11: Lancet Neurol. 2006 Feb;5(2):105-6.
Comment in:
Lancet Neurol. 2006 Mar;5(3):203.
Lancet Neurol. 2006 Feb;5(2):140-7.
Evidence-based care in amyotrophic lateral sclerosis.
Piepers S, van den Berg LH.
Publication Types:
Comment
Letter
PMID: 16426982 [PubMed - indexed for MEDLINE]
10: Lancet Neurol. 2006 Feb;5(2):140-7.
Comment in:
Lancet Neurol. 2006 Apr;5(4):291-2; author reply 292-3.
Lancet Neurol. 2006 Feb;5(2):105-6.
Effects of non-invasive ventilation on survival and quality of life in patients
with amyotrophic lateral sclerosis: a randomised controlled trial.
Bourke SC, Tomlinson M, Williams TL, Bullock RE, Shaw PJ, Gibson GJ.
Department of Respiratory Medicine, University of Newcastle upon Tyne and the
Newcastle Hospitals Trust, Newcastle upon Tyne, UK.
Stephen.bourke@northumbria-healthcare.nhs.uk
BACKGROUND: Few patients with amyotrophic lateral sclerosis currently receive
non-invasive ventilation (NIV), reflecting clinical uncertainty about the role
of this intervention. We aimed to assess the effect of NIV on quality of life
and survival in amyotrophic lateral sclerosis in a randomised controlled trial.
METHODS: 92 of 102 eligible patients participated. They were assessed every 2
months and randomly assigned to NIV (n=22) or standard care (n=19) when they
developed either orthopnoea with maximum inspiratory pressure less than 60% of
that predicted or symptomatic hypercapnia. Primary validated quality-of-life
outcome measures were the short form 36 mental component summary (MCS) and the
sleep apnoea quality-of-life index symptoms domain (sym). Both time maintained
above 75% of baseline (T(i)MCS and T(i)sym) and mean improvement (microMCS and
microsym) were measured. FINDINGS: NIV improved T(i)MCS, T(i)sym, microMCS,
microsym, and survival in all patients and in the subgroup with better bulbar
function (n=20). This subgroup showed improvement in several measures of quality
of life and a median survival benefit of 205 days (p=0.006) with maintained
quality of life for most of this period. NIV improved some quality-of-life
indices in those with poor bulbar function, including microsym (p=0.018), but
conferred no survival benefit. INTERPRETATION: In patients with amyotrophic
lateral sclerosis without severe bulbar dysfunction, NIV improves survival with
maintenance of, and improvement in, quality of life. The survival benefit from
NIV in this group is much greater than that from currently available
neuroprotective therapy. In patients with severe bulbar impairment, NIV improves
sleep-related symptoms, but is unlikely to confer a large survival advantage.
Publication Types:
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
PMID: 16426990 [PubMed - indexed for MEDLINE]
9: J Palliat Med. 2006 Feb;9(1):209-10.
From generation to generation.
Gustafson PR.
Christus-VNA Hospice, Houston, Texas 77007, USA. palliadoc@aol.com
PMID: 16430361 [PubMed - indexed for MEDLINE]
8: Brain Res. 2006 Feb 16;1073-1074:20-4. Epub 2006 Jan 26.
Genetic analysis of the cystatin C gene in familial and sporadic ALS patients.
Watanabe M, Jackson M, Ikeda M, Mizushima K, Amari M, Takatama M, Hirai S, Ikeda
Y, Shizuka-Ikeda M, Okamoto K.
Department of Neurology, Gunma University Graduate School of Medicine, Maebashi,
Gunma 371-8511, Japan. miwata@showa.gunma-u.ac.jp
Bunina bodies, small eosinophilic intraneuronal inclusions, stain positive for
cystatin C and are the only specific pathological hallmark of amyotrophic
lateral sclerosis (ALS). We screened the cystatin C gene (CST3) for mutations in
57 sporadic ALS patients and 12 familial ALS cases that did not possess a SOD1
mutation. We detected the known polymorphism in exon 1, a G/A transition at +73,
in both familial and sporadic ALS patients. However, the allelic and genotypic
frequencies of the +73 G/A polymorphism did not differ between ALS patients and
control samples. No other mutation was detected in the ALS patients. The results
reported here indicate that there may not be a direct genetic link between
cystatin C and ALS, and it may be that deficits occur in proteins that interact
with cystatin C.
