ABSTRACT
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Autophagy/genetics , Exome/genetics , Genetic Predisposition to Disease , Protein Serine-Threonine Kinases/genetics , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Cell Cycle Proteins , Female , Genes , Genetic Association Studies , Humans , Male , Membrane Transport Proteins , Middle Aged , Protein Binding , Protein Serine-Threonine Kinases/metabolism , Risk , Sequence Analysis, DNA , Sequestosome-1 Protein , Transcription Factor TFIIIA/genetics , Transcription Factor TFIIIA/metabolism , Young AdultABSTRACT
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.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Founder Effect , Frontotemporal Dementia/genetics , Mutation , Proteins/genetics , Age of Onset , Amyotrophic Lateral Sclerosis/epidemiology , C9orf72 Protein , Cohort Studies , Europe/epidemiology , Frontotemporal Dementia/epidemiology , Gene Frequency , Genomic Instability , Haplotypes , Humans , Polymorphism, Single Nucleotide , Repetitive Sequences, Nucleic AcidABSTRACT
Primary lateral sclerosis (PLS) is a diagnosis of exclusion in patients with progressive spinobulbar spasticity and could be part of the clinical spectrum of ALS. Unlike ALS, which is familial in 5 to 10% of the cases, PLS has been described as a sporadic disorder in adults. The authors report two patients with PLS from unrelated SOD1-negative familial ALS families. These observations provide further evidence that PLS can be linked pathophysiologically to ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/physiopathology , Genetic Predisposition to Disease/genetics , Motor Neuron Disease/genetics , Motor Neuron Disease/physiopathology , Adult , Aged , Aged, 80 and over , Amyotrophic Lateral Sclerosis/diagnosis , Brain Stem/pathology , Brain Stem/physiopathology , Comorbidity , DNA Mutational Analysis , Disease Progression , Family Health , Female , Genetic Testing , Genotype , Humans , Male , Middle Aged , Motor Neuron Disease/diagnosis , Motor Neurons/pathology , Muscle, Skeletal/innervation , Muscle, Skeletal/physiopathology , Mutation/genetics , Pedigree , Spinal Cord/pathology , Spinal Cord/physiopathology , Superoxide Dismutase/genetics , Superoxide Dismutase-1ABSTRACT
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a disease that causes progressive paralysis leading to respiratory failure. Patients with ALS may consider physician-assisted suicide. However, it is not known how many patients, if given the option, would actually decide to end their lives by physician-assisted suicide or euthanasia nor at what stage of the disease they would choose to do so. METHODS: We identified physicians of 279 patients in the Netherlands with a diagnosis of ALS who died between 1994 and 1999. Physicians were asked to fill out a validated questionnaire about the end-of-life decisions that were made. Of 241 eligible physicians, 203 returned the questionnaire (84 percent). RESULTS: Of the 203 patients, 35 (17 percent) chose euthanasia and died that way. An additional six patients (3 percent) died as a result of physician-assisted suicide. Patients to whom religion was important were less likely to have died as a result of euthanasia or physician-assisted suicide. The choice of euthanasia or physician-assisted suicide was not associated with any particular characteristics of the disease or of the patient's care, nor was it associated with income or educational level. Disability before death was significantly more severe in patients who died as a result of euthanasia than among those who died in other ways. Physician-assisted suicide appeared to occur somewhat earlier in the course of the disease than did euthanasia. An additional 48 patients (24 percent) received palliative treatment, which probably shortened their lives. CONCLUSIONS: In the Netherlands, we found that one in five patients with ALS died as a result of euthanasia or physician-assisted suicide.
