Clinical characteristics.

In this GeneReview, TARDBP amyotrophic lateral sclerosis-frontotemporal dementia (TARDBP-ALS-FTD) refers to the spectrum of phenotypes caused by pathogenic variants in TARDBP, the gene encoding TDP-43. The phenotypic spectrum encompasses pure (i.e., without other neurologic findings) amyotrophic lateral sclerosis (ALS; most common), pure (i.e., without other neurologic findings) frontotemporal dementia (FTD; rare), a combination of ALS and FTD, and atypical neurologic phenotypes (very rare). Individuals with the same TARDBP pathogenic variant (even within the same family) may have clinical features that vary in both type and severity. Common manifestations are dysarthria and dysphagia; less common manifestations can include parkinsonism, cognitive deterioration, and behavioral and psychological manifestations of dementia. Life expectancy for TARDBP-ALS is highly variable and mainly associated with an individual's clinical features; overall disease duration averages three to five years. For TARDBP-FTD, disease duration averages one to 16 years.

Diagnosis/testing.

The diagnosis of TARDBP-ALS-FTD is established in a proband with suggestive findings and most commonly a heterozygous pathogenic (or likely pathogenic) variant in TARDBP identified by molecular genetic testing. Rarely, homozygous pathogenic (or likely pathogenic) variants in TARDBP have been reported.

Management.

Treatment of manifestations: There is no cure for TARDBP-ALS-FTD. Individuals benefit from multidisciplinary supportive care to improve quality of life, maximize function, and reduce complications. This can include care by specialists in neurology, physiotherapy, occupational therapy, speech-language therapy, nutrition, respiratory therapy, pulmonology, psychology, social work, genetic counselling, palliative care, and special nursing.

Surveillance: Frequent monitoring of existing manifestations, the individual's response to supportive care, and the emergence of new manifestations by the treating clinicians is recommended.

Genetic counseling.

TARDBP-ALS-FTD is inherited in an autosomal dominant manner. About half of individuals diagnosed with TARDBP-ALS-FTD have an affected parent. Each child of an individual with TARDBP-ALS-FTD has a 50% chance of inheriting the TARDBP pathogenic variant. Once a TARDBP pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal and preimplantation genetic testing for the presence of the TARDBP pathogenic variant are possible. (Note: Because the clinical presentation of TARDBP-ALS-FTD may differ among heterozygous family members, accurate prediction of future possible clinical manifestations in an individual found to have a familial TARDBP pathogenic variant is not possible.)

Suggestive Findings

TARDBP-ALS-FTD should be suspected in probands with the following clinical and neuroimaging findings and family history.

Clinical findings

• Age at onset ranges from 22 to 80 years, with a mean of 53 ± 10-12 years [Newell et al 2019, Sprovieri et al 2019].
• Amyotrophic lateral sclerosis (ALS), the most common clinical presentation of TARDBP-ALS-FTD, is characterized by progressive degeneration of both upper and lower motor neurons resulting in muscle weakness and paralysis.
• Frontotemporal dementia (FTD), the second most common presentation, includes behavior and/or language dysfunction. Of the three FTD clinical syndromes, behavioral FTD (bvFTD) is more widespread than the two language variants, semantic variant PPA (svPPA) and nonfluent variant PPA (nfvPPA), which are collectively identified as primary progressive aphasia (PPA) [Jo et al 2020].

Brain MRI

• ALS. Although conventional structural MRI scans are usually normal in individuals with the ALS phenotype, corticospinal tract high signal intensity may be seen. Of note, research studies demonstrate widespread volumetric changes beyond the frontotemporal and motor regions.
• FTD. Although frontotemporal atrophy is prominent, these findings are general features of ALS/FTD of all causes. There are no systematic MRI studies of TARDBP-ALS-FTD.