Publication Types:
Comparative Study
Research Support, Non-U.S. Gov't
PMID: 16443201 [PubMed - indexed for MEDLINE]
7: Magn Reson Imaging. 2006 Feb;24(2):173-9. Epub 2005 Dec 27.
Amyotrophic lateral sclerosis with predominant pyramidal signs -- early
diagnosis by magnetic resonance imaging.
Pradhan S, Yadav R, Mishra VN, Aurangabadkar K, Sawlani V.
Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical
Sciences, Lucknow 226014, India. spradhan@sgpgi.ac.in
OBJECTIVE: To evaluate the role of magnetic resonance imaging (MRI) in the early
diagnosis of amyotrophic lateral sclerosis (ALS) with predominant upper motor
neuron (UMN) signs in the initial stage of the disease. PATIENTS AND METHOD: Two
patients with ALS were found to have spastic quadriparesis with no wasting or
fasciculation in the limbs in the early stage of the disease. Both were
subjected to MRI of the head and cervical spine to look for any specific
diagnostic feature. Both of them were followed with clinical evaluation and
electroneuromyography (ENMG) for the definitive diagnosis of ALS. RESULTS:
Magnetic resonance imaging showed selective degeneration of the pyramidal tracts
in the contiguous axial cuts from subcortical white matter to cerebral
peduncles. The finding was more visible in the coronal section. In addition,
there was T1 hyperintensity visible along the anterior aspect of the spinal cord
in the cervical region. These findings were suggestive of ALS, the diagnosis
that was subsequently confirmed by serial clinical follow-up and ENMG.
CONCLUSION: It is difficult to diagnose ALS in the early stage of the disease
especially if the pyramidal signs predominate over the lower motor neuron (LMN)
signs; MRI might be useful in such cases.
Publication Types:
Case Reports
PMID: 16455406 [PubMed - indexed for MEDLINE]
6: Lancet Neurol. 2006 Feb;5(2):119.
SOD1 mutant protein gets loose in ALS.
McCaffrey P.
Publication Types:
News
PMID: 16456939 [PubMed - indexed for MEDLINE]
5: Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2404-9. Epub 2006 Feb 6.
S-nitrosothiol depletion in amyotrophic lateral sclerosis.
Schonhoff CM, Matsuoka M, Tummala H, Johnson MA, Estevez AG, Wu R, Kamaid A,
Ricart KC, Hashimoto Y, Gaston B, Macdonald TL, Xu Z, Mannick JB.
Department of Medicine and Biochemistry and Molecular Pharmacology, University
of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605,
USA.
Recent data suggest that either excessive or deficient levels of protein
S-nitrosylation may contribute to disease. Disruption of S-nitrosothiol (SNO)
homeostasis may result not only from altered nitric oxide (NO) synthase activity
but also from alterations in the activity of denitrosylases that remove NO
groups. A subset of patients with familial amyotrophic lateral sclerosis (ALS)
have mutations in superoxide dismutase 1 (SOD1) that increase the denitrosylase
activity of SOD1. Here, we show that the increased denitrosylase activity of
SOD1 mutants leads to an aberrant decrease in intracellular protein and peptide
S-nitrosylation in cell and animal models of ALS. Deficient S-nitrosylation is
particularly prominent in the mitochondria of cells expressing SOD1 mutants. Our
results suggest that SNO depletion disrupts the function and/or subcellular
localization of proteins that are regulated by S-nitrosylation such as
glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and thereby contributes to ALS
pathogenesis. Repletion of intracellular SNO levels with SNO donor compounds
rescues cells from mutant SOD1-induced death. These results suggest that
aberrant depletion of intracellular SNOs contributes to motor neuron death in
ALS, and raises the possibility that deficient S-nitrosylation is a general
mechanism of disease pathogenesis. SNO donor compounds may provide new
therapeutic options for diseases such as ALS that are associated with deficient
S-nitrosylation.
