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The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism underlying many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72
Tertiary care academic medical center.
The members of the family affected by the mutation with features of FTD and/or ALS.
Clinical, neuropsychological, and neuroimaging assessments.
All three examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and one had ALS. MRI showed symmetric bilateral frontal, temporal, insular and cingulate atrophy.
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the clinico-neuroimaging-neuropathologic correlations.
Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by significant abnormalities of frontal and/or temporal lobes which result clinically in personality/behavioral changes and /or progressive aphasia.1–3 FTD may occur in a sporadic or familial form. The first major gene associated with frontotemporal dementia +/− parkinsonism was microtubule associated protein tau (MAPT), mutations of which lead to the cascade of hyperphoshorylated tau.4 Mutations in the gene encoding progranulin (PGRN) also cause frontotemporal dementia +/− parkinsonism, with ubiquitin- and TDP-43-immunoreactive inclusions being the pathologic hallmark.5, 6 Many kindreds with FTD +/− amyotrophic lateral sclerosis (ALS) with TDP-43-immunoreactive inclusions were linked to chromosome 9, 7–14 and the hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the pathogenic mechanism.15, 16 Such cases are now collectively termed under the c9FTD/ALS terminology.15, 17, 18 We are reporting the clinical, neuropsychological, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism and ALS spectrum.
Three subjects underwent clinical evaluations at other clinics and then were referred to our institution, and were then enrolled in the Mayo Alzheimer Disease Research Center—a Mayo Foundation Institutional Review Board-approved program. The subjects and/or their spouses provided written consent for participation. All additional data from affected relatives was collected and analyzed.
Age of onset for dementia was the age at which the subject first demonstrated behavioral/personality, cognitive +/− parkinsonism as noted by themselves, their relatives, or their clinicians. Age of onset for ALS was the age at which any symptom reflecting upper motor neuron and/or lower motor neuron dysfunction was noted by themselves, their relatives, or their clinicians. Survival (in years) was based on the number of years from onset of any neurologic symptoms to death. All neurologic clinical data were reviewed. The presence or absence of the following clinical features were recorded: personality/behavior changes (self explanatory), executive dysfunction (defined as impairment in sustained attention, multitasking, decision-making, problem solving, etc.), memory impairment (defined as forgetfulness for details of recent events or upcoming plans and poor delayed word list recall), and aphasia (defined as difficulties with object or person naming, or receptive or expressive language functioning). Parkinsonism was defined as some combination of masked facies, stooped posture, shuffling gait, rest tremor, bradykinesia, rigidity, postural instability. Features of upper motor neuron and lower motor neuron dysfunction were considered present when specifically recorded in the clinical record. Neuropsychological testing was performed using standard measures.19 Clinical diagnoses were based on published criteria for FTD, progressive nonfluent aphasia, semantic dementia, amyotrophic lateral sclerosis, etc.,1, 20 and each case was reclassified using the updated behavioral variant FTD and primary progressive aphasia criteria.2, 3 Patients with ALS were classified as according to published criteria.20
MRIs were performed at either at 1.5 Tesla or 3 Tesla (GE Healthcare). At 1.5 Tesla, a 3D high resolution spoiled gradient recalled acquisition in steady state (SPGR) and at 3 Tesla magnetization prepared rapid gradient echo acquisition were used for the high resolution T1 weighted images. A fluid attenuated inversion recovery (FLAIR) sequence was performed at both 1.5 and 3 Tesla. To visualize the patterns of gray matter atrophy in individual subjects, we created Z-score maps or STAND-Maps (Structural Abnormality due to NeuroDegeneration-Maps) which indicate the atrophy in terms of Z-scores relative to a group of cognitively normal controls in 120 brain regions. SPM5 (statistical parametric mapping version 5) software21 was used for tissue segmentation and normalization of each of these scans to a custom template to assess atrophy patterns at the group level was used for tissue segmentation and normalization of each of these scans to a custom template to assess atrophy patterns at the group.22 Voxel-wise image differences in gray matter density between the two patients in whom MRI was available and age, gender and field strength matched cognitively normal subjects was assessed using two-sided T-tests within the general linear model framework of SPM. The voxel level analyses were corrected for multiple comparisons using family wise error (FWE) at p<0.05 and a cluster threshold of 20 voxels.