Family history. Because TARDBP-ALS-FTD can be associated with significant intrafamilial clinical variability, a thorough family history should be taken with a high index of suspicion for both motor and psychiatric signs regardless of the presenting features in the proband. The family history may be positive and consistent with autosomal dominant inheritance (e.g., males and females in multiple generations with ALS and/or FTD) or the family history may be negative (i.e., the proband represents a simplex case). Absence of a known family history does not preclude the diagnosis.

Note: Simplex cases (i.e., a single occurrence of the disorder in a family) are sometimes referred to as "sporadic cases"; however, because the term "sporadic" can imply a non-recurring (non-genetic) cause, the term "simplex" is preferred.

Establishing the Diagnosis

The diagnosis of TARDBP-ALS-FTD is established in a proband with suggestive findings and most commonly a heterozygous pathogenic (or likely pathogenic) variant in TARDBP identified by molecular genetic testing (see Table 1). Rarely, homozygous pathogenic (or likely pathogenic) variants in TARDBP have been reported (see Molecular Genetics, TARDBP-specific laboratory technical considerations).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Because TARDBP-ALS-FTD is clinically indistinguishable from ALS/FTD due to other causes, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of TARDBP, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An ALS multigene panel that includes TARDBP and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. (5) Because some ALS panels may be limited to the most frequently associated genes (e.g., C9orf72 and SOD1 [see ALS Overview]), care needs to be taken to choose a multigene panel that includes TARDBP.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is increasingly performed.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Most individuals with TARDBP-related amyotrophic lateral sclerosis-frontotemporal dementia (TARDBP-ALS-FTD) present with manifestations of amyotrophic lateral sclerosis (ALS) with upper and lower motor neuron disease (MND). Rarely, affected individuals present with pure (i.e., without other neurologic findings) frontotemporal dementia (FTD), a combination of ALS and FTD, or an atypical neurologic phenotype such as FTD with supranuclear palsy. Additional manifestations within the TARDBP-ALS-FTD phenotypic spectrum may appear during the disease course [Van Deerlin et al 2008, Yokoseki et al 2008] (see Table 2).

Of note, the clinical presentation of TARDBP-ALS-FTD may differ between and within families, causing an unpredictable pattern and age of onset of clinical manifestations.

ALS. The entire clinical spectrum of ALS (which includes abnormal muscle tone and tendon reflexes, fasciculations, muscle cramps, and gait disturbances) may be present. In one study, spinal onset (involving limb muscles) occurred in 62.5% of affected individuals, bulbar onset (including involvement of swallowing and speech) in 10%, and both bulbar and spinal onset in ~27% [Lattante et al 2013]. Some early cognitive impairment may be present even in individuals previously diagnosed with pure ALS [Gregory et al 2020].

FTD. The three main FTD clinical syndromes are behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent/agrammatic variant primary progressive aphasia (nfvPPA). Studies of the rare instances of pure TARDBP-FTD show that affected individuals usually present with bvFTD with common behavioral features such as irritability, repetitive behavior, aggressiveness, and delusions that worsen progressively. These behavioral features can overlap with executive dysfunction, memory deficits, and changes in eating habits. Some individuals also manifest primary progressive aphasia (PPA) with language impairment resembling semantic dementia [Floris et al 2015].

Parkinsonism. Heterozygous TARDBP pathogenic variants have also been associated with parkinsonism. The manifestations include Parkinson-like weakness in the legs, overlapping with bvFTD, hallucinations, REM sleep behavior disorder, and mild cognitive impairment [Rayaprolu et al 2013].

Life expectancy for TARDBP-ALS is highly variable and mainly associated with an individual's clinical features. Overall disease duration averages three to five years from onset with a steady rate of decline.

For TARDBP-FTD, disease duration averages one to 16 years from onset, depending on the cohort [Floris et al 2015]. As expected, survival in FTD is markedly compromised when ALS manifestations become apparent [Geser et al 2009].

