Genome-wide genotyping in Parkinson's disease and neurologically normal controls: first stage analysis and public release of data

BACKGROUND: Several genes underlying rare monogenic forms of Parkinson's disease have been identified over the past decade. Despite evidence for a role for genetics in sporadic Parkinson's disease, few common genetic variants have been unequivocally linked to this disorder. We sought to identify any common genetic variability exerting a large effect in risk for Parkinson's disease in a population cohort and to produce publicly available genome-wide genotype data that can be openly mined by interested researchers and readily augmented by genotyping of additional repository subjects. METHODS: We did genome-wide, single-nucleotide-polymorphism (SNP) genotyping of publicly available samples from a cohort of Parkinson's disease patients (n=267) and neurologically normal controls (n=270). More than 408,000 unique SNPs were used from the Illumina Infinium I and HumanHap300 assays. FINDINGS: We have produced around 220 million genotypes in 537 participants. This raw genotype data has been and as such is the first publicly accessible high-density SNP data outside of the International HapMap Project. We also provide here the results of genotype and allele association tests. INTERPRETATION: We generated publicly available genotype data for Parkinson's disease patients and controls so that these data can be mined and augmented by other researchers to identify common genetic variability that results in minor and moderate risk for disease.     

Characterization of DNA and RNA in circulating immunocomplexes in multiple sclerosis, amyotrophic lateral sclerosis and normal controls

The total levels of DNA and RNA in serum immunocomplexes from multiple sclerosis (MS) patients and healthy control persons were compared. Furthermore, the levels of single-stranded DNA (ss DNA) and double-stranded DNA (ds DNA) in serum immunocomplexes from MS patients, amyotrophic lateral sclerosis (ALS) patients and controls were studied. The mean values of DNA and RNA were found to be elevated (P less than 0.01) in MS compared to the control means. Furthermore, the RNA/DNA ratio and the ratio ss DNA/ds DNA were decreased in MS. In contrast the ss:ds DNA ratio in ALS was increased. In ALS, however, the sum of ss DNA and ds DNA was lower (P less than 0.05) than the control mean value.     

Familial amyotrophic lateral sclerosis: first report from India

We report two patients diagnosed to have familial amyotrophic lateral sclerosis (FALS). A 40 year old lady had progressive weakness and atrophy of the limbs and bulbar palsy from the age of 39 years and with electrophysiological evaluation was confirmed as definite ALS. Her mother had presented in 1978 at the age of 42 years with symptoms and signs of ALS. The other patient was a 43 year old male with rapidly progressive weakness, wasting and spasticity of the limbs and bulbar palsy of 4 months duration and with electrophysiological evidence of diffuse anterior horn cell involvement. His father also had onset of illness at 43 years of age with gradually progressive spasticity and atrophy of the extremities followed by bulbar palsy. In the first instance the mother had a duration of illness of 8 years while in the second the father lived for 15 years after the onset of illness.     

Linkage analysis in familial amyotrophic lateral sclerosis

Familial amyotrophic lateral sclerosis (FALS) constitutes 5 to 10% of cases of ALS and, in most families, its inheritance is consistent with an autosomal dominant trait with age-dependent penetrance. The biochemical abnormality underlying the disorder is unknown. We analyzed DNA from 131 members of 6 multigenerational ALS families, which included 13 affected members, for genetic linkage to 39 expressed and DNA markers, using the techniques of 2-point linkage analysis, multilocus linkage analysis, and exclusion mapping. We identified FALS families with structures suitable for linkage, by computer simulation techniques. A DNA bank established to provide optimum use of available FALS families provided DNA from immortalized lymphoblast cell lines and frozen postmortem tissue. We could not link FALS to any of the markers studied, but excluded chromosome regions unlikely to be a locus of the FALS gene. With the help of this exclusion data, we will concentrate on regions of the human genome that remain unexcluded.     

