0
Original Contribution |

Two German Kindreds With Familial Amyotrophic Lateral Sclerosis Due to TARDBP Mutations FREE

Peter Kühnlein, MD; Anne-Dorte Sperfeld, MD; Ben Vanmassenhove, MTA; Vivianna Van Deerlin, MD, PhD; Virginia M.-Y. Lee, PhD; John Q. Trojanowski, MD, PhD; Hans A. Kretzschmar, MD; Albert C. Ludolph, MD; Manuela Neumann, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, University of Ulm, Ulm (Drs Kühnlein, Sperfeld, and Ludolph), and Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich (Mr Vanmassenhove and Drs Kretzschmar and Neumann), Germany; and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine (Drs Van Deerlin, Lee, and Trojanowski), University of Pennsylvania School of Medicine, Philadelphia.


Arch Neurol. 2008;65(9):1185-1189. doi:10.1001/archneur.65.9.1185.
Text Size: A A A
Published online

Background  Abnormal neuronal inclusions composed of the transactivation response DNA-binding protein 43 (TDP-43) are characteristic neuropathologic lesions in sporadic and familial forms of amyotrophic lateral sclerosis (ALS). This makes TARDBP, the gene encoding for TDP-43, a candidate for genetic screening in ALS.

Objectives  To investigate the presence and frequency of TARDBP mutations in ALS.

Design  Genetic analysis.

Setting  Academic research.

Participants  One hundred thirty-four patients with sporadic ALS, 31 patients with familial non–superoxide dismutase 1 gene (non-SOD1) (OMIM 147450) ALS, and 400 healthy control subjects.

Main Outcome Measures  We identified 2 missense mutations (G348C and the novel N352S) in TARDBP in 2 small kindreds with a hereditary form of ALS with early spinal onset resulting in fatal respiratory insufficiency without clinical relevant bulbar symptoms or signs of cognitive impairment.

Results  The mutations located in the C-terminus of TDP-43 were absent in 400 controls of white race/ethnicity. The novel identified N352S mutation is predicted to increase TDP-43 phosphorylation, while the G348C mutation might interfere with normal TDP-43 function by forming intermolecular disulfide bridges.

Conclusions  Mutations in TARDBP are a rare cause of familial non-SOD1 ALS. The identification of TARDBP mutations provides strong evidence for a direct link between TDP-43 dysfunction and neurodegeneration in ALS.

Figures in this Article

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder leading to degeneration of upper and lower motor neurons in the brain and spinal cord. Clinical hallmarks are spasticity, brisk tendon reflexes, pyramidal signs, and progressive atrophy and weakness of the skeletal musculature. The patients die within a few years after onset, usually of respiratory failure.1 Most cases are sporadic (sALS), but about 10% are familial (fALS). About 15% to 20% of patients with autosomal dominant fALS have mutations in the superoxide dismutase gene (SOD1),2 while mutations in other genes (including senataxin [OMIM 608465],3 dynactin 1 [OMIM 601143],4 and vesicle-associated membrane protein B [OMIM 605704]5) are described as rare causes of fALS.

Recently, transactivation response DNA-binding protein 43 (TDP-43) was identified as a major disease protein in the abnormal inclusions in neurons and glial cells in sALS and fALS except fALS forms due to SOD1 mutations.6,7 The TDP-43 is a highly conserved 414–amino acid nuclear protein first cloned as a protein capable of binding to the transactive response DNA element of human immunodeficiency virus type 1 and later identified as part of a complex involved in splicing of the cystic fibrosis transmembrane conductance regulator gene.8,9 It contains 2 RNA recognition motifs and a glycine-rich C-terminal region. Described functions include involvement in transcription regulation and exon skipping and a role as scaffold for nuclear bodies through an interaction with survival motor neuron protein.10 These findings make TARDBP (OMIM 605078), the gene on chromosome 1p36.22 encoding TDP-43, an auspicious candidate for genetic screening in ALS. While this study was in progress, 13 different mutations in TARDBP were reported in fALS (G290A, G298S, A315T, M337V, and A382T) and sALS (D169G, G287S, G294A, Q331K, G348C, R361S, N390D, and N390S) cases.1114

