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1.  Prominent Phenotypic Variability Associated with Mutations in Progranulin 
Neurobiology of aging  2007;30(5):739-751.
Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer’s disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.
doi:10.1016/j.neurobiolaging.2007.08.022
PMCID: PMC3164546  PMID: 17949857
Frontotemporal dementia; FTDP-17; Progranulin; PGRN; MRI
2.  Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72 
Acta Neuropathologica  2011;122(6):673-690.
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.
doi:10.1007/s00401-011-0907-y
PMCID: PMC3277860  PMID: 22083254
3.  C9ORF72 repeat expansions and other FTD gene mutations in a clinical AD patient series from Mayo Clinic 
Alzheimer disease (AD) and frontotemporal dementia (FTD) are two frequent forms of primary neurodegenerative dementias with overlapping clinical symptoms. Pathogenic mutations of the amyloid precursor protein (APP) and presenilins 1 and 2 (PSEN1, PSEN2) genes have been linked to familial early-onset forms of AD; however, more recently mutations in the common FTD genes encoding the microtubule associated protein tau (MAPT), progranulin (GRN) and C9ORF72, have also been reported in clinically diagnosed AD patients. To access the contribution of mutations in a well-characterized series of patients, we systematically performed genetic analyses of these EOAD and FTD genes in a novel cohort of 227 unrelated probands clinically diagnosed as probable AD which were ascertained at Mayo Clinic Florida between 1997 and 2011. All patients showed first symptoms of dementia before 70 years. We identified 9 different pathogenic mutations in the EOAD genes in a total of 11 patients explaining 4.8% of the patient population. Two mutations were novel: PSEN1 p.Pro218Leu and PSEN2 p.Phe183Ser. Importantly, mutations were also identified in all FTD genes: one patient carried a MAPT p.R406W mutation, one patient carried the p.Arg198Glyfs19X loss-of-function mutation in GRN and two patients were found to carry expanded GGGGCC repeats in the non-coding region of C9ORF72. Together the FTD genes explained the disease in 1.8% of our probable AD population. The identification of mutations in all major FTD genes in this novel cohort of clinically diagnosed AD patients underlines the challenges associated with the differential diagnosis of AD and FTD resulting from overlapping symptomatology and has important implications for molecular diagnostic testing and genetic counseling of clinically diagnosed AD patients. Our findings suggest that in clinically diagnosed AD patients, genetic analyses should include not only the well-established EOAD genes APP, PSEN1 and PSEN2 but also genes that are usually associated with FTD. Finally, the overall low frequency of mutation carriers observed in our study (6.6%) suggests the involvement of other as yet unknown genetic factors associated with AD.
PMCID: PMC3560455  PMID: 23383383
Alzheimer’s disease; frontotemporal dementia; amyloid precursor protein; presenilin 1; presenilin 2; progranulin; microtubule associated protein tau; C9ORF72; mutation; diagnosis.
4.  Frontotemporal dementia in a Brazilian Caucasian kindred with the C9orf72 mutation 
Archives of neurology  2012;69(9):1149-1153.
Objective
Describe the clinical features of a Brazilian C9orf72 frontotemporal dementia – amyotrophic lateral sclerosis (FTD-ALS) kindred, and compare them to other reported C9orf72 families and FTD-ALS causing mutations.
Design
Report of a kindred.
Setting
Dementia center at an University hospital.
Patients
One kindred encompassing 3 generations.
Results
The presence of a hexanucleotide (GGGGCC) expansion in C9orf72 was confirmed by repeat-primed PCR and Southern blot. The observed phenotypes were behavioral variant FTD and ALS with dementia, with significant variability in age of onset and duration of disease. Parkinsonian features with focal dystonia, visual hallucinations and more posterior atrophy on neuroimaging than is typical for FTD were seen.
Conclusions
bvFTD due to C9orf72 expansions displays some phenotypic heterogeneity, and may be associated with hallucinations, parkinsonism, focal dystonia, and posterior brain atrophy. Personality changes may precede by many years the diagnosis of dementia and may be a distinguishing feature of this mutation.
doi:10.1001/archneurol.2012.650
PMCID: PMC3625641  PMID: 22964910
5.  Juvenile myoclonic epilepsy. 
Archives of Disease in Childhood  1988;63(9):1049-1053.