High content analysis in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating disease characterized by the progressive loss of motor neurons. Neurons, astrocytes, oligodendrocytes and microglial cells all undergo pathological modifications in the onset and progression of ALS. A number of genes involved in the etiopathology of the disease have been identified, but a complete understanding of the molecular mechanisms of ALS has yet to be determined. Currently, people affected by ALS have a life expectancy of only two to five years from diagnosis. The search for a treatment has been slow and mostly unsuccessful, leaving patients in desperate need of better therapies. Until recently, most pre-clinical studies utilized the available ALS animal models. In the past years, the development of new protocols for isolation of patient cells and differentiation into relevant cell types has provided new tools to model ALS, potentially more relevant to the disease itself as they directly come from patients. The use of stem cells is showing promise to facilitate ALS research by expanding our understanding of the disease and help to identify potential new therapeutic targets and therapies to help patients. Advancements in high content analysis (HCA) have the power to contribute to move ALS research forward by combining automated image acquisition along with digital image analysis. With modern HCA machines it is possible, in a period of just a few hours, to observe changes in morphology and survival of cells, under the stimulation of hundreds, if not thousands of drugs and compounds. In this article, we will summarize the major molecular and cellular hallmarks of ALS, describe the advancements provided by the in vitro models developed in the last few years, and review the studies that have applied HCA to the ALS field to date.     

Reproducibility of the motor unit number index (MUNIX) in normal controls and amyotrophic lateral sclerosis patients

The motor unit number index (MUNIX) refers to an electrophysiologic technique that measures the approximate number of motor units using the surface electromyographic interference pattern (SIP) recorded during voluntary contraction. This study was done to assess the reproducibility of MUNIX performed on hypothenar muscles in 62 normal controls and 22 amyotrophic lateral sclerosis (ALS) patients. Inter- and intraoperator correlation coefficients for MUNIX were 0.74 and 0.86, respectively, in normal controls, and 0.95 and 0.93, respectively, in ALS patients (P < 0.01 in all). Inter- and intraoperator coefficients of variation for MUNIX measurements were 17.5% and 15.3%, respectively, in normal controls, and 23.7% and 24.0%, respectively, in ALS patients. This study shows a good correlation for MUNIX between intra- and interoperator results in both normal controls and ALS patients. The test-retest variability seems to be greater in ALS patients compared with normal controls, but this will need to be confirmed in future studies. Sources of variability should be identified and corrected for clinical use.     

肌萎缩侧索硬化患者的睡眠分析

目的 探讨肌萎缩侧索硬化(Amyotrophic lateral sclerosis,ALS)的睡眠障碍患病率、睡眠质量与ALS功能评分的各重要功能域的相关性。方法 收集2018年9月-2021年9月于武汉大学人民医院神经内科就诊的115例诊断为ALS的患者,通过问卷调查获取患者的一般人口统计学数据、匹兹堡睡眠质量量表(Pittsburgh sleep quality scale,PSQI)评分、爱泼沃斯嗜睡量表(Epworth sleepiness score,ESS)评分、肌萎缩侧索硬化功能评分量表(Amyotrophic lateral sclerosis function rating scale,ALSFRS-R)评分,并计算进展率(ΔFS),分析各因素与睡眠质量的相关性。结果 ①不同起病部位亚组的睡眠质量、功能评分未见明显差异; ②43%的ALS患者PSQI>7分,15%的患者ESS>9分; ③PSQI与ALSFRS-R评分呈负相关(r=-0.36,P<0.01),与ΔFS呈正相关(r=0.25,P=0.01)。此外,PSQI与ALSFRS-R延髓功能域评分呈负相关(r=-0.21,P=0.03),与ALSFRS-R精细功能域评分呈负相关(r=-0.29,P<0.01),与ALSFRS-R粗大动作域评分呈负相关(r=-0.41,P<0.0001),与ALSFRS-R呼吸功能域评分呈负相关(r=-0.34,P<0.01)。结论 ALS患者存在明显夜间睡眠问题,且睡眠质量与疾病进展、各区域功能丧失均显著相关。     

Sleep-disordered breathing at an early stage of amyotrophic lateral sclerosis.

Eighteen amyotrophic lateral sclerosis (ALS) patients having neither respiratory complaints nor subjective symptoms of sleep disturbance were studied by using an ambulatory multi-parameter monitoring system during sleep. They were divided into two groups: 11 patients with predominantly bulbar form and seven with non-bulbar form. After performing daytime pulmonary function tests, the presence of sleep-disordered breathing (SDB) was evaluated by using a portable device. ALS patients did not show significant SDB as a whole, and the respiratory disturbance index (RDI) was not significantly different between the bulbar group and the non-bulbar group. However, three patients of the bulbar group showed significant SDB, and the patterns of apnea/hypopnea suggested that both bulbar weakness and minimal diaphragmatic weakness might cause SDB in ALS patients at an early clinical stage. Multi-parameter respiratory monitoring during sleep should be included in the routine evaluation of ALS patients at an early clinical stage, especially those with predominantly bulbar involvement, in order to predict early respiratory failure.     

