Family History Of ALS Research Articles

Intermediate Repeat Expansion in the ATXN2 Gene as a Risk Factor in the ALS and FTD Spanish Population.

Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093-4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375-4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype.

Recent advances in the genetics of familial and sporadic ALS.

ALS shows complex genetic inheritance patterns. In about 5% to 10% of cases, there is a family history of ALS or a related condition such as frontotemporal dementia in a first or second degree relative, and for about 80% of such people a pathogenic gene variant can be identified. Such variants are also seen in people with no family history because of factor influencing the expression of genes, such as age. Genetic susceptibility factors also contribute to risk, and the heritability of ALS is between 40% and 60%. The genetic variants influencing ALS risk include single base changes, repeat expansions, copy number variants, and others. Here we review what is known of the genetic landscape and architecture of ALS.

Facial Onset Sensory and Motor Neuronopathy: A Case Series and Literature Review

Introduction: Facial Onset Sensory and Motor Neuronopathy (FOSMN) typically presents with paresthesias in the trigeminal nerve distribution and weakness that progresses rostro-caudally.&#x0D; Objective: To present two new cases of FOSMN, summarize the current literature, and address areas for future study.&#x0D; Methods: Observational data was collected from two patients with FOSMN from our institution. A literature review of FOSMN was completed using PubMed.&#x0D; Results: We identified 100 cases of FOSMN, including our two new cases. 93% presented with facial paresthesias. 97% had bulbar symptoms. Five had family history of ALS. Abnormal Blink reflex was most common on EMG/NCS. CSF was typically normal, but a rare severe case showed elevated protein. Mutations included: TARDBP, OPMD, D90A-SOD1, CHCHD10, VCP, and SQSTM1. Neuropathological studies showed neurodegenerative changes without inflammation. Some cases have reported transient stabilization or improvement to immunomodulatory therapy.&#x0D; Case Reports: A 72-year-old man presented with right-sided trigeminal paresthesias that progressed in a rostro-caudal fashion, dysphagia, and hand weakness. He died 4-5 years after symptom onset. A 69-year-old man presented with left-sided jaw paresthesias, dysphagia and dysarthria. He was trialed on IVIG for 1.5 years without improvement and died 2.6 years after symptom onset.&#x0D; Conclusion: FOSMN is a rare disorder with a unique clinical and electrophysiological phenotype. The pathophysiology has been associated with neurodegeneration and multiple gene mutations have correlated to FOSMN. Some reports suggest transient response to immunomodulatory therapy, though prospective studies are lacking. CSF protein elevation may be seen in severe disease. Future studies will help further elucidate the approach to diagnosis, treatment, and prognostic counseling (biomarkers).&#x0D;

FP.31 ANXA11 related adult-onset muscular dystrophy in Greek families

Pathogenic mutations in the low complexity domain of many RNA binding proteins have been reported in both neurogenic and myopathic disorders. Frequent involvement of multiple organs in patients often leads to associated diseases classified as multisystem proteinopathies (MSP) because of the shared aggregate pathology in the affected tissues. These mutations and associated molecular pathomechanisms are part of the dysfunctional cellular clearance of protein aggregates and stress responses. Interestingly, the same causative variant has often been observed in patients with ALS and large families with primary myopathies with or without ALS. Recently, we identified the c.118G>T; p.D40Y variant in <i>ANXA11</i> (NM_0145869.1) segregating with an autosomal dominant myopathy phenotype in five large Greek families from the relatively isolated island of Aegean Sea. However, this variant has been reported in French ALS patients and Brazilian MSP families with ALS patients. In our cohort, none of the patients have an ALS phenotype or family history of ALS. The age of onset in our patients was in the 3^rd-5^th decade of life. Muscle MRI shows myopathic fatty degeneration-replacement of adductors, semitendinosus, semimembranosus, and gastrocnemius muscles. However, none of our patients report any axial involvement with head drop described in the Brazilian MSP families with the same mutation. We present strong genetic evidence that <i>ANXA11</i> p.D40Y causes the observed phenotype in the Greek families. Further studies will unravel the additional molecular factors that can explain the involvement of different target organs causing either ALS or the primary myopathy phenotype.

