AMYOTROPHIC LATERAL SCLEROSIS 10 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA
General Information (adopted from Orphanet):
Synonyms, Signs:
ALS10 FRONTOTEMPORAL LOBAR DEGENERATION WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED
FTLD-TDP, TARDBP-RELATED, INCLUDED
FRONTOTEMPORAL DEMENTIA WITH TDP43 INCLUSIONS, TARDBP-RELATED, INCLUDED
Tagawa et al. (2007) described a Japanese family in which 4 members in 2 generations had adult onset of amyotrophic lateral sclerosis characterized by relatively rapid progression of bulbar symptoms. Autopsy of one of the patients showed neuropathology ... Tagawa et al. (2007) described a Japanese family in which 4 members in 2 generations had adult onset of amyotrophic lateral sclerosis characterized by relatively rapid progression of bulbar symptoms. Autopsy of one of the patients showed neuropathology of the classic form, with degenerative changes restricted to the upper and lower motor neuron systems. In addition, Bunina bodies and ubiquitin-positive skein-like inclusions were found in the remaining lower motor neurons, and ubiquitin-positive intracytoplasmic inclusions were also found in the putaminal small neurons. The authors noted that these findings were typical of patients with sporadic ALS. Autosomal dominant inheritance was proposed, but no mutations were identified in the SOD1 gene (147450). Sreedharan et al. (2008) described a Caucasian family of English descent segregating autosomal dominant amyotrophic lateral sclerosis with male-to-male transmission. Four of the affected individuals had definite ALS by the El Escorial criteria, and another recently symptomatic individual had probable ALS. Three had limb-onset ALS and 2 had bulbar-onset ALS. The mean age of symptoms onset was 47 years (range 44 to 52). Mean disease duration was 5.5 years (range 4 to 7) from symptom onset to death. The obligate carrier (who died aged 54 from severe coronary atheroma) was reported by family members to have had gait disturbance and declining upper limb strength consistent with ALS. There was no history of dementia or any atypical features in the kindred. Sreedharan et al. (2008) also reported a man who developed limb-onset ALS at age 72 with a disease duration of 3 years, and in a man who developed limb-onset ALS at age 65, with a disease duration of 5 years and no atypical features. Van Deerlin et al. (2008) reported a Caucasian father and daughter with rapidly progressive ALS inherited in an autosomal dominant pattern. The daughter presented with dysarthria and dysphagia at age 51 years and had a rapidly progressive course involving the limbs and respiration. She died after 13 months. Her father had presented with arm weakness at age 47 years and died after 16 months. Postmortem examination showed findings consistent with ALS. Van Deerlin et al. (2008) also reported a Chinese family in which 5 members spanning 2 generations had ALS with onset between ages 41 and 60 years. Most showed rapid progression with death within 1 or 2 years. Both spinal and bulbar onset were reported. Postmortem examination of 2 patients showed changes consistent with ALS as well as TDP43-positive inclusions in upper and lower motor neurons and in various brain regions. Kuhnlein et al. (2008) reported a German family with ALS10 confirmed by genetic analysis (G348C; 605078.0007). The proband presented at age 55 years with paresis of the right hand, which progressed rapidly to involve the arms and lower limbs and left her wheelchair-bound within 2.5 years. She died of respiratory insufficiency 3 years after disease onset. The patient's mother had died of respiratory insufficiency due to a similar disorder. There were no clinically relevant bulbar symptoms and no cognitive impairment. - Clinical Variability Benajiba et al. (2009) reported a patient with onset of semantic dementia at age 50 years. She later developed ritual behaviors, apathy, social avoidance, aggressiveness, and bulimia, consistent with frontotemporal dementia (see 600274). She also had bulbar symptoms of ALS and upper and lower motor neuron disease in all 4 limbs. Her sister had dysarthria and dysphagia at age 57, later developed upper and lower limb motor neuron disease, and died at age 60. Their father reportedly had motor neuron disease without dementia. An unrelated patient had behavior disorders at age 52 consistent with frontotemporal dementia. She developed bulbar symptoms at age 54, and later motor neuron disease in the limbs. She died at age 58. All patients were found to carry the same heterozygous mutation in the TARDBP gene (G295S; 605078.0010). The findings expanded the phenotypic spectrum associated