Survival and epidemiology of amyotrophic lateral sclerosis (ALS) cases in the Chicago and Detroit metropolitan cohort: incident cases 2009-2011 and survival through 2018.

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disorder. The National ALS Registry launched surveillance projects to understand the distribution of ALS in targeted geographic cohorts. OBJECTIVE: To describe the demographics, incidence, and survival of persons with ALS (PALS) identified in the Chicago and Detroit area population-based cohort. METHODS: Neurologists in the catchment area provided case reports for eligible ALS cases diagnosed and/or cared for from 1 January 2009 through 31 December 2011. Crude incidence rates were calculated for 2009-2011 and stratified by race and ethnicity. Using data from the National Death Index through 2018, we modeled the effect of patient covariates on mortality using the Cox proportional hazard regression. RESULTS: Of the 574 cases, 372 (64.8%) were diagnosed from 2009 to 2011. The combined crude incidence rates for 2009, 2010, and 2011 were 1.44, 1.53, and 1.73 cases per 100,000 person-years, respectively. Of the 486 subjects with complete survival data, 81% were deceased at the end of follow-up. Median survival time was 2.2 years, with 30% and 9% of subjects surviving past 5 and 10 years after diagnosis, respectively. Additionally, female PALS and PALS with longer time between symptom onset and diagnosis experienced longer survival. Nonwhites also experienced longer survival than Whites, except for those cases diagnosed in the younger age categories. CONCLUSION: Understanding the survival of ALS patients can aid in understanding variable prognostic factors, which can potentially extend survival and improve disease management.

Effect of racial background on motor cortical function as measured by threshold tracking transcranial magnetic stimulation.

A previous study using traditional paired-pulse TMS methods (amplitude-tracking) has reported differences in resting motor threshold (RMT) and short-interval intracortical inhibition (SICI) between healthy subjects of Caucasian and Han Chinese backgrounds, probably due to differences in the skull shape. The amplitude-tracking method delivers stimuli with constant intensity and causes substantial variabilities in motor-evoked potential amplitudes. To overcome this variability, threshold tracking transcranial magnetic stimulation (TT-TMS) has been developed. The present study aimed to investigate whether racial differences in motor cortical function exist, using TT-TMS. A total of 83 healthy volunteers (30 Caucasians, 25 Han Chinese, and 28 Japanese) were included in the present series. In TT-TMS and nerve conduction studies, electrodes were placed on the dominant limb, with measures recorded from the abductor pollicis brevis muscle. Stimulations were delivered with a circular coil, directly above the primary motor cortex. There were no significant differences at all the SICI intervals between races. Similarly, there were no significant differences in other measures of excitability including mean RMT, intracortical facilitation, and cortical silent period. Contrary to traditional amplitude-tracking TMS, motor cortical excitability and thereby motor cortical function is minimally influenced by racial differences when measured by TT-TMS. Recent studies have disclosed that SICI measured by TT-TMS differentiates amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.NEW & NOTEWORTHY Threshold tracking transcranial magnetic stimulation (TT-TMS) was applied for Caucasians, Han Chinese, and Japanese. No significant differences were found in TMS excitability indexes among races. Recent studies have disclosed that TT-TMS indexes differentiate amyotrophic lateral sclerosis (ALS) from ALS mimic disorders, with high sensitivity and specificity, in Caucasians. This study suggested that TT-TMS can be applied for the ALS diagnosis in Asian patients, as well as Caucasians.

Mutation analysis of SOD1, C9orf72, TARDBP and FUS genes in ethnically-diverse Malaysian patients with amyotrophic lateral sclerosis (ALS).

