinopathy, extra-ocular movement C.f. Table 6 and 7 anomalies, etc. Abbreviations: AVED, ataxia with vitamin E deficiency; CBC, complete blood count; CDG, congenital disorders of glycosylation; CTX, cerebrotendinous xanthomatosis; MSUD, maple syrup urine disease; VLCFA, very long chain fatty acids; XLSA/A, X-linked sideroblastic anemia and ataxia. ectasia. However, it is important to note that the telangiecta- fibers, the later finding being very typical, if not pathogno- sias observed in this disorder are typically not present when monic, of autosomal recessive spastic ataxia of Charlevoix- the child first presents with ataxia and often only become Saguenay. The extraocular movements may show oculomo- apparent later in the first decade of life. On the neurologic tor apraxia, slow saccades, hypermetric, or hypometric examination, examination of the cranial nerves may reveal a saccades as well as abnormal saccadic pursuits. The motor pigmentary retinopathy, optic atrophy, or hypermyelinated examination may reveal some spasticity with or without up- 204 G. Bernard and M. Shevell

Table 9 Genetic Defects and Testing of Hereditary Ataxias (see also table 4) Disease Gene OMIM Comments Protein Chromosome Testing Autosomal dominant conditions SCA1 ATXN1 Ataxin-1 6 Clinical OMIM 164400 CAG SCA2 ATXN2 Ataxin-2 12 Clinical OMIM 183090 CAG SCA3 ATXN3 Ataxin-3 14 Clinical OMIM 109150 CAG SCA4 — — 16 Research OMIM 600223 SCA5 SPTBN2 Puratrophin-1 11 Clinical OMIM 600224 SCA6 CACNA1A Voltage-dependent P/Q-type 19 Clinical OMIM 183086 CAG calcium channel alpha-1A subunit SCA7 ATXN7 Ataxin-7 3 Clinical OMIM 164500 CAG SCA8 ATXN8 and — 13 Clinical ATXN80S OMIM 608768 CTG SCA9 SCA10 ATXN10 Ataxin-10 22 Clinical OMIM 603516 SCA11 TTBK2 Tau-tubulin kinase 2 15 Research OMIM 604432 SCA12 PPP2R2B Serine/threonine protein 5 Clinical OMIM 604326 phosphatase 2A 55-kd regulatory subunit B beta isoform SCA13 KCNC3 Voltage-gated potassium 19 Clinical OMIM 605259 subfamily C member 3 SCA14 PRKCG Protein kinase C gamma 19 Clinical OMIM 605361 type SCA15 ITPR1 Inositol 1,4,5-triphosphate 3 Research OMIM 606658 receptor type 1 SCA16 SCA17 TBP TATA-box binding protein 6 Clinical OMIM 607136 CAG SCA18 SCA18 — 7 — OMIM 607458 SCA19 SCA19 — 1 Research OMIM 607346 SCA20 SCA20 — 11 Clinical OMIM 608687 SCA21 SCA21 — 7 Research OMIM 607454 SCA22 — — 1 — OMIM 607346 SCA23 — — 20 Research OMIM 610245 Pediatric-inherited ataxias 205

Table 9 Continued Disease Gene OMIM Comments Protein Chromosome Testing

SCA24 SCA25 SCA25 — 2 — OMIM 608703 SCA26 — — 19 Research OMIM 609306 SCA27 FGF14 Fibroblast growth factor 14 13 Clinical OMIM 609307 SCA28 — — 18 Research OMIM 610246 SCA29 — — 3 Research OMIM 117360 DRPLA ATN Atrophin-1 12 Clinical OMIM 125370 CAG EA1 KCNA1 Voltage-gated potassium 12 Clinical OMIM 160120 channel subfamily A member 1 EA2 CACNA1A Voltage-dependent P/Q-type 19 Clinical OMIM 108500 calcium channel alpha-1A subunit Non-repeat mutations EA3 — — 1 Research OMIM 606554 EA4 — — — Research OMIM 606552 EA5 CACNB4 Voltage-dependent L-type 2 Research OMIM 601949 calcium beta-4 subunit EA6 SLC1A3 5 Research OMIM 600111 EA7 — — 19 Research OMIM 611907 ADSA SAX1 — 12 Research OMIM 108600 Hypobetalipoproteinemia APOB Apolipoprotein B 2 Research OMIM 107730

Autosomal recessive conditions Abetalipoproteinemia MTP Microsomal triglyceride 4 Research OMIM 200100 transfer protein ARCA-1 SYNE1 Synaptic nuclear envelope 6 Research OMIM 610743 protein 1 or Nesprin-1 AOA-1 APTX Aprataxin 9 Clinical OMIM 208920 AOA-2 SETX Senataxin 9 Clinical OMIM 606002 ARSACS SACS Sacsin 13 Clinical OMIM 270550 Ataxia Telangiectasia ATM Serin-protein kinase ATM 11 Clinical OMIM 208900 206 G. Bernard and M. Shevell

Table 9 Continued Disease Gene OMIM Comments Protein Chromosome Testing