Genomic DNA (gDNA) was extracted from peripheral blood samples using standard procedures. For each subject, gDNA was screened for the presence of the expanded hexanucleotide repeat in C9ORF72 using the repeat primed PCR method as previously described.15 Genetic analysis and DNA sequencing for C9ORF72, MAPT and PGRN were performed as previously described.15
The pedigree is shown in Figure 1. The proband developed increased slowness, decreased spontaneous speech, and difficulties with ambulation at 62 years of age. After 3–4 months from the onset of symptoms, the patient reported slowness in motor functioning and cognition, difficulties with the daily living, and weakness in the right lower limb, and was forced to use a wheeled walker to walk unassisted. The patient was evaluated at another institution and underwent an electromyogram (EMG) that showed moderate fibrillation potentials in the right gastrocnemius, right peroneus longus, left gastrocnemius and upper rectus abdominis muscles, prompting the suspicion of a diagnosis of ALS. The patient was started on carbidopa/levodopa to treat bradykinesia without any significant benefit. On our first encounter, the proband had a total score of 22 of 38 on the Kokmen Short Test of Mental Status (STMS).23 Additional findings included pseudobulbar affect, apraxia, poor mirror imaging, right/left confusion, and decreased prosody. There was generalized hyperreflexia with the Babinski sign present on the right, as well as weakness only in the proximal and distal right lower extremity. Gait was bradykinetic and apraxic with freezing and decreased ability to turn. There was spasticity in the right greater than left upper and lower extremity. Sensory examination was normal. Neuropsychological assessment showed moderate to marked impairment in attention, processing speed, and phonemic and semantic verbal fluency, with relative preservation of anterograde memory function. MRI of the brain showed moderate generalized atrophy most pronounced in the frontoparietal regions (scan not available). The patient died at 63 years of age, and no autopsy was performed.
The proband’s sibling started to present symptoms around 65 years of age. The family observed personality changes characterized by dampened emotions, reduced interests in family business matters, and lack of motivation. The patient had difficulty in performing calculations and taking care of finances without any significant impairment in short- or long-term memory at this time. The family also noted word finding difficulties, and the tendency to speak more in common phrases instead of full sentences,
At 67 years old the patient was seen by a local primary care physician as well as a neurologist and underwent neuropsychological testing, and MRI and PET scans. The FDG-PET scan of the brain (Figure 2) showed mild frontotemporal hypometabolism, slightly more apparent in the left cerebral hemisphere. The parietal, occipital and posterior cingulate cortices were preserved.
The clinical, neuropsychological, and neuroimaging features led to the diagnosis of behavioral variant FTD, and with the knowledge of the positive family history, a genetically-mediated disorder was suspected.
Over the following year the family noticed progressive functional dependence, the tendency to overeat and to consume multiple meals, and fecal and urinary incontinence. At our first encounter at age 69, the STMS was 7/38, with significant impairment of language. Prominent agrammatism was present, responding only with “yes” and “no”, as well as apraxia of speech and non verbal oral apraxia. There was also mild generalized hyperreflexia, pyramidal signs left more than right, and no definitive parkinsonian signs. On MRI there was a generalized cerebral and cerebellar atrophy and moderate volume loss, especially in the bilateral frontal, insular, and temporal cortices (Figure 3). Confluent bifrontal T2 sequence white matter hyperintensity was noted. Two years later (age 71) the MRI brain scan showed a progression of the atrophy, with the posterior cingulate more obviously involved. The subcortical white matter findings showed moderate progression as well.
She was commenced on memantine and rivastigmine patch. At the most recent visit at 71 years of age, the patient had generalized bradykinesia but was not exhibiting agitation nor socially disinhibited behavior.
The proband’s child developed symptoms around 44 years of age, with verbal perseveration and difficulties remembering events and facts. After one year the patient quit driving and needed help taking care of personal finances. Language was not compromised. The patient behaved inappropriately by touching people, talking with strangers and being garrulous. The patient was functioning reasonably well in taking telephone orders for the family business. The patient did not show emotional lability but clearly had apathy. There was no hyperphagia or parkinsonian features.
At the initial neurological evaluation at our institution at age 50, the patient scored 16/38 on the STMS, with difficulties in digit span, arithmetic, similarities, construction, and recall. The neurological examination was otherwise within normal limits. Neuropsychological testing showed impairment in category fluency, confrontation naming, psychomotor speed, divided attention, visuospatial functioning, and delayed recall. Initial MRI showed generalized cortical and cerebellar atrophy most marked in the frontal, temporal, and mesial parietal and occipital regions (Figure 3). The clinical diagnosis was behavioral variant FTD, likely familial, realizing the degree of impairment on visuospatial tasks and degree of atrophy in non-frontal and temporal lobe structures were atypical.
By age 53 the patient had become more passive and apathetic, and engaged in more compulsive behavior such as constantly tidying things up, making the bed, folding newspapers, and flipping the channels of TV. The patient bought items excessively, and the business failed resulting in the need to quit working. The patient bathed and dressed independently but sometimes only changed clothing, if prompted. Examination at this time revealed a score 9/18 on the STMS, and the patient was more withdrawn with the tendency toward verbal perseveration. There was a reduction of the facial expression and in the speech volume. The neuropsychological assessment showed global cognitive impairment. The MRI showed progression of atrophy in previously affected structures (Figure 3). EMG was normal.
A parent of the proband had a diagnosis of dementia with onset at 62 years of age and died at age 64. This person’s two siblings exhibited dementia also -one at age 50 and the other at age 85. Another sibling of the proband received a diagnosis of dementia at 55 years of age and died at age 81; no other details are known.
DNA was available for analysis in the three examined subjects, each of whom had the hexanucleotide expansion detected in C9ORF72. No mutation was present in MAPT nor PGRN.
This is one of the first family descriptions of c9FTD/ALS associated with the GGGGCC intronic repeat expansion in C9ORF72. The phenotype is typically FTD, ALS, or a combination of both. All of the cases had personality/behavioral changes early in the course of the disease; they were characterized by pseudobulbar affect, obsessions (collecting newspaper), social inappropriateness, and apathy. As previously reported,18 some cases may have parkinsonism. In our family, the proband developed features of parkinsonism that was not levodopa responsive. Moreover, our proband manifested signs and symptoms of motor neuron disease. All the cases in the family reported a decline in memory and cognitive status either early or late in the course of disease. Two of the cases developed severe aphasia in the end stages of the disease, but prominent aphasia early in the course was absent.
The demographic and clinical heterogeneity is one of the features of c9FTD/ALS. The affected individuals may express the mutation with different phenotypes such as behavioral variant FTD, FTD/ALS, FTD/ALS/parkinsonism, ALS, or parkinsonism. It is also possible that some of the unexamined cases in this kindred had underlying Alzheimer’s disease and were thus phenocopies, but an AD-like phenotype has been identified associated with this mutation.18 Although there is growing knowledge of the role of the hexanucleotide repeat expansion in C9ORF72, the explanation(s) for the variable phenotypical expression is/are not known. The age of onset and duration of disease are also highly variable for unclear reasons.
As the apparent mechanism of disease involves a hexanucleotide repeat expansion, it is intriguing to ponder if the variable age of onset (including what may be anticipation in this and other kindreds)18 and/or variable duration of disease are due in part to the degree of the expansion; this issue warrants further study.
All three of the examined patients were rather advanced in the illness by the time neuropsychological testing was performed, and thus insights into the early neuropsychological profile of impairment cannot be inferred. However, the imaging findings are consistent with other recent analyses in c9FTD/ALS cases.18, 24 Relatively symmetric bilateral frontal, temporal, and insular cortical atrophy has been most consistent across cases, with some also demonstrating atrophy in the anterior and/or posterior cingulate regions. Unexpectedly for an FTLD-spectrum disorder, parietal, occipital, and cerebellar atrophy can also be present,18, 24 as shown in our cases with imaging. The newly appreciated ubiquitin-positive inclusions in the cerebellum in c9FTD/ALS cases17, 18 likely reflects cerebellar degeneration that can be detected on quantitative neuroimaging techniques.
This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the possible anticipation mechanism, the phenotypical variability, and clinical-neuroimaging-neuropathologic correlations in other patients affected by the C9ORF72 hexanucleotide expansion.
This work was supported by the “Mayo Alzheimer’s Disease Research Center” (P50 AG016574), the “Identifying Mechanisms of Dementia: Role for MRI in the Era of Molecular Imaging” (RO1 AG011378), the ALS Association (R.R), and the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer’s Disease Research Program of the Mayo Foundation. R.R. is also funded by NIH grants R01 NS065782 and R01 AG026251.
We thank the patients and their families for participating in aging and neurodegenerative disease research.
Dr. Savica - nothing to disclose
Dr. Adeli - nothing to disclose
Dr. Knopman serves as Deputy Editor for Neurology®; has served on a data safety monitoring board for Eli Lilly and Company; has served as a consultant for Elan/Janssen AI; is an investigator in clinical trials sponsored by Elan/Janssen AI, Baxter International Inc., and Forest Laboratories, Inc.; and receives research support from the NIH (R01 AG011378 [Coinvestigator], P50 AG016574 [Coinvestigator], U01 AG006786 [Coinvestigator], AG029550 [Coinvestigator], AG032306 [Coinvestigator], and U01 096917 [Coinvestigator]).
Dr. Vemuri - nothing to disclose
Ms. DeJesus-Hernandez - nothing to disclose
Dr. Rademakers - nothing to disclose
Dr. Fields - nothing to disclose
Dr. Whitwell - nothing to disclose
Dr. Jack serves on scientific advisory boards for Elan/Janssen AI, Eli Lilly & Company, GE Healthcare, and Eisai Inc.; receives research support from Baxter International Inc., Allon Therapeutics, Inc., Pfizer Inc, the NIH/NIA (R01 AG011378 [Principal investigator], P50 AG016574 [Coinvestigator]), and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Foundation; and holds stock/stock options in Johnson & Johnson.
Dr. Lowe serves on scientific advisory boards for Bayer Schering Pharma and GE Healthcare and receives research support from GE Healthcare, Siemens Molecular Imaging, the NIH (NIA, NCI), the MN Partnership for Biotechnology and Medical Genomics, and the Leukemia & Lymphoma Society.
Dr. Petersen serves on Safety Monitoring Committees for Elan Pharmaceuticals, Wyeth Pharmaceuticals, and as a consultant for Elan Pharmaceuticals and GE Healthcare; receives royalties from the publication of a book entitled Mild Cognitive Impairment (Oxford University Press, 2003); and receives research support from the NIH (P50 AG016574 [Principal Investigator], U01 AG006786 [Principal Investigator], R01 AG011378 [Coinvestigator], and U01 AG024904 [Coinvestigator]).
Dr. Boeve serves as an investigator for clinical trials sponsored by Cephalon, Inc., Allon Pharmaceuticals, and GE Healthcare; receives royalties from the publication of a book entitled Behavioral Neurology Of Dementia (Cambridge Medicine, 2009); and receives research support from the NIH (P50 AG016574 [Coinvestigator], U01 AG006786 [Coinvestigator], and R01 AG032306 [Coinvestigator]), and the Mangurian Foundation.