sign in sign up
<<
Home , Fasciculation, Motor neuron disease

Research

Case Report/Case Series Multiple System and Amyotrophic Lateral Sclerosis in a Family With Hexanucleotide Repeat Expansions in

Jill S. Goldman, MS, MPhil; Catarina Quinzii, MD; Jane Dunning-Broadbent, PhD; Cheryl Waters, MD; Hiroshi Mitsumoto, MD; Thomas H. Brannagan III, MD, DSc; Stephanie Cosentino, PhD; Edward D. Huey, MD; Peter Nagy, MD, PhD; Sheng-Han Kuo, MD

Video at jamaneurology.com IMPORTANCE Here we report a family with coexistence of (MSA) and amyotrophic lateral sclerosis (ALS) with hexanucleotide repeat expansions in C9orf72.

OBSERVATIONS A 65-year-old woman had a 2-year history of with autonomic dysfunction but without signs. She was diagnosed as having MSA based on her clinical history and the hot cross bun sign on brain magnetic resonance imaging. Her 62-year-old brother had progressive weakness, , , and active denervation on without . He was diagnosed as having ALS. Both patients had a greater than 1000/2 hexanucleotide expansion in C9orf72.

Author Affiliations: Author CONCLUSIONS AND RELEVANCE Patients with hexanucleotide repeat expansions in C9orf72 affiliations are listed at the end of this can present with MSA as well as ALS or frontotemporal . We report this family with article. coexisting MSA and ALS, highlighting the phenotypic variability in neurologic presentations Corresponding Author: Jill S. with hexanucleotide repeat expansions in C9orf72. Goldman, MS, MPhil, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia JAMA Neurol. 2014;71(6):771-774. doi:10.1001/jamaneurol.2013.5762 University, 630 W 168th St, PO Box Published online April 14, 2014. 16, New York, NY 10032 (jg2673 @cumc.columbia.edu).

he differential diagnosis of cerebellar ataxia is very ported in 2 cases with pathological hexanucleotide repeat ex- broad, with both genetic and nongenetic causes. Non- pansions in C9orf72, both with a family history of ALS.7,8 One T genetic causes of ataxia include vascular disease, tu- case had ataxia onset at the age of 20 years with hyperreflexia mors and paraneoplastic syndrome, alcoholism, and vitamin but no sign.8 The other case was diag- E deficiencies. Genetic causes of ataxia include autosomal- nosed as having olivopontocerebellar atrophy with the dis- dominant, autosomal-recessive, X-linked, or mitochondrial ease onset at age 53 years.7 However, few detailed clinical char- DNA mutations. Genetic testing for ataxia is expensive, and acteristics in these 2 cases were described. Here, we present a about half of the patients with a family history of ataxia still family with pathological hexanucleotide repeat expansions in do not have identifiable mutations in genes that are known to C9orf72 with the diagnosis of ALS and ataxia, and we de- be associated with ataxia.1 In addition, many new ataxia ge- scribe the detailed clinical history, neurological examina- netic mutations are not yet available for testing in commer- tion, video, and imaging studies. This case history highlights cial laboratories. the importance of considering genetic testing for hexanucleo- Growing evidence suggests an association between re- tide repeat expansions in C9orf72 in ataxia patients with a fam- peat expansion disorders and both cerebellar ataxia and mo- ily history of ALS or dementia. tor neuron diseases. Pathological CAG repeat expansions of ataxin-1 (ATXN1) usually present as cerebellar ataxia, spino- cerebellar ataxia type 1 (SCA1); however, the large CAG repeat Report of a Case expansion of ATXN1 can present as amyotrophic lateral scle- rosis (ALS)–like disorders.1 Full CAG repeat expansions (>34) When first seen at our medical center, the patient was a 65- in ATXN2 cause SCA2,2 whereas an intermediate CAG repeat year-old woman with a 2-year history of progressive gait ataxia, expansion (between 27 and 33) in ATXN2 is a risk factor for frequent falling, poor handwriting, cognitive symptoms, uri- ALS.3,4 Another repeat expansion, the GGGGCC hexanucleo- nary incontinence, Raynaud phenomenon in her toes, ortho- tide repeat in C9orf72, has been discovered as the major ge- static hypotension, and constipation. She did not take any netic cause of ALS and (FTD), ac- medications. On examination, her sitting blood pressure was counting for 23% to 46% of familial ALS, 7% to 24% of familial 100/80 mm Hg and her standing blood pressure was 90/60 FTD, approximately 4% to 7% of sporadic ALS, and 3% to 6% mm Hg. She scored 25 out of 30 on the Montreal Cognitive As- of sporadic FTD.4-6 Interestingly, cerebellar ataxia has been re- sessment, losing 2 points in the visuospatial domain (copying