ATLD MRE11A Meiotic recombination 11 11 Research OMIM 604391 AVED TTPA Alpha-tocopherol transfer 8 Clinical OMIM 277460 protein Cayman ATCAY Caytaxin 19 Research OMIM 601238 CDG 13 different 13 different enzymes Transferrin isoforms analysis (13 types) genes (N-glycolysation) by isoelectric focusing Clinical for 9 types CTX CYP27A1 Sterol 27-hydroxylase 2 Clinical OMIM 213700 Friedreich ataxia FXN Frataxin 9 Clinical OMIM 229300 FRDA X25 IOSCA PEO1 Twinkle protein 10 Clinical OMIM 271245 LOTS HEXA ␤-Hexosaminidase A 15 Clinical OMIM 272800 Marinesco-Sjögren SIL1 Nulceotide exchange factor 5 Research OMIM 248800 SIL1 MIRAS POLG DNA polymerase gamma 15 Clinical OMIM 174763 Refsum PAHX or Phytanoyl-CoA hydroxylase 10 Clinical PHYH OMIM 266500 PEX7 Peroxin-7 6 SCAN1 TDP1 Tyrosyl-DNA 14 Research OMIM 607250 phosphodiesterase 1 X-Linked conditions FXTAS FMR1 Fragile X mental retardation X Clinical OMIM 300623 1 XLSA/A ABC7 ATP-binding cassette X Clinical OMIM 301310 subfamily B member 7 Mitochondrial diseases (maternally inherited conditions) KSS Large mtDNA deletions Clinical OMIM 530000 (typically sporadic; when inherited, is transmitted maternally) MERRF mtDNA gene MT-TK Clinical OMIM 545000 encoding for tRNALys MELAS mtDNA mutations Clinical OMIM 540000 MT-TL1 gene encoding for tRNA Leu(UUR) NARP mtDNA gene MTATP6 Clinical OMIM 551500 Abbreviations: ADSA, autosomal dominant spastic ataxia; AOA-1, ataxia with oculomotor apraxia type 1; AOA-2, ataxia with oculomotor apraxia type 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, cerebrotendinous xanthomatosis; DRPLA, dentatorubral-pallidoluysian atrophy; EA, episodic ataxia; FXTAS, fragile X–associated tremor ataxia syndrome; IOSCA, infantile-onset spinocerebellar ataxia; KSS, Kearns-Sayre syndrome; LOTS, late-onset Tay-Sachs disease; MERRF, myoclonic 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. Pediatric-inherited ataxias 207 per motor neuron signs, suggesting a spinocerebellar degen- can be seen on magnetic resonance imaging with certain syn- eration (eg., Friedreich ataxia, SCA, ataxia with vitamin E dromes (eg., Dandy-Walker, Joubert syndrome, and so on). deficiency, and so on). On the other hand, amyotrophy may These diseases will not be discussed further here. To com- be present, as it is in the case of ARSACS or SCA3, among plete the initial investigations, an electromyogram and nerve- other diseases. The sensory and/or motor examinations may conduction studies should be performed to document the suggest a peripheral neuropathy, which may help in the di- presence or absence of a neuropathy or myopathy. An elec- agnostic process. Moreover, knowing that the patient has a trocardiogram should also be performed because some dis- peripheral neuropathy has an impact on clinical management eases have associated potentially life-threatening arrhythmias (eg., use of plantar-foot orthoses for a foot drop). The rapid (ie., Kearns-Sayre). A consultation in ophthalmology (ideally alternating movements typically show dysdiadochokinesia. to a neuro-ophthalmologist) is also recommended because Finger-to-nose and heel-to-shin testing reveals limb dysme- several abnormalities on the ophthalmological examination tria. When the patient is sitting, truncal ataxia can be seen. can target specific diagnoses (eg., retinitis pigmentosa in abe- Ataxia is seen on the tandem gait only in mild cases and on talipoproteinemia or hypermyelinated retinal fibers in regular gait in more severe cases. When the Romberg is per- ARSACS). Consultations in occupational therapy, physio- formed, the patient is often noticed to be initially unstable therapy, and possibly speech and language pathology may be when standing with the eyes open. If there is a significant needed if the patient has significant fine-motor, gross-motor, sensory neuropathy or posterior column involvement, the and speech difficulties (dysarthria), respectively. patient will be significantly more unstable with the eyes For most patients, the clinical assessment and initial inves- closed (positive Romberg). tigations help in formulating a diagnostic hypothesis. When a specific