with mutations in the TARDBP gene. Kovacs et al. (2009) reported a Hungarian man who showed marked personality changes beginning at age 35 years. This was followed by a rapid deterioration in attention and thinking with psychomotor agitation and insomnia, consistent with FTD. Neurologic examination showed supranuclear gaze palsy, hyperkinetic choreiform movements, motor stereotypies, and primitive reflexes. Motor neuron disease signs, rigidity, and cerebellar ataxia were not present. Brain MRI showed prominent atrophy of the mesencephalic tectum and caudate nuclei. He died at age 37 years of pulmonary edema secondary to cardiac failure. There was no family history of a similar disorder. Neuropathologic examination showed moderate atrophy of the frontal lobes and caudate nuclei, severe atrophy of tectum and tegmentum, and severe depigmentation of the substantia nigra. Microscopic analysis showed mild microvacuolar changes in the superficial cortical layers of the frontal and cingulate gyri, and neuronal loss and astrogliosis in the subcortical gray matter. Phospho-TDP43-immunoreactive deposits were present in neuronal cytoplasmic inclusions in various brain regions, including the cortex, basal ganglia, thalamus, and brainstem. Genetic analysis excluded a pathologic HTT (613004) expansion and identified a heterozygous mutation in the TARDBP gene (K263E; 605078.0011). The findings indicated that TARDBP mutations can be associated with a wider clinicopathologic spectrum of disorders than originally thought. Gitcho et al. (2009) identified a heterozygous 2076G-A transition in the 3-prime untranslated region of the TARDBP gene (605078.0012) in affected members of 2 unrelated families with either ALS10 with or without frontotemporal dementia or isolated FTLD. The first family had 2 mutation carriers with a variable phenotype: the proband was a woman with frontotemporal dementia without motor disease, whereas her brother had lower motor neuron disease without dementia. The father and mother, from whom DNA was not available, had ALS and lower motor neuron disease, respectively, and it was not clear which parent likely transmitted the TARDBP mutation. Neuropathologic analysis of the proband, who did not have motor neuron disease, showed cortical atrophy, neuronal loss in the hippocampus, hippocampal sclerosis, and TDP43-positive neuronal cytoplasmic inclusions in the cortex and hippocampus. There was no evidence of motor neuron loss from the motor nuclei of the brainstem. The brother's neuropathologic findings were consistent with ALS and showed TDP43-immunoreactivity in the anterior horn cells of the spinal cord and neuronal cytoplasmic inclusions in the hippocampus. The second family included a patient with familial ALS; no neuropathology was available for that patient. These findings suggested that a common molecular pathology can result in clinically heterogeneous phenotypes.
Corcia et al. (2012) identified 19 patients from 9 families with ALS10 and 9 patients with apparently sporadic ALS10. The patients were French, and all carried mutations in the TARDBP gene. The mean age at onset was 53.4 ... Corcia et al. (2012) identified 19 patients from 9 families with ALS10 and 9 patients with apparently sporadic ALS10. The patients were French, and all carried mutations in the TARDBP gene. The mean age at onset was 53.4 years, and the upper limb was the most common site of onset. Only 2 patients had dementia. The median disease duration was 63 months; 2 patients were alive after 8 years. This group of patients was compared to 3 cohorts: 737 patients with sporadic ALS; 192 patients with familial ALS and no mutation in the SOD1 (147450), TARDPB (605078), or FUS (137070) genes; and 58 patients with familial ALS due to SOD1 mutations. In TARDBP-positive patients, onset was earlier (p = 0.0003), upper limb onset was predominant (p = 0.002), and duration was longer (p = 0.0001) than in patients with sporadic ALS. The mean age at onset was not significantly different between TARDBP-positive and SOD1-positive groups. TARDBP-positive and SOD1-positive groups had the longest duration, but differed in site of onset: 60.7% upper limb onset for TARDBP-positive and 74.1% lower limb onset for SOD1+ (p less than 0.0001). The TARDBP-positive patients were pooled with 117 ALS10 patients reported in the literature. Among all those with TARDBP mutations, Caucasians tended to have upper limb onset, while Asians tended to have bulbar onset. Among those with TARDBP mutations, G298S (605078.0005) was associated with the shortest survival, whereas A315T (605078.0009) and M337V (605078.0001) were associated with longest duration.