Recent studies have identified SOD1, FUS, TARDBP and C9orf72 as major ALS-related genes in both European and Asian populations. However, significant differences exist in the mutation frequencies of these genes between various ancestral backgrounds. This study aims to identify the frequency of mutations in the common causative ALS genes in a multi-ethnic Malaysian cohort. We screened 101 Malaysian ALS patients including 3 familial and 98 sporadic cases for mutations in the coding regions of SOD1, FUS, and TARDBP by Sanger sequencing. The C9orf72 hexanucleotide repeat expansion was screened using the repeat-primed polymerase chain reaction assay. Mutations were found in 5.9% (6 of 101) of patients including 3.0% (3 of 101) of patients with the previously reported SOD1 missense mutations (p.V48A and p.N87S) and 3.0% (3 of 101) of patients with the C9orf72 repeat expansion. No mutations were found in the FUS and TARDBP genes. This study is the first to report the mutation frequency in an ethnically diverse Malaysian ALS population and warrants further investigation to reveal novel genes and disease pathways.

The utility of ALS staging systems in a multi-ethnic patient cohort.

Objective: To compare two ALS staging systems, King's clinical staging and Milano-Torino (MiToS) functional staging, using prospective data from a multi-ethnic cohort of ALS patients. Methods: The stages of disease were determined prospectively based on existing definitions. The two systems were compared for timing of stages using box plots, correspondence using chi-square tests and association using Spearman's rank correlation. Results: The distribution of stages differed between the two systems. The proportions of disease stages of the King's staging system were more evenly distributed whereas in MiToS, there was greater weight seen at the later stages of disease. At the early stages, patients moved consecutively in the MiToS staging system but not in the King's staging system where patients tended to skip stages to reach later stages. Both systems had good correlation (Spearman's rho = 0.869) and the King's stage 4 most frequently corresponded to MiToS stage 2. Conclusion: We found the King's staging was helpful in determining the stages of disease burden, whereas both were helpful in determining the time to functional dependence with MiToS further refining the levels of dependence.

Comparison of Phenotypic Characteristics and Prognosis Between Black and White Patients in a Tertiary ALS Clinic.

OBJECTIVE: To compare characteristics between Black and White patients with amyotrophic lateral sclerosis (ALS) in order to identify disparities and phenotypic variability. METHODS: We performed database review for patients seen between 1997 and 2020 at the Emory ALS Center in Atlanta, Georgia. Patients with ALS were included for analyses if race was self-reported as Black or White and symptom onset was prior to January 1, 2017. Variables examined include race, age at onset, diagnostic delay, site of onset, median income, C9orf72 mutation status, feeding tube and tracheostomy status, vital capacity, Amyotrophic Lateral Sclerosis Functional Rating Scale-revised(ALSFRS-R) score, and survival time. RESULTS: A total of 2,363 patient records were queried, and 1,298 were included in analysis; 203 self-identified as Black and 1,095 as White. Black patients had younger age at symptom onset, lower frequency of C9orf72 mutations, lower median income, longer diagnostic delay, and lower baseline ALSFRS-R and vital capacity compared to White patients. Black patients had a longer median survival than White patients; however, race was not an independent predictor of survival time when controlling for age at symptom onset, bulbar onset, and C9orf72 positivity. CONCLUSIONS: Black patients with ALS had longer median survival compared to White patients, but race was not independently associated with survival after controlling for age, site of onset, and C9orf72 status, factors known to predict prognosis. Black patients with ALS had longer diagnostic delay and lower baseline ventilatory and functional status at first clinic visit compared to White patients, which could be suggestive of barriers to tertiary care. Further studies are needed to identify the underlying causes of ALS racial differences.

Loss-of-function variants in NEK1 are associated with an increased risk of sporadic ALS in the Japanese population.

Loss-of-function (LoF) variants in NEK1 have recently been reported to be associated with amyotrophic lateral sclerosis (ALS). In this study, we investigated the association of NEK1 LoF variants with an increased risk of sporadic ALS (SALS) and the clinical characteristics of patients with SALS carrying LoF variants in a Japanese case series. Whole-exome sequencing analysis was performed for a series of 446 SALS patients in whom pathogenic variants in familial ALS-causative genes have not been identified and 1163 healthy control subjects in our Japanese series. We evaluated LoF variants, defined as nonsense, splice-site disrupting single-nucleotide variants (SNVs), or short insertion/deletion (indel) variants predicted to cause frameshifts in NEK1. We identified seven NEK1 LoF variants in patients with SALS (1.57%), whereas only one was identified in control subjects (0.086%) (P = 0.00073, Fisher's exact test). This finding is consistent with those in recent reports from other regions in the world. In conclusion, we demonstrated that NEK1 LoF variants are also associated with an increased risk of SALS in the Japanese population.

