Abstracts
Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. They are mostly related to different pathophysiological processes, notably in family forms in which the clinical and genetic heterogeneity are lush. In the last decade, much knowledge has been acumulated about the genetics of neurodegenerative diseases, making it essential in cases of motor neuron disease and frontotemporal dementia the repeat expansions of C9orf72 gene. This review analyzes the main clinical, radiological and genetic aspects of the phenotypes related to the hexanucleotide repeat expansions (GGGGCC) of C9orf72 gene. Future studies will aim to further characterize the neuropsychological, imaging and pathological aspects of the extra-motor features of motor neuron disease, and will help to provide a new classification system that is both clinically and biologically relevant.
neurodegenerative diseases; motor neuron disease; frontotemporal dementia; parkinsonism; C9orf72
As doenças neurodegenerativas representam um grupo heterogêneo de condições neurológicas envolvendo fundamentalmente síndromes demenciais, doenças do neurônio motor e distúrbios de movimento. Relacionam-se, em sua maioria, a processos fisiopatológicos distintos, destacadamente nas formas familiares em que a heterogeneidade clínica e genética são exuberantes. Na última década, muito conhecimento se acumulou a respeito da genética das doenças neurodegenerativas, tornando-se bastante importante nos casos de doenças do neurônio motor e de demência frontotemporal as expansões de repetições do gene C9orf72. Esta revisão aborda os principais aspectos clínicos, radiológicos e genéticos relativos aos fenótipos relacionados à expansão de repetição do hexanucleotídeo (GGGGCC) no gene C9orf72. Estudos futuros vão objetivar a caracterização dos aspectos neuropsicológicos, de imagem e patológicos dos achados extra-motores da doença do neurônio motor e ajudarão a fornecer um novo sistema de classificação relevante em termos clínicos e biológicos.
doenças neurodegenerativas; doença do neurônio motor; demência frontotemporal; parkinsonismo; C9orf72
Neurodegenerative diseases represent a heterogeneous group of neurological conditions primarily involving dementia, motor neuron disease and movement disorders. A wide group of different pathophysiological and genetic mechanisms are involved in this group. Knowledge regarding the genetic basis of sporadic and familial cases of neurodegenerative disorders is growing and new evidences about the involvement of previously unknown genes are the rule. This is particularly true in cases with complex motor and cognitive phenotypes.
Motor neuron disease comprises four main different clinical forms of upper and lower
motor neuron involvement: primary lateral sclerosis; progressive muscular atrophy;
progressive bulbar palsy; and amyotrophic lateral sclerosis (ALS). ALS represents the
most common form of progressive neurodegenerative motor neuron disease with upper and
lower motoneuron compromise, clinically defined through specific clinical and
electroneuromyographic diagnostic criteria, the so-called El Escorial revised criteria
and the Awaji-shima electrodiagnostic criteria. However, ALS is more than a pure motor
neuron disease. It is a heterogeneous syndrome with clinical, pathological and genetic
overlap with frontotemporal dementia11 Oliveira AS, Pereira RD. Amyotrophic lateral sclerosis (ALS): three
letters that change the people’s life. For ever. Arq Neuropsiquiatr.
2009;67(3A):750-82.
http://dx.doi.org/10.1590/S0004-282X2009000400040
https://doi.org/10.1590/S0004-282X200900...
.
Frontotemporal lobar degeneration (or simply frontotemporal dementia) (FTD) represents
one of the most common and wide studied neurodegenerative group of cognitive and
behavioural conditions, generally giving rise to an early-onset dementia with
behavioural disturbances involving three particular clinical syndromes22 Kaivorinne AL, Bode MK, Paavola L, Tuominen H, Kallio M, Renton AE
et al. Clinical characteristics of C9ORF72-linked frontotemporal lobar
degeneration. Dement Geriatr Cogn Dis Extra. 2013;3(1):251-62.
http://dx.doi.org/10.1159/000351859
https://doi.org/10.1159/000351859...
,33 Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S et al.
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with
amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional
study. Lancet Neurol. 2012;11(4):323-30.
http://dx.doi.org/10.1016/S1474-4422(12)70043-1
https://doi.org/10.1016/S1474-4422(12)70...
,44 Rademakers R, Neumann M, Mackenzie IR. Recent advances in the
molecular basis of frontotemporal dementia. Nat Rev Neurol. 2012;8(8):423-34.
http://dx.doi.org/10.1038/nrneurol.2012.117
https://doi.org/10.1038/nrneurol.2012.11...
: the so-called behavioural variant frontotemporal dementia
(bvFTD), semantic variant of primary progressive aphasia (svPPA) and
nonfluent/agrammatic variant of primary progressive aphasia (nflvPPA). A logopenic
variant of primary progressive aphasia has also been considered.
Despite its major presentation as a cognitive and behavioral disturbance, in some cases
of FTD, motor involvement is prominent. Since 2006, there is growing evidence about the
participation of a major gene locus involved in FTD and ALS phenotypes located on
chromosome 9p (the previously known chromosome 9p-linked FTD with ALS)44 Rademakers R, Neumann M, Mackenzie IR. Recent advances in the
molecular basis of frontotemporal dementia. Nat Rev Neurol. 2012;8(8):423-34.
http://dx.doi.org/10.1038/nrneurol.2012.117
https://doi.org/10.1038/nrneurol.2012.11...
,55 Takada LT, Sha SJ. Neuropsychiatric features of C9orf72-associated
behavioral variant frontotemporal dementia and frontotemporal dementia with
motor neuron disease. Alzheimers Res Ther. 2012;4(5):38.
http://dx.doi.org/10.1186/alzrt141
https://doi.org/10.1186/alzrt141...
, which subsequently in 2011 proved to represent an
hexanucleotide repeat expansion in the non-coding region of C9orf72
gene66 DeJesus-Hernandez M, Mackenzie IR, Boeve BF, Boxer Al, Baker M,
Rutherford NJ et al. Expanded GGGGCC hexanucleotide repeat in noncoding region
of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011;72(2):245-56.
http://dx.doi.org/10.1016/j.neuron.2011.09.011
https://doi.org/10.1016/j.neuron.2011.09...
,77 Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson
S, Gibbs JR et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of
chromosome 9p21-linked ALS-FTD. Neuron. 2011;72(2):257-68.
http://dx.doi.org/10.1016/j.neuron.2011.09.010
https://doi.org/10.1016/j.neuron.2011.09...
.
ALS can be viewed as resulting from a complex convergence of genetic susceptibility, age-related loss of cellular homeostasis, and possible environment influences. The rapid increase in recent years of the number of genes in which mutations have been associated with ALS has led to in vitro and in vivo models that have generated a wealth of data indicating disruption of specific biochemical pathways and sub-cellular compartments, including protein misfolding, mRNA splicing, axonal transport, oxidative stress, proteasome and mitochondrial dysfunctions (Figure 1). Since the identification of the C9orf72 gene, the mechanisms of the interaction between cellular degeneration and system level degeneration have been better elucidated, providing a roadmap for developing novel treatments based on specific targeting of gene mutations. The aim of this review is to focus in the main information regarding genetic, pathophysiological, clinical and neuroimaging features of C9orf72-related disorders.
Schematic representation of the main pathophysiological mechanisms involved with motor neuron disease, (1) including protein misfolding, (2) altered RNA processing (mainly disturbed mRNA splicing), (3) defects in axonal transport, (4) abnormal accumulation of reactive oxygen species, (5) mitochondrial dysfunctions, (6) microglial neuroinflammatory mechanisms, (7) direct excitotoxicity by astrocytes, (8) disturbances of autophagy, (9) proteosome abnormalities and (10) ion channel defects.
EPIDEMIOLOGICAL PROFILE
The overall prevalence of ALS ranges from 2-7 cases per 100,000 inhabitants11 Oliveira AS, Pereira RD. Amyotrophic lateral sclerosis (ALS): three
letters that change the people’s life. For ever. Arq Neuropsiquiatr.
2009;67(3A):750-82.
http://dx.doi.org/10.1590/S0004-282X2009000400040
https://doi.org/10.1590/S0004-282X200900...