Because TAR DNA-binding protein (TDP43) is the major protein in ubiquitinated inclusions in ALS, Sreedharan et al. (2008) investigated its role in the pathogenesis of the disorder. They screened 154 index familial ALS cases for mutations in the ... Because TAR DNA-binding protein (TDP43) is the major protein in ubiquitinated inclusions in ALS, Sreedharan et al. (2008) investigated its role in the pathogenesis of the disorder. They screened 154 index familial ALS cases for mutations in the TARDBP gene, which encodes TDP43. Mutations in other genes associated with ALS had been excluded from these cases. They identified a missense mutation in exon 6 of the TARDBP gene in the index case from kindred ALS85, a Caucasian family of English descent. The mutation was predicted to result in substitution of valine for methionine at codon 337 (M337V; 605078.0001) and resides in a strongly phylogenetically conserved region of TDP43. The mutation segregated with disease and was present in 4 other affected individuals in 3 branches and 2 generations of the extended kindred and was absent from 9 unaffected sibs. Genomewide scan confirmed that linkage was restricted to chromosome 1p36, to a region containing the TARDBP locus. Sreedharan et al. (2008) sequenced all 6 exons of TARDBP in a cohort of 200 British sporadic ALS cases and identified another missense mutation (Q331L; 605078.0002) in a man who developed limb-onset ALS at age 72 with a disease duration of 3 years. No mutation was detected in a screen of all 6 exons from 500 British Caucasian controls. In a screen of TARDBP in 2 further cohorts, 172 Australian Caucasian sporadic ALS patients and 172 controls, as well as 200 British Caucasian controls, Sreedharan et al. (2008) found a missense mutation (G294A; 605078.0003) in a man who developed limb-onset ALS at age 65 with a disease duration of 5 years and no atypical features. In affected members of the Japanese family with ALS previously described by Tagawa et al. (2007), Yokoseki et al. (2008) identified a heterozygous mutation in the TARDBP gene (Q343R; 605078.0008). In affected members of a European family with ALS10, Gitcho et al. (2008) identified a heterozygous mutation in the TARDBP gene (A315T; 605078.0009). Van Deerlin et al. (2008) identified heterozygous mutations in the TARDBP gene (605078.0004; 605078.0005) in affected individuals of 2 unrelated families with autosomal dominant ALS10. Kabashi et al. (2008) screened a panel of familial and sporadic ALS cases for TARDBP mutations and found 8 missense mutations in 9 individuals. Protein lysates from individuals with ALS expressing TDP43 mutants showed accumulation of a smaller (approximately 28 kD) TDP43 protein product, mainly in a detergent-insoluble fraction. Kuhnlein et al. (2008) identified mutations in the TARDBP gene in 2 (6.5%) of 31 probands with non-SOD1 familial ALS. Millecamps et al. (2010) identified 6 different missense mutations in the TARDBP gene in 7 (4.3%) of 162 French probands with familial ALS. Three of the families had been previously reported. Patients with TARDBP mutations had disease onset predominantly in the upper limb. One-third of patients had rapid disease progression, two-thirds had a medium disease course, and 1 had a slow disease course. There was evidence of incomplete penetrance. One TARDBP mutation carrier developed frontotemporal dementia 1 year after the onset of motor weakness. Corrado et al. (2009) identified 12 different missense mutations in the TARDBP gene (see, e.g., A382T; 605078.0013) in 18 of 666 Italian probands with ALS. Six were familial, and 12 were apparently sporadic. All patients had motor neuron disease, and none had dementia. All mutations were located in exon 6 of the gene, and the most common mutation was A382T, occurring in 7 patients. Haplotype analysis of A382T carriers suggested a founder effect. Chio et al. (2010) identified a heterozygous A382T mutation in affected members of 3 unrelated Italian families with ALS10 with frontotemporal dementia. Affected individuals developed rapidly progressive muscle atrophy and weakness associated with hyperreflexia, dysarthria, dysphagia, and respiratory insufficiency between ages 25 and 78 years. Frontotemporal dementia, characterized by disinhibition, emotional lability, apathy, and executive dysfunction, developed soon after the onset of ALS. One mutation carrier did not manifest neurologic symptoms at age 65 years.