MOTOR NEURON DISORDERS AND NEUROPATHIES: EP.244 Clinical characteristics of SOD1 and c9ORF72 positive ALS: findings from the Canadian neuromuscular disease registry

The Canadian Neuromuscular Disease Registry (CNDR) is a nationwide neuromuscular disease registry. The CNDR collects data in affiliated clinics across Canada and currently has over 4100 total and 1500 ALS patients registered. Therapies for genetic-based ALS are under development targeting two of the most common genes associated with ALS, c9ORF72 and SOD1. The objective of this study is to characterize SOD1+ and c9ORF72+ ALS patients in Canada. Data from consenting ALS patients were recorded at 13 affiliated ALS clinics across Canada. Patients with a known SOD1 or c9ORF72 mutation and gender- and age-matched control individuals without a known genetic mutation or family history of ALS were included in the analyses. Progression rates were calculated in the first-year post-diagnosis by change in ALSFRS-R/time. Patients without multiple visits within the first-year post-diagnosis were excluded from progression analyses. Similarly, patients whose ALSFRS-R scores coincided with clinical trial participation were excluded from progression analyses. Baseline data from 25 SOD1 patients, 51 c9ORF72 patients, and 76 age- and gender-matched sporadic controls are presented. Median age at diagnosis was 58.3, 59.6, and 59.5 years for SOD1, c9ORF72, and controls respectively. SOD1 patients were 54% male, c9ORF72 65%, and controls 63%. Of the 25 SOD1 patients with mutation recorded, 48% had the Ile113Thr mutation. Progression analyses was performed on the subset of 12 SOD1 cases, 33 c9ORF72 cases, and 45 controls with complete data, and without clinical trial participation. ALSFRS-R progression rates were 1.0 points/month (range: 0-2.8) for SOD1, 1.2 points/month (0-3.4) for c9ORF72, and 0.9 points/month (0-2.4) for controls. Further longitudinal analyses incorporating potential confounders will be presented.

Theme 2 Genetics and genomics

Background: A genetic basis is found in ∼70% of familial and ∼15% of sporadic ALS, in research cohorts. Clinical trials of gene-targeted therapies are underway, heralding a new era of personalized medicine in ALS treatment. However, ALS management guidelines do not include recommendations for the offer of genetic testing. Many persons with ALS who desire genetic testing are not currently offered it, and the yield of genetic testing in clinic-based ALS populations is unknown. The ALS GAP program, sponsored by the Northeast ALS (NEALS) Consortium, provides free genetic testing for patients with ALS who have a family history of ALS or dementia. We report genetic testing outcomes in the first 142 patients tested in the program.Objectives: 1) To create a pilot ALS genetic testing program for NEALS clinics, 2) To study the rate of ALS gene identification in a US clinic-based populationMethods: Persons with ALS and a family history of ALS (fALS) or dementia (dALS) who receive care at a US NEALS clinic are eligible for testing. Patients classified as fALS (having a positive family history of ALS in a 1st, 2nd, or 3rd degree relative) are eligible for C9orf72 testing, with the option to reflex to a 5 gene (SOD1, FUS, TARDBP, TBK1, VCP) panel. Patients classified as dALS (having a positive family history of dementia of any type in a 1st or 2nd degree relative) are eligible for C9orf72 testing only.Results: Currently, 29.5% (34/115) of US NEALS clinics have participated in the program. Of 142 patients who have completed testing to date, 78 (54.9%) were classified as fALS and 64 (45.1%) as dALS. Among fALS cases, 42/78 (53.9%) tested positive, including 32/78 (41%) with a C9orf72 repeat expansion, and 10/78 (12.8%) with other pathogenic or likely pathogenic variants in SOD, FUS, TARDP or VCP. Variants of uncertain significance (VUS) in FUS were identified in 2/78 (2.6%). Among dALS cases, 12/60 (20%) tested positive for C9orf72.Discussion and conclusions: Participation in ALS-GAP indicates significant clinician and patient interest in ALS genetic testing. This program addresses several current barriers to testing access, including cost, identifying appropriate candidates for testing, and appropriate test selection. Although 38% of patients who participated in the program have thus far received a genetic diagnosis, our testing outcome data suggests that the gene identification rate in fALS cases may be lower in clinic-based patients than in research cohorts, particularly for genes other than C9orf72. This program may serve as a model for the practice of ALS genetic testing in the clinic setting. Consistent, equitable testing policies, as well as an accurate understanding of the genetic profile of clinic-based ALS populations, are needed as gene-targeted therapies reach patient care.

Frontotemporal Dementia Associated With theC9ORF72Mutation

While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear. To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)-FTD cohort. A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD-amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained. Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale. In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD. The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.

侵襲的陽圧補助換気導入後の筋萎縮性側索硬化症における意思伝達能力障害―Stage 分類の提唱と予後予測 因子の検討―

ALS patients supported by a ventilator often suffered from difficulty in communicating with others. We herein proposed a new classification of clinical stages of advanced ALS focusing on the degree of communication disturbance. We analyzed the relationship between clinical findings and the prognosis for communication disturbance. Twenty-nine ALS patients without dementia were enrolled in the study. The proposed classification consisted of five stages. Stage I: communicate in sentences, stage II: communicate with one word answers only, stage III: communicate with nonverbal yes/no response only, stage IV: cannot communicate occasionally due to uncertain yes/no responses, stage V: cannot communicate by any means. Clinical analysis showed that patients who reached stage V had begun to use the ventilator significantly earlier than patients with the final stages of IV or less. In addition, patients in stage V frequently had a family history of ALS. Rapid disease progression before ventilator use in patients with a family history might predict a poor long-term prognosis for communication disorder after using the ventilator.