Genotype-Phenotype Correlations

Since most TARDBP pathogenic variants have incomplete age-related penetrance, identifying genotype-phenotype correlations becomes difficult. No clear genotype-phenotype correlations have been identified.

However, of note:

• Three TARDBP variants occurring at lysine residues, c.527A>T (p.Lys176Ile) [Chen et al 2021], c.541A>G (p.Lys181Glu) [Chen et al 2019], and c.787A>G (p. Lys263Glu) [Kovacs et al 2009], have been associated with FTD phenotypes including cognitive deficits and personality and behavioral changes such as apathy and lack of motivation (see Table 6). Nevertheless, these associations cannot be made conclusively without additional reports.
• Phenotypic manifestations of TARDBP variants can vary by ethnicity [Acosta-Uribe et al 2022].
• In a Sardinian population with FTD caused by TARDBP variant c.1144G>A (p.Ala382Thr), most affected individuals had a bvFTD phenotype with temporal lobe atrophy [Floris et al 2015].

Penetrance

While there is intra- and interfamilial variability in the age of onset and clinical presentation, the pathogenicity of missense variants shows high penetrance and males and females are similarly affected [Hardiman et al 2022].

Prevalence

Dedicated online databases provide detailed information on geographic prevalence of TARDBP pathogenic variants [Pinto et al 2011, Cruts et al 2012, Abel et al 2013].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TARDBP-ALS-FTD, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for TARDBP-ALS-FTD.

Individuals with TARDBP-ALS-FTD benefit from supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by a neurologist, physiotherapist, occupational therapist, speech-language therapist, dietitian, respiratory therapist, pulmonologist, psychologist, social worker, genetic counsellor, palliative care physician, and specially trained nurses (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, see Table 5 for recommended evaluations.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Incidences of ALS complicating pregnancy are rare, since the disease shows a low prevalence in women of reproductive age. Pregnancy of women with ALS is largely complicated by impaired respiratory function due to underlying weakness of the diaphragm and costal muscles and the increased respiratory and weight-bearing demands of pregnancy [Lupo et al 1993]. However, the influence of pregnancy on ALS disease progression itself remains speculative.

Maternal ALS is not particularly associated with poorer neonatal outcomes and does not appear to cause obstetric complications. However, the method and timing of delivery may be influenced by the severity of the disease. Although natural delivery is possible because ALS does not affect the motor and sensory nerves of the uterus [Chiò et al 2003], cæsarean delivery may be required due to restricted mobility and the increased respiratory demands of labor [Sarafov et al 2009, Pathiraja & Ranaraja 2020].

Riluzole can safely be used during pregnancy, although its effects on fetal growth remain unclear. Low birth weight has previously been reported when used during pregnancy [Scalco et al 2012].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Unlike SOD1-ALS-FTD (see ALS Overview), for which tofersen has recently been approved by the FDA, there are no approved antisense oligonucleotide therapies for TARDBP-ALS-FTD.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

TARDBP-related amyotrophic lateral sclerosis-frontotemporal dementia (TARDBP-ALS-FTD) is inherited in an autosomal dominant manner.

Note: Rarely, homozygous pathogenic (or likely pathogenic) variants in TARDBP have been reported (see Molecular Genetics, TARDBP-specific laboratory technical considerations). Genetic counseling for individuals homozygous for a TARDBP pathogenic and their family members is not discussed in this chapter.

Risk to Family Members (Autosomal Dominant Inheritance)

Parents of a proband

• About half of individuals diagnosed with TARDBP-ALS-FTD have an affected parent.
• About half of individuals diagnosed with TARDBP-ALS-FTD represent simplex cases (i.e., the only family member known to have TARDBP-ALS-FTD.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• The family history of some individuals diagnosed with TARDBP-ALS-FTD may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The clinical presentation of TARDBP-ALS-FTD may differ among family members who are heterozygous for the same pathogenic variant, causing an unpredictable pattern and age of onset of clinical manifestations (see Penetrance).
• If the TARDBP pathogenic variant identified in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
• If both parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for TARDBP-ALS-FTD because of the possibility of age-related penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with TARDBP-ALS-FTD has a 50% chance of inheriting the TARDBP pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the TARDBP pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

Predictive testing (i.e., testing of asymptomatic at-risk individuals)

• Predictive testing for at-risk relatives is possible once the TARDBP pathogenic variant has been identified in an affected family member.
• Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Predictive testing may facilitate recruitment into future gene-specific clinical trials (see Therapies Under Investigation).