jamaneurology.com JAMA June 2014 Volume 71, Number 6 771

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Research Case Report/Case Series MSA and Amyotrophic Lateral Sclerosis

Figure 1. Brain Magnetic Resonance Imaging of the Proband With Ataxia

A B

A, T2-weighted axial magnetic resonance image of the brain of the 65-year-old woman with ataxia showed marked cerebellar degeneration and the hot cross bun sign in the pons (arrowhead). B, T1-weighted sagittal magnetic resonance image of the brain revealed marked pontocerebellar atrophy.

years after ataxia onset revealed impairment in semantic pro- Figure 2. Family Pedigree cessing and socioemotional functioning, consistent with fron- totemporal lobe dysfunction, but was too mild to meet the di- agnostic criteria of FTD.9 Additionally, she displayed some 47 y Amyotrophic emotional lability. She was diagnosed as having possible mul- lateral sclerosis tiple system atrophy (MSA) based on clinical presentation of ataxia, , autonomic dysfunction, and fast progression.10

65 y 62 y Written informed consent was obtained from the patient. Ataxia Amyotrophic The patient’s family history is shown in Figure 2.Her lateral sclerosis father developed at the age of 47 years The filled circle indicates multiple system atrophy; filled square, amyotrophic and was diagnosed as having ALS. He died 2 years later. Her lateral sclerosis. Ages shown are ages at diagnosis. brother also developed muscle weakness and atrophy in his right leg at the age of 62 years. He developed difficulty in the cube and drawing the clock), 1 for language (fluency), 1 for drinking and right arm weakness 2 months later, when he abstraction, and 1 for delayed recall. Her muscle strength was came to Columbia University for an evaluation. On examina- 5/5 throughout without fasciculations. Her reflexes were nor- tion, he had weak tongue strength and tongue atrophy with mal except for absent ankle jerks. Her facial expression was hy- . He had 5/5 arm strength, 3/5 strength in the right pomimic and she had 1+ bradykinesia in bilateral hand open- hip flexor, 5−/5 strength in the left hip flexor, 4/5 strength in close and finger taps in the Unified Parkinson Disease Rating the right hamstring and right tibialis anterior and evertor, Scale. She did not have any rigidity, rest , or spasticity. and 4+/5 strength in the right extensor halluces longus and She had normal sensory examination findings. She had promi- invertor. His left leg had otherwise 5/5 strength. He had spas- nent scanning speech, in bilateral finger-nose- ticity in all 4 extremities and fasciculations in the right arm finger test, finger chase, and heel-shin slides. She had im- and bilateral quadriceps. His reflexes were 3+ in the left paired fast alternating movements. Her gait was wide based biceps and 3+ in both knees. His plantar responses were and unsteady. She was unable to perform tandem gait or stance, flexor bilaterally and he had no jaw jerks. He had bilateral and she could not stand on 1 foot. Thirty-five months later, she Hoffmann reflexes and a normal finger-nose-finger test find- fell frequently, even with a walker. She could only walk with ing. He had and slight difficulty in tandem gait. maximal assistance. She also had short stride length and loss His nerve conduction study findings showed essentially nor- of heel strikes in addition to ataxia (Video). Her brain mag- mal motor and sensory nerve conduction studies. Electro- netic resonance imaging showed pontine and cerebellar atro- myography revealed diffuse and phy with the hot cross bun sign in the T2-weighted images potentials in many muscles tested. He was diagnosed as hav- (Figure 1). Autonomic test results revealed mild ing ALS. He did not have any sequence alteration in the neurogenic orthostatic hypotension. Urodynamic study con- familial ALS genes available at the first clinical visit includ- firmed the diagnosis of neurogenic bladder. Her initial nerve ing SOD1, TARDBP, ANG,orFUS assessed by Athena Diag- conduction study and electromyography findings showed nor- nostics. The patient’s condition progressed rapidly and sub- mal motor and sensory nerve conduction and no evidence of sequently was treated with tracheostomy and long-term fasciculation or denervation, and repeat electromyography 4 ventilation. years after ataxia symptom onset showed similar findings. More Based on our previous report of the diverse presentations extensive neuropsychological evaluation also performed 4 of ataxia and in a family with full CAG