ALS-Parkinsonism-Dementia complex of Kii and other related diseases in Japan

The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and 1980s. In the 1990 s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990 s, and PDC replaced ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC. We recently found a new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or environmental factors.

Co-occurrence of progressive anarthria with an S393L TARDBP mutation and ALS within a family

Progressive anarthria is usually classified as a tau pathology. We report an 87-year-old female with a family history of ALS and Parkinsonism, presenting with progressive anarthria. Molecular genetics analyses showed a heterozygous mutation S393L on exon 6 of the TARDBP gene. It has been previously reported in sporadic and familial amyotrophic lateral sclerosis. This case strengthens the hypothesis of a continuum between motor neuron disease and frontotemporal lobar degeneration among TDP-43 proteinopathies.

Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation

Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). Patients underwent a single clinical assessment, MRI, and [(18)F]fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B.II.1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A-->G (A.III.1), R493X (B.II.1), and R433W (C.III.1). IVS6-2A-->G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation (R433W) was found in an FTD patient with family history of ALS.

Trouble on the pitch: are professional football players at increased risk of developing amyotrophic lateral sclerosis?

With the exception of some rare familial forms of the disease, the cause of amyotrophic lateral sclerosis (ALS; motor neuron disease) is unknown (Bruijn et al ., 2004). Although 90–95% of ALS cases are apparently sporadic, SOD1 gene mutations with low penetrance (Cudkowicz et al ., 1997; Anderson et al ., 1997; Shaw et al ., 1998; Al-Chalabi et al ., 1999; Orrell et al ., 1999; Andersen et al ., 2003; Majoor-Krakauer et al ., 2003; Nogales-Gadea et al ., 2004) and other gene variants or mutations may contribute to the population risk (Al-Chalabi et al ., 1999; Mitchell, 2000; Lambrechts et al ., 2003; Majoor-Krakauer et al ., 2003). Advances in understanding the molecular basis of neurodegenerative diseases point clearly to the importance of genetic factors in conditions that until recently we took to be determined mainly, if not solely, by environmental factors, for example, Alzheimer's disease and Parkinson's disease. Genetic predisposing factors may, of course, require an environmental trigger to activate disease processes. There has been no shortage of epidemiological research into ALS attempting to identify a link between ALS and trauma, exposure to toxins, physical activity and a variety of other possible risk factors (Mitchell, 2000; Worms, 2001; Armon, 2003 a , b ). However, the only really consistent epidemiological risk factors for ALS are increasing age, male sex and a family history of ALS (Kurtzke, 1991; Mitchell, 2000; Worms, 2001; Armon, 2003a), although cigarette smoking may also be a risk factor (Nelson et al ., 2000; Armon, 2003 a ; Weisskopf et al ., 2004). Even in Guam, where a restricted population with high risk of developing ALS has been under intense (albeit intermittent) scrutiny for over 50 years, controversy …

The overlap of amyotrophic lateral sclerosis and frontotemporal dementia.

Patients with frontotemporal dementia (FTD) with no known diagnosis of ALS or family history of ALS were clinically and electrophysiologically assessed for the presence of ALS. Of 36 patients studied, five met criteria for a definite diagnosis of ALS and two had EMG findings suggestive of denervation in one limb. An additional five patients had prominent fasciculations and six other patients had trouble swallowing but all had normal results on EMG studies. One of the patients with fasciculations and a normal EMG study progressed to definite ALS over the course of 1 year.

Receptor site specificity for the acute effects of DL(±)-BMAA in mice : Stuart E. Smith and Brian S. Meldrum, Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, U.K.

The ALS/parkinsonism-dementia complex (PDC) of Kii is an endemic disease with a diverse phenotypic expression characteristic of classical ALS, parkinsonism and dementia. Its clinical and neuropathological manifestations are similar to a syndrome found in Guam, sharing classical ALS pathology together with many neurofibrillary tangles in the brain. The incidence rates of ALS declined dramatically between the 1950s and 1980s. In the 1990s, Kuzuhara found a high incidence of PDC with abundant neurofibrillary tangles, similar to Guamanian PDC. The incidence rates of PDC dramatically rose during the 1980s and 1990s, and PDC replaced ALS. More than 70% of patients in the endemic region had a family history of ALS or PDC.We recently found a new gene OPTN causing ALS, and have extended its clinical survey in Japan. Two autopsied cases showed involvement of basal ganglia and/or cerebral cortex with neurofibrillary tangles. A few family members also showed dementia and parkinsonism without evidence of motor neuron disease. Moreover the penetrance seems to be incomplete. Despite these similarities, OPTN mutations were not found in the Kii patients. We speculate that the Kii/ALS-PDC could primarily be a genetic disease, and its clinical manifestation is modified by other genes or environmental factors.