Predictive testing in minors (i.e., testing of asymptomatic at-risk individuals younger than age 18 years)

• For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.
• For more information, see the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

In a family with an established diagnosis of TARDBP-ALS-FTD, it is appropriate to consider testing of symptomatic individuals regardless of age.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

Prenatal Testing and Preimplantation Genetic Testing

Once the TARDBP pathogenic variant or, rarely, pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Accurate prediction of future possible clinical manifestations in a fetus found to have a familial TARDBP pathogenic variant is not possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. For more information, see the National Society of Genetic Counselors position statement on prenatal testing in adult-onset conditions.

Molecular Pathogenesis

TARDBP encodes the TAR DNA-binding protein 43 (TDP-43). As a ubiquitously expressed protein, TDP-43 regulates many aspects of RNA metabolism, including alternative splicing, microRNA processing, RNA transport, and local translation. Although predominantly nuclear, TDP-43 shuttles into the cytoplasm. A prominent feature of TARDBP-related amyotrophic lateral sclerosis-frontotemporal dementia (TARDBP-ALS-FTD) is the loss of TDP-43 from the nucleus and its deposition in the cytoplasm, where it forms hyperphosphorylated and ubiquitinated aggregates [Arai et al 2006, Neumann et al 2006]. This abnormal redistribution of TDP-43 suggests a loss of normal nuclear function and a toxic gain of function in the cytoplasm. These proposed disease mechanisms are not mutually exclusive and may occur at the same time.

Most pathogenic variants are found in exon 6, which encodes for the glycine-rich C-terminal region of TDP-43 [LOVD].

Mechanism of disease causation. Importantly, TDP-43 regulates its own expression by binding to its transcript and triggering alternative splicing of intron 7 within its 3' untranslated region (UTR), leading to the destruction of its mRNA. The existence of 3' UTR variants associated with amyotrophic lateral sclerosis, and the discovery that one of these variants leads to increased transcript expression, suggests that perturbed autoregulation may result in disease [Gitcho et al 2009]. Recent findings point to the importance of TDP-43 liquid-liquid phase separation in mediating autoregulation, as disease-associated variants may lead to defects in self-regulation by modulating TDP-43 condensation properties [Hallegger et al 2021, Koehler et al 2022].

TARDBP-specific laboratory technical considerations. Two variants in TARDBP (c.881G>T; p.Gly294Val and c.1144G>A; p.Ala382Thr) have been reported in the homozygous state in individuals with ALS-FTD [Borghero et al 2011, Mosca et al 2012, Corrado et al 2020]. Therefore, these variants can cause disease when heterozygous (most common) or homozygous.

Author History

Robert H Baloh, MD, PhD; Washington University School of Medicine (2009–2022)
Leon Crowley, MSc (2022–present)
Matthew M Harms, MD; Washington University School of Medicine (2009–2022)
Vaishnavi Manohar, MTech (2022–present)
Timothy M Miller, MD, PhD; Washington University School of Medicine (2009–2022)
Jemeen Sreedharan, BSc, MBBS, MRCP, PhD (2022–present)

Revision History

• 5 January 2023 (bp) Comprehensive update posted live
• 12 March 2015 (me) Comprehensive update posted live
• 28 May 2009 (cd) Revision: prenatal testing available
• 23 April 2009 (et) Review posted live
• 14 November 2008 (rhb) Original submission

Literature Cited

• Abel O, Powell JF, Andersen PM, Al-Chalabi A. Credibility analysis of putative disease-causing genes using bioinformatics. PLoS One. 2013;8:e64899. [PMC free article: PMC3674010] [PubMed: 23755159]
• Acosta-Uribe J, Aguillón D, Cochran JN, Giraldo M, Madrigal L, Killingsworth BW, Singhal R, Labib S, Alzate D, Velilla L, Moreno S, García GP, Saldarriaga A, Piedrahita F, Hincapié L, López HE, Perumal N, Morelo L, Vallejo D, Solano JM, Reiman EM, Surace EI, Itzcovich T, Allegri R, Sánchez-Valle R, Villegas-Lanau A, White CL 3rd, Matallana D, Myers RM, Browning SR, Lopera F, Kosik KS. A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects. Genome Med. 2022;14:27. [PMC free article: PMC8902761] [PubMed: 35260199]
• Andersen PM, Abrahams S, Borasio GD, de Carvalho M, Chio A, Van Damme P, Hardiman O, Kollewe K, Morrison KE, Petri S, Pradat PF, Silani V, Tomik B, Wasner M, Weber M, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)--revised report of an EFNS task force. Eur J Neurol. 2012;19:360–75. [PubMed: 21914052]
• Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006;351:602–11. [PubMed: 17084815]
• Borghero G, Floris G, Cannas A, Marrosu MG, Murru MR, Costantino E, Parish LD, Pugliatti M, Ticca A, Traynor BJ, Calvo A, Cammarosano S, Moglia C, Cistaro A, Brunetti M, Restagno G, Chiò A. A patient carrying a homozygous p.A382T TARDBP missense mutation shows a syndrome including ALS, extrapyramidal symptoms, and FTD. Neurobiol Aging. 2011;32:2327.e1–5. [PMC free article: PMC3192246] [PubMed: 21803454]
• Borroni B, Bonvicini C, Alberici A, Buratti E, Agosti C, Archetti S, Papetti A, Stuani C, Di Luca M, Gennarelli M, Padovani A. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat. 2009;30:E974–83. [PubMed: 19655382]
• Chen HJ, Topp SD, Hui HS, Zacco E, Katarya M, McLoughlin C, King A, Smith BN, Troakes C, Pastore A, Shaw CE. RRM adjacent TARDBP mutations disrupt RNA binding and enhance TDP-43 proteinopathy. Brain. 2019;142:3753–70. [PMC free article: PMC6885686] [PubMed: 31605140]
• Chen S, Zhou RL, Zhang W, Che CH, Feng SY, Huang HP, Liu CY, Zou ZY. Novel TARDBP missense mutation caused familial amyotrophic lateral sclerosis with frontotemporal dementia and parkinsonism. Neurobiol Aging. 2021;107:168–73. [PubMed: 34175147]
• Chiò A, Calvo A, Di Vito N, Vercellino M, Ghiglione P, Terreni A, Mutani R, Mora G. Amyotrophic lateral sclerosis associated with pregnancy: report of four new cases and review of the literature. Amyotroph Lateral Scler Other Motor Neuron Disord. 2003;4:45–8. [PubMed: 12745618]
• Cooper-Knock J, Julian TH, Feneberg E, Highley JR, Sidra M, Turner MR, Talbot K, Ansorge O, Allen SP, Moll T, Shelkovnikova T, Castelli L, Hautbergue GM, Hewitt C, Kirby J, Wharton SB, Mead RJ, Shaw PJ. Atypical TDP-43 protein expression in an ALS pedigree carrying a p.Y374X truncation mutation in TARDBP. Brain Pathol. 2022. Epub ahead of print. [PMC free article: PMC9836368] [PubMed: 35871544]
• Corcia P, Camu W, Brulard C, Marouillat S, Couratier P, Camdessanché JP, Cintas P, Verschueren A, Soriani MH, Desnuelle C, Fleury MC, Guy N, Cassereau J, Viader F, Pittion-Vouyovitch S, Danel V, Kolev I, Le Masson G, Beltran S, Salachas F, Bernard E, Pradat PF, Blasco H, Lanznaster D, Hergesheimer R, Laumonnier F, Andres CR, Meininger V, Vourc'h P. Effect of familial clustering in the genetic screening of 235 French ALS families. J Neurol Neurosurg Psychiatry. 2021;92:479–84. [PubMed: 33408239]
• Corrado L, Pensato V, Croce R, Di Pierro A, Mellone S, Dalla Bella E, Salsano E, Paraboschi EM, Giordano M, Saraceno M, Mazzini L, Gellera C, D'Alfonso S. The first case of the TARDBP p.G294V mutation in a homozygous state: is a single pathogenic allele sufficient to cause ALS? Amyotroph Lateral Scler Frontotemporal Degener. 2020;21:273–9. [PubMed: 31852254]
• Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat. 2012;33:1340–4. [PMC free article: PMC3465795] [PubMed: 22581678]
• Devenney E, Hornberger M, Irish M, Mioshi E, Burrell J, Tan R, Kiernan MC, Hodges JR. Frontotemporal dementia associated with the C9ORF72 mutation: a unique clinical profile. JAMA Neurol. 2014;71:331–9. [PubMed: 24445580]
• Floris G, Borghero G, Cannas A, Di Stefano F, Murru MR, Corongiu D, Cuccu S, Tranquilli S, Cherchi MV, Serra A, Loi G, Marrosu MG, Chiò A, Marrosu F. Clinical phenotypes and radiological findings in frontotemporal dementia related to TARDBP mutations. J Neurol. 2015;262:375–84. [PubMed: 25408367]
• Floris G, Borghero G, Di Stefano F, Melis R, Puddu R, Fadda L, Murru MR, Corongiu D, Cuccu S, Tranquilli S, Cannas A, Marrosu MG, Chiò A, Marrosu F. Phenotypic variability related to C9orf72 mutation in a large Sardinian kindred. Amyotroph Lateral Scler Frontotemporal Degener. 2016;17:245–8. [PubMed: 26575405]
• Geser F, Martinez-Lage M, Robinson J, Uryu K, Neumann M, Brandmeir NJ, Xie SX, Kwong LK, Elman L, McCluskey L, Clark CM, Malunda J, Miller BL, Zimmerman EA, Qian J, Van Deerlin V, Grossman M, Lee VM, Trojanowski JQ. Clinical and pathological continuum of multisystem TDP-43 proteinopathies. Arch Neurol. 2009;66:180–9. [PMC free article: PMC2774117] [PubMed: 19204154]
• Gitcho MA, Bigio EH, Mishra M, Johnson N, Weintraub S, Mesulam M, Rademakers R, Chakraverty S, Cruchaga C, Morris JC, Goate AM, Cairns NJ. TARDBP 3'-UTR variant in autopsy-confirmed frontotemporal lobar degeneration with TDP-43 proteinopathy. Acta Neuropathol. 2009;118:633–45. [PMC free article: PMC2783457] [PubMed: 19618195]
• Gregory JM, McDade K, Bak TH, Pal S, Chandran S, Smith C, Abrahams S. Executive, language and fluency dysfunction are markers of localised TDP-43 cerebral pathology in non-demented ALS. J Neurol Neurosurg Psychiatry. 2020;91:149–57. [PMC free article: PMC6996101] [PubMed: 31515300]
• Hallegger M, Chakrabarti AM, Lee FCY, Lee BL, Amalietti AG, Odeh HM, Copley KE, Rubien JD, Portz B, Kuret K, Huppertz I, Rau F, Patani R, Fawzi NL, Shorter J, Luscombe NM, Ule J. TDP-43 condensation properties specify its RNA-binding and regulatory repertoire. Cell. 2021;184:4680–96.e22. [PMC free article: PMC8445024] [PubMed: 34380047]
• Hardiman O, Heverin M, Rooney J, Lillo P, Godoy G, Sáez D, Valenzuela D, Hughes R, Perna A, Ketzoian CN, Vazquez C, Gutierrez Gil J, Arias Morales A, Lara Fernandez G, Zaldivar T, Horton K, Mehta P, Logroscino G. The Latin American Epidemiology Network for ALS (Laenals). Amyotroph Lateral Scler Frontotemporal Degener. 2022;23:372–7. [PubMed: 35060421]
• Jo M, Lee S, Jeon YM, Kim S, Kwon Y, Kim HJ. The role of TDP-43 propagation in neurodegenerative diseases: integrating insights from clinical and experimental studies. Exp Mol Med. 2020;52:1652–62. [PMC free article: PMC8080625] [PubMed: 33051572]
• Koehler LC, Grese ZR, Bastos ACS, Mamede LD, Heyduk T, Ayala YM. TDP-43 Oligomerization and phase separation properties are necessary for autoregulation. Front Neurosci. 2022;16:818655. [PMC free article: PMC9048411] [PubMed: 35495061]
• Kovacs GG, Murrell JR, Horvath S, Haraszti L, Majtenyi K, Molnar MJ, Budka H, Ghetti B, Spina S. TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea. Mov Disord. 2009;24:1843–7. [PubMed: 19609911]
• Lattante S, Rouleau GA, Kabashi E. TARDBP and FUS mutations associated with amyotrophic lateral sclerosis: summary and update. Hum Mutat. 2013;34:812–26. [PubMed: 23559573]
• Lupo VR, Rusterholz JH, Reichert JA, Hanson AS. Amyotrophic lateral sclerosis in pregnancy. Obstet Gynecol. 1993;82:682–5. [PubMed: 8378011]
• Mackenzie IR, Rademakers R, Neumann M. TDP-43 and FUS in amyotrophic lateral sclerosis and frontotemporal dementia. Lancet Neurol. 2010;9:995–1007. [PubMed: 20864052]
• Morgan S, Shatunov A, Sproviero W, Jones AR, Shoai M, Hughes D, Al Khleifat A, Malaspina A, Morrison KE, Shaw PJ, Shaw CE, Sidle K, Orrell RW, Fratta P, Hardy J, Pittman A, Al-Chalabi A. A comprehensive analysis of rare genetic variation in amyotrophic lateral sclerosis in the UK. Brain. 2017;140:1611–18. [PMC free article: PMC5445258] [PubMed: 28430856]
• Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. 2020;27:1918–29. [PMC free article: PMC7540334] [PubMed: 32526057]
• Mosca L, Lunetta C, Tarlarini C, Avemaria F, Maestri E, Melazzini M, Corbo M, Penco S. Wide phenotypic spectrum of the TARDBP gene: homozygosity of A382T mutation in a patient presenting with amyotrophic lateral sclerosis, Parkinson's disease, and frontotemporal lobar degeneration, and in neurologically healthy subject. Neurobiol Aging. 2012;33:1846.e1–4. [PubMed: 22398199]
• Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130–3. [PubMed: 17023659]
• Newell K, Paron F, Mompean M, Murrell J, Salis E, Stuani C, Pattee G, Romano M, Laurents D, Ghetti B, Buratti E. Dysregulation of TDP-43 intracellular localization and early onset ALS are associated with a TARDBP S375G variant. Brain Pathol. 2019;29:397–413. [PMC free article: PMC6875182] [PubMed: 30461104]
• Oskarsson B, Gendron TF, Staff NP. Amyotrophic lateral sclerosis: an update for 2018. Mayo Clin Proc. 2018;93:1617–28. [PubMed: 30401437]
• Pang SY, Hsu JS, Teo KC, Li Y, Kung MHW, Cheah KSE, Chan D, Cheung KMC, Li M, Sham PC, Ho SL. Burden of rare variants in ALS genes influences survival in familial and sporadic ALS. Neurobiol Aging. 2017;58:238.e9–238.e15. [PubMed: 28709720]
• Pathiraja PDM, Ranaraja SK. A successful pregnancy with amyotrophic lateral sclerosis. Case Rep Obstet Gynecol. 2020;2020:1247178. [PMC free article: PMC7071795] [PubMed: 32190393]
• Piguet O, Kumfor F, Hodges J. Diagnosing, monitoring and managing behavioural variant frontotemporal dementia. Med J Aust. 2017;207:303–8. [PubMed: 28954617]
• Pinto S, Vlahoviček K, Buratti E. PRO-MINE: A bioinformatics repository and analytical tool for TARDBP mutations. Hum Mutat. 2011;32:E1948–58. [PMC free article: PMC3038324] [PubMed: 21031599]
• Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
• Rayaprolu S, Fujioka S, Traynor S, Soto-Ortolaza AI, Petrucelli L, Dickson DW, Rademakers R, Boylan KB, Graff-Radford NR, Uitti RJ, Wszolek ZK, Ross OA. TARDBP mutations in Parkinson's disease. Parkinsonism Relat Disord. 2013;19:312–5. [PMC free article: PMC3582838] [PubMed: 23231971]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Sarafov S, Doitchinova M, Karagiozova Z, Slancheva B, Dengler R, Petri S, Kollewe K. Two consecutive pregnancies in early and late stage of amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2009;10:483–6. [PubMed: 19922145]
• Scalco RS, Vieira MC, da Cunha Filho EV, Lago EG, da Silva IG, Becker J. Amyotrophic lateral sclerosis and riluzole use during pregnancy: a case report. Amyotroph Lateral Scler. 2012;13:471–2. [PubMed: 22670879]
• Siuda J, Fujioka S, Wszolek ZK. Parkinsonian syndrome in familial frontotemporal dementia. Parkinsonism Relat Disord. 2014;20:957–64. [PMC free article: PMC4160731] [PubMed: 24998994]
• Sprovieri T, Ungaro C, Perrone B, Naimo GD, Spataro R, Cavallaro S, La Bella V, Conforti FL. A novel S379A TARDBP mutation associated to late-onset sporadic ALS. Neurol Sci. 2019;40:2111–8. [PubMed: 31165305]
• Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319:1668–72. [PMC free article: PMC7116650] [PubMed: 18309045]
• Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
• Sun CS, Wang CY, Chen BP, He RY, Liu GC, Wang CH, Chen W, Chern Y, Huang JJ. The influence of pathological mutations and proline substitutions in TDP-43 glycine-rich peptides on its amyloid properties and cellular toxicity. PLoS One. 2014;9:e103644. [PMC free article: PMC4121164] [PubMed: 25090004]
• Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7:409–16. [PMC free article: PMC3546119] [PubMed: 18396105]
• Vicente-Pascual M, Rossi M, Gámez J, Lladó A, Valls J, Grau-Rivera O, Ávila Polo R, Llorens F, Zerr I, Ferrer I, Nos C, Parchi P, Sánchez-Valle R, Gelpí E. Variably protease-sensitive prionopathy presenting within ALS/FTD spectrum. Ann Clin Transl Neurol. 2018;5:1297–302. [PMC free article: PMC6186932] [PubMed: 30349865]
• Xu F, Huang S, Li XY, Lin J, Feng X, Xie S, Wang Z, Li X, Zhu J, Lai H, Xu Y, Huang X, Yao X, Wang C. Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in southern China. BMC Med Genomics. 2022;15:173. [PMC free article: PMC9356425] [PubMed: 35932023]
• Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A, Okamoto K, Nishizawa M, Takahashi H, Onodera O. TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008;63:538–42. [PubMed: 18438952]