. A minor proportion of 5% of ALS
cases represent familial autosomal dominant ALS cases88 Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ
et al. Clinical characteristics of patients with familial amyotrophic lateral
sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of
C9ORF72. Brain. 2012;135(Pt 3):784-93.
http://dx.doi.org/10.1093/brain/awr366
https://doi.org/10.1093/brain/awr366...
. In the last decade, SOD1 mutations were considered the
most common genetic form of familial ALS11 Oliveira AS, Pereira RD. Amyotrophic lateral sclerosis (ALS): three
letters that change the people’s life. For ever. Arq Neuropsiquiatr.
2009;67(3A):750-82.
http://dx.doi.org/10.1590/S0004-282X2009000400040
https://doi.org/10.1590/S0004-282X200900...
. However, great knowledge was obtained from new gene
discovery allowing a more comprehensive approach in the previously unidentified
familial cases. Mutations in the C9orf72 gene represent up to
50%-60% of cases of familial ALS and up 10% of sporadic ALS in some locations, but
with an average of one third of familial cases99 Hodges J. Familial frontotemporal dementia and amyotrophic lateral
sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain.
2012;135(3):652-5. http://dx.doi.org/10.1093/brain/aws033
https://doi.org/10.1093/brain/aws033...
,1010 Al-Chalabi A., Hardiman O. The epidemiology of ALS: a conspiracy of
genes, environment and time. Nat Rev Neurol. 2013;9(11):617-28.
http://dx.doi.org/10.1038/nrneurol.2013.203
https://doi.org/10.1038/nrneurol.2013.20...
. It is also believed that most sporadic cases of ALS
under the general assignment of unknown or unidentified genetic cause may be
originated by C9orf72 mutations1111 Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic
lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23.
http://dx.doi.org/10.1038/nn.3584
https://doi.org/10.1038/nn.3584...
,1212 Rheenen W, Blitterswijk M, Huisman MH, Vlam L, Doormaal PT, Seelen M
et al. Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor
neuron diseases. Neurology. 2012;79(9):878-82.
http://dx.doi.org/10.1212/WNL.0b013e3182661d14
https://doi.org/10.1212/WNL.0b013e318266...
.
FTD presents with a global average prevalence of 15-22 cases per 100,000 inhabitants.
Around 40%-50% of FTD cases present with a positive family history of dementia,
mainly with autosomal dominant inheritance pattern1313 Sha SJ, Boxer A. Treatment implications of C9ORF72. Alzheimers Res
Ther. 2012;4(6):46. http://dx.doi.org/10.1186/alzrt149
https://doi.org/10.1186/alzrt149...
. It is estimated that up to 18%-24% cases of familial
FTD and 6%-10% of sporadic cases of bvFTD are due to C9orf72
expansions55 Takada LT, Sha SJ. Neuropsychiatric features of C9orf72-associated
behavioral variant frontotemporal dementia and frontotemporal dementia with
motor neuron disease. Alzheimers Res Ther. 2012;4(5):38.
http://dx.doi.org/10.1186/alzrt141
https://doi.org/10.1186/alzrt141...
,1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y.
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat
expansion: a perspective. J Nucleic Acids. 2013;2013:208245.
http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245...
,1515 Zee J, Gijselinck I, Dillen L, Van Langenhove T, Theuns J,
Engelborghs S et al. A pan-European study of the C9orf72 repeat associated with
FTLD: geographic prevalence, genomic instability, and intermediate repeats. Hum
Mutat. 2013;34(2):363-73. http://dx.doi.org/10.1002/humu.22244
https://doi.org/10.1002/humu.22244...
.
C9orf72 repeat expansions have a wide global distribution, mainly in
European-derived populations, and an exceptionally low prevalence in East Asian
populations and probably in South and Southern Asia regions1616 Woollacott IO, Mead S. The C9ORF72 expansion mutation: gene
structure, phenotypic and diagnostic issues. Acta Neuropathol.
2014;127(3):319-32. http://dx.doi.org/10.1007/s00401-014-1253-7
https://doi.org/10.1007/s00401-014-1253-...
. In cases of FTD in Europe (including patients
from 15 countries), C9orf72 repeat expansions were detected with
high frequency in Finland (29.3% of all cases), in Spain (25.5%) and in Sweden
(20.7%), and low prevalence was detected in Germany (4.8%). In a large group of
patients from USA, Europe and Australia, the overall C9orf72
prevalence was 7% of sporadic ALS, 39.3% of familial ALS, 6% of sporadic FTD and
24.8% of familial FTD33 Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S et al.
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with
amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional
study. Lancet Neurol. 2012;11(4):323-30.
http://dx.doi.org/10.1016/S1474-4422(12)70043-1
https://doi.org/10.1016/S1474-4422(12)70...
. Other
series form London patients with the FTD-ALS phenotype, 26% presented with the
C9orf72 expansion followed by 24% in SOD1
gene, 4% in FUS gene and 1% in TARDPB
gene1717 Smith BN, Newhouse S, Shatunov A, Vance C, Topp S, Johnson L et al.
The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has
a single founder. Eur J Hum Genet. 2013;21(1):102-8.
http://dx.doi.org/10.1038/ejhg.2012.98
https://doi.org/10.1038/ejhg.2012.98...
, showing that
C9orf72 represents the most common genetic cause of familial
cases of FTD-ALS in Europe1818 Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V
et al. C9ORF72, implicated in amyotrophic lateral sclerosis and frontotemporal
dementia, regulates endosomal trafficking. Hum Mol Genet. 2014;23(13):3579-95.
http://dx.doi.org/10.1093/hmg/ddu06
https://doi.org/10.1093/hmg/ddu06...
.
GENETIC ASPECTS AND PATHOPHYSIOLOGY
Familial and sporadic cases of ALS and FTD have been linked to several genomic
regions, most related to one or more different mechanisms of neurodegeneration1111 Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic
lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23.
http://dx.doi.org/10.1038/nn.3584
https://doi.org/10.1038/nn.3584...
,1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
,2020 He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA. Amyotrophic
lateral sclerosis genetic studies: from genome-wide association mapping to
genome sequencing. Neuroscientist 2014 Nov 5. pii: 1073858414555404. [Epub
ahead of print]. doi: 10.1177/1073858414555404. An extensive number of genes located in different
chromosome regions and related to distinct patophysiological mechanisms have been
linked to clinical and neuropathological findings of FTD and ALS (Tables 1 and 2)44 Rademakers R, Neumann M, Mackenzie IR. Recent advances in the
molecular basis of frontotemporal dementia. Nat Rev Neurol. 2012;8(8):423-34.
http://dx.doi.org/10.1038/nrneurol.2012.117
https://doi.org/10.1038/nrneurol.2012.11...
,1111 Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic
lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23.
http://dx.doi.org/10.1038/nn.3584
https://doi.org/10.1038/nn.3584...
,1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y.
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat
expansion: a perspective. J Nucleic Acids. 2013;2013:208245.
http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245...
,2020 He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA. Amyotrophic
lateral sclerosis genetic studies: from genome-wide association mapping to
genome sequencing. Neuroscientist 2014 Nov 5. pii: 1073858414555404. [Epub
ahead of print]. doi: 10.1177/1073858414555404,2121 Van Langenhove T, Zee J, Van Broeckhoven C. The molecular basis of
the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum.
Ann Med. 2012;44(8):817-28.
http://dx.doi.org/10.3109/07853890.2012.665471
https://doi.org/10.3109/07853890.2012.66...
.
Genetic causes of frontotemporal dementia44 Rademakers R, Neumann M, Mackenzie IR. Recent advances in the molecular basis of frontotemporal dementia. Nat Rev Neurol. 2012;8(8):423-34. http://dx.doi.org/10.1038/nrneurol.2012.117
https://doi.org/10.1038/nrneurol.2012.11... ,2020 He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA. Amyotrophic lateral sclerosis genetic studies: from genome-wide association mapping to genome sequencing. Neuroscientist 2014 Nov 5. pii: 1073858414555404. [Epub ahead of print]. doi: 10.1177/1073858414555404,2121 Van Langenhove T, Zee J, Van Broeckhoven C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med. 2012;44(8):817-28. http://dx.doi.org/10.3109/07853890.2012.665471
https://doi.org/10.3109/07853890.2012.66... .