In this study, we present genetic analysis data on TARDBP in a German cohort of 134 sALS cases and 31 index patients with non-SOD1 fALS to further define the spectrum and frequency of TARDBP mutations. Although no mutations were found in sALS, 2 heterozygous missense mutations, G348C and the novel N352S, were identified in fALS. The occurrence of TARDBP mutations in 6.5% of our cohort with non-SOD1 fALS not only underlines the direct role of TDP-43 dysfunction in the pathogenesis of ALS but also implicates that screening for TARDBP mutations should be considered in all non-SOD1 fALS cases.

SUBJECTS

DNA samples from 134 patients with sALS (mean [SD] age at onset, 57.7 [11.9] years) and 31 index patients with non-SOD1 fALS (mean [SD] age at onset, 46.5 [13.2] years) were included in the study. All patients were neurologically examined at the Department of Neurology, University of Ulm, and were diagnosed as having probable or definite ALS according to El Escorial criteria.15 Additional family members of 2 families with identified TARDBP mutations were tested. DNA sampling and genetic analysis were approved by the local ethics committee. Written informed consent for genetic analysis was obtained from each individual. In all fALS cases, mutations in SOD1, DCNT1 (OMIM 601143), and VAPB (OMIM 605704) were excluded before their inclusion in the present study.

Control samples were obtained from the following sources: 276 control subjects from the Coriell Institute (neurologically normal white control panels [mean age, 70 years]; Camden, New Jersey;), 63 clinical controls from the Alzheimer Disease Center at the University of Pennsylvania, Philadelphia (47 controls [mean age, 76 years]) or from the University of Ulm, Ulm, Germany (16 controls [mean age, 49 years), and 61 brain autopsy samples without evidence of neurodegenerative diseases from the University of Pennsylvania (41 samples [mean age, 69 years]) or from the Center for Neuropathology and Prion Research, Munich, Germany (20 samples [mean age, 71 years]).

GENETIC ANALYSIS

Genomic DNA was extracted from blood or frozen brain using standard procedures. The coding region of TARDBP, exons 2 through 5 and the first 528 nucleotides of exon 6, was amplified by polymerase chain reaction using primers from adjacent intronic or noncoding regions. Polymerase chain reaction products were sequenced using a terminator cycle sequencing kit (BigDye; Applied Biosystems, Foster City, California) and were run on a capillary sequencer (ABI3130, Applied Biosystems).

SINGLE-NUCLEOTIDE POLYMORPHISM GENOTYPING OF TARDBP VARIANTS

Four hundred control samples were analyzed for TARDBP variants NM_007375 as follows: c.1176G>T (p.G348C) and c.1189A>G (p.N352S) by a chemistry-based allelic discrimination assay with “Assay by Design” probes (TaqMan) on a sequence analyzer (model 7900) followed by software analysis (Sequence Detection System 2.2.1, all from Applied Biosystems) or by sequencing.

The genetic analysis of 31 index patients from families with ALS led to the identification of 2 heterozygous missense mutations (G348C and N352S) in exon 6 of TARDBP in 2 small German kindreds. Clinical information on family members of both kindreds is summarized in the Table.

Table Graphic Jump LocationTable. Clinical Features of Families With TARDBP Mutationsa

The mutations were absent in 400 control samples. Except for a synonymous mutation at amino acid 66 in 1 sALS case, no variants were detected in TARDBP among the other 133 sALS cases or among 36 controls in which all exons were sequenced.