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10-8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10-4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10-11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS.

Common mutations of interest in the diagnosis of amyotrophic lateral sclerosis: how common are common mutations in ALS genes?

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease predominantly affecting upper and lower motor neurons. Diagnosis of this devastating pathology is very difficult because the high degree of clinical heterogeneity with which it occurs and until now, no truly effective treatment exists. AREAS COVERED: Molecular diagnosis may be a valuable tool for dissecting out ALS complex heterogeneity and for identifying new molecular mechanisms underlying the characteristic selective degeneration and death of motor neurons. To date, pathogenic variants in ALS genes are known to be present in up to 70% of familial and 10% of apparently sporadic ALS cases and can be associated with risks for ALS only or risks for other neurodegenerative diseases. This paper shows the procedure currently used in diagnostic laboratories to investigate most frequent mutations in ALS and evaluating the utility of involved molecular techniques as potential tools to discriminate 'common mutations' in ALS patients. EXPERT OPINION: Genetic testing may allow for establishing an accurate pathological diagnosis and a more precise stratification of patient groups in future drug trials.

Objectively Monitoring Amyotrophic Lateral Sclerosis Patient Symptoms During Clinical Trials With Sensors: Observational Study.

BACKGROUND: Objective symptom monitoring of patients with Amyotrophic Lateral Sclerosis (ALS) has the potential to provide an important source of information to evaluate the impact of the disease on aspects of real-world functional capacity and activities of daily living in the home setting, providing useful objective outcome measures for clinical trials. OBJECTIVE: This study aimed to investigate the feasibility of a novel digital platform for remote data collection of multiple symptoms-physical activity, heart rate variability (HRV), and digital speech characteristics-in 25 patients with ALS in an observational clinical trial setting to explore the impact of the devices on patients' everyday life and to record tolerability related to the devices and study procedures over 48 weeks. METHODS: In this exploratory, noncontrolled, nondrug study, patients attended a clinical site visit every 3 months to perform activity reference tasks while wearing a sensor, to conduct digital speech tests and for conventional ALS monitoring. In addition, patients wore the sensor in their daily life for approximately 3 days every month for the duration of the study. RESULTS: The amount and quality of digital speech data captured at the clinical sites were as intended, and there were no significant issues. All the home monitoring sensor data available were propagated through the system and were received as expected. However, the amount and quality of physical activity home monitoring data were lower than anticipated. A total of 3 or more days (or partial days) of data were recorded for 65% of protocol time points, with no data collected for 24% of time points. At baseline, 24 of 25 patients provided data, reduced to 13 of 18 patients at Week 48. Lower-than-expected quality HRV data were obtained, likely because of poor contact between the sensor and the skin. In total, 6 of 25 patients had mild or moderate adverse events (AEs) in the skin and subcutaneous tissue disorders category because of skin irritation caused by the electrode patch. There were no reports of serious AEs or deaths. Most patients found the sensor comfortable, with no or minimal impact on daily activities. CONCLUSIONS: The platform can measure physical activity in patients with ALS in their home environment; patients used the equipment successfully, and it was generally well tolerated. The quantity of home monitoring physical activity data was lower than expected, although it was sufficient to allow investigation of novel physical activity end points. Good-quality in-clinic speech data were successfully captured for analysis. Future studies using objective patient monitoring approaches, combined with the most current technological advances, may be useful to elucidate novel digital biomarkers of disease progression.

UNC13A variant rs12608932 is associated with increased risk of amyotrophic lateral sclerosis and reduced patient survival: a meta-analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with both genetic and environmental risk factors. Previous studies trying to find an association between ALS and unc-13 homolog A (UNC13A) gene variants have shown inconsistent results. This study aimed to conduct a meta-analysis of the association between the C allele of rs12608932, a single-nucleotide polymorphism located in an intron of UNC13A, and risk of ALS and patient survival. METHODS: PubMed, Web of Science, Embase, Chinese National Knowledge Infrastructure, Wanfang, and SinoMed databases were systematically searched for genome-wide association studies or case-control studies published up to January 2019 on the association between this variant in UNC13A and risk and/or prognosis of ALS. Data from eligible studies were extracted and analyzed. RESULTS: The pooled data (28,072 patients with sporadic ALS and 56,545 controls) showed that rs12608932(C) was associated with an increased risk of ALS (OR = 1.13, 95%CI 1.07-1.20). Subgroup analysis revealed that rs12608932(C) increased the risk of sporadic ALS in non-Asian individuals, including those from the USA and Europe (OR 1.17, 95%CI 1.10-1.25, P < 0.000), but not in Japanese or Chinese subjects (OR 1.01, 95%CI 0.92-1.10, P = 0.85). The available data demonstrated that the CC genotype decreased the survival time of patients with ALS (OR 1.33, 95%CI 1.19-1.49, P < 0.001). CONCLUSION: The present meta-analysis suggests that rs12608932(C) is associated with increased ALS susceptibility, especially in Caucasian and European subjects, and that the CC genotype of rs12608932 is associated with reduced ALS patient survival.

Amyotrophic lateral sclerosis mortality rates among ethnic groups in a predominant admixed population in Latin America: a population-based study in Ecuador.

Current evidence suggests heterogeneity of amyotrophic lateral sclerosis (ALS) among geographic areas and populations. Lower mortality rates have been reported in admixed populations compared to European origin populations. We aimed to describe and compare ALS mortality rates among ethnic groups using a population-based approach in a multiethnic country. Annual mortality cause registers were searched to determine ALS deaths from the National Institute of Statistics and Censuses in Ecuador (INEC) from 1990 to 2016. Mid-year population was considered for each year. The time trend was assessed using a negative binomial regression. Rate ratio statistics were performed to compare the age and sex standardized rates based on the 2010 US population among ethnic groups. Overall, 570 ALS deaths were identified. ALS mortality showed an age-related profile with a peak between 55 and 70 years. After age-sex standardization on the 2010 US population, mortality rate was 0.33 (CI 0.30-0.36) per 100,000. The time trend showed an increase of ALS mortality (p < 0.001). There was no statistical difference in age-sex standardized mortality rates per 100,000 when admixed was compared to white (p = 0.231) and black (p = 0.125). Differences reached statistical significance between admixed and other ethnics (p = 0.015). Our population-based study supports the hypothesis that ALS occurrence is lower in predominant admixed populations from Latin America compared to European and Northern American populations. Further studies are needed to clarify the role of ancestral origin in ALS susceptibility.

Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations.

Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of "large normal alleles" defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.

Prevalence of Amyotrophic Lateral Sclerosis - United States, 2015.

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a progressive and fatal neuromuscular disease; the majority of ALS patients die within 2-5 years of receiving a diagnosis (1). Familial ALS, a hereditary form of the disease, accounts for 5%-10% of cases, whereas the remaining cases have no clearly defined etiology (1). ALS affects persons of all races and ethnicities; however, whites, males, non-Hispanics, persons aged ≥60 years, and those with a family history of ALS are more likely to develop the disease (2). No cure for ALS has yet been identified, and the lack of proven and effective therapeutic interventions is an ongoing challenge. Treatments currently available, Edaravone and Riluzole, do not cure ALS, but slow disease progression in certain patients (3,4). This report presents National ALS Registry findings regarding ALS prevalence in the United States for the period January 1-December 31, 2015. In 2015, the estimated prevalence of ALS cases was 5.2 per 100,000 population with a total of 16,583 cases identified. Overall, these findings are similar to the 2014 ALS prevalence and case count (5.0 per 100,000; 15,927 cases) (2). Prevalence rates by patient characteristics (most common in whites, males, and persons aged ≥60 years) and U.S. Census regions are consistent with ALS demographics and have not changed from 2014 to 2015 calendar years. The algorithm used to identify cases from national administrative databases was updated from the International Classification of Diseases, Ninth Revision (ICD-9) to the ICD-10 codes for claims starting on October 1, 2015, with no apparent effect on case ascertainment. Data collected by the National ALS Registry are being used to better describe the epidemiology of ALS in the United States and to facilitate research on the genetics, potential biomarkers, environmental pollutants, and etiology for ALS.

CDC Grand Rounds: National Amyotrophic Lateral Sclerosis (ALS) Registry Impact, Challenges, and Future Directions.

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a rapidly progressive fatal neurologic disease. Currently, there is no cure for ALS and the available treatments only extend life by an average of a few months. The majority of ALS patients die within 2-5 years of diagnosis, though survival time varies depending on disease progression (1,2). For approximately 10% of patients, ALS is familial, meaning it and has a genetic component; the remaining 90% have sporadic ALS, where etiology is unknown, but might be linked to environmental factors such as chemical exposures (e.g., heavy metals, pesticides) and occupational history (3).

Cross-ethnic meta-analysis identifies association of the GPX3-TNIP1 locus with amyotrophic lateral sclerosis.

Cross-ethnic genetic studies can leverage power from differences in disease epidemiology and population-specific genetic architecture. In particular, the differences in linkage disequilibrium and allele frequency patterns across ethnic groups may increase gene-mapping resolution. Here we use cross-ethnic genetic data in sporadic amyotrophic lateral sclerosis (ALS), an adult-onset, rapidly progressing neurodegenerative disease. We report analyses of novel genome-wide association study data of 1,234 ALS cases and 2,850 controls. We find a significant association of rs10463311 spanning GPX3-TNIP1 with ALS (p = 1.3 × 10-8), with replication support from two independent Australian samples (combined 576 cases and 683 controls, p = 1.7 × 10-3). Both GPX3 and TNIP1 interact with other known ALS genes (SOD1 and OPTN, respectively). In addition, GGNBP2 was identified using gene-based analysis and summary statistics-based Mendelian randomization analysis, although further replication is needed to confirm this result. Our results increase our understanding of genetic aetiology of ALS.Amyotrophic lateral sclerosis (ALS) is a rapidly progressing neurodegenerative disease. Here, Wray and colleagues identify association of the GPX3-TNIP1 locus with ALS using cross-ethnic meta-analyses.

DCTN1 gene analysis in Chinese patients with sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. Missense mutations of DCTN1 have been identified as a possible genetic risk factor for ALS. Here, we tested the DCTN1 protein-coding exons in 510 sporadic ALS patients in whom SOD1, TARDBP, FUS, and C9orf72 genes were screened before. Polymerase chain reaction and Sanger sequencing were used for mutation discovery. The results revealed two rare heterozygous missense variants, c.1867C>T (p.R623W) and c.2798C>T (p.A933V). These two patients exhibited spinal disease onset without cognitive impairment, and their onset age and diagnosis delay was within the average range of Chinese ALS patients. Our results suggested that variants in DCTN1 are not common risk factors for Chinese sporadic ALS and that the frequency of variants of unknown significance in the cohort study was 0.39%.

Risk factors for respiratory failure of motor neuron disease in a multiracial Asian population.