diagnosis is suspected, molecular genetic testing should be performed if available. Table 9 summarizes the Investigations genetic information presently available for the different ataxic Multiple investigations are available to the clinician. We syndromes and relevant molecular testing. When the diagno- suggest an initial and a more detailed subsequent workup. sis is not as evident after the initial workup, a consultation to These investigations can obviously be modified according genetics or neurogenetics is suggested. If a significant neu- to the most probable diagnoses suggested by the clinical ropathy is present on electromyography, a nerve biopsy careful assessment as described previously. Table 8 lists could be performed. A muscle and skin biopsy is often per- the initial and more detailed investigations, the possible formed at the same time as the nerve biopsy. The muscle biopsy abnormalities that can be ascertained, and their associated may show ragged-red fibers on Gomori-trichome staining in the conditions. case of a mitochondrial disease. Rarely, muscle weakness can be The initial investigations should include blood work, im- confused with ataxia, especially in the young child. In these aging, electrophysiology, and consultations to other relevant cases, a muscle biopsy may be useful as well. A skin biopsy can specialists. Once acquired causes of ataxia have been ruled be useful to diagnose a few neurodegenerative diseases that can out (eg., malabsorption, celiac disease, vitamin B12 or folate have ataxia among other neurological findings (eg., Lafora dis- deficiency, tabes dorsalis, and so on) and a genetic cause is ease and neuronal ceroid lipofuscinosis). If fibroblasts are considered, the initial blood workup should include the fol- grown from the skin biopsy, molecular genetic testing for lowing: complete blood count with smear, biochemistry different diseases can be performed as the disease evolves (electrolytes, blood urea nitrogen, creatinine, liver function and results from different investigations become available. tests, and glucose), thyroid function tests (hypothyroidism Finally, one should not forget other classes of rare diseases can rarely present with ataxia), vitamin E and lipid profile, that can present as slowly progressive ataxia such as vita- albumin, alpha-fetoprotein, immunoglobulins, and a meta- min B12 or folate deficiency (sensory ataxia), paraneoplas- bolic work up including a blood gas, lactate, pyruvate, am- tic disorders (eg., opsoclonus myoclonus, often associated with ataxia), celiac disease, and new variant Creutzfeldt monia, serum amino acids, urine organic acids, very long Jakob disease, among others.19 chain fatty acids, total carnitine, and an acylcarnitine profile. In conclusion, pediatric-onset hereditary ataxias can be Other metabolic investigations can be performed according challenging for the pediatric neurologist; there are a growing to the clinical context (eg., urine orotic acid if a urea cycle number of diseases known, and the phenotypes are not al- defect is suspected). Of note, when the ataxia seems to have ways typical or, more commonly, certain characteristics of a an intermittent pattern, the metabolic workup should ideally given disease may not be present when the child is first seen be performed during an episode of decompensation because by the clinician. Moreover, other neurologic diseases can be it could well be completely normal between episodes. Mag- mistaken for ataxia, especially in the young child. In this netic resonance imaging of the brain must be obtained in all review, we have tried to provide an approach to this complex patients. Abnormalities noted on the magnetic resonance im- problem and suggest a stepwise rational investigative ap- aging can help tremendously in targeting further investiga- proach. tions. One should not forget that diseases that have ataxia as a main sign or symptom are presented here, but multiple References other diseases can have ataxia as one of their manifestations. 1. Subramony SH: Ataxic disorders, in Bradley WG, Daroff RB, Fenichel For example, most patients with leukodystrophy have some GM (eds): Neurology in Clinical Practice (ed 4). Philadelphia, PA, degree of ataxia. Moreover, malformations of the cerebellum Elsevier, 2004, pp 287-292 208 G. Bernard and M. Shevell