Publication Types:
Research Support, N.I.H., Extramural
PMID: 16461917 [PubMed - indexed for MEDLINE]
4: Neurosurgery. 2006 Feb;58(2):E384; discussion E384.
Chronic cortical stimulation for amyotropic lateral sclerosis: a report of four
consecutive operated cases after a 2-year follow-up: technical case report.
Sidoti C, Agrillo U.
Department of Neurosurgery, Sandro Pertini Hospital, Rome, Italy.
neurocarmelos@yahoo.it
OBJECTIVE AND IMPORTANCE: From April to July 2002, four consecutive patients
affected by amyotrophic lateral sclerosis (ALS) were surgically treated with
bilateral chronic cortical stimulation.. CLINICAL PRESENTATION: The preoperative
diagnostic assessment was based on the results of a neurological examination,
integrated by the ALS functional rating scale, electromyography, magnetic
resonance imaging, and single-photon emission computed tomography (SPECT). In
particular, SPECT provided a remarkable contribution in terms of its ability to
demonstrate specific morphological and metabolic ALS lesions of the brain.
INTERVENTION: The postoperative neurological follow-up was based mainly on the
assessment of neurological status and the ALS functional rating scale, together
with SPECT. Two years after surgery, at clinical examination, two patients
demonstrated mild progression of their illness, and SPECT findings disclosed
complete disappearance of ALS cerebral lesions, with apparent recovery of brain
anatomic integrity. The third patient committed suicide. In the fourth patient,
the disease seemed to have progressed inexorably at the time of clinical and
SPECT monitoring, after transient improvement during the first 3 months after
surgery.. CONCLUSION: These preliminary results are surprising, because they
suggest that chronic cortical stimulation can play a role against ALS and
deserve confirmation in larger numbers of patients and for a longer follow-up.
We present the theoretical grounds for these findings, as well as the diagnostic
and surgical procedures and results..
Publication Types:
Case Reports
PMID: 16462467 [PubMed - indexed for MEDLINE]
3: Curr Mol Med. 2006 Feb;6(1):79-86.
ER stress and UPR in familial amyotrophic lateral sclerosis.
Turner BJ, Atkin JD.
Howard Florey Institute, University of Melbourne, Victoria, Australia.
b.turner@hfi.unimelb.edu.au
The primary mechanism by which mutations in Cu, Zn-superoxide dismutase (SOD1)
contribute to progressive motor neuron loss in familial amyotrophic lateral
sclerosis (FALS) remains unknown. Misfolded protein aggregates,
ubiquitin-proteasome system impairment and neuronal apoptosis mediated by death
receptor or mitochondrial-dependent pathways are implicated in mutant
SOD1-induced toxicity. Recent evidence from cellular and transgenic rodent
models of FALS proposes activation of a third apoptotic pathway linked to
sustained endoplasmic reticulum (ER) stress. Here, we review the emerging role
of ER stress and the unfolded protein response (UPR) in the pathogenesis of
mutant SOD1-linked FALS. The UPR observed in FALS rodents is described which
encompasses induction of key ER-resident chaperones during presymptomatic
disease, leading to activation of stress transducers and pro-apoptotic molecules
by late stage disease. Importantly, mutant SOD1 co-aggregates with UPR
components and recruits to the ER, suggesting a direct adverse effect on ER
function. By contrast, the opposing neuroprotective effects of wild-type SOD1
overexpression on UPR signalling are also highlighted. In addition, the
potential impact of neuronal Golgi apparatus (GA) fragmentation and subsequent
disturbances in intracellular protein trafficking on motor neuron survival in
FALS is also discussed. We propose that ER stress and UPR may be coupled to GA
dysfunction in mutant SOD1-mediated toxicity, promoting ER-initiated cell death
signalling in FALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16472115 [PubMed - indexed for MEDLINE]
2: Arch Neurol. 2006 Feb;63(2):262-7.