Genetic causes of amyotrophic lateral sclerosis (familial and sporadic cases)1111 Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23. http://dx.doi.org/10.1038/nn.3584
https://doi.org/10.1038/nn.3584... ,1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y. Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat expansion: a perspective. J Nucleic Acids. 2013;2013:208245. http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245... ,2020 He J, Mangelsdorf M, Fan D, Bartlett P, Brown MA. Amyotrophic lateral sclerosis genetic studies: from genome-wide association mapping to genome sequencing. Neuroscientist 2014 Nov 5. pii: 1073858414555404. [Epub ahead of print]. doi: 10.1177/1073858414555404.
C9orf72 (chromosome 9 open reading frame 72) gene (MIM *614260)
represents a reasonably recently described gene linked to sporadic and familial
cases of neurodegenerative disorders. Heterozygous hexanucleotide repeat expansions
in a noncoding region of the gene are responsible for its pathogenesis, in a similar
pattern of other repeat expansion disorders2222 La Spada AR, Taylor JP. Repeat expansion disease: progress and
puzzles in disease pathogenesis. Nat Rev Genet. 2010;11(4):247-58.
http://dx.doi.org/10.1038/nrg2748
https://doi.org/10.1038/nrg2748...
,2323 Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion:
mechanisms and common principles. Nat Rev Genet. 2005;6(10):743-55.
http://dx.doi.org/10.1038/nrg1691
https://doi.org/10.1038/nrg1691...
,2424 Van Blitterswijk M, DeJesus-Hernandez M, Rademakers R. How do
C9ORF72 repeat expansions cause ALS and FTD: can we learn from other non-coding
repeat expansion disorders? Curr Opin Neurol. 2012;25:689-700.
http://dx.doi.org/10.1097/WCO.0b013e32835a3efb
https://doi.org/10.1097/WCO.0b013e32835a...
(Table 3).
C9orf72-related disorders represent clinical and pathologically
heterogeneous autosomal dominant neurodegenerative diseases with partial (or
incomplete) penetrance, giving rise to pleiotropic manifestations. The pathogenic
repeat expansion is fully penetrant around 80 years, but no penetrance is found in
individuals younger than 35 years33 Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S et al.
Frequency of the C9orf72 hexanucleotide repeat expansion in patients with
amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional
study. Lancet Neurol. 2012;11(4):323-30.
http://dx.doi.org/10.1016/S1474-4422(12)70043-1
https://doi.org/10.1016/S1474-4422(12)70...
.
In some cases, anticipation has been observed, but less prominent than in other
expansion repeat expansion diseases. An european founder effect has been detected
for the expansion in Scandinavia, more specifically in Finland1616 Woollacott IO, Mead S. The C9ORF72 expansion mutation: gene
structure, phenotypic and diagnostic issues. Acta Neuropathol.
2014;127(3):319-32. http://dx.doi.org/10.1007/s00401-014-1253-7
https://doi.org/10.1007/s00401-014-1253-...
.
Clinical neurological diseases associated with the genetic mechanism of unstable nucleotide repeat expansion2222 La Spada AR, Taylor JP. Repeat expansion disease: progress and puzzles in disease pathogenesis. Nat Rev Genet. 2010;11(4):247-58. http://dx.doi.org/10.1038/nrg2748
https://doi.org/10.1038/nrg2748... ,2323 Gatchel JR, Zoghbi HY. Diseases of unstable repeat expansion: mechanisms and common principles. Nat Rev Genet. 2005;6(10):743-55. http://dx.doi.org/10.1038/nrg1691
https://doi.org/10.1038/nrg1691... ,2424 Van Blitterswijk M, DeJesus-Hernandez M, Rademakers R. How do C9ORF72 repeat expansions cause ALS and FTD: can we learn from other non-coding repeat expansion disorders? Curr Opin Neurol. 2012;25:689-700. http://dx.doi.org/10.1097/WCO.0b013e32835a3efb
https://doi.org/10.1097/WCO.0b013e32835a... .
The C9orf72 gene is located on 9p21.2 and is formed by 12 exons,
coding 3 transcription variants and two protein isoforms (a, b). Transcript variants
1, which contains nonconding exons 1b, and 3, which contains noncoding exon 1a, are
fused to coding exons 2 through 5 and encode a longer isoform of the protein with
481 amino acid (called isoform a). Transcript variant 2, which contains exon 1a,
encodes a shorter protein with 222 amino acid (called isoform b), highly expressed
in testis, fetal brain, cerebellum and frontal cortex1616 Woollacott IO, Mead S. The C9ORF72 expansion mutation: gene
structure, phenotypic and diagnostic issues. Acta Neuropathol.
2014;127(3):319-32. http://dx.doi.org/10.1007/s00401-014-1253-7
https://doi.org/10.1007/s00401-014-1253-...
.
The expansion site is located in the 5’ regulatory region upstream of the
transcription start site between two non-coding exons (1a, 1b) in the core promoter
for transcript variant 1, leading to haploinsufficiency mechanism with variable
degrees of reduction of isoform a. For transcription variants 2 and 3, the expansion
is located in intron 1, leading to aberrant and abnormal production with classical
gain-of-function mechanisms participating in toxic pathogenetic mechanisms and
influencing the processing of precursor mRNAs (Figure
2). Hexanucleotide repeat expansion also forms DNA and RNA G-quadruplexes
which promotes the formation of RNA/DNA hybrids (R-loops), originating a repeat
length-dependent accumulation of transcripts which bind to ribonucleoproteins, such
as nucleolin, giving rise to nucleolar stress1616 Woollacott IO, Mead S. The C9ORF72 expansion mutation: gene
structure, phenotypic and diagnostic issues. Acta Neuropathol.
2014;127(3):319-32. http://dx.doi.org/10.1007/s00401-014-1253-7
https://doi.org/10.1007/s00401-014-1253-...
,2525 Reddy K, Zamiri B, Stanley SYR, Macgregor Jr RB, Pearson CE. The
disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract
length-dependent uni- and multimolecular RNA G-quadruplex structures. J Biol
Chem. 2013;288(14):9860-6.
http://dx.doi.org/10.1074/jbc.C113.452532
https://doi.org/10.1074/jbc.C113.452532...
.
Schematic representation of C9orf72 gene structure and its transcript variants produced by alternative splicing.
Loss-of-function by means of happloinsufficiency represents the main mechanism
involved in its pathogenesis (Figure 3). The
C9orf72 encoded protein is found in presynaptic terminals and
cytoplasmic regions of neurons in a diffuse pattern and is still poorly understood.
One of the main hypotheses regarding its function propose a similar function to
guanine nucleotide exchange factors for small GTPases associated with the regulation
of Rab protein system during endosomal trafficking regulation of exocytosis and
endocytosis (with the Rab protein system) in neuronal cell lines, primary cortical
neurons and spinal cord motor neurons. It gives rise to a higher rate of lysosomal
protein degradation and abnormal accumulation of ubiquinated proteins2626 Yokoyama JS, Sirkis DW, Miller BL. C9ORF72 hexanucleotide repeats in
behavioral and motor neuron disease: clinical heterogeneity and pathological
diversity. Am J Neurodegener Dis. 2014;3(1):1-18.
http://dx.doi.org/10.1186/2051-5960-2-70
https://doi.org/10.1186/2051-5960-2-70...
. The C9orf72
encoded protein also participates in mechanisms of neuronal autophagic process and
interacts with nuclear proteins involved with regulation of splicing and RNA
metabolism1818 Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RA, Levina V
et al. C9ORF72, implicated in amyotrophic lateral sclerosis and frontotemporal
dementia, regulates endosomal trafficking. Hum Mol Genet. 2014;23(13):3579-95.
http://dx.doi.org/10.1093/hmg/ddu06
https://doi.org/10.1093/hmg/ddu06...
.
Pathophysiological mechanisms involved with abnormal RNA processing in C9orf72-related disorders. The aborted RNA transcript can migrate to cytoplasm and give rise rybosomal traduction of abnormal misfolded protein with unknown functions and originate aggregates of C9-related abnormal proteins, frequently seen in immunohistochemical analysis as intraneuronal intracytoplasmic inclusions. The aborted RNA transcript can also participate in complex intranuclear interactions and promote nucleolar stress. Both mechanisms participate as particular pathophysiological mechanisms seen in C9orf72-related FTD-ALS.