FAMILY A

The G348C mutation was found in the index patient (III-1) of family A (Figure 1A and B). She initially demonstrated pareses of her right hand at the age of 55 years, which spread to proximal muscles and to the opposite arm and both lower limbs, leaving her wheelchair dependent after 2½ years. Electromyography showed acute and chronic changes in distal and proximal muscles of upper and lower limbs. Cerebrospinal fluid and routine blood variables showed no abnormalities; brain and spine magnetic resonance (MR) imaging was normal. She died of respiratory insufficiency 3 years after disease onset. The daughter (IV-1) of the index patient is 38 years old and healthy. The proband's mother (II-1) initially manifested progressive lower motor neuron disease (MND) at the age of 31 years. The disease was classified as multiple sclerosis, although she had only slowly progressive motor symptoms. The site of onset was the right hand. During the course of her disease, she progressed to have a gait disturbance. After 5 years, she experienced asymmetric tetraparesis, and 1 year later she was wheelchair dependent. She died after a 13-year disease course of respiratory insufficiency. Only limited information is available about the proband's grandfather (I-1). He was wheelchair dependent during the last few years of his life and died at the age of 54 years. His wife (I-2) died early at the age of 45 years without clinical signs of MND or dementia. The proband has 2 siblings aged 67 years (III-2) and 64 years (III-3). DNA was available from the nonaffected III-3 family member, who did not show the G348C mutation. DNA from other affected or unaffected older family members was unavailable. No autopsy was performed in the deceased family members.

Place holder to copy figure label and caption
Figure 1.

Pedigrees of families A and B with chromatograms of part of exon 6 of TARDBP showing G348C and N352S mutations in the index patients, respectively. A, Family A with the G348C mutation in TARDBP. B, Chromatogram of part of exon 6 of TARDBP showing G348C mutation in the index patient. C, Family B with the N352S mutation in TARDBP. D, Chromatogram of part of exon 6 of TARDBP showing N352S mutation in the index patient. Square indicates male; circle, female; slash, deceased; solid symbol, affected; ?, possibly affected; and arrow, index patient.

Graphic Jump Location
FAMILY B

The N352S mutation was found in the index patient of family B (Figure 1C and D). This subject (III-1) showed first clinical signs at the age of 40 years with impairment of fine motor skills of the right hand. Motor and sensory nerve conduction was normal, but electromyography showed acute and chronic changes in distal and proximal muscles of upper and lower limbs. Cerebrospinal fluid and routine blood variables showed no abnormalities; brain and cervical MR images were normal. Noninvasive ventilation therapy was necessary 4 years after disease onset. After 5 years, she developed severe tetraparesis and became wheelchair dependent. No bulbar impairment, autonomic dysfunction, or incontinence of bladder or bowel was present at the time of the analysis, 7 years after onset. No subjective complaints or evident cognitive deficits were recognized during interviews; however, no formal neuropsychologic testing was performed. The index patient's mother (II-2) showed no clinical signs of MND or dementia until she died at age 72 years of stroke. However, the index patient's aunt (II-3) had MND with onset in the distal upper limbs at about age 50 years. During 3 to 4 years, severe tetraparesis developed, and she died of respiratory insufficiency. The proband's grandfather (I:2) died at age 80 years of stroke without clinical signs of MND. The grandmother died at age 65 years of heart failure. The proband's grandfather (I-2) had 11 siblings born between 1890 and 1910. Many of these siblings died early of unknown causes. Motor neuron disease was reported for 1 woman (II-1) whose father (I-1) was a brother of I-2. She died at age 72 years of respiratory insufficiency after a 3- to 4-year course of progressive MND with spinal onset. Her father (I-1) died early at the age of 30 years without clinical signs of MND. III-2 and III-3, ages 56 and 52 years, are brothers of the index patient and are not reporting signs of MND. DNA was available only from III-3. He carries the N352S mutation; however, because of the age of this subject relative to the range of disease onset in this family, these data are uninformative. No autopsy was performed on deceased individuals.

PREDICTED EFFECTS OF G348C AND N352S MUTATIONS

Both amino acid exchanges affect highly conserved residues of TDP-43 (Figure 2A). Glycine at codon 348 is fully conserved in TDP-43 across the phylogenic spectrum from Homo sapiens to Danio rerio, whereas asparagine at codon 352 is conserved across all examined mammals and Gallus gallus.

Place holder to copy figure label and caption
Figure 2.