Erratum in:
Arch Neurol. 2006 Jul;63(7):963.
The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and
prognosis.
Regal L, Vanopdenbosch L, Tilkin P, Van den Bosch L, Thijs V, Sciot R,
Robberecht W.
Department of Neurology and Experimental Neurology, University Hospital
Gasthuisberg, University of Leuven, Leuven, Belgium.
BACKGROUND: Twenty percent of familial amyotrophic lateral sclerosis (ALS) is
caused by mutations in the superoxide dismutase 1 gene (SOD1). Few data exist on
their clinicopathologic phenotypes. OBJECTIVES: To determine the clinical and
pathologic phenotype associated with the G93C mutation in SOD1 and to compare
survival in familial ALS related to this mutation with survival in other ALS
subgroups. DESIGN: Retrospective study. SETTING: Tertiary referral center for
neuromuscular disorders. PATIENTS: Twenty patients with the G93C mutation for
whom clinical data were available and 1 patient with pathologic data. MAIN
OUTCOME MEASURES: Characteristics and survival compared with other ALS
subgroups, adjusting for known prognostic factors. RESULTS: The G93C mutation
was associated with a purely lower motor neuron phenotype without bulbar
involvement. Presence of the mutation independently predicted longer survival
compared with other ALS subgroups. Pathologic examination showed degeneration of
the anterior horn, spinocerebellar tracts, and posterior funiculi, with minimal
involvement of corticospinal tracts and no degeneration of brainstem motor
nuclei. Survival motor neuron gene copy number had no significant influence on
age at onset or survival in patients with the G93C mutation. CONCLUSIONS: These
findings add to the knowledge of SOD1-related familial ALS and demonstrate
further clinicopathologic variability between different SOD1 mutations. Finally,
they demonstrate the independent prognostic value of the G93C mutation.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16476815 [PubMed - indexed for MEDLINE]
1: Proc Natl Acad Sci U S A. 2006 Feb 28;103(9):3147-52. Epub 2006 Feb 17.
Common dynamical signatures of familial amyotrophic lateral sclerosis-associated structurally diverse Cu, Zn superoxide dismutase mutants.
Khare SD, Dokholyan NV.
Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, 27599, USA.
More than 100 structurally diverse point mutations leading to aggregation in the dimeric enzyme Cu, Zn superoxide dismutase (SOD1) are implicated in familial amyotrophic lateral sclerosis (FALS). Although SOD1 dimer dissociation is a known requirement for its aggregation, the common structural basis for diverse FALS mutations resulting in aggregation is not fully understood. In molecular dynamics simulations of wild-type SOD1 and three structurally diverse FALS mutants (A4V, G37R, and H46R), we find that a common effect of mutations on SOD1 dimer is the mutation-induced disruption of dynamic coupling between monomers.
In the wild-type dimer, the principal coupled motion corresponds to a "breathing motion" of the monomers around an axis parallel to the dimer interface, and an opening-closing motion of the distal metal-binding loops. These coupled motions are disrupted in all three mutants independent of the mutation location. Loss of coupled motions in mutant dimers occurs with increased disruption of a key stabilizing structural element (the beta-plug) leading to the de-protection of edge strands. To rationalize disruption of coupling, which is independent of the effect of the mutation on global SOD1 stability, we analyze the residue-residue interaction network formed in SOD1. We find that the dimer interface and metal-binding loops, both involved in coupled motions, are regions of high connectivity in the network. Our results suggest that independent of the effect on protein stability, altered protein dynamics, due to long-range communication within its structure, may underlie the aggregation of mutant SOD1 in FALS.
Publication Types:
Research Support, Non-U.S. Gov't
PMID: 16488975 [PubMed - indexed for MEDLINE]