C9orf72 expansion-mediated toxicity occurs by accumulation of toxic
RNA foci and RNA-binding proteins with secondary dysregulation of RNA splicing and
trafficking, and inappropriate formation of novel dipeptide aggregates resulting
from non-ATG mediated (RAN) translation of the hexanucleotide repeat (colocalized
with p62+ inclusions)2727 Davidson YS, Barker H, Robinson AC, Thompson JC, Harris J, Troakes C
et al. Brain distribution of dipeptide repeat proteins in frontotemporal lobar
degeneration and motor neurone disease associated with expansions in C9ORF72.
Acta Neuropathol Commun. 2014;2(1):70.. Most
cases result from gain-of-function mechanisms directly related or not to the encoded
protein. RNA-mediated cytotoxic nuclear and cytoplasmic mechanisms may occur first
in astrocytes and result from RNA foci formation, not found in sporadic ALS or
familial FTD-ALS causes by other gene mutations2828 Cruts M, Gijselinck I, Van Langenhove T, van der Zee J, Van
Broeckhoven C. Current insights into the C9orf72 repeat expansion diseases of
the FTLD/ALS spectrum. Trends Neurosci. 2013;36(8):450-9.
http://dx.doi.org/10.1016/j.tins.2013.04.010
https://doi.org/10.1016/j.tins.2013.04.0...
,2929 Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR et al.
Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS
and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013;110(47):E4530-9.
http://dx.doi.org/10.1073/pnas.1318835110
https://doi.org/10.1073/pnas.1318835110...
. Aggregate formation occur mainly through proteasome
dysfunction, commonly found in C9orf72-related ALS and FTD cases.
Genetic instability, dysfunction of the promoter region, abnormal mRNA distribution,
splicing and translation are also linked to the formation of G-quadruplexes (or
G-tetrads) of uni and multimolecular RNA2424 Van Blitterswijk M, DeJesus-Hernandez M, Rademakers R. How do
C9ORF72 repeat expansions cause ALS and FTD: can we learn from other non-coding
repeat expansion disorders? Curr Opin Neurol. 2012;25:689-700.
http://dx.doi.org/10.1097/WCO.0b013e32835a3efb
https://doi.org/10.1097/WCO.0b013e32835a...
. Besides this intraneuronal mechanisms, it has been
demonstrated that ALS patients carrying C9orf72 mutations have
astrocytes that convey toxicity towards motor neurons3030 Meyer K, Ferraiuolo L, Miranda CJ, Likhite S, McElroy S, Renusch S
et al. Direct conversion of patient fibroblasts demonstrates non-cell autonomous
toxicity of astrocytes to motor neurons in familial and sporadic ALS. Proc Natl
Acad Sci USA. 2014;111(2):829-32.
http://dx.doi.org/10.1073/pnas.1314085111
https://doi.org/10.1073/pnas.1314085111...
.
The so-called GGGGCC (G4C2)n hexanucleotide repeat expansion, in the
normal asymptomatic individual, ranges from 2 to 19 repeats, despite the fact of up
to 30 repeats being also considered normal. However, asymptomatic patients have also
been described in cases with the repeats in the pathogenic interval. Symptomatic
patients are described in cases with more than 30 repeats, generally with 250 to
1,600 repeats, and more symptomatic in cases with more than 400 repeats1616 Woollacott IO, Mead S. The C9ORF72 expansion mutation: gene
structure, phenotypic and diagnostic issues. Acta Neuropathol.
2014;127(3):319-32. http://dx.doi.org/10.1007/s00401-014-1253-7
https://doi.org/10.1007/s00401-014-1253-...
,1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
.
NEUROPATHOLOGICAL ASPECTS
Neuropathological studies have been widely performed in
C9orf72-related disorders. Gross pathology examination generally
shows global brain atrophy, particularly of the frontal and temporal lobes with mild
to moderate subcortical involvement. Microscopic evaluation unveils neuronal
degeneration and loss with variable degrees of gliosis and superficial laminar
spongiosis (depending on disease stage), but rarely with Pick bodies and with
relative paucity of amyloid plaques and neurofibrillary tangles. Myelin loss in the
corticospinal tracts with moderate to severe degeneration of the motor system is
also described in cases of FTD even without clinical features of motor neuron
disease99 Hodges J. Familial frontotemporal dementia and amyotrophic lateral
sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain.
2012;135(3):652-5. http://dx.doi.org/10.1093/brain/aws033
https://doi.org/10.1093/brain/aws033...
,1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
. Marked loss of lower motor
neurons in cranial nerve motor nuclei in the brainstem (mainly in the medulla) and
in the anterior horns of the spinal cord with marked microglial reaction is observed
in all levels of the pyramidal tract in cases with associated ALS phenotype1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
.
Immunohistochemistry patterns represent important findings in
C9orf72 neuropathological studies. The finding of TDP-43
(TAR/transactive response DNA-binding protein 43) positive cytoplasmic inclusions in
spinal motor neurons and eventually in glial cells, commonly associated with
cytoplasmic neuronal ubiquitin-positive and Tau-negative inclusions in the cortex
and spinal cord1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
,3131 Hsiung GY, DeJesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr
P, Dwosh E et al. Clinical and pathological features of familial frontotemporal
dementia caused by C9ORF72 mutation on chromosome 9p. Brain. 2012;135(3):709-22.
http://dx.doi.org/10.1093/brain/awr354
https://doi.org/10.1093/brain/awr354...
,3232 Murray ME, DeJesus-Hernandez M, Rutherford NJ, Baker M, Duara R,
Graff-Radford NR et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS
associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol.
2011;122(6):673-90. http://dx.doi.org/10.1007/s00401-011-0907-y
https://doi.org/10.1007/s00401-011-0907-...
. The absence of FUS and Ubiquilin 2 positive
inclusions differentiate C9orf72 spectrum from other genetic forms
of FTD-ALS disorders1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y.
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat
expansion: a perspective. J Nucleic Acids. 2013;2013:208245.
http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245...
.
Another highly specific, nearly pathognomonic, molecular signature of
C9orf72-related neuropathology is the finding of TDP-43
negative and p62-positive neuronal cytoplasmic inclusions in extra-motor regions
within the dentate gyrus granule cells, in the CA4 pyramidal cells of the
hyppocampus, in the frontal neocortex and in granule cells of the cerebellum1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
,3333 Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros
M et al. Clinical and pathological features of amyotrophic lateral sclerosis
caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol.
2012;123(3):409-17. http://dx.doi.org/10.1007/s00401-011-0937-5
https://doi.org/10.1007/s00401-011-0937-...
. These represent dipeptide repeat proteins,
previously described, formed as a result of sense and antisense repeat associated
non ATG-initiated translation of the expanded repeat noncoding region99 Hodges J. Familial frontotemporal dementia and amyotrophic lateral
sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain.
2012;135(3):652-5. http://dx.doi.org/10.1093/brain/aws033
https://doi.org/10.1093/brain/aws033...
,2727 Davidson YS, Barker H, Robinson AC, Thompson JC, Harris J, Troakes C
et al. Brain distribution of dipeptide repeat proteins in frontotemporal lobar
degeneration and motor neurone disease associated with expansions in C9ORF72.
Acta Neuropathol Commun. 2014;2(1):70.. Dopaminergic neuron loss in substantia nigra is
also common in C9orf72 cases of ALS with p62-positive inclusions
and without α-synuclein-positive Lewy bodies thus in a distinct pattern of
involvement than in idiopathic Parkinson disease3434 Cooper-Knock J, Frolov A, Highley JR, et al. C9ORF72 expansions,
parkinsonism, and Parkinson disease. A clinicopathologic study. Neurology.
2013;81(9):808-11.
http://dx.doi.org/10.1212/WNL.0b013e3182a2cc38
https://doi.org/10.1212/WNL.0b013e3182a2...
.