The clinical and electroencephalographic features of 10 adolescents with juvenile myoclonic epilepsy are presented. The mean age on onset was 12.3 years. Myoclonic jerks, predominantly on awakening, occurred in all 10 and were associated with infrequent generalised tonic-clonic seizures in nine. Five had first degree relatives with seizures. The neurodevelopmental status was normal in eight and social integration good in seven. Waking interictal electroencephalograms showed normal background activity in nine, polyspike and wave in six, and single spike and wave in eight. Four were photosensitive. Failure to respond to other antiepileptic drugs was usual, but valproate monotherapy resulted in good or complete seizure control. Juvenile myoclonic epilepsy is a well defined clinical entity that responds well to valproate and is usually associated with a good outlook.
PMCID: PMC1779097  PMID: 3140737
6.  MRS in Early and Presymptomatic Carriers of a Novel Octapeptide Repeat Insertion in the Prion Protein Gene 
To evaluate the proton MR spectroscopy (1H MRS) changes in carriers of a novel octapeptide repeat insertion in the Prion Protein Gene (PRNP) and family history of frontotemporal dementia with ataxia. Four at-risk mutation carriers and 13 controls were compared using single voxel, short TE, 1H MRS from the posterior cingulate gyrus. The mutation carriers had an increased choline/creatine, p=0.003 and increased myoinositol/creatine ratio, p=0.003. 1H MRS identified differences in markers of glial activity and choline metabolism in pre- and early symptomatic carriers of a novel PRNP gene octapeptide insertion. These findings expand the possible diagnostic utility of 1H MRS in familial prion disorders.
doi:10.1111/j.1552-6569.2012.00717.x
PMCID: PMC3480551  PMID: 22612156
MRS; MRI; familial prion disorders; frontotemporal dementia
7.  Familial prion disease in a Hungarian family with a novel 144‐base pair insertion in the prion protein gene 
About 15% of human prion diseases are inherited, and are associated with point or insertional mutations of the prion protein gene (PRNP). Four families with six octapeptide repeat insertions (OPRI) in the PRNP gene have been described in the literature so far. Here we report two cases in a Hungarian family with a new six OPRI (R1R2R2R3R2R3gR3R2R2R3R4) in the PRNP gene. The clinical features (progressive ataxia, dementia and anosmia), the age of onset and the duration of disease were almost identical. In addition to the cerebellar and parahippocampal pathological changes already described, we also found deposits of pathological prion protein in the olfactory system.
doi:10.1136/jnnp.2006.104372
PMCID: PMC2117636  PMID: 17308293
8.  Familial Prion Disease with Alzheimer Disease-Like Tau Pathology and Clinical Phenotype 
Annals of neurology  2011;69(4):712-720.
Objective
To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP).
Methods
Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aβ deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology.
Results
The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aβ, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP.
Interpretation
We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs.
doi:10.1002/ana.22264
PMCID: PMC3114566  PMID: 21416485
9.  Electroclinical features of idiopathic generalised epilepsy with persisting absences in adult life. 
OBJECTIVES: To describe the electroclinical features of typical absences persisting in adult life. METHODS: Twelve adult patients (aged 21 to 56 years) with idiopathic generalised epilepsy featuring typical absences as the prominent clinical feature were studied. All patients underwent a full clinical and neurophysiological investigation including ictal documentation of seizures. RESULTS: Neurological examination and neuroradiological investigations were normal in all cases. Clinical findings included a median age at onset of absences of 14 (range 4-32) years, almost constant tonic-clonic seizures (in 83% of patients), frequent episodes of absence status (in 33% of patients), and associated cognitive or psychiatric disturbances. Interictal EEG findings showed normal background activity, generalised paroxysms of spike waves or polyspike waves, and inconstant focal spikes (in five patients); runs of polyspikes were seen during non-REM sleep. Ictal EEG findings showed generalised spike waves at 3 Hz, sometimes preceded by multiple spikes, or more complex EEG patterns with sequences of polyspikes intermingled with spike waves or polyspike waves, showing discharge fragmentation or variation of intradischarge frequency. CONCLUSION: The results of the present study show that absences persisting in adult life may show particular clinical and EEG patterns, distinct from those in childhood or adolescence.