Neurochemical markers in the cerebrospinal fluid of patients with Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis and normal controls

Summary Several neurotransmitter markers were investigated in the cerebrospinal fluid (CSF) from patients with Alzheimer's disease (AD) (n=27), Parkinson's disease (PD) (n=35) and ALS (n=26) and from control subjects (n=34) to compare the possible alterations in the biochemical profiles of these different neurodegenerative diseases. The main proportion of the patients represented an early phase of the illness at the time of the diagnosis. Correlations of the degree of dementia and the stage of the disease with CSF measures were evaluated. The CSF levels of somatostatin like-immunoreactivity (SLI) were significantly reduced in AD patients when compared with those of normals and ALS patients. The CSF concentrations of homovanillic acid (HVA) were significantly decreased for PD patients and the decrease focused on the nondemented patients. A trend of decreasing HVA values towards the most advanced stage of Parkinson's disease assessed by Webster's scale was also displayed. The content of 3-methoxy-4-hydroxyphenylglycol (MHPG) in the CSF was higher for ALS patients than for other groups. The lowest 5-hydroxy-indoleacetic acid (5HIAA) levels were observed in the PD group and the lowest acetylcholinesterase (AChE) activities were found in the PD patients with the most severe disease. Changes in CSF measures were too subtle to be beneficial for diagnostic purposes, but adequate for reflecting the different neurochemical profiles of these three degenerative neurological disorders.     

散发性肌萎缩侧索硬化患者Senataxin基因的突变检测和分析

目的 探讨散发性肌萎缩侧索硬化(SAIS)患者Senataxin(SETX)基因突变特点.方法 采用聚合酶链反应(PCR)扩增60例SALS患者SETX基因的26个外显子,应用直接基因测序法筛查其突变和多态,同时与200名健康对照进行比较.结果 我们检出2个新的同义突变,分别为Asp844Asp(GAC→CAT)和Phe998Phe(TTC→TTT).尽管在200名健康对照中未检出这2个同义突变,但经过不同物种间的同源序列比对,发现这2个序列不是保守序列,提示它们不是致病性突变.除此之外,我们还检出了19个多态.结论 我们发现了SETX基因的2个同义突变和19个多态,进一步扩大了SETX基因的突变谱和多态谱.     

Usefulness of polysomnography at an early stage of amyotrophic lateral sclerosis]

A 47-year-old man who presented moderate muscle weakness in the neck and all the extremities was diagnosed as having early stage of amyotrophic lateral sclerosis (ALS). He did not have bulbar dysfunction and respiratory distress. His pulmonary function tests and arterial blood gas analysis showed no abnormalities, but polysomnography (PSG) revealed sleep-disordered breathing requiring mechanical support ventilation. Bi-level positive airway pressure treatment was started only at night, which improved both sleep-disordered breathing and daytime activity. PSG should be considered in ALS patients at an early clinical stage in order to predict mild respiratory dysfunction.     

Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations

Insights into the mechanisms of amyotrophic lateral sclerosis (ALS) have relied predominantly on the study of postmortem tissue. Modern technology has improved the ability of scientists to probe effectively the underlying biology of ALS by examination of genomic, proteomic and physiological changes in patients, as well as to monitor functional and structural changes in patients over the course of disease. While effective treatments for ALS are lacking, the discovery of biomarkers for this disease offers clinicians tools for rapid diagnosis, improved ways to monitor disease progression, and insights into the pathophysiology of sporadic ALS. The ultimate aim is to broaden the therapeutic options for patients with this disease.     

Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis

Journal of Neurology - To assess the changes of muscle-related biomarkers at the early stage of amyotrophic lateral sclerosis, and to confirm these findings in an experimental animal model....     

The concurrence of multiple sclerosis and amyotrophic lateral sclerosis

We report the clinical and pathological findings of the unusual combination of two idiopathic central nervous system diseases, multiple sclerosis and amyotrophic lateral sclerosis in a 56 year old physician with a twenty-seven year history of a disease initially characterized by relapses and remissions, followed by an eight year quiescent period. During the last year of life there was rapid deterioration with development of generalized weakness, atrophy, weight loss and fasciculations of body and tongue, and associated difficulty with swallowing and sudden respiratory failure. The autopsy confirmed characteristic "burned out" plaques of multiple sclerosis and anterior horn cell and axonal degeneration of amyotrophic lateral sclerosis.