Although classically described in motor neurons in anterior horn of the spinal cord
in ALS cases and rarely in association with atypical Pick’s disease,
eosinophilic intraneuronal inclusions rich in transferrin and cystatin C, the
so-called Bunina bodies, have also been reported in cases of FTD-ALS in
C9orf72-related repeat expansion, despite not representing a
significant finding in this context3535 Okamoto K, Mizuno Y, Fujita Y. Bunina bodies in amyotrophic lateral
sclerosis. Neuropathology. 2008;28(2):109-15.
http://dx.doi.org/10.1111/j.1440-1789.2007.00873.x
https://doi.org/10.1111/j.1440-1789.2007...
.
CLINICAL AND LABORATORY CHARACTERIZATION
The association of ALS and FTD with other neurological phenotypes is widely known
from the past3636 Hudson AJ. Amyotrophic lateral sclerosis and its association with
dementia, parkinsonism and other neurological disorders: a review. Brain.
1981;104(2):217-47. http://dx.doi.org/10.1093/brain/104.2.217
https://doi.org/10.1093/brain/104.2.217...
, including the
first descriptions of FTD-ALS complex about 40 years ago. C9orf72
repeat expansions are involved with a wide spectrum of neurological
manifestations3737 Boeve BF, Boylan KB, Graff-Radford NR, DeJesus-Hernandez M, Knopman
DS, Pdraza O et al. Characterization of frontotemporal dementia and/or
amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in
C9ORF72. Brain. 2012;135(3):765-83.
http://dx.doi.org/10.1093/brain/aws004
https://doi.org/10.1093/brain/aws004...
,3838 Cooper-Knock J, Shaw PJ, Kirby J. The widening spectrum of
C9ORF72-related disease; genotype/phenotype correlations and potential modifiers
of clinical phenotype. Acta Neuropathol. 2014;127(3):333-45.
http://dx.doi.org/10.1007/s00401-014-1251-9
https://doi.org/10.1007/s00401-014-1251-...
, involving motor and non-motor (cognitive and behavioral)
phenotypes (syndromes)3838 Cooper-Knock J, Shaw PJ, Kirby J. The widening spectrum of
C9ORF72-related disease; genotype/phenotype correlations and potential modifiers
of clinical phenotype. Acta Neuropathol. 2014;127(3):333-45.
http://dx.doi.org/10.1007/s00401-014-1251-9
https://doi.org/10.1007/s00401-014-1251-...
(Figure 4). Most clinical data come from
populational studies in European countries and in US. It is possible to extend
concepts obtained from the analysis of such populations to propose a proper overall
analysis. Hexanucleotide repeat expansions in C9orf72 gene have
been described in different contexts of neurodegenerative syndromes, ranging from
classical bvFTD to sporadic Creutzfeldt-Jakob disease-like phenotype3939 Beck J, Poulter M., Hensman D, Rohrer JD, Mahoney CJ, Adamson G et
al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple
neurodegenerative syndromes and are more frequent than expected in the UK
population. Am J Hum Genet. 2013;92(3):345-53.
http://dx.doi.org/10.1016/j.ajhg.2013.01.011
https://doi.org/10.1016/j.ajhg.2013.01.0...
. Few data regarding Brazilian
patients with C9orf72-related disorders exist, but in general
presenting with classical behavioural and extrapyramidal (focal dystonia,
parkinsonism) compromise findings4040 Takada LT, Pimentel ML, DeJesus-Hernandez M, Fong JC, Yokoyama JS,
Karydas A et al. Frontotemporal dementia in a Brazilian kindred with the c9orf72
mutation. Arch Neurol. 2012;69(9):1149-53.
http://dx.doi.org/10.1001/archneurol.2012.650
https://doi.org/10.1001/archneurol.2012....
.
Summary of motor and non-motor (cognitive and behavioral) syndromes associated with C9orf72 gene hexanucleotide repeat expansion. FTD: Frontotemporal dementia; ALS: Amyotrophic lateral sclerosis; HD: Huntington disease; CJD: Creutzfeldt-Jakob disease.
Since 2011, C9orf72 gene has become a leading figure in the genetics
of neurodegenerative processes involving motor neuron disease and dementia. There is
frequent misunderstood regarding the FTD-ALS complex and the lytico-bodig disease or
amyotrophic lateral sclerosis-parkinsonism-dementia complex, previously described in
the Chamorro population from Guam Island in USA. The clinical picture arises from
mutations in the TRPM7 gene (Transient receptor potential
cation channel, subfamily M, member 7; 15q21.2), as a consequence from
direct exposure to the neurotoxic effects of β-methylamino-L-alanine found in
local Guam species of flying fox (Pteropus tokudae)4141 Morris HR, Al-Sarraj S, Schwab C, Gwinn_Hardy K, Perez-Tur J, Wood
NW et al. A clinical and pathological study of motor neurone disease on Guam.
Brain. 2001;124(11):2215-22.
http://dx.doi.org/10.1093/brain/124.11.2215
https://doi.org/10.1093/brain/124.11.221...
.
The most common clinical presentation related to C9orf72 is
represented by adult-onset of bvFTD phenotype followed in the disease course by
variable signs of a motor neuron disease, resembling ALS55 Takada LT, Sha SJ. Neuropsychiatric features of C9orf72-associated
behavioral variant frontotemporal dementia and frontotemporal dementia with
motor neuron disease. Alzheimers Res Ther. 2012;4(5):38.
http://dx.doi.org/10.1186/alzrt141
https://doi.org/10.1186/alzrt141...
. Semantic dementia and progressive non-fluent
aphasia have rarely been described in association with motor neuron signs99 Hodges J. Familial frontotemporal dementia and amyotrophic lateral
sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain.
2012;135(3):652-5. http://dx.doi.org/10.1093/brain/aws033
https://doi.org/10.1093/brain/aws033...
, but might not exclude the
hypothesis of C9orf72 gene hexanucleotide repeat expansion1313 Sha SJ, Boxer A. Treatment implications of C9ORF72. Alzheimers Res
Ther. 2012;4(6):46. http://dx.doi.org/10.1186/alzrt149
https://doi.org/10.1186/alzrt149...
. Neuropsychiatric profile
involves early disinhibition (up to 85%), lack of insight (up to 78%),
hallucinations (up to 50%), delusion (up to 50%), anxiety (up to 52%), hyperorality
(up to 100%), early apathy (up to 100%), loss of empathy (up to 77%) and
obsessive-compulsive symptoms (up to 12%)55 Takada LT, Sha SJ. Neuropsychiatric features of C9orf72-associated
behavioral variant frontotemporal dementia and frontotemporal dementia with
motor neuron disease. Alzheimers Res Ther. 2012;4(5):38.
http://dx.doi.org/10.1186/alzrt141
https://doi.org/10.1186/alzrt141...
,4242 Fong JC, Karydas AM, Goldman JS. Genetic counseling for FTD/ALS
caused by the C9ORF72 hexanucleotide expansion. Alzheimers Res Ther.
2012;4(4):27. http://dx.doi.org/10.1186/alzrt130
https://doi.org/10.1186/alzrt130...
,4343 Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T et
al. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion:
clinical, neuroanatomical and neuropathological features. Brain.
2012;135(3):736-50. http://dx.doi.org/10.1093/brain/awr361
https://doi.org/10.1093/brain/awr361...
. There is an important clinical overlap with probable
Alzheimer’s disease in the early-onset cases, mainly in Caucasian
patients4545 Harms M, Benitez BA, Cairns N, Cooper B, Coper P, Mayo K et al.
C9orf72 hexanucleotide repeat expansions in clinical Alzheimer disease. JAMA
Neurol. 2013;70(6):736-41.
http://dx.doi.org/10.1001/2013.jamaneurol.537
https://doi.org/10.1001/2013.jamaneurol....
,4646 Wojtas A, Heggeli KA, Finch N, Baker M, DeJesus-Hernandez M, Youkin
SG et al. C9ORF72 repeat expansions and other FTD gene mutations in a clinical
AD patient series from Mayo Clinic. Am J Neurodegener Dis.