Predicted effects of G348C and N352S mutations. A, Sequence alignment of amino acids 340 through 360 of transactivation response DNA-binding protein 43 (TDP-43) from diverse vertebrate species. Mutation sites are boldfaced. B, Effects of TARDBP mutations G348C and N352S on protein structure and function predicted using a software program (PolyPhen; http://coot.embl.de/PolyPhen/) and on phosphorylation site prediction using a network service (NetPhos 2.0; http://www.cbs.dtu.dk/services/NetPhos). aThe lower the score, the more benign the substitution. bThe higher the score, the higher the probability for phosphorylation. Phosphorylation sites for predicted scores are boldfaced. WT indicates wild-type TDP-43.

Graphic Jump Location

Using a software program (PolyPhen; http://coot.embl.de/PolyPhen/) to predict effects on protein structure or function, the G348C mutation was predicted to have a probable damaging function, whereas no deleterious effect was predicted for the N352S mutation (Figure 2B). A network service was used to predict putative effects on phosphorylation sites (NetPhos 2.0; http://www.cbs.dtu.dk/services/NetPhos). The N352S mutations not only introduce a new serine residue at position 352 but also lead to an increased phosphorylation prediction score for serine residues at positions 347 and 350 of TDP-43 (Figure 2B).

We describe 2 kindreds with a familial form of ALS with autosomal dominant inheritance due to the G348C and novel N352S missense mutations in TARDBP. These mutations were not found in 400 control samples and were not reported in more than 1000 controls of white race/ethnicity sequenced in other articles.12,14 Because DNA was unavailable from other affected family members of either kindred, we cannot definitively prove that the mutations cosegregate with the disease in the families. However, as discussed herein, their critical locations and predicted functional changes, together with the family history and their absence in numerous control samples, strongly support the idea that both mutations are pathogenic.

The clinical phenotype in both families with spinal onset and predominance of lower motor neuron signs with absence of bulbar signs or evidence for cognitive impairment is in accord with previous findings reported in TARDBP mutation cases. So far, spinal onset is described in 77% of TARDBP mutation cases, lower motor neuron signs were predominant in 39%, and the absence of cognitive impairment is a consistent finding.1114 However, this clinical phenotype does not allow separating TARDBP mutation cases from other forms of ALS, with similar features being reported in sALS and in SOD1 fALS.16,17

Disease onset in our 2 kindreds is within the range of described disease onset at 30 to 83 years among other reported TARDBP mutation cases.1114 However, it is notable that the G348C mutation, which has been reported recently in a single sALS case,14 leads to the earliest disease onset among all TARDBP mutation cases, with onset at 31 years (in the present study) and at 30 years,14 suggesting that this amino acid exchange evokes severe functional changes of TDP-43.

Except for the D169G mutation, all other TARDBP mutations, including the G348C and novel N352S mutations reported herein, are located in exon 6 encoding for the C-terminus of TDP-43. The importance of the glycine-rich C-terminal domain of TDP-43 in mediating its exon skipping and splicing inhibitory ability has been demonstrated and has been observed to correlate with its ability to interact with other members of the heterogeneous nuclear ribonuclear A and B protein families with well-known splicing inhibitory properties.10

The introduction of a cysteine residue due to the G348C mutation in the C-terminal region of TDP-43 is predicted to affect protein function (Figure 2B),14 possibly by the formation of intermolecular disulfide bridges, which might interfere with protein-protein interaction or might increase the aggregation tendency of TDP-43. The most likely effect of the N352S mutation is increased TDP-43 phosphorylation. This might lead to impaired nuclear cytoplasmic transport or protein-protein interaction, thereby leading to TDP-43 accumulation. Abnormal phosphorylation of TDP-43, by introducing new threonine or serine residues or by increasing the probability of phosphorylation of adjacent serine sites, has been previously discussed as a putative effect for several other TARDBP mutations.1214

So far, the functional analysis of TARDBP mutations is limited and needs to be investigated in detail in future studies, including the generation of transgenic animal models. However, preliminary functional data on the M337V and Q331K mutations suggest that mutated TDP-43 might fragment more readily and lead to increased apoptotic cell death in chick embryos12 or, as reported for the G348C, R361S, and N390D mutations, might lead to increased aggregation properties of TDP-43.14

In summary, the identification of 2 kindreds with fALS due to TARDBP mutations, including the novel N352S mutation, extends the spectrum of TARDBP mutations. Moreover, the occurrence of TARDBP mutations in 6.5% (2 of 31) of our non-SOD1 fALS cohort, similar to the described frequency of 5.1% in another study,13 not only underlines the direct role of TDP-43 dysfunction and neurodegeneration in ALS but also implicates that screening for TARDBP mutations should be considered in all non-SOD1 fALS cases.