Corrado et al. (2009) noted that the frequency of TARDBP mutations is not homogeneous among different populations. In particular, 26 of 39 ALS patients carrying TARDBP mutations had an Italian or French origin, suggesting higher frequency of TARDBP ... Corrado et al. (2009) noted that the frequency of TARDBP mutations is not homogeneous among different populations. In particular, 26 of 39 ALS patients carrying TARDBP mutations had an Italian or French origin, suggesting higher frequency of TARDBP mutations in southern Europe (average 3.4%; 8% in France and 2.7% in Italy) than in other Caucasian populations (average 0.7%). After exclusion of the A382T (605078.0013) mutation, which is likely to be a founder mutation, the frequency of TARDBP mutations was still 3 times higher in southern European than in northern European populations. Chio et al. (2011) identified the A382T mutation in 39 (28.7%) of 135 Sardinian patients with ALS, including 15 with familial disease and 24 with apparently sporadic disease. None of 156 ethnically matched controls carried the mutation. Haplotype analysis of 5 patients with the mutation identified a 94-SNP common risk haplotype spanning 663 kb across the TARDBP locus on chromosome 1p36.22. The findings suggested a founder effect in this population.
A diagnosis of TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is established when a pathogenic TARDBP mutation is identified in an individual meeting clinical diagnostic criteria for ALS (i.e., characteristic signs and symptoms of progressive degeneration of upper motor neurons (UMNs) and lower motor neurons [LMNs]). ...
DiagnosisClinical Diagnosis A diagnosis of TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is established when a pathogenic TARDBP mutation is identified in an individual meeting clinical diagnostic criteria for ALS (i.e., characteristic signs and symptoms of progressive degeneration of upper motor neurons (UMNs) and lower motor neurons [LMNs]). UMN manifestations include stiffness, spasticity, hyperreflexia, and pseudobulbar affectLMN manifestations include weakness accompanied by muscle atrophy, fasciculations, and cramping(See the El Escorial criteria [Brooks et al 2000]) Note: TARDBP-related ALS is clinically indistinguishable from ALS due to other causes. For a more detailed description of these features, please refer to the Amyotrophic Lateral Sclerosis Overview. Testing Clinical testing in TARDBP-related ALS is identical to that for other forms of ALS, employing multiple modalities to exclude alternative diagnoses and to provide support for the diagnosis of ALS. Following a diagnosis of ALS, genetic testing for TARDBP mutations can be considered (see Testing Strategy).Electromyography and nerve conduction studies (EMG/NCS). EMG/NCS are often used to support a diagnosis of ALS and to exclude mimics of ALS (e.g., polyradiculopathy, mononeuritis multiplex, multifocal motor neuropathy, sensory motor neuropathies). EMG/NCS in TARDBP-related ALS, as in other causes of ALS, demonstrates widespread denervation due to LMN loss in the setting of relatively preserved sensory responses [Gitcho et al 2008, Kühnlein et al 2008]. Neuroimaging. MRI of the brain and spinal cord are used in the evaluation to exclude alternate explanations for the observed symptoms, including polyradiculopathy and spinal cord or brain lesions. Although several imaging abnormalities have been directly attributed to ALS, including abnormal T2 signal along the corticospinal tracts and atrophy of the precentral gyrus, the poor sensitivity and specificity of these findings limit their usefulness in confirming the diagnosis of ALS [Grosskreutz et al 2008]. Although the imaging characteristics of TARDBP-related ALS have not been systematically investigated, single cases have had unremarkable MRI of the brain and cervical spinal cord [Kühnlein et al 2008, Pamphlett et al 2009]. Cerebrospinal fluid (CSF). Analysis of the CSF is primarily used to exclude mimics of ALS, including infectious polyradiculitis and carcinomatosis or lymphomatosis. TAR DNA-binding protein 43 (TDP-43), the protein encoded by TARDBP, has been detected in the CSF of individuals with ALS [Steinacker et al 2008, Kasai et al 2009], but has not yet been examined in persons with TARDBP-related ALS.Neuropathology. Pathologic evaluation of the brain and spinal cord can be utilized to confirm a diagnosis of ALS post-mortem. One of the pathologic hallmarks of ALS is the presence of ubiquitin-immunoreactive cytoplasmic inclusions in degenerating cortical and spinal cord neurons. In non-SOD1 ALS, these cytoplasmic inclusions typically contain TDP-43, which is also reduced or absent from the nuclei of inclusion-containing cells [Neumann et al 2006, Davidson et al 2007]. TDP-43-positive inclusions have also been described in other neurodegenerative diseases [Freeman et al 2008, Uryu et al 2008, Arai et al 2009] and in several diseases of muscle [Weihl et al 2008, Küsters et al 2009, Olivé et al 2009].The post-mortem pathology of five individuals with TARDBP-related ALS has been reported. One individual with simplex/sporadic ALS (SALS) and one individual with familial ALS (FALS) had histologic changes and TDP-43 inclusions that were typical of SALS without TARDBP mutations [Yokoseki et al 2008, Pamphlett et al 2009]. Two individuals with FALS had more numerous TDP-43 inclusions than are typically found [Van Deerlin et al 2008]. Molecular Genetic TestingGene. TARDBP is the only gene in which mutation causes TARDBP-related ALS.Clinical testing Sequence analysis. Mutation detection rate for sequence analysis should approach 100%, but will only identify single nucleotide substitutions or small insertions/deletions within exons or near exon/intron junctions. No large deletions or insertions have been reported, but screening for these types of mutations have been limited to copy number analysis in 279 ALS patients [Guerreiro et al 2008] and to multiplexed amplicon quantification (MAQ) in another 237 ALS cases [Gijselinck et al 2009]. These findings should be considered preliminary until larger cohorts have been screened.Table 1. Summary of Molecular Genetic Testing Used in TARDBP-Related Amyotrophic Lateral Sclerosis View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTARDBPSequence analysisNucleotide substitutions, small insertions and deletionsApproaches 100% 2Clinical 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Because TARDBP-related ALS is defined by the presence of a mutation in the causative gene, TARDBP, and because mutation types that are not detected by sequence analysis (such as exonic or whole-gene deletions) have not been reported, the mutation detection rate for TARDBP using sequence analysis approaches 100%. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To establish the diagnosis in a proband Establish a clinical diagnosis of ALS using clinical examination, neurophysiologic testing, and neuroimaging. Note: TARDBP-related ALS is clinically indistinguishable from ALS due to other causes. Obtain a three-generation family history. The presence of ALS in a closely related family member (usually a parent) increases the probability that a TARDBP mutation may be found. If the proband is the only occurrence of ALS in their family, i.e. a simplex case, the likelihood of identifying a TARDBP mutation is lower. Note: To date, all reported pedigrees with TARDBP-related ALS show autosomal dominant inheritance.Familial ALS (FALS) (i.e., presence of at least two affected family members) Because ~20% of FALS is caused by mutations in SOD1, a tiered approach to testing a proband with autosomal dominant FALS should begin with SOD1 sequencing. If no SOD1 mutation is identified, sequencing of TARDBP should then be performed (see Differential Diagnosis). In some cases testing for other rare genetic causes of FALS can be considered, although these typically have a distinctive clinical presentation or autosomal recessive inheritance pattern (see Amyotrophic Lateral Sclerosis Overview). Simplex/sporadic ALS (SALS) (i.e., single occurrence in a family). Sequencing of TARDBP in SALS can be performed, but the lower mutation prevalence (1.1%) in this population should be taken into consideration. Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersAlthough typical ALS is the predominant phenotype associated with TARDBP mutations, frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) has been reported in a single pedigree and a single simplex case [Benajiba et al 2009].
More than 80 persons with TARDBP-related ALS have been described in the literature. The spectrum of clinical disease in these individuals appears to overlap significantly with idiopathic and SOD1-related ALS, including gender ratio, age of onset, symptom distribution, and severity of disease. ...
Natural History More than 80 persons with TARDBP-related ALS have been described in the literature. The spectrum of clinical disease in these individuals appears to overlap significantly with idiopathic and SOD1-related ALS, including gender ratio, age of onset, symptom distribution, and severity of disease. The male to female ratio is 1.6 to 1.Mean age of onset is 54 ± 12 years (mean ± SD). The range of onset is age 20 to 83 years. This is similar to the age of onset in SALS and non-SOD1-related FALS. Most patients with TARDBP-related ALS meet El Escorial criteria for ALS [Brooks et al 2000] and have both UMN and LMN involvement. Although LMN involvement is predominantly common [Gitcho et al 2008, Kabashi et al 2008, Kühnlein et al 2008, Corrado et al 2009], no individuals with pure UMN involvement (primary lateral sclerosis) have been reported.Limb-onset is noted in 80% of TARDBP-related ALS and bulbar-onset in 20%. Intra- and interfamilial variability in the site of onset is observed even with the same mutation (see Genotype-Phenotype Correlations). Although ALS and FTLD frequently share TDP-43 aggregates on pathology, no TARDBP mutations have yet been identified in patients with pure FTLD. However, several patients with FTLD and FTLD-MND were recently found to have the p.Gly295Ser mutation [Benajiba et al 2009] (see Genetically Related Disorders). Other neurocognitive symptoms reported amongst TARDBP-ALS patients include Alzheimer-type dementia [Corrado et al 2009], anxiety, apathy, and agitation [Kabashi et al 2008]. As with other forms of ALS, individuals with TARDBP-related ALS die of respiratory failure when phrenic and thoracic motor neurons become severely involved. The mean disease duration prior to death is 50 ± 36 months (mean ± SD) but ranges from one to 13 years and may vary by mutation (see Genotype-Phenotype Correlations).
For a detailed discussion of these disorders and the differential diagnosis of ALS, see Amyotrophic Lateral Sclerosis Overview....
Differential DiagnosisFor a detailed discussion of these disorders and the differential diagnosis of ALS, see Amyotrophic Lateral Sclerosis Overview.TARDBP-associated ALS must be differentiated from mimics of ALS. Detailed clinical evaluation (as outlined above) usually allows the exclusion of other disorders. The rate of misdiagnosis in ALS is highest in individuals presenting with purely LMN findings [Traynor et al 2000]. The mimics of ALS from any cause are numerous and include: Multifocal motor neuropathyCervical spondylosisAdult-onset spinal muscular atrophy (SMA)Kennedy disease (X-linked spinobulbar muscular atrophy [SBMA])Acquired and hereditary motor neuropathies (see Charcot-Marie-Tooth Hereditary Neuropathy Overview)Late-onset GM2 gangliosidosis (see Hexosaminidase A Deficiency)Adult polyglucosan body disease Other genes associated with FALS* include:ALS1. SOD1 (encoding the protein superoxide dismutase)ALS4. SETX (encoding the protein senataxin)ALS6. FUS/TLS (encoding the protein fused in sarcoma/translated in liposarcoma)ALS8. VAPB (encoding the protein vesicle-associated membrane protein-associated protein B/C) ALS9. ANG (encoding the protein angiogenin)DCTN1 (encoding the protein dynactin) * Mutations in many of these genes have also been identified in small numbers of simplex cases of ALS (i.e., a single occurrence in a family).