2012;1(1):107-18., making it difficult to promote a
proper genetic evaluation in association with classical genes (APP, PSEN1,
PSEN2)4747 Simón-Sánchez J, Dopper EG, Cohn-Hokke PE, Hukema RK,
Nicolaou N, Seelaar H et al. The clinical and pathological phenotype of C9ORF72
hexanucleotide repeat expansions. Brain. 2012;135(3):723-35.
http://dx.doi.org/10.1093/brain/awr353
https://doi.org/10.1093/brain/awr353...
,4848 Blitterswijk M, Baker MC, DeJesus-Hernandez M, Ghidoni R, Benussi L,
Finger E et al. C9ORF72 repeat expansions in cases with previously identified
pathogenic mutations. Neurology. 2013;81(15):1332-41.
http://dx.doi.org/10.1212/WNL.0b013e3182a8250c
https://doi.org/10.1212/WNL.0b013e3182a8...
, although such cases generally present with an older age
than with the FTD clinical spectrum2626 Yokoyama JS, Sirkis DW, Miller BL. C9ORF72 hexanucleotide repeats in
behavioral and motor neuron disease: clinical heterogeneity and pathological
diversity. Am J Neurodegener Dis. 2014;3(1):1-18.
http://dx.doi.org/10.1186/2051-5960-2-70
https://doi.org/10.1186/2051-5960-2-70...
. UBQLN2 gene mutations are great
mimickers frequently differentiated in clinical means by the absence of psychiatric
features (not behavioural symptoms) and lower motor neuron involvement1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y.
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat
expansion: a perspective. J Nucleic Acids. 2013;2013:208245.
http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245...
. In cases with pleiotropic
heterogeneous phenotypic variability of repeat expansions, association with
previously described pathogenic mutations in GRN or
MAPT genes must be done4949 Goldman JS, Quinzii C, Dunning-Broadbent J, Waters C, Mitsumoto H,
Brannagan TH 3rd et al. Multiple system atrophy and amyotrophic lateral
sclerosis in a family with hexanucleotide repeat expansions in C9ORF72. JAMA
Neurol. 2014;71(6):771-4.
http://dx.doi.org/10.1001/jamaneurol.2013.5762
https://doi.org/10.1001/jamaneurol.2013....
.
During the natural history of ALS, up to 50% of patients have cognitive decline, but
only 15%-20% full-fill clinical criteria for FTD1010 Al-Chalabi A., Hardiman O. The epidemiology of ALS: a conspiracy of
genes, environment and time. Nat Rev Neurol. 2013;9(11):617-28.
http://dx.doi.org/10.1038/nrneurol.2013.203
https://doi.org/10.1038/nrneurol.2013.20...
,1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y.
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat
expansion: a perspective. J Nucleic Acids. 2013;2013:208245.
http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245...
. In C9orf72 related ALS, despite the
prevalence of 35% with at least one family member with dementia1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
and the higher rate of cognitive dysfunction, the
most significant manifestations include psychiatric symptoms (delusions and
hallucinations) and higher rates of familial members with parkinsonism88 Chiò A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ
et al. Clinical characteristics of patients with familial amyotrophic lateral
sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of
C9ORF72. Brain. 2012;135(Pt 3):784-93.
http://dx.doi.org/10.1093/brain/awr366
https://doi.org/10.1093/brain/awr366...
.
There are no specific clinical hallmarks which differentiate FTD and ALS phenotypes
linked to C9orf72 to those associated with other genes.
C9orf72-spectrum disorders tend to have a lower age of onset,
shorter survival, more rapid clinical course, bulbar symptoms at onset (in cases of
ALS phenotype), propensity toward psychosis, early-onset delusions (up to 45%),
paranoia or late-onset hallucinations (up to 50%). Early-onset delusion in the
context of ALS is highly suggestive of C9orf72 expansions55 Takada LT, Sha SJ. Neuropsychiatric features of C9orf72-associated
behavioral variant frontotemporal dementia and frontotemporal dementia with
motor neuron disease. Alzheimers Res Ther. 2012;4(5):38.
http://dx.doi.org/10.1186/alzrt141
https://doi.org/10.1186/alzrt141...
, despite the absence of a specific
neuropsychiatric symptom pattern22 Kaivorinne AL, Bode MK, Paavola L, Tuominen H, Kallio M, Renton AE
et al. Clinical characteristics of C9ORF72-linked frontotemporal lobar
degeneration. Dement Geriatr Cogn Dis Extra. 2013;3(1):251-62.
http://dx.doi.org/10.1159/000351859
https://doi.org/10.1159/000351859...
.
There is also an increased incidence of neurodegenerative disease in relatives
(mainly dementia in 33% of cases) when compared to patients with other forms of ALS
or FTD, even in the rare cases without clear cognitive dysfunction55 Takada LT, Sha SJ. Neuropsychiatric features of C9orf72-associated
behavioral variant frontotemporal dementia and frontotemporal dementia with
motor neuron disease. Alzheimers Res Ther. 2012;4(5):38.
http://dx.doi.org/10.1186/alzrt141
https://doi.org/10.1186/alzrt141...
,99 Hodges J. Familial frontotemporal dementia and amyotrophic lateral
sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain.
2012;135(3):652-5. http://dx.doi.org/10.1093/brain/aws033
https://doi.org/10.1093/brain/aws033...
,1010 Al-Chalabi A., Hardiman O. The epidemiology of ALS: a conspiracy of
genes, environment and time. Nat Rev Neurol. 2013;9(11):617-28.
http://dx.doi.org/10.1038/nrneurol.2013.203
https://doi.org/10.1038/nrneurol.2013.20...
,1919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
.
Parkinsonism is a key feature in C9orf72-spectrum phenotype.
Early-onset mild parkinsonism (mainly akinetic-rigid) with focal dystonia and poor
response to levodopa is the typical clinical picture, rarely presenting with diffuse
Lewy body dementia parkinsonism. It is also documented the predisposition of some
populations to parkinsonism in cases of C9orf72 repeat
expansion1212 Rheenen W, Blitterswijk M, Huisman MH, Vlam L, Doormaal PT, Seelen M
et al. Hexanucleotide repeat expansions in C9ORF72 in the spectrum of motor
neuron diseases. Neurology. 2012;79(9):878-82.
http://dx.doi.org/10.1212/WNL.0b013e3182661d14
https://doi.org/10.1212/WNL.0b013e318266...
. Atypical
parkinsonism with cerebellar ataxia mimicking multiple system atrophy has also been
described4949 Goldman JS, Quinzii C, Dunning-Broadbent J, Waters C, Mitsumoto H,
Brannagan TH 3rd et al. Multiple system atrophy and amyotrophic lateral
sclerosis in a family with hexanucleotide repeat expansions in C9ORF72. JAMA
Neurol. 2014;71(6):771-4.
http://dx.doi.org/10.1001/jamaneurol.2013.5762
https://doi.org/10.1001/jamaneurol.2013....
, the same way as
cerebellar ataxia with retained reflexes5050 Fogel BL, Pribadi M, Pi S, Perlman SL, Geschwind DH, Coppola G.
C9ORF72 expansion is not a significant cause of sporadic spinocerebellar ataxia.
Mov Disord. 2012;27(14):1832-3.
http://dx.doi.org/10.1002/mds.25245
https://doi.org/10.1002/mds.25245...
and isolated olivopontocerebellar atrophy with
hot-cross bun sign in the pons2626 Yokoyama JS, Sirkis DW, Miller BL. C9ORF72 hexanucleotide repeats in
behavioral and motor neuron disease: clinical heterogeneity and pathological
diversity. Am J Neurodegener Dis. 2014;3(1):1-18.
http://dx.doi.org/10.1186/2051-5960-2-70
https://doi.org/10.1186/2051-5960-2-70...
,5151 Lindquist SG, Duno M, Batbayli M, Puschmann A, Braendgaard H,
Mardosiene S et al. Corticobasal and ataxia syndromes widen the spectrum of
C9ORF72 hexanucleotide expansion disease. Clin Genet. 2013;83(3):279-83.
http://dx.doi.org/10.1111/j.1399-0004.2012.01903.x
https://doi.org/10.1111/j.1399-0004.2012...
. Due to its exceptionality, cerebellar ataxia as a
clinical manifestations of C9orf72 expansion should be suspected
only in cases with proper familial dementia or especially with motor neuron disease.