Correspondence: Manuela Neumann, MD, Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Feodor-Lynen-Strasse 23, 81377 Munich, Germany (manuela.neumann@med.uni-muenchen.de).

Accepted for Publication: April 24, 2008.

Author Contributions:Study concept and design: Kühnlein, Van Deerlin, Kretzschmar, Ludolph, and Neumann. Acquisition of data: Kühnlein, Sperfeld, Vanmassenhove, Van Deerlin, Ludolph, and Neumann. Analysis and interpretation of data: Kühnlein, Vanmassenhove, Van Deerlin, Lee, Trojanowski, Ludolph, and Neumann. Drafting of the manuscript: Kühnlein and Neumann. Critical revision of the manuscript for important intellectual content: Kühnlein, Sperfeld, Vanmassenhove, Van Deerlin, Lee, Trojanowski, Kretzschmar, and Ludolph. Obtained funding: Lee, Trojanowski, and Neumann. Administrative, technical, and material support: Kühnlein, Sperfeld, Van Deerlin, Kretzschmar, and Ludolph. Study supervision: Lee, Trojanowski, and Ludolph.

Financial Disclosure: None reported.

Funding/Support: This work was funded by grants 0017/2007 from the Friedrich-Baur Stiftung (Dr Neumann) and AG 17586 and AG 10124 (Drs Lee and Trojanowski) from the National Institutes of Health.

Mitchell  JDBorasio  GD Amyotrophic lateral sclerosis. Lancet 2007;369 (9578) 2031- 2041
PubMed
Valdmanis  PNRouleau  GA Genetics of familial amyotrophic lateral sclerosis. Neurology 2008;70 (2) 144- 152
PubMed
Chen  YZBennett  CLHuynh  HM  et al.  DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004;74 (6) 1128- 1135
PubMed
Puls  IJonnakuty  CLaMonte  BH  et al.  Mutant dynactin in motor neuron disease. Nat Genet 2003;33 (4) 455- 456
PubMed
Nishimura  ALMitne-Neto  MSilva  HC  et al.  A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 2004;75 (5) 822- 831
PubMed
Neumann  MSampathu  DMKwong  LK  et al.  Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314 (5796) 130- 133
PubMed
Mackenzie  IRBigio  EHInce  PG  et al.  Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 2007;61 (5) 427- 434
PubMed
Buratti  EDörk  TZuccato  EPagani  FRomano  MBaralle  FE Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 2001;20 (7) 1774- 1784
PubMed
Ou  SHWu  FHarrich  DGarcia-Martínez  LFGaynor  RB Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 1995;69 (6) 3584- 3596
PubMed
Buratti  EBaralle  FE Multiple roles of TDP-43 in gene expression, splicing regulation,and human disease. Front Biosci 2008;13867- 878
PubMed
Gitcho  MABaloh  RHChakraverty  S  et al.  TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 2008;63 (4) 535- 538
PubMed
Sreedharan  JBlair  IPTripathi  VB  et al.  TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008;319 (5870) 1668- 1672
PubMed
Van Deerlin  VMLeverenz  JBBekris  LM  et al.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 2008;7 (5) 409- 416
PubMed
Kabashi  EValdmanis  PNDion  P  et al.  TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 2008;40 (5) 572- 574
PubMed
Brooks  BRMiller  RGSwash  MMunsat  TLWorld Federation of Neurology Research Group on Motor Neuron Diseases, El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1 (5) 293- 299
PubMed
Ravits  JPaul  PJorg  C Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology 2007;68 (19) 1571- 1575
PubMed
Battistini  SGiannini  FGreco  G  et al.  SOD1 mutations in amyotrophic lateral sclerosis: results from a multicenter Italian study. J Neurol 2005;252 (7) 782- 788
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Pedigrees of families A and B with chromatograms of part of exon 6 of TARDBP showing G348C and N352S mutations in the index patients, respectively. A, Family A with the G348C mutation in TARDBP. B, Chromatogram of part of exon 6 of TARDBP showing G348C mutation in the index patient. C, Family B with the N352S mutation in TARDBP. D, Chromatogram of part of exon 6 of TARDBP showing N352S mutation in the index patient. Square indicates male; circle, female; slash, deceased; solid symbol, affected; ?, possibly affected; and arrow, index patient.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Predicted effects of G348C and N352S mutations. A, Sequence alignment of amino acids 340 through 360 of transactivation response DNA-binding protein 43 (TDP-43) from diverse vertebrate species. Mutation sites are boldfaced. B, Effects of TARDBP mutations G348C and N352S on protein structure and function predicted using a software program (PolyPhen; http://coot.embl.de/PolyPhen/) and on phosphorylation site prediction using a network service (NetPhos 2.0; http://www.cbs.dtu.dk/services/NetPhos). aThe lower the score, the more benign the substitution. bThe higher the score, the higher the probability for phosphorylation. Phosphorylation sites for predicted scores are boldfaced. WT indicates wild-type TDP-43.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Clinical Features of Families With TARDBP Mutationsa