772 JAMA Neurology June 2014 Volume 71, Number 6 jamaneurology.com

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 MSA and Amyotrophic Lateral Sclerosis Case Report/Case Series Research

repeat expansions of ATXN2 presenting with ataxia and mo- sis of olivopontocerebellar atrophy, a variant of MSA, and the tor neuron disease,11 we sent the blood samples to Athena Di- patient also had a family history of ALS.7 Our case adds to the agnostics and determined the CAG repeat expansions of literature of C9orf72 hexanucleotide repeat expansion in a fam- ATXN2. The proband had a normal CAG repeat length 22/22 in ily with both MSA and ALS. the ATXN2 gene. Because the hexanucleotide repeat expan- Neuroimaging of patients with C9orf72 hexanucleotide re- sions in C9orf72 can also either present as ataxia or motor peat expansions shows brain atrophy in the various parts of neuron disease,7,8 we tested this gene. Both the proband the brains. Cerebellar atrophy is much more common in pa- and her brother were found to have hexanucleotide repeat tients with FTD with the C9orf72 expansion than in patients expansions of greater than 44/2 in C9orf72.Wealsoper- with FTD with mutations in other FTD genes such as MAPT formed Southern blot analysis at the Columbia University or GRN.16,17 Interestingly, /p62-positive, TDP-43– research laboratory to determine the size of hexanucleotide negative neuronal cytoplasmic inclusions in the granular and repeat expansions4 of C9orf72 and found that both the pro- molecular layers of the cerebellum have been found to be char- band and her brother had repeats of more than 1000 with simi- acteristic of C9orf72 repeat expansion pathology.18 These stud- lar expansion size. In addition, we also excluded the COQ2 se- ies suggested that the cerebellum is commonly involved in the quence variant V343A associated with MSA12 and the C9orf72 repeat expansion disorders, although clinically cer- pathological repeat expansions13 of SCA36 in the proband. ebellar ataxia might not be apparent in most cases. Other fac- tors, such as environmental factors or genetic backgrounds, could determine the degree of cerebellar involvement. Inter- Discussion estingly, we found that the proband and her brother had simi- lar size of C9orf72 repeat expansions, which indicates that other We present a patient and her sibling with cerebellar ataxia and genetic modifiers or environmental factors might partly ac- ALS, respectively, with pathological hexanucleotide repeat ex- count for the phenotypic variability. pansions in C9orf72. C9orf72 hexanucleotide repeat expan- sion disease has very diverse clinical presentations, ALS and 4-6 FTD being the most common. Parkinsonism and cortico- Conclusions basal syndrome can also occur in patients with C9orf72 re- peat expansions.14,15 A study investigating the prevalence of C9orf72 hexanucleotide repeat expansion disease can have di- C9orf72 hexanucleotide repeat expansions among patients with verse clinical presentations including ALS, FTD, and cerebel- adult-onset sporadic ataxia found only 1 case out of 209 pa- lar ataxia. The exact prevalence of C9orf72 hexanucleotide re- tients carrying this mutation. Interestingly, this patient also peat expansions in patients with ataxia with a family history had a strong family history of ALS.8 Another reported case of of ALS has not been investigated but clinicians might con- ataxia with a C9orf72 repeat expansion had a clinical diagno- sider such genetic tests in this specific population.

