Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

ISSN: 2167-8421 (Print) 2167-9223 (Online) Journal homepage: http://www.tandfonline.com/loi/iafd20

Pure cerebellar ataxia linked to large C9orf72 repeat expansion Philippe Corcia, Patrick Vourc’h, Anne-Marie Guennoc, Maria Del Mar Amador, Hélène Blasco, Christian Andres, Philippe Couratier, Paul H. Gordon & Vincent Meininger To cite this article: Philippe Corcia, Patrick Vourc’h, Anne-Marie Guennoc, Maria Del Mar Amador, Hélène Blasco, Christian Andres, Philippe Couratier, Paul H. Gordon & Vincent Meininger (2016) Pure cerebellar ataxia linked to large C9orf72 repeat expansion, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 17:3-4, 301-303, DOI: 10.3109/21678421.2015.1113298 To link to this article: http://dx.doi.org/10.3109/21678421.2015.1113298

Published online: 26 Nov 2015.

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Date: 13 July 2016, At: 14:20

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 2016; 17: 301–303

REPORT

Pure cerebellar ataxia linked to large C9orf72 repeat expansion

PHILIPPE CORCIA1,2, PATRICK VOURC’H2,3, ANNE-MARIE GUENNOC1, ´ LE ` NE BLASCO2,3, CHRISTIAN ANDRES2,3, MARIA DEL MAR AMADOR6, HE 4 PHILIPPE COURATIER , PAUL H. GORDON5 & VINCENT MEININGER1 Centre SLA, CHU Tours, 2UMR INSERM U930, Universite´ Franc¸ois-Rabelais de Tours, Tours, 3Service de Biochimie et Biologie Mole´culaire, CHRU de Tours, Tours, 4Centre SLA Service de Neurologie, CHU Dupuytren, Limoges, France, 5Northern Navajo Medical Center, Shiprock, NM, USA, and 6Fe´de´ration des Maladies du Syste`me Nerveux, Hoˆpital de la Salpeˆtrie`re, Paris, France

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Introduction Excessive repeats of the hexaplet GGGGCC in intron 1 of the C9orf72 gene are the most frequent genetic mutations so far identified that are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FLTD) (1). Since the first description of mutations in the C9orf72 gene, several groups have reported a link to other neurodegenerative syndromes, including Parkinson’s disease, corticobasal ganglionic degeneration, Huntington’s disease and rare anecdotal descriptions of an ataxia syndrome (2–5). In this report we describe the case of a 36-yearsold female who developed a pure cerebellar syndrome and who was found to have a C9orf72 mutation. This observation widens the spectrum of neurodegenerative conditions linked to C9orf72 mutations. Case report A 36-years-old female was first seen in June 2013 following a six-month history of speech disturbance. She had a pituitary adenoma that was resected in 2007 without any endocrine complications. She had no other medical history and did not take any medication. Her grandmother died of Parkinson’s disease and her 70-years-old mother suffered from frontotemporal dementia (FTD) associated with a C9orf72 mutation since the age of 62 years.

Her first symptoms occurred while she was pregnant. She developed scanning and explosive speech along with clumsiness of the left hand. Examination showed a broad based gait. She was unable to stand on one foot. Strength was graded 5 in all muscle groups. Deep tendon reflexes were present in the arms and legs with flexor plantar responses. There had an intention tremor most revealed during finger-nose testing and a marked incoordination of the legs during heel-shin tests. Sensory and cranial nerve examinations were normal. There was no Parkinsonism and no oculomotor apraxia. Visual pursuit was smooth. Saccades were slow and hypometric. Brain MRI showed a marked cerebellar atrophy, which was predominant in the vermis without parietal and frontaltemporal involvement (Figure 1a). The cerebellar atrophy was retrospectively noted in 2007 during work-up of the pituitary adenoma (Figure 1b). Nerve conduction studies and electromyography of the four limbs and bulbar muscles were normal. Fundoscopy examination was normal. Dopamine transporter (DAT) imaging with (123) PE2I-SPECT was normal. Neuropsychological testing found no cognitive disturbances (Mini Mental State Examination ¼ 30/30; Frontal Assessment Battery ¼ 18). Spinal fluid analysis and the following blood tests were normal or negative: liver function, onconeuronal antibodies,

Correspondence: P.Corcia, Centre SLA, CHU Bretonneau, 2 Boulevard Tonnell e´, 37044 Tours CEDEX1, France. Fax: 33 218370809. E-mail: [email protected] (Received 15 July 2015; revised 20 September 2015; accepted 29 September 2015) ISSN 2167-8421 print/ISSN 2167-9223 online ß 2015 Taylor & Francis DOI: 10.3109/21678421.2015.1113298

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Figure 1. (A) Coronal T2 weighted sequence showed no cortical atrophy. (B) Sagittal enhanced-T1 weighted sequence showed diffuse cerebellar atrophy. The black line defines the localization of the sagittal section.

antigangliosides anti-GAD antibodies, antigliadin and transglutaminase antibodies, thyroid function; B1, B12, B9 and, vitamin E level; homocysteinaemia, ammonia, VDRL-TPHA, alpha-foetoprotein and albumin; heavy metals, tropheryma whipelli PCR in CSF, urine and faeces. Genetic testing found no mutations in SCA1 (29/29 repeats), SCA2 (22/22 repeats), SCA3 (14/ 23 repeats), SCA6 (7/12 repeats), SCA7 (10/12 repeats), SCA12 (11/11 repeats), SCA17 (29/30 repeats), DRPLA (8/10 repeats) or Frataxin genes. Because of the known C9orf72 expansion carried by her mother, our patient underwent analysis of the C9orf72 gene using the established fluorescent repeat primed (RP) polymerase chain reaction approach, which revealed a classical pattern of large expansion of GGGGCC repeats (6). No other member of her family made requests for determination of C9orf72 gene status.

Discussion In our patient, the progressive mode of onset, slow rate of evolution, cerebellar atrophy found on neuroimaging, strong family history and the exclusion of other causes of progressive cerebellar syndromes by biological screening strongly support a genetic cause for our patient’s ataxia (7). Since there was no mutation in major genes classically linked to cerebellar ataxias and that C9orf72 abnormal expansion was identified both in her mother suffering from FTD and our patient strongly supported that a link between a C9orf72 mutation and the development of cerebellar ataxias existed.

This paucity of reports raised the question of the relationships between the C9orf72 mutation and the cerebellar degeneration. Several lines of evidence support a causative link (between abnormal C9orf72 expansions and cerebellar disturbances: 1) p62positive-TDP-43 negative neuronal intranuclear inclusions are found in the cerebellar granular layer of all carriers with abnormal C9orf72 expansion but not in ALS patients without abnormal C9orf72 expansion – these inclusions may prove to be a pathognomonic neuropathological signature of C9orf72-linked conditions; 2) imaging studies favouring consideration of cerebellar atrophy as a signature of C9orf72-linked FTLD since this was absent in cases of FTLD linked to PRGN or TAU mutations; 3) 18Fluoro FDG PET imaging detects changes in cerebellar metabolism early in the course of FTLD in patients with but not in those without C9orf72 mutations (8–10). Numerous genes involved in MND development have also been linked to cerebellar ataxias; some are known to be causative in both conditions as shown for the Senataxin, CHCHD10 and NOP56 genes (11,12). In the case of the Ataxin2 gene (ATXN2), the pathogenic effect depends on the number of abnormal CAG repeats: ATXN2 increases the risk of ALS when CAG repeats range from 27 to 34 and leads to SCA2 when CAG repeats exceed 34 (13). While we cannot state with absolute certainty that our patient might develop MND linked to C9orf72 mutation in the future, our observation is consistent with other reports of C9orf72 mutations in a widening array of neurological conditions. These potentially important associations deserve

Cerebellar ataxia linked to C9orf72 greater scrutiny. A first step could be to systematically analyse C9orf72 in relatives of C9orf72linked ALS or FTLD developing neurodegenerative conditions.

Declaration of interest: The authors report no conflicts of interest in this manuscript.

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Pure cerebellar ataxia linked to large C9orf72 repeat expansion.

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