References

Mitchell  JDBorasio  GD Amyotrophic lateral sclerosis. Lancet 2007;369 (9578) 2031- 2041
PubMed
Valdmanis  PNRouleau  GA Genetics of familial amyotrophic lateral sclerosis. Neurology 2008;70 (2) 144- 152
PubMed
Chen  YZBennett  CLHuynh  HM  et al.  DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004;74 (6) 1128- 1135
PubMed
Puls  IJonnakuty  CLaMonte  BH  et al.  Mutant dynactin in motor neuron disease. Nat Genet 2003;33 (4) 455- 456
PubMed
Nishimura  ALMitne-Neto  MSilva  HC  et al.  A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet 2004;75 (5) 822- 831
PubMed
Neumann  MSampathu  DMKwong  LK  et al.  Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314 (5796) 130- 133
PubMed
Mackenzie  IRBigio  EHInce  PG  et al.  Pathological TDP-43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations. Ann Neurol 2007;61 (5) 427- 434
PubMed
Buratti  EDörk  TZuccato  EPagani  FRomano  MBaralle  FE Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J 2001;20 (7) 1774- 1784
PubMed
Ou  SHWu  FHarrich  DGarcia-Martínez  LFGaynor  RB Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J Virol 1995;69 (6) 3584- 3596
PubMed
Buratti  EBaralle  FE Multiple roles of TDP-43 in gene expression, splicing regulation,and human disease. Front Biosci 2008;13867- 878
PubMed
Gitcho  MABaloh  RHChakraverty  S  et al.  TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 2008;63 (4) 535- 538
PubMed
Sreedharan  JBlair  IPTripathi  VB  et al.  TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 2008;319 (5870) 1668- 1672
PubMed
Van Deerlin  VMLeverenz  JBBekris  LM  et al.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 2008;7 (5) 409- 416
PubMed
Kabashi  EValdmanis  PNDion  P  et al.  TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 2008;40 (5) 572- 574
PubMed
Brooks  BRMiller  RGSwash  MMunsat  TLWorld Federation of Neurology Research Group on Motor Neuron Diseases, El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1 (5) 293- 299
PubMed
Ravits  JPaul  PJorg  C Focality of upper and lower motor neuron degeneration at the clinical onset of ALS. Neurology 2007;68 (19) 1571- 1575
PubMed
Battistini  SGiannini  FGreco  G  et al.  SOD1 mutations in amyotrophic lateral sclerosis: results from a multicenter Italian study. J Neurol 2005;252 (7) 782- 788
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles