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

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 remark- able 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 evo- lution 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.

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