2. Timmann D, Diener HC: Coordination and ataxia, in Goetz: Textbook (database online). Copyright, University of Washington, Seattle. of Clinical Neurology (ed 2). Philadelphia, PA, Elsevier, 2003, pp 299- 1997-2008. Available from: http://www.ncbi.nlm.nih.gov/bookshelf/ 315 br.fcgi?bookϭgene&partϭaoa2. Accessed July 27, 2008 3. Fogel BL, Perlman S: Clinical features and molecular genetics of auto- 23. Schuelke M: Ataxia with vitamin E deﬁciency, in GeneReviews at somal recessive cerebellar ataxias. Lancet Neurol 6:245-257, 2007 GeneTests: Medical Genetics Information Resource (database online). 4. Schöls L, Bauer P, Schmidt T, et al: Autosomal dominant cerebellar Copyright, University of Washington, Seattle. 1997-2008. Available at: ataxias: clinical features, genetics, and pathogenesis. Lancet 3:291-304, http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭaved. 2004 Accessed July 27, 2008 5. Gatti RA: Ataxia-Telangiectasia, in GeneReviews at GeneTests: Medical 24. Concannon PJ, Gatti RA: Nijmegen breakage syndrome, in GeneR- Genetics Information Resource (database online). Copyright, University of eviews at GeneTests: Medical Genetics Information Resource (database Washington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih. online). Copyright, University of Washington, Seattle. 1997-2008. gov/bookshelf/br.fcgi?bookϭgene&partϭataxia-telangiectas. Accessed Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭ July 27, 2008 gene&partϭnijmegen. Accessed July 27, 2008 6. Nikali K, Suomalainen A, Saharinen J, et al: Infantile onset spinocere- 25. Robitaille Y, Richter A, Mathieu J, et al: ARSACS [autosomal recessive bellar ataxia is caused by recessive mutations in mitochondrial proteins spastic ataxia of Charlevoix-Saguenay], in GeneReviews at GeneTests: twinkle and twinky. Hum Mol Genet 14:2981-2990, 2005 Medical Genetics Information Resource (database online). Copyright, 7. Lonnqvist T, Paetau A, Nikali K, et al: Infantile onset spinocerebellar University of Washington, Seattle. 1997-2008. Available at: http://www. ϭ ϭ ataxia with sensory neuropathy (IOSCA): Neuropathological features. ncbi.nlm.nih.gov/bookshelf/br.fcgi?book gene&part arsacs. Accessed J Neurol Sci 161:57-65, 1998 July 27, 2008 8. Pagon RA, Bird TD: X-linked sideroblastic anemia and ataxia (2008), in 26. Spacey S: Episodic ataxia type 2, in GeneReviews at GeneTests: Medical GeneReviews at GeneTests: Medical Genetics Information Resource Genetics Information Resource (database online). Copyright, Univer- (database online). Copyright, University of Washington, Seattle. 1997- sity of Washington, Seattle. 1997-2008. Available at: http:// ϭ ϭ 2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi? www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book gene&part ea2. Ac- bookϭgene&partϭsider-anemia. Accessed July 27, 2008 cessed July 27, 2008 9. Freeze HH: Congenital disorders of glycosylation: CDG-I, CDG-II, and 27. Saul RA, Tarleton JC: FMR1-related disorders, in GeneReviews at beyond. Curr Mol Med 7:389-396, 2007 GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2008. Available at: 10. Easton DF: Cancer risks in A-T heterozygotes. Int J Radiat Biol 66: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭ S177-S182, 1994 (suppl) fragilex. Accessed July 27, 2008 11. Geoffroy-Perez B, Janin N, Ossian K, et al: Cancer risk in heterozygotes 28. Bidichandani SI, Delatycki MB, Ashizawa T: Friedreich ataxia, in Ge- for ataxia-telangiectasia. Int J Cancer 93:288-293, 2001 neReviews at GeneTests: Medical Genetics Information Resource (da- 12. Jacquemont S, Hagerman RJ, Leehey MA, et al: Penetrance of the fragile tabase online). Copyright, University of Washington, Seattle. 1997- X-associated tremor/ataxia syndrome in a premutation carrier popula- 2008. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi? tion. JAMA 291:460-469, 2004 bookϭgene&partϭfriedreich. Accessed July 27, 2008 13. Hagerman RJ, Leavitt BR, Farzin F, et al: Fragile-X-associated tremor/ 29. Lin X, Ashizawa T: Spinocerebellar ataxia type 1, in GeneReviews at ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J GeneTests: Medical Genetics Information Resource (database online). Hum Genet 74:1051-1056, 2004 Copyright, University of Washington, Seattle. 1997-2008. Available at: 14. Hellier KD, Hatchwell E, Duncombe AS, et al: X-linked sideroblastic http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭsca1. anaemia with ataxia: Another mitochondrial disease? J Neurol Neuro- Accessed July 27, 2008 surg Psychiatry 70:65-69, 2001 30. Pulst SM: Spinocerebellar ataxia type 2, in GeneReviews at GeneTests: 15. Pagon RA, Bird TD, Detter JC, et al: Hereditary sideroblastic anaemia Medical Genetics Information Resource (database online). Copyright, and ataxia: an X linked recessive disorder. J Med Genet 22:267-273, University of Washington, Seattle. 1997-2008. Available at: http://www. 1985 ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭsca2. Accessed 16. DiMauro S, Schon EA: Mitochondrial respiratory-chain diseases. July 27, 2008 N Engl J Med 348:2656-2668, 2003 31. Paulson H: Spinocerebellar ataxia type 3 (2007), in GeneReviews at 17. Hart PE, Lodi R, Rajagopalan B, et al: Antioxidant treatment of patients GeneTests: Medical Genetics Information Resource (database online). with Friedreich ataxia: Four-year follow-up. Arch Neurol 62:621-626, Copyright, University of Washington, Seattle. 1997-2008. Available at: 2005 http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭsca3. 18. Mariotti C, Solari A, Torta D, et al: Idebenone treatment in Friedreich Accessed July 27, 2008 patients: One-year-long randomized placebo-controlled trial. Neurol- 32. Gomez CM: Spinocerebellar ataxia type 6, in GeneReviews at ogy 60:1676-1679, 2003 GeneTests: Medical Genetics Information Resource (database online). 19. Perlman SL: Ataxias. Clin Geriatr Med 22:859-877, 2006 Copyright, University of Washington, Seattle. 1997-2008. Available at: 20. Bird TD: Hereditary ataxia overview, in GeneReviews at GeneTests: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭsca6. Medical Genetics Information Resource (database online). Copyright, Accessed July 27, 2008 University of Washington, Seattle. 1997-2008. Available at: http://www. 33. Hirano R, Salih MAS, Takashima H, et al: Spinocerebellar ataxia with ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭataxias. Ac- axonal neuropathy, autosomal recessive, in GeneReviews at GeneTests: cessed July 27, 2008 Medical Genetics Information Resource (database online). Copyright, 21. Coutinho P, Barbot C, Moreira da Silva MC, et al: Ataxia with oculo- University of Washington, Seattle. 1997-2008. Available at: http://www. motor apraxia type 1, in GeneReviews at GeneTests: Medical Genetics ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭscan1. Accessed Information Resource (database online). Copyright, University of July 27, 2008 Washington, Seattle. 1997-2008. Available at: http://www. 34. Dupré N, Gros-Louis F, Bouchard JP, et al: SYNE1-related autosomal re- ncbi.nlm.nih.gov/bookshelf/br.fcgi?bookϭgene&partϭaoa. Accessed cessive cerebellar ataxia, in GeneReviews at GeneTests: Medical Genetics July 27, 2008 Information Resource (database online). Copyright, University of Wash- 22. Moreira MC, Koenig M: Ataxia with oculomotor apraxia type 2 (2007), ington, Seattle. 1997-2008. Available at: http://www.ncbi.nlm.nih.gov/ in GeneReviews at GeneTests: Medical Genetics Information Resource bookshelf/br.fcgi?bookϭgene&partϭsyne1ca-ar. Accessed July 27, 2008