PMCID: PMC1074044  PMID: 8937341
10.  Idiopathic generalised epilepsy in adults manifested by phantom absences, generalised tonic-clonic seizures, and frequent absence status 
OBJECTIVES—To describe the clinical and EEG features of adult patients with very mild absences, late onset generalised tonic clonic seizures, and frequent absence status.
METHODS—Patients were referrals to a clinic for epilepsies. They all had clinical assessment and EEG, video EEG, or both for documentation of absences.
RESULTS—Of 86 adults with idiopathic generalised epilepsies and EEG/video-EEG documented absences, 13 patients showed similar clinico-EEG features with: (a) "phantom absences" consisting of mild ictal impairment of cognition associated with brief (3-4 s), generalised 3-4 Hz spike/multiple spike and slow wave discharges; (b) infrequent, mainly late onset, generalised tonic clonic seizures, and (c), absence status which occurred in six of them either in isolation or terminating with generalised tonic clonic seizures. None of the patients had myoclonic jerks or photosensitivity. Two patients were father and daughter and another patient had a family history of infrequent generalised tonic clonic seizures.
CONCLUSION—It seems that this is an idiopathic generalised epilepsy syndrome in adults which has not been previously recognised.


PMCID: PMC2169820  PMID: 9408104
11.  Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72 
Brain  2012;135(3):765-783.
Numerous kindreds with familial frontotemporal dementia and/or amyotrophic lateral sclerosis have been linked to chromosome 9, and an expansion of the GGGGCC hexanucleotide repeat in the non-coding region of chromosome 9 open reading frame 72 has recently been identified as the pathogenic mechanism. We describe the key characteristics in the probands and their affected relatives who have been evaluated at Mayo Clinic Rochester or Mayo Clinic Florida in whom the hexanucleotide repeat expansion were found. Forty-three probands and 10 of their affected relatives with DNA available (total 53 subjects) were shown to carry the hexanucleotide repeat expansion. Thirty-six (84%) of the 43 probands had a familial disorder, whereas seven (16%) appeared to be sporadic. Among examined subjects from the 43 families (n = 63), the age of onset ranged from 33 to 72 years (median 52 years) and survival ranged from 1 to 17 years, with the age of onset <40 years in six (10%) and >60 in 19 (30%). Clinical diagnoses among examined subjects included behavioural variant frontotemporal dementia with or without parkinsonism (n = 30), amyotrophic lateral sclerosis (n = 18), frontotemporal dementia/amyotrophic lateral sclerosis with or without parkinsonism (n = 12), and other various syndromes (n = 3). Parkinsonism was present in 35% of examined subjects, all of whom had behavioural variant frontotemporal dementia or frontotemporal dementia/amyotrophic lateral sclerosis as the dominant clinical phenotype. No subject with a diagnosis of primary progressive aphasia was identified with this mutation. Incomplete penetrance was suggested in two kindreds, and the youngest generation had significantly earlier age of onset (>10 years) compared with the next oldest generation in 11 kindreds. Neuropsychological testing showed a profile of slowed processing speed, complex attention/executive dysfunction, and impairment in rapid word retrieval. Neuroimaging studies showed bilateral frontal abnormalities most consistently, with more variable degrees of parietal with or without temporal changes; no case had strikingly focal or asymmetric findings. Neuropathological examination of 14 patients revealed a range of transactive response DNA binding protein molecular weight 43 pathology (10 type A and four type B), as well as ubiquitin-positive cerebellar granular neuron inclusions in all but one case. Motor neuron degeneration was detected in nine patients, including five patients without ante-mortem signs of motor neuron disease. While variability exists, most cases with this mutation have a characteristic spectrum of demographic, clinical, neuropsychological, neuroimaging and especially neuropathological findings.
doi:10.1093/brain/aws004
PMCID: PMC3286335  PMID: 22366793
frontotemporal dementia; amyotrophic lateral sclerosis; motor neuron disease; TDP-43; neurogenetics; chromosome 9
12.  A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy 
The New England journal of medicine  2013;369(20):10.1056/NEJMoa1214747.
BACKGROUND
Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multi-focal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.
METHODS
We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.
RESULTS
We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.
CONCLUSIONS
Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.)
doi:10.1056/NEJMoa1214747
PMCID: PMC3863770  PMID: 24224623
13.  Idiopathic generalised epilepsy of adult onset: clinical syndromes and genetics 
Objective: To study the clinical features and genetics of idiopathic generalised epilepsy (IGE) beginning in adult life.
Methods: Consecutive patients with IGE, defined as generalised seizures with spike or polyspike and wave on EEG, were studied in the setting of a first seizure clinic where an early postictal EEG record is part of the protocol. Patients were divided into two groups: "classical IGE" with onset before 20 years and inclusive of all the IGE subsyndromes recognised by the international classification; and "adult onset IGE", when seizure onset was at age 20 years or later. Seizure patterns, clinical features, and genetics of the adult onset group were examined.
Results: Of 121 patients with an electro-clinical diagnosis of IGE, 34 (28%) were diagnosed as adult onset IGE. The seizure patterns in these 34 cases were tonic–clonic seizures + absences (3), tonic–clonic seizures + myoclonus (6), and tonic–clonic seizures alone (25). Tonic–clonic seizures were often precipitated by alcohol or sleep deprivation. The proportion of affected first and second degree relatives did not differ between the classical and adult onset IGE groups. Twenty adult onset cases were treated with sodium valproate, four with other antiepileptic drugs, and 10 were untreated. Follow up of 32 of the 34 cases (for 31 (22) months (mean (SD)) showed that tonic–clonic seizures recurred in eight patients: five with identified provocative factors and three without.
Conclusions: Adult onset IGE is a relatively frequent and benign disorder. Seizures are usually provoked and are easy to control. Patients in this age group may often be misdiagnosed as having non-lesional partial epilepsy. Early postictal EEG and sleep deprivation studies may improve the detection of these patients. Pedigree analysis suggests that adult onset IGE, like classical IGE, has a genetic aetiology.
doi:10.1136/jnnp.74.2.192
PMCID: PMC1738270  PMID: 12531947
14.  Absence epilepsy in apathetic, a spontaneous mutant mouse lacking the h channel subunit, HCN2 
Neurobiology of disease  2008;33(3):499-508.
Analysis of naturally occurring mutations that cause seizures in rodents has advanced understanding of the molecular mechanisms underlying epilepsy. Abnormalities of Ih and h channel expression have been found in many animal models of absence epilepsy. We characterized a novel spontaneous mutant mouse, apathetic (ap/ap), and identified the ap mutation as a 4 base pair insertion within the coding region of Hcn2, the gene encoding the h channel subunit 2 (HCN2). We demonstrated that Hcn2ap mRNA is reduced by 90% compared to wild type, and the predicted truncated HCN2ap protein is absent from the brain tissue of mice carrying the ap allele. ap/ap mice exhibited ataxia, generalized spike-wave absence seizures, and rare generalized tonic-clonic seizures. ap/+ mice had a normal gait, occasional absence seizures and an increased severity of chemoconvulsant-induced seizures. These findings help elucidate basic mechanisms of absence epilepsy and suggest HCN2 may be a target for therapeutic intervention.
doi:10.1016/j.nbd.2008.12.004
PMCID: PMC2643333  PMID: 19150498
15.  “Fantastic Thinking” in Pathologically Proven Pick Disease 
Background
Reports of false beliefs may be a unique feature of behavioral variant frontotemporal dementia (bvFTD) but the nature of these experiences is unclear.
Objective
To report a case of pathologically verified Pick disease in a patient presenting with prominent and recurrent fantasies.
Methods
We describe the clinical, neuroradiologic, and neuropathologic findings of a 53-year-old woman presenting with fantasies and meeting Clinical Consensus Criteria for bvFTD.
Results
Early in her course, she reported interactions with different actors, having torrid affairs with them, and other related fantasies. When confronted with her false beliefs, she admitted that these relationships were imaginary. Autopsy revealed Pick disease with τ-immunoreactive Pick bodies in the frontal and temporal cortices, and in the hippocampi.