ARTICLE INFORMATION Conflict of Interest Disclosures: None reported. data; preparation, review, or approval of the Accepted for Publication: November 6, 2013. Funding/Support: Ms Goldman received funding manuscript; and decision to submit the manuscript for publication. Published Online: April 14, 2014. from the National Institute on Aging [NIA]/National doi:10.1001/jamaneurol.2013.5762. Institutes of Health [NIH] (grant P50 AG08702; principal investigator: Michael Shelanski, MD, PhD), REFERENCES Author Affiliations: Taub Institute for Research on the National Institute of Neurological Disorders and 1. Dürr A. Autosomal dominant cerebellar : Alzheimer’s Disease and the Aging Brain, Columbia (NINDS)/NIH (grant R01NS076837-01A1; polyglutamine expansions and beyond. Lancet University, New York, New York (Goldman); principal investigator: Edward D. Huey, MD), and Neurol. 2010;9(9):885-894. Department of Neurology, Columbia University, the Parkinson’s Disease Foundation. Dr Mitsumoto New York, New York (Quinzii, Waters, Mitsumoto, 2. Pulst SM, Nechiporuk A, Nechiporuk T, et al. received funding from the NIH (grant Moderate expansion of a normally biallelic Brannagan, Cosentino, Huey, Kuo); Department of R01-ES016348), the Spastic Paraplesia Foundation, Psychiatry, Columbia University, New York, New trinucleotide repeat in type and the Muscular Dystrophy Association. Dr 2. Nat Genet. 1996;14(3):269-276. York (Huey); Department of Pathology and Cell Cosentino is funded by the NINDS/NIH (grant Biology, Columbia University, New York, New York R01NS076837) and NIA/NIH (grant 3. Elden AC, Kim HJ, Hart MP, et al. Ataxin-2 (Dunning-Broadbent, Nagy). P50AG008702). Dr Huey is funded by the intermediate-length polyglutamine expansions are Author Contributions: Ms Goldman and Dr Kuo NINDS/NIH (grants R01NS076837 and associated with increased risk for ALS. Nature. had full access to all of the data in the study and R00NS060766), the Florence and Herbert Irving 2010;466(7310):1069-1075. take responsibility for the integrity of the data and Clinical Research Career Award, and the NIA/NIH 4. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, the accuracy of the data analysis. (grants P50AG008702, R01AG041795, and et al. Expanded GGGGCC hexanucleotide repeat in Study concept and design: Kuo. R0103873402). Drs Dunning-Broadbent and Nagy noncoding region of C9ORF72 causes chromosome Acquisition, analysis, or interpretation of data: All are funded by the NINDS/NIH (grant 9p-linked FTD and ALS. Neuron. 2011;72(2): authors. 5R01NS64253-5). Dr Kuo received funding from the 245-256. Drafting of the manuscript: Kuo. NIH (grant K08 NS083738), the Louis V. Gerstner 5. Renton AE, Majounie E, Waite A, et al; ITALSGEN Critical revision of the manuscript for important Jr Scholar Award, the Parkinson’s Disease Consortium. A hexanucleotide repeat expansion in intellectual content: Goldman, Quinzii, Foundation, the American Academy of Neurology C9ORF72 is the cause of chromosome 9p21-linked Dunning-Broadbent, Waters, Mitsumoto, Research Fellowship, and the American Parkinson’s ALS-FTD. Neuron. 2011;72(2):257-268. Brannagan, Cosentino, Huey, Nagy. Disease Association. Administrative, technical, or material support: 6. Majounie E, Renton AE, Mok K, et al; Role of the Sponsor: The funders had no role in the Chromosome 9-ALS/FTD Consortium; French Goldman, Quinzii, Dunning-Broadbent, Waters. design and conduct of the study; collection, Study supervision: Cosentino, Huey, Kuo. Research Network on FTLD/FTLD/ALS; ITALSGEN management, analysis, and interpretation of the Consortium. Frequency of the C9orf72