There are no specific repeat intervals involved with atypical parkinsonism and
cerebellar ataxia2626 Yokoyama JS, Sirkis DW, Miller BL. C9ORF72 hexanucleotide repeats in
behavioral and motor neuron disease: clinical heterogeneity and pathological
diversity. Am J Neurodegener Dis. 2014;3(1):1-18.
http://dx.doi.org/10.1186/2051-5960-2-70
https://doi.org/10.1186/2051-5960-2-70...
.
Another phenotype on growing evidence and importance is represented by
Huntington’s disease (HD) phenocopies, cases in which typical or suspected
cases of HD present with negative genetic testing5252 Martino D, Stamelou M, Bhatia KP. The differential diagnosis of
Huntington’s disease-like syndromes: ‘red flags’ for the
clinician. J Neurol Neurosurg Psychiatry. 2013;84(6):650-6.
http://dx.doi.org/10.1136/jnnp-2012-302532
https://doi.org/10.1136/jnnp-2012-302532...
(Table 4). Most
cases studied presented with earlier age at onset and a different combination of
movement disorders, including dystonia, tremor, rigidity, myoclonus and chorea, thus
with a broader spectrum than HD classical phenotype. One highly suggestive clinical
context is the presence of upper motor neuron features in cases of HD-like
phenotype. ALS-like phenotype mainly with lower motor neuron signs in this context
is rarely associated with the HD, FTD and C9orf72 clinical
spectrum. There is no specific size of repeat expansion linked to this phenotype,
making part of the set of most expansion sizes in other clinical situations linked
to C9orf725353 Hensman Moss DJ, Poulter M, Beck J, Hehir J, Polke JM, Campbell T et
al. C9orf72 expansions are the most common genetic cause of Huntington disease
phenocopies. Neurology. 2014;82(4):292-9.
http://dx.doi.org/10.1212/WNL.0000000000000061
https://doi.org/10.1212/WNL.000000000000...
.
Differential diagnoses of genetic causes of Huntington’s disease-like syndromes5252 Martino D, Stamelou M, Bhatia KP. The differential diagnosis of Huntington’s disease-like syndromes: ‘red flags’ for the clinician. J Neurol Neurosurg Psychiatry. 2013;84(6):650-6. http://dx.doi.org/10.1136/jnnp-2012-302532
https://doi.org/10.1136/jnnp-2012-302532... .
During a large screening for genetic causes of early-onset autosomal dominant
inherited dementia, atypical clinical presentations of
C9orf72-related disease were found and disclosed a rare
presentation of an olivopontocerebellar degeneration and a corticobasal
syndrome-like phenotype5151 Lindquist SG, Duno M, Batbayli M, Puschmann A, Braendgaard H,
Mardosiene S et al. Corticobasal and ataxia syndromes widen the spectrum of
C9ORF72 hexanucleotide expansion disease. Clin Genet. 2013;83(3):279-83.
http://dx.doi.org/10.1111/j.1399-0004.2012.01903.x
https://doi.org/10.1111/j.1399-0004.2012...
.
Visuospatial dysfunction has also been described, but the phenotype of pure spastic
paraparesis is not associated with repeat expansion3838 Cooper-Knock J, Shaw PJ, Kirby J. The widening spectrum of
C9ORF72-related disease; genotype/phenotype correlations and potential modifiers
of clinical phenotype. Acta Neuropathol. 2014;127(3):333-45.
http://dx.doi.org/10.1007/s00401-014-1251-9
https://doi.org/10.1007/s00401-014-1251-...
. It has also been identified a higher prevalence of
multiple sclerosis within families with ALS, mainly those associated with
C9orf721919 Cooper-Knock J, Hewitt C, Highley JR, Brockington A, Milano A, Man S
et al. Clinico-pathological features in amyotrophic lateral sclerosis with
expansions in C9ORF72. Brain. 2012;135(Pt 3):751-64.
http://dx.doi.org/10.1093/brain/awr365
https://doi.org/10.1093/brain/awr365...
.
It has also been described an uncommon psychiatric phenotype with familial bipolar
disorder with C9orf72 expansion with one family member with
late-onset features which progressed to frontotemporal lobe degeneration5454 Meisler MH, Grant AE, Jones JM, Lenk GM, He F, Todd PK et al.
C9ORF72 expansion in a family with bipolar disorder. Bipolar Disord.
2013;15(3):326-32. http://dx.doi.org/10.1111/bdi.12063
https://doi.org/10.1111/bdi.12063...
. Repeat expansions were rarely
described in cases of men with refractory depression that harboured a previous
suspected diagnosis of depressive pseudodementia5555 Bieniek KF, Blitterswijk M, Baker MC, Petrucelli L, Rademakers R,
Dickson DW. Expanded C9ORF72 hexanucleotide repeat in depressive pseudodementia.
JAMA Neurol. 2014;71(6):775-81.
http://dx.doi.org/10.1001/jamaneurol.2013.6368
https://doi.org/10.1001/jamaneurol.2013....
. Some authors even suggest the possibility of
performing C9orf72 gene evaluation in cases of late-onset
psychosis5656 Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL,
Richardson AM et al. Distinct clinical and pathological characteristics of
frontotemporal dementia associated with C9ORF72 mutations. Brain.
2012;135(3):693-708. http://dx.doi.org/10.1093/brain/awr355
https://doi.org/10.1093/brain/awr355...
. Suicide attempt
is also a clinical presentation linked to the repeat expansion. Those carrying the
C9orf72 repeat expansion are also more likely to have family
members with neuropsychiatric conditions, including psychosis and a history of
suicide5757 Synofzik M, Biskup S, Leyhe T, Reimold M, Fallgatter AJ, Metzger F.
Suicide attempt as the presenting symptom of C9orf72 dementia. Am J Psychiatry.
2012;169(11):1211-3.
http://dx.doi.org/10.1176/appi.ajp.2012.12060733
https://doi.org/10.1176/appi.ajp.2012.12...
.
General serum laboratory profile is completely normal. Expansions can be properly
detected with repeat-primed PCR and Southern blotting approaches. Large series of
electroneuromyographic pattern evaluations and muscle biopsies in
C9orf72 have not been studied, but do not differ from sporadic
cases of ALS without this same genetic profile. No specific CSF examination findings
and biomarkers are available and most range usually in normal levels (beta amyloid,
tau, phosphorylated tau, tau-to-beta amyloid ratio), although some patients present
with an Alzheimer’s disease-like CSF profile1616 Woollacott IO, Mead S. The C9ORF72 expansion mutation: gene
structure, phenotypic and diagnostic issues. Acta Neuropathol.
2014;127(3):319-32. http://dx.doi.org/10.1007/s00401-014-1253-7
https://doi.org/10.1007/s00401-014-1253-...
.
NEUROIMAGING STUDIES
There is a wide radiological and pathological correlation in cases of
C9orf72. However, no pathognomonic findings on cranial CT and
brain MRI have been described22 Kaivorinne AL, Bode MK, Paavola L, Tuominen H, Kallio M, Renton AE
et al. Clinical characteristics of C9ORF72-linked frontotemporal lobar
degeneration. Dement Geriatr Cogn Dis Extra. 2013;3(1):251-62.
http://dx.doi.org/10.1159/000351859
https://doi.org/10.1159/000351859...
.
Most neuroimaging descriptions were performed in cases linked to any degree of
cognitive of compromise or behavioral disturbances. Symmetrical frontal and temporal
lobe, insular, and posterior cortical (parietal and occipital) atrophy are the rule
mainly when associated with subcortical involvement of the thalamus and cerebellum,
rarely described in other genetic forms of FTD and which tend to progress and accent
during disease course (Figure 5). The degree
of temporal involvement may be less prominent than that seen in other genetic causes
of FTD, despite severe clinical involvement. One notorious exception with
predominant temporal atrophy is represented by C9orf72-related
cases with primary progressive aphasia phenotype5858 Yokoyama JS, Rosen HJ. Neuroimaging features of C9ORF72 expansion.
Alzheimers Res Ther. 2012;4(6):45.
http://dx.doi.org/10.1186/alzrt148
https://doi.org/10.1186/alzrt148...