Conclusions
Fantastic thinking, or vividly experienced imagination, may be a manifestation of bvFTD that is distinct from delusions and confabulations and could be the source of previously reported delusions and confabulations in bvFTD.
doi:10.1097/WNN.0b013e3181df3007
PMCID: PMC3139563  PMID: 20535063
frontotemporal dementia; Pick disease; confabulations; delusions; fantasy
16.  Atrophy patterns in histologic vs clinical groupings of frontotemporal lobar degeneration 
Neurology  2009;72(19):1653-1660.
Objective:
Predictable patterns of atrophy are associated with the clinical subtypes of frontotemporal dementia (FTD): behavioral variant (bvFTD), semantic dementia (SEMD), and progressive nonfluent aphasia (PNFA). Some studies of pathologic subtypes have also suggested specific atrophy patterns; however, results are inconsistent. Our aim was to test the hypothesis that clinical, but not pathologic, classification (FTD with ubiquitin inclusions [FTD-U] and FTD with tau inclusions [FTD-T]) is associated with predictable patterns of regional atrophy.
Methods:
Magnetic resonance scans of nine FTD-U and six FTD-T patients (histologically confirmed) were compared with 25 controls using voxel-based morphometry (VBM). Analyses were conducted with the patient group classified according to histologic or clinical variant. Additionally, three Alzheimer pathology patients who had the syndrome of SEMD in life (FTD-A) were analyzed.
Results:
The VBM studies in clinical variants confirmed established patterns of atrophy (SEMD, rostral temporal; bvFTD, mesial frontal; PNFA, left insula). FTD-U and FTD-T VBM results were very similar, showing severe atrophy in the temporal poles, mesial frontal lobe, and insulae. A conjunction analysis confirmed this similarity. Subgroup analysis found that SEMD associated with either FTD-T or FTD-U was associated with similar rostral temporal atrophy; however, FTD-A had a qualitatively different pattern of left hippocampal atrophy.
Conclusions:
While there is predictable atrophy for clinical variants of frontotemporal dementia (FTD), histologic FTD variants show no noticeable differences. Reports of specific atrophy profiles are likely the result of idiosyncrasies in small groups. Semantic dementia associated with Alzheimer pathology, however, presented a distinct atrophy pattern.
GLOSSARY
= Alzheimer disease;
= behavioral variant frontotemporal dementia;
= frontotemporal dementia;
= Alzheimer pathology with semantic dementia;
= frontotemporal dementia with tau inclusions;
= frontotemporal dementia with ubiquitin inclusions;
= frontotemporal lobar degeneration;
= Mini-Mental State Examination;
= progressive nonfluent aphasia;
= semantic dementia;
= voxel-based morphometry.
doi:10.1212/WNL.0b013e3181a55fa2
PMCID: PMC2827263  PMID: 19433738
17.  Clinical and EEG characteristics of Juvenile Myoclonic Epilepsy 
Objective : To determine the clinical and electroencephalographic characteristics of patients with Juvenile Myoclonic Epilepsy (JME).
Methods: In this descriptive case series study, 60 patients of Juvenile myoclonic epilepsy (JME) were included. After detailed history clinical examination, Electroencephalography (EEG) with standard protocol was performed in all patients and was analyzed by a neurologist.
Results: Out of 60 patients, 26 (43.3%) were males and 34 (56.6%) were females. Mean age at the onset of myoclonic jerks (MJ) and generalized tonic clonic seizures (GTCS) was 13.7 ± 2.12 years and 14.15 ± 1.79 years respectively. Average delay in the diagnosis was 5.2 years. Myoclonic jerks (MJ) were present in all patients, GTCS in 52 (86.6%), and absence seizures in 8 (13.33%) patients. 6 (10%) had only Myoclonic Jerks. First seizure type was MJ in 52 (86.6%) and absence in 8 (13.3%). Most common precipitating factors were sleep deprivation in 80% and fatigue in 66.6%. Family history for epilepsy was positive in 20%. Diagnosis by referring physicians was JME in only 6 (10%) patients. EEG was abnormal in 42 patients (70%) showing generalized , 4- to 6-Hz polyspike and wave in 27 (45%), generalized single spike/ sharp waves in 7 patients (11.6%), 8 (13.3%) patients had 3-Hz spike-and-wave (SW) activity in addition to the polyspike-and-wave (PSW) pattern. Independent focal EEG abnormalities were noted in 12 patients (20%).