To establish the extent of disease in an individual diagnosed with TARDBP-related ALS (or any other form of ALS), the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with TARDBP-related ALS (or any other form of ALS), the following evaluations are recommended:EMG/NCS to document the regions of involvementPulmonary function testing to detect and stage respiratory involvementSpeech and swallowing evaluation if dysarthria and/or dysphagia are present, to direct care to minimize risk of aspiration and to initiate augmentative communication strategies for possible loss of verbal communicationPhysical and occupational therapy evaluation to determine what adaptive devices are needed to maximize functionNutritional evaluationScreening for depression and need for psychosocial supportTreatment of ManifestationsThe management of TARDBP-related ALS is identical to that of ALS due to other causes, and is outlined in the American Academy of Neurology practice parameter on this topic [Miller et al 1999].Spasticity can be treated with a spasmolytic such as baclofen or a benzodiazepine.Pseudobulbar affect can be treated with a tricyclic antidepressant or combination of quinidine and dextromethorphan.Sialorrhea is often managed with anticholinergic medications (tricyclic antidepressants, scopolamine, atropine drops) or botulinum toxin injection of the salivary glands.Antidepressants are often required to treat concurrent depression.Riluzole is the only FDA-approved treatment for any type of ALS. Although there are no efficacy data specifically for TARDBP-related ALS, strong consideration should be given to its use [Miller et al 2007]. Prevention of Secondary ComplicationsAdequate nutrition and weight maintenance are essential. Percutaneous gastrostomy is often appropriate to maintain adequate caloric intake in persons with significant bulbar involvement.Joint contractures can occur, are often painful, and can interfere with care-giving. Appropriate bracing and stretching can minimize contractures.Early initiation of noninvasive ventilation has been shown to prolong survival [Farrero et al 2005].SurveillanceMonitoring of the forced vital capacity and other parameters of ventilation should be performed at clinic visits to determine the appropriate time to offer noninvasive ventilation. Routine screening for depression at clinic visits is appropriate.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationAlthough no current clinical trials are specifically designed to target TARDBP-related ALS, many are addressed in the broader category of ALS. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. TARDBP-Related Amyotrophic Lateral Sclerosis: Genes and DatabasesView in own windowLocus NameGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDALS10TARDBP1p36.22TAR DNA-binding protein 43alsod/TARDBP genetic mutations ALS mutation database TARDBP homepage - Mendelian genesTARDBPData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for TARDBP-Related Amyotrophic Lateral Sclerosis (View All in OMIM) View in own window 605078TAR DNA-BINDING PROTEIN; TARDBP 612069AMYOTROPHIC LATERAL SCLEROSIS 10, WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA; ALS10Normal allelic variants. TARDBP has six exons, five of which are coding. A p.Asp65Glu substitution was identified in one normal individual of African descent and is a presumed normal variant [Guerreiro et al 2008].The p.Ala90Val variant was found in one individual with FTLD-MND [Winton et al 2008] and in multiple controls of northern European background [Guerreiro et al 2008, Kabashi et al 2008, Sreedharan et al 2008]. Despite being present in controls, experimental data suggests that this allele may produce abnormal cytoplasmic aggregation of the TDP-43 [Winton et al 2008]. Therefore, the p.Ala90Val substitution may be a normal variant, or alternatively may convey susceptibility to developing FTD/ALS.Pathologic allelic variants. More than 30 potentially pathogenic TARDBP variants have been identified in familial (FALS) and/or simplex cases of ALS (SALS) (see Table 2). Although four of these variants have been found in more than one family, and