. The finding of hot-cross bun sign in the pons has
also been described in the context of C9orf72-spectrum in a single
case of late-onset cerebellar variant of multiple system atrophy-like phenotype4949 Goldman JS, Quinzii C, Dunning-Broadbent J, Waters C, Mitsumoto H,
Brannagan TH 3rd et al. Multiple system atrophy and amyotrophic lateral
sclerosis in a family with hexanucleotide repeat expansions in C9ORF72. JAMA
Neurol. 2014;71(6):771-4.
http://dx.doi.org/10.1001/jamaneurol.2013.5762
https://doi.org/10.1001/jamaneurol.2013....
.
Neuroimaging features described during early (A) and advanced (B) stages of C9orf72-related spectrum disorders. (A) Axial FLAIR-weighted brain MRI disclosing early stage changes represented by mild frontal and temporal lobe atrophy; and (B) Axial T2-weighted brain MRI disclosing a typical end-stage pattern represented by marked symmetrical frontal and temporal atrophy with cerebellar and thalamic atrophy.
In cases of C9orf72-related ALS, volumetry and morphometry brain MRI
studies also disclosed prominent atrophy of right inferior and superior frontal
gyri, right precentral gyri and left anterior cingulate cortex1010 Al-Chalabi A., Hardiman O. The epidemiology of ALS: a conspiracy of
genes, environment and time. Nat Rev Neurol. 2013;9(11):617-28.
http://dx.doi.org/10.1038/nrneurol.2013.203
https://doi.org/10.1038/nrneurol.2013.20...
. The same group of changes linked to the FTD
phenotype are also present in the ALS phenotype99 Hodges J. Familial frontotemporal dementia and amyotrophic lateral
sclerosis associated with the C9ORF72 hexanucleotide repeat. Brain.
2012;135(3):652-5. http://dx.doi.org/10.1093/brain/aws033
https://doi.org/10.1093/brain/aws033...
, although the presence of bilateral thalamic atrophy is
rarely described in cases of isolated ALS phenotype5959 Sha SJ, Takada LT, Rankin KP, Yokoyama JS, Tutherford NJ, Fong JC et
al. Frontotemporal dementia due to C9ORF72 mutations: clinical and imaging
features. Neurology. 2012;79(10):1002-11.
http://dx.doi.org/10.1212/WNL.0b013e318268452e
https://doi.org/10.1212/WNL.0b013e318268...
. The presence of the “bright tongue
sign” in the context of a frontotemporal dementia points to the possibility
of associated motor neuron disease6060 Souza PV, Pinto WB, Oliveira AS. Bright tongue sign: a diagnostic
marker for amyotrophic lateral sclerosis. Arq Neuropsiquiatr. 2014;72(7):572.
http://dx.doi.org/10.1590/0004-282X20140077
https://doi.org/10.1590/0004-282X2014007...
.
No specific or highly-suggestive patterns have been described in positron emission
tomography (PET) and single-photon emission computed tomography (SPECT). However,
some pathological changes have been pointed out. SPECT shows hypoperfusion in the
anterior and middle cingulate gyri, and variable degrees of frontal cortical
hypometabolism in PET, although these findings do not represent a rule and depend on
disease stage of evolution5858 Yokoyama JS, Rosen HJ. Neuroimaging features of C9ORF72 expansion.
Alzheimers Res Ther. 2012;4(6):45.
http://dx.doi.org/10.1186/alzrt148
https://doi.org/10.1186/alzrt148...
.
It is also possible to differentiate general neuroimaging patterns in the FTD
spectrum with impaired C9orf72 with other high prevalence genes as
GRN and MAPT. Exceptionally mutations in these
genes originate thalamic and cerebellar atrophy, which represents important
differential diagnostic findings. GRN gene mutations are commonly
associated with asymmetric hemispheric atrophy, predominantly in the inferior
frontal, superior temporal and inferior parietal gyri, eventually associated with
any degree of leukoencephalopathy. MAPT gene mutations are
associated with symmetric frontotemporal atrophy, predominantly in the anterior and
medial portions of the temporal lobes, the fornix and orbitofrontal cortex, possibly
with cerebellar involvement1010 Al-Chalabi A., Hardiman O. The epidemiology of ALS: a conspiracy of
genes, environment and time. Nat Rev Neurol. 2013;9(11):617-28.
http://dx.doi.org/10.1038/nrneurol.2013.203
https://doi.org/10.1038/nrneurol.2013.20...
,5858 Yokoyama JS, Rosen HJ. Neuroimaging features of C9ORF72 expansion.
Alzheimers Res Ther. 2012;4(6):45.
http://dx.doi.org/10.1186/alzrt148
https://doi.org/10.1186/alzrt148...
.
THERAPEUTIC PERSPECTIVES
Symptomatic therapy remains the exclusive drug measure in cases of FTD and ALS besides the proper use of multidisciplinary approaches. Developing new therapy modalities provide new multimodal treatment perspectives for most inherited and sporadic cases of FTD-ALS patients. Most data regarding C9orf72-targeted therapies derive from other repeat expansion neurodegenerative disorders. New disease-modifying therapies are being studied as new attempts on ALS and FTD therapeutics rather than neuroprotective approaches. However, few specific clinical trials, none exclusively with C9orf72 mutations.
Dexpramipexole, Riluzole and Fingolimod represent neuroprotective perspectives in
cases of FTD-ALS1313 Sha SJ, Boxer A. Treatment implications of C9ORF72. Alzheimers Res
Ther. 2012;4(6):46. http://dx.doi.org/10.1186/alzrt149
https://doi.org/10.1186/alzrt149...
.
Patient-specific induced pluripotent stem cell therapy, immunotherapies, antioxidant
agents, minocycline, insulin-like growth factor-1 (IGF-1) and lithium carbonate are
other alternative treatment options used in preclinical studies1313 Sha SJ, Boxer A. Treatment implications of C9ORF72. Alzheimers Res
Ther. 2012;4(6):46. http://dx.doi.org/10.1186/alzrt149
https://doi.org/10.1186/alzrt149...
,1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y.
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat
expansion: a perspective. J Nucleic Acids. 2013;2013:208245.
http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245...
. Most recent attempts target mRNA dysfunctions in
FTD-ALS, mainly the aberrant splicing process, the nuclear RNA-binding proteins and
contentes from nuclear inclusions. The use of antisense oligonucleotides to silence
targeted mRNA or to modulate splicing represents an important perspective in the
therapy of C9orf72-related disorders, applying clinical research
data obtained from muscular dystrophies, spinocerebellar ataxias and chronic
lymphocytic leukemia1414 Fernandes SA, Douglas AG, Varela MA, Wood MJ, Aoki Y.
Oligonucleotide-based therapy for FTD/ALS caused by the C9orf72 repeat
expansion: a perspective. J Nucleic Acids. 2013;2013:208245.
http://dx.doi.org/10.1155/2013/208245
https://doi.org/10.1155/2013/208245...
,2929 Lagier-Tourenne C, Baughn M, Rigo F, Sun S, Liu P, Li HR et al.
Targeted degradation of sense and antisense C9orf72 RNA foci as therapy for ALS
and frontotemporal degeneration. Proc Natl Acad Sci U S A. 2013;110(47):E4530-9.
http://dx.doi.org/10.1073/pnas.1318835110
https://doi.org/10.1073/pnas.1318835110...
.
CONCLUSION
The spectrum of neurological conditions associated with hexanucleotide repeat expansion of C9orf72 gene is very broad, ranging from the classic phenotype of motor neuron disease and frontotemporal dementia to the most recently descriptions of parkinsonian syndromes, Huntington’s disease-like phenocopies, Alzheimer’s disease-like phenotypes and rarely cerebellar ataxias and other psychiatric disorders. Extensive studies of neuroimaging, molecular neurogenetics and neuropathology allowed the knowledge of specific information related to C9orf72 phenotypes. Clinicians must be aware about such clinical and neuroimaging spectrum related to C9orf72 for proper investigation of suspected cases in the setting of neurodegenerative disorders.
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Publication Dates
-
Publication in this collection
Mar 2015
History
-
Received
03 Oct 2014 -
Reviewed
05 Nov 2014 -
Accepted
25 Nov 2014