Conclusion: Many of our patients were misdiagnosed by the referring physicians and were prescribed inappropriate antiepileptic drugs. Factors causing misdiagnosis were failure to elicit history of myoclonic jerks, misinterpreting myoclonic jerks as partial seizures and misinterpretation of EEG abnormalities.
doi:10.12669/pjms.301.4465
PMCID: PMC3955533  PMID: 24639822
Clinical; Electroencephalography; Juvenile; Myoclonic Epilepsy
18.  A novel seven-octapeptide repeat insertion in the prion protein gene (PRNP) in a Dutch pedigree with Gerstmann–Sträussler–Scheinker disease phenotype: comparison with similar cases from the literature 
Acta Neuropathologica  2010;121(1):59-68.
Human prion diseases can be sporadic, inherited or acquired by infection and show considerable phenotypic heterogeneity. We describe the clinical, histopathological and pathological prion protein (PrPSc) characteristics of a Dutch family with a novel 7-octapeptide repeat insertion (7-OPRI) in PRNP, the gene encoding the prion protein (PrP). Clinical features were available in four, neuropathological features in three and biochemical characteristics in two members of this family. The clinical phenotype was characterized by slowly progressive cognitive decline, personality change, lethargy, depression with anxiety and panic attacks, apraxia and a hypokinetic-rigid syndrome. Neuropathological findings consisted of numerous multi- and unicentric amyloid plaques throughout the cerebrum and cerebellum with varying degrees of spongiform degeneration. Genetic and molecular studies were performed in two male family members. One of them was homozygous for valine and the other heterozygous for methionine and valine at codon 129 of PRNP. Sequence analysis identified a novel 168 bp insertion [R2–R2–R2–R2–R3g–R2–R2] in the octapeptide repeat region of PRNP. Both patients carried the mutation on the allele with valine at codon 129. Western blot analysis showed type 1 PrPSc in both patients and detected a smaller ~8 kDa PrPSc fragment in the cerebellum in one patient. The features of this Dutch kindred define an unusual neuropathological phenotype and a novel PRNP haplotype among the previously documented 7-OPRI mutations, further expanding the spectrum of genotype–phenotype correlations in inherited prion diseases.
doi:10.1007/s00401-010-0656-3
PMCID: PMC3015204  PMID: 20198483
Creutzfeldt–Jakob disease; Prion protein; Genetic CJD; Base pair insertion; Neurodegeneration; Amyloidosis; Gerstmann–Sträussler–Scheinker disease
19.  Neuropsychiatric features of C9orf72-associated behavioral variant frontotemporal dementia and frontotemporal dementia with motor neuron disease 
Earlier reports of chromosome 9p-linked frontotemporal dementia (FTD) with amyotrophic lateral sclerosis (ALS) kindreds observed psychosis as a prominent feature in some patients. Since the discovery of chromosome 9 open reading frame 72 (C9orf72) hexanucleotide expansions as a cause of FTD and ALS, research groups and consortia around the world have reported their respective observations of the clinical features associated with this mutation. We reviewed the recent literature on C9orf72-associated FTD and ALS with focus on the neuropsychiatric features associated with this mutation, as well as the experience at University of California, San Francisco. The results and methodologies varied greatly across studies, making comparison of results challenging. Four reports found that psychotic features (particularly delusions) were frequent among mutation carriers, particularly when present early during the disease course, suggesting that this symptom category may be a marker for the mutation. Disinhibition and apathy were the most commonly reported early behavioral symptoms, but these may not be helpful in distinguishing carriers and noncarriers because of the symptoms' frequency in sporadic behavioral variant FTD. Other neuropsychiatric features were reported in different frequencies across studies, suggesting either a similar behavioral phenotype in carriers and noncarriers or reflecting the heterogeneity in clinical presentation of behavioral variant FTD due to C9orf72 expansions. Further studies with larger cohorts will be necessary to determine the neuropsychiatric presentation associated with this mutation.
doi:10.1186/alzrt141
PMCID: PMC3580395  PMID: 23034079
20.  A novel PRNP-P105S mutation associated with atypical prion disease and a rare PrPSc conformation 
Neurology  2008;71(18):1431-1438.
Objective:
To define the clinicopathologic, genetic, and pathogenic prion protein (PrPSc) characteristics associated with a novel mutation of the prion protein gene (PRNP).
Methods:
The coding segment of PRNP from the proband and family members was sequenced and the brain of the proband was histologically studied. The Western blot profile of the proteinase K (PK) resistant fraction of PrPSc, an approximation of its conformation, or “PrPSc-type,” was determined.
Results:
We detected a novel mutation at codon 105 of PRNP that results in a serine (S) substitution of proline (P) (P105S), in a young woman who developed progressive aphasia, behavioral changes, dementia, and parkinsonism, lasting 10 years to her death. Histopathologic findings included an intense focus of multicentric PrP-plaques within the hippocampus, punctate plaques scattered throughout the cerebellum, and intense spongiform degeneration focally within the putamen, suggesting a variant of Gerstmann-Sträussler-Scheinker syndrome (GSS). However, PrPSc-typing revealed two PK-resistant PrPSc fragments (∼21 and 26 kDa), a pattern not previously detected in GSS.
Conclusions:
This mutation is the third sequence variation at codon 105 of PRNP. The unusual phenotype and PrPSc-type distinguishes this genetic prion disease from typical Gerstmann-Sträussler-Scheinker syndrome and other codon 105 substitutions, suggesting that, in addition to the loss of proline at this position, the PrPSc conformation and phenotype is dependent on the specific amino acid substitution.
GLOSSARY
= familial Creutzfeldt-Jakob disease;
= familial fatal insomnia;
= frontotemporal dementia;
= Gerstmann-Sträussler-Scheinker syndrome;
= proteinase K.
doi:10.1212/01.wnl.0000330237.94742.fa
PMCID: PMC2676963  PMID: 18955686
21.  Idiopathic generalized epilepsy: Phenotypic and electroencephalographic observations in a large cohort from South India 
Purpose:
We studied the phenotype and electroencephalographic (EEG) features, and therapeutic aspects of idiopathic generalized epilepsies (IGEs) in South Indian population.
Patients and Methods:
This prospective cross-sectional hospital-based study was carried out on non-consecutive 287 patients (age 22.2 ± 7.7 years; M:F = 139:148) with IGE syndrome. Their clinical and EEG observations were analyzed.
Results:
Majority of the patients had onset of seizures <20 years of age (n = 178; 62%). Thirty one patients (10.8%) had family history of epilepsy. Nearly half of them (49.9%) had <5 years of duration of seizures. The type of IGEs included Juvenile myoclonic epilepsy (JME): 115 (40.1%); IGE with generalized tonic-clonic seizures (GTCS) only: 102 (39.02%); childhood absence epilepsy (CAE): 35 (12.2%); GTCS on awakening: 15 (5.2%); Juvenile absence epilepsy (JAE): 11 (3.8%); and unclassified seizures: 9 (3.1%). The triggering factors noted in 45% were sleep deprivation (20%), non-compliance and stress in 5% each. The EEG (n = 280) showed epileptiform discharges in about 50% of patients. Epileptiform discharges during activation was observed in 40/249 patients (16.1%): Hyperventilation in 32 (12.8%) and photic stimulation in 19 (7.6%). The seizures were well controlled with anti-epileptic drugs (AEDs) in 232 (80.8%) patients and among them, 225 (78.4%) patients were on monotherapy. Valproate (n = 131) was the most frequently prescribed as monotherapy.
Conclusions:
This is one of the largest cohort of patients with IGE. This study reiterates the importance of segregating IGE syndrome and such analysis will aid to the current understanding and management.
doi:10.4103/0972-2327.112455
PMCID: PMC3724066  PMID: 23956556
Electroencephalographic; idiopathic generalized epilepsy; epilepsy syndromes; seizure types
22.  Epilepsy in Biotinidase Deficiency After Biotin Treatment 
JIMD Reports  2011;4:75-78.
Patients with severe biotinidase deficiency (BD), if untreated, may exhibit seizures, psychomotor delay, deafness, ataxia, visual pathology, conjunctivitis, alopecia, and dermatitis. Clinical features normally appear within the first months of life, between two and five. Seizures are one of the most common symptoms in these patients (55%), usually presented as generalized tonic–clonic, and improving within 24 h of biotin treatment. Treatment delay has been associated with irreversible neurological damage, mental retardation, ataxia, paraparesis, deafness, and epilepsy exceptionally.
We report the case of a girl who was admitted at 2.5 months because of vomiting, failure to thrive, flexor spasms, dermatitis, and neurological depression for 1 month. BD was identified and was treated with biotin, stopping seizures and improving symptoms. Developmental delay, paraparesis, optic atrophy, and seizures during febrile illness were observed at follow-up. At the age of 8, she suffered hemigeneralized seizures despite appropriate biotin treatment, so levetiracetam was administered, and epilepsy was controlled. Organic acid measurement was performed to determine whether the child was receiving enough or no biotin.
Even though BD is a rare condition, because the biotinidase screening is a reliable procedure and the disorder is readily treatable, the implementation of extended biotinidase screening will effectively help to prevent any acute and long-term neurological problems as well as the significant morbidity associated with untreated disease. In addition, neonatal screening and early treatment with biotin prevents severe neurological sequelae, such as epilepsy, which has not been thoroughly described in the literature.
doi:10.1007/8904_2011_74
PMCID: PMC3509878  PMID: 23430899
23.  Polyspike and Waves Do Not Predict Generalized Tonic-Clonic Seizures in Childhood Absence Epilepsy 
Journal of child neurology  2010;25(4):475-481.
About 40% of children with childhood absence epilepsy develop generalized tonic-clonic seizures. It is commonly held that polyspike–wave pattern on the electroencephalogram (EEG) can predict this development of generalized tonic-clonic seizures. However, there is no firm evidence in support of this proposition. To test this assumption, we used survival analysis and compared the incidence of generalized tonic-clonic seizures in 115 patients with childhood absence epilepsy having either isolated 3-Hz spike–wave or coexisting 3 Hz and polyspike–waves and other variables. There was no evidence that polyspike–waves predicted development of generalized tonic-clonic seizures in patients with childhood absence epilepsy. Later age of onset (≥8 years) and family histories of generalized tonic-clonic seizures were the only independent predictors. These results have implications for counseling and in the choice of first-line antiepileptic drugs used for childhood absence epilepsy, especially if valproate is chosen based on the observation of polyspike–waves.
doi:10.1177/0883073809341665
PMCID: PMC3782855  PMID: 20382952
childhood absence epilepsy; prognosis; generalized tonic-clonic seizures; antiepileptic drugs
24.  The C9ORF72 expansion mutation is a common cause of ALS+/−FTD in Europe and has a single founder 
A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/−FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/−FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/−FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10−8). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.
doi:10.1038/ejhg.2012.98
PMCID: PMC3522204  PMID: 22692064
ALS; common founder; C9ORF72
25.  Alzheimer's Disease-Like Phenotype Associated With the c.154delA Mutation in Progranulin 
Archives of neurology  2010;67(2):171-177.
Objective
To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), emphasizing the unique clinical features in this kindred.
Design
Clinical, radiologic, pathologic, and genetic characterization of a kindred with a familial neurodegenerative disorder.
Setting
Multispecialty group academic medical center.
Patients
Affected members of a kindred with dementia +/- parkinsonism associated with a unique mutation in PGRN.
Main Outcome Measure
Genotype-phenotype correlation.
Results
Ten affected individuals were identified, among whom six presented with initial amnestic complaints resulting in initial diagnoses of AD or amnestic mild cognitive impairment (MCI). A minority of individuals presented with features characteristic of FTD. The ages of onset of generation II (mean 75.8 years, range 69-80 years) were far greater than those of generation III (mean 60.7 years, range 55-66 years). The pattern of cerebral atrophy varied widely among affected individuals. Neuropathology in six individuals showed frontotemporal lobar degeneration with ubiquitin positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U + NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), causing a frameshift (p.Thr52Hisfs×2) and therefore creation of a premature termination codon and likely null allele.
Conclusions
We describe a large kindred in which the majority of affected individuals had clinical presentations resembling AD or amnestic MCI in association with a mutation in PGRN and underlying FTLD-U + NII neuropathology. This is in distinct contrast to previously reported kindreds, where clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age of onset between generations will require further study.
doi:10.1001/archneurol.2010.113
PMCID: PMC2902004  PMID: 20142525
MRI; progranulin; frontotemporal dementia; PGRN

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