jamaneurology.com JAMA Neurology June 2014 Volume 71, Number 6 773

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/29/2021 Research Case Report/Case Series MSA and Amyotrophic Lateral Sclerosis

hexanucleotide repeat expansion in patients with 11. Tazen S, Figueroa K, Kwan JY, et al. Amyotrophic 15. Snowden JS, Rollinson S, Thompson JC, et al. amyotrophic lateral sclerosis and frontotemporal lateral sclerosis and spinocerebellar ataxia type 2 in Distinct clinical and pathological characteristics of dementia: a cross-sectional study. Lancet Neurol. a family with full CAG repeat expansions of ATXN2. frontotemporal dementia associated with C9ORF72 2012;11(4):323-330. JAMA Neurol. 2013;70(10):1302-1304. mutations. Brain. 2012;135(Pt 3):693-708. 7. Lindquist SG, Duno M, Batbayli M, et al. 12. Multiple-System Atrophy Research 16. Mahoney CJ, Downey LE, Ridgway GR, et al. Corticobasal and ataxia syndromes widen the Collaboration. Mutations in COQ2 in familial and Longitudinal neuroimaging and neuropsychological spectrum of C9ORF72 hexanucleotide expansion sporadic multiple-system atrophy. N Engl J Med. profiles of frontotemporal dementia with C9ORF72 disease. Clin Genet. 2013;83(3):279-283. 2013;369(3):233-244. expansions. Alzheimers Res Ther. 2012;4(5):41. 8. Fogel BL, Pribadi M, Pi S, Perlman SL, Geschwind 13. Kobayashi H, Abe K, Matsuura T, et al. 17. Whitwell JL, Weigand SD, Boeve BF, et al. DH, Coppola G. C9ORF72 expansion is not a Expansion of intronic GGCCTG hexanucleotide Neuroimaging signatures of frontotemporal significant cause of sporadic spinocerebellar ataxia. repeat in NOP56 causes SCA36, a type of dementia genetics: C9ORF72, tau, progranulin and Mov Disord. 2012;27(14):1832-1833. spinocerebellar ataxia accompanied by motor sporadics. Brain. 2012;135(pt 3):794-806. 9. Rascovsky K, Hodges JR, Knopman D, et al. neuron involvement. Am J Hum Genet. 2011;89(1): 18. Mori K, Weng SM, Arzberger T, et al. The Sensitivity of revised diagnostic criteria for the 121-130. C9orf72 GGGGCC repeat is translated into behavioural variant of frontotemporal dementia. 14. Boeve BF, Boylan KB, Graff-Radford NR, et al. aggregating dipeptide-repeat proteins in FTLD/ALS. Brain. 2011;134(pt 9):2456-2477. Characterization of frontotemporal dementia Science. 2013;339(6125):1335-1338. 10. Gilman S, Wenning GK, Low PA, et al. Second and/or amyotrophic lateral sclerosis associated with consensus statement on the diagnosis of multiple the GGGGCC repeat expansion in C9ORF72. Brain. system atrophy. Neurology. 2008;71(9): 2012;135(pt 3):765-783. 670-676.

774 JAMA Neurology June 2014 Volume 71, Number 6 jamaneurology.com

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 09/29/2021