BACKGROUND: Motor neuron disease (MND) is a devastating degenerative disorder. Amyotrophic Lateral Sclerosis (ALS) is the most common and severe form of MND. Respiratory failure arising from ventilator musculature atrophy is the most common cause of death for ALS patients. Exploring the factors correlated with respiratory failure can contribute to disease management. PURPOSE: To characterize the clinical features of MND and determine the factors that may affect respiratory failure of MND patients. METHODS: The case records of all MND patients seen in Singapore General Hospital (SGH) between January 2004 and December 2014 were examined. Demographic, clinical information were collected by reviewing case records. Mortality data, if not available from records, were obtained via phone call interview of family members. Demographic data and clinical treatments were compared between Respiratory support group and Non-respiratory support group. RESULTS: There were 73 patients included in our study. 49 (67.1%) patients died during follow-up. The mean age of onset was 58±11.1years. With regard to treatment, 63% needed feeding support, and 42.5% required ventilation aid. The median overall survival was 36months from symptom onset. Chi-square tests showed there was significantly higher percentage of respiratory support needed in Chinese than in other races (P=0.016). Compared with non-feeding support patients, patients with feeding support were more likely to require assisted ventilation (P=0.001). CONCLUSIONS: We report for the first time that the need of feeding support is significantly associated with assisted ventilation. Chinese MND patients may be more inclined to require respiratory support.

Association between estimated total daily energy expenditure and stage of amyotrophic lateral sclerosis.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, and nutritional status is one of the major prognostic factors of ALS. The aim of this study was to investigate the relationship between total daily energy expenditure (TDEE) and progression of disease in ALS patients, as well as sex differences in TDEE. METHODS: Patients with ALS (N = 370) were diagnosed according to El Escorial criteria and categorized into stage 2, 3, or 4 using a clinical staging system. TDEEs were calculated by summing resting energy expenditure (REE) and physical activity. REE was calculated using equations of Harris-Benedict or Mifflin St. Jeor, and physical activity was calculated using the ALS Functional Rating Scale-Revised, a physical activity coefficient, or adding 30% of REE. RESULTS: TDEE significantly decreased with progression of ALS stage and did not vary by sex. Actual energy intake was lower than TDEE in patients in all stages and lowest in patients with stage 3 ALS. Comparing TDEEs 1 to 5, TDEE 2 decreased with progression of ALS stage and was similar to the average TDEE. CONCLUSIONS: The present study suggests that TDEE decreases with progression of ALS, and patients consume insufficient energy compared with required intake at all stages, particularly at stage 3, suggesting that nutrition support should be started at least before stage 3. Additionally, among the five equations for TDEE, TDEE 2 could be the best for evaluating the nutritional status of patients with ALS.

Race/ethnicity, socioeconomic status, and ALS mortality in the United States.

OBJECTIVE: To determine whether race/ethnicity and socioeconomic status are associated with amyotrophic lateral sclerosis (ALS) mortality in the United States. METHODS: The National Longitudinal Mortality Study (NLMS), a United States-representative, multistage sample, collected race/ethnicity and socioeconomic data prospectively. Mortality information was obtained by matching NLMS records to the National Death Index (1979-2011). More than 2 million persons (n = 1,145,368 women, n = 1,011,172 men) were included, with 33,024,881 person-years of follow-up (1,299 ALS deaths , response rate 96%). Race/ethnicity was by self-report in 4 categories. Hazard ratios (HRs) for ALS mortality were calculated for race/ethnicity and socioeconomic status separately and in mutually adjusted models. RESULTS: Minority vs white race/ethnicity predicted lower ALS mortality in models adjusted for socioeconomic status, type of health insurance, and birthplace (non-Hispanic black, HR 0.61, 95% confidence interval [CI] 0.48-0.78; Hispanic, HR 0.64, 95% CI 0.46-0.88; other races, non-Hispanic, HR 0.52, 95% CI 0.31-0.86). Higher educational attainment compared with < high school was in general associated with higher rate of ALS (high school, HR 1.23, 95% CI 1.07-1.42; some college, HR 1.24, 95% CI 1.04-1.48; college, HR 1.10, 95% CI 0.90-1.36; postgraduate, HR 1.31, 95% CI 1.06-1.62). Income, household poverty, and home ownership were not associated with ALS after adjustment for race/ethnicity. Rates did not differ by sex. CONCLUSION: Higher rate of ALS among whites vs non-Hispanic blacks, Hispanics, and non-Hispanic other races was not accounted for by multiple measures of socioeconomic status, birthplace, or type of health insurance. Higher rate of ALS among whites likely reflects actual higher risk of ALS rather than ascertainment bias or effects of socioeconomic status on ALS risk.

Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.