Tardbp-Related Amyotrophic Lateral Sclerosis

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2021-01-18
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Summary

Clinical characteristics.

TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is characterized by upper motor neuron (UMN) and lower motor neuron (LMN) disease that appears indistinguishable from ALS of other known and unknown causes based on 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. UMN manifestations can include stiffness, spasticity, hyperreflexia, and pseudobulbar affect; LMN manifestations often include weakness accompanied by muscle atrophy, fasciculations, and cramping. Limb onset occurs in 80% and bulbar onset in 20%. Affected individuals typically succumb to respiratory failure when phrenic and thoracic motor neurons become severely involved.

Diagnosis/testing.

The diagnosis of ALS is established by clinical examination, neurophysiologic testing, and neuroimaging. TARDBP is the only gene associated with TARDBP-related ALS.

Management.

Treatment of manifestations: 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; it is reasonable to consider use of riluzole, the only FDA-approved treatment for any type of ALS.

Prevention of secondary complications: Percutaneous gastrostomy can be used to maintain adequate caloric intake in persons with significant bulbar involvement; appropriate bracing and stretching can minimize contractures; noninvasive ventilation can be initiated when appropriate.

Surveillance: At clinic visits: monitoring of ventilatory function and screening for depression.

Agents/circumstances to avoid: Long-term use of minocycline; excessive exercise to the point of inducing fatigue.

Genetic counseling.

TARDBP-related ALS is inherited in an autosomal dominant manner. The proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with TARDBP-related ALS has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for TARDBP-related ALS is possible if the pathogenic variant has been identified in the family.

Diagnosis

A diagnosis of TARDBP-related amyotrophic lateral sclerosis (TARDBP-related ALS) is established when a TARDBP pathogenic variant 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 affect
  • LMN 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.

See Amyotrophic Lateral Sclerosis Overview for a more detailed description of these features.

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 pathogenic variants 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]. If frontotemporal dementia is also present, atrophy of the frontal and temporal lobes may be present [Floris et al 2015]. 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 conditions with overlapping features 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 of unknown cause [Steinacker et al 2008, Kasai et al 2009]. It has only been examined in a single individual with TARDBP-related ALS, and this individual had substantially higher levels than individuals with sporadic ALS [Nozaki et al 2010].

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 (including TARBP-associated 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]. However, TDP-43-positive inclusions are not specific for ALS and 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].

Molecular Genetic Testing

Gene. TARDBP is the only gene in which pathogenic variants are known to cause TARDBP-related ALS.

Table 1.

Molecular Genetic Testing Used in TARDBP-Related Amyotrophic Lateral Sclerosis

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by This Method
TARDBPSequence analysis 2Approaches 100% 3
Deletion/duplication analysis 4See footnote 5
1.

See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

2.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3.

Because TARDBP-related ALS is defined by the presence of a pathogenic variant in TARDBP, and because variant types that are not detected by sequence analysis (e.g., exon or whole-gene deletions) have not been reported, the variant detection rate for TARDBP using sequence analysis approaches 100%.

4.

Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5.

No large deletions or insertions have been reported. Screening for these types of variants has been reported in 714 patients using rt-PCR or multiplexed amplicon quantification (MAQ) [Guerreiro et al 2008, Rutherford et al 2008, Bäumer et al 2009, Benajiba et al 2009, Gijselinck et al 2009]. Since the proposed mechanism that leads to TARDBP-related ALS is gain-of-function of TARDBP, it is unlikely that copy number variants in TARDBP will comprise a significant number of cases.

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 resulting from 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 pathogenic variant 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 pathogenic variant is lower.
    Note: (1) To date, all reported pedigrees with TARDBP-related ALS show autosomal dominant inheritance; (2) Several genetic causes of ALS are more common than TARDBP-related ALS (see below).

Familial ALS (FALS) (i.e., presence of at least two affected family members)

Single-gene testing. One genetic testing strategy is serial single-gene molecular genetic testing based on the order in which pathogenic variants most commonly occur.

  • In most white populations, molecular genetic testing in the following order is recommended:
    • Testing for an expansion of the hexanucleotide repeat in C9ORF72 (accounting for ~40%-50% of FALS) should be done first.
    • If no expansion is identified in C9ORF72, molecular genetic testing of SOD1 (accounting for ~20% of FALS) should be considered next.
    • If molecular genetic testing of C9ORF72 and SOD1 does not reveal a pathogenic variant, molecular genetic testing of TARDBP and/or FUS (together accounting for <5% of cases) should be considered next.
  • In individuals of Asian or African background, molecular genetic testing of SOD1 should be considered first.
  • In Sardinia, where C9ORF72 expansions and TARDBP pathogenic variants account for most cases and at times coexist in the same family, simultaneous molecular genetic testing of both genes could be considered.

Multigene panel. An alternative genetic testing strategy is use of a multigene panel that includes C9ORF72, SOD1, TARDBP, and other genes of interest (see Differential Diagnosis). 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

More comprehensive genomic testing (when available) including exome sequencing, genome sequencing and mitochondrial sequencing may be considered if single-gene testing (and/or use of a multigene panel) fails to confirm a diagnosis in an individual with features of ALS. For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Other. 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.

Clinical Characteristics

Clinical Description

More than 200 individuals with TARDBP-related ALS have been described in the literature. The spectrum of clinical disease has been defined by a recent analysis of all published reports of individuals with a TARDBP pathogenic variant, noting substantial differences between Asian and non-Asian individuals [Corcia et al 2012].

The average age of symptom onset is 53.5 ± 12.3 years (mean ± SD), which is similar to affected individuals with SOD1 pathogenic variants but substantially earlier than those with simplex ALS and familial ALS without an identified pathogenic variant.

Most individuals with TARDBP-related ALS have both UMN and LMN involvement and during disease course will meet El Escorial criteria for ALS [Brooks et al 2000]. Although predominantly LMN involvement is