three are present in both FALS and SALS cases, more than 50% of these potentially pathogenic variants have been identified in a single individual with SALS. This may suggest a high percentage of private (i.e., unique) mutations in TARDBP-related ALS [Corrado et al 2009]. In contrast, the p.Ala382Thr pathologic variant has been frequently detected in French and Italian ALS patients on a shared haplotype, indicating a shared ancestral founder [Kabashi et al 2008, Corrado et al 2009, Del Bo et al 2009].All pathologic variants appear to affect highly conserved amino acids, and 93% of known mutations reside in exon 6. The two non-exon 6 variants are p.Asp169Gly (in exon 4) [Kabashi et al 2008] and the 3’ UTR variant c.1462 T>C [Daoud et al 2009]. Each has been found in only one individual with SALS. Only one nonsense mutation has been described to date (a single base-pair insertion producing frameshift and a premature stop codon p.Tyr374X [Daoud et al 2009]), with the rest being missense mutations. Table 2. Selected TARDBP Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1) Protein Amino Acid ChangeReference SequencesNormal c.269C>Tp.Ala90Val 2NM_007375.3 NP_031401.1c.195T>A or c.195T>G 3p.Asp65GluPathologicc.506A>Gp.Asp169Glyc.800A>Gp.Asn267Serc.859G>Ap.Gly287Serc.859G>Cp.Gly290Alac.881G>Cp.Gly294Alac.881G>Tp.Gly294Val 4c.883G>Ap.Gly295Ser 4c.883G>Cp.Gly295Argc.892G>Ap.Gly298Serc.931A>Gp.Met311Valc.943G>Ap.Ala315Thr 5c.991C>Ap.Gln331Lysc.995G>Ap.Ser332Asnc.1004G>Ap.Gly335Aspc.1009A>Gp.Met337Val 5c.1028A>Gp.Gln343Argc.1035C>A p.Asn345Lysc.1042G>Tp.Gly348Cys 5c.1055A>Gp.Asn352Serc.1083G>Tp.Arg361Serc.1097C>Gp.Pro363Alac.1121_1122dupAp.Tyr374Xc.1135T>Cp.Ser379Proc.1136C>Gp.Ser379Cysc.1144G>Cp.Ala382Proc.1144G>Ap.Ala382Thr 4, 5c.1147A>Gp.Ile383Valc.1168A>Gp.Asn390Aspc.1169A>Gp.Asn390Serc.1178C>Tp.Ser393Leuc.*83T>C 6(1462T>C)--See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org). 1. Variant designation that does not conform to current naming conventions2. May be a variant that is normal or confers susceptibility to FTD/ALS. See Normal allelic variants.3. The precise nucleotide change is not known.4. Identified in both FALS and SALS5. Identified in affected individuals in more than one family6. * indicates location in 3’UTR, number of nucleotides beyond stop codonNormal gene product. TDP-43 comprises 414 amino acids encoded by TARDBP exons 2-6. TDP-43 is a ubiquitously expressed nuclear protein with structural similarities to the hnRNP A/B family of RNA binding proteins and is known to regulate DNA transcription, alternative splicing, and mRNA stability [Buratti & Baralle 2008]. Although information regarding the role of TDP-43 in normal cellular function is limited, it has been shown to influence cell cycle progression by modulating CDK6 mRNA levels in dividing cells [Ayala et al 2008]. Abnormal gene product. All but one of the clearly pathologic variants thus far identified are located in exon 6. These cluster in the C-terminal glycine-rich domain of the TDP-43, an area that interacts with other hnRNPs to regulate alternative splicing [Buratti et al 2005]. Mutations in TARDBP may promote TDP-43 aggregation in cortical and spinal motor neurons. In TARDBP-related ALS, TDP-43 positive aggregates are made up of phosphorylated, ubiquitinated C-terminal fragments of the protein, and are typically cytosolic. Furthermore, a decrease in normal nuclear TDP-43 staining is often seen in these cells [Neumann et al 2006, Davidson et al 2007]. How the disease-associated mutations in TARDBP influence TDP-43 function, proteolysis, and aggregation is unknown. Notably, TDP-43 inclusions are not present in humans with SOD1-related ALS or in mouse models that overexpress disease mutant SOD1, suggesting that SOD1-related ALS may have a different underlying pathophysiology than TARDBP-related ALS [Mackenzie et al 2007, Robertson et al 2007]. Furthermore, TDP-43 positive inclusions are not specific to ALS, and are found in other neurodegenerative diseases [Freeman et al 2008, Uryu et al 2008, Arai et al 2009] as well as several diseases of muscle [Weihl et al 2008, Küsters et al 2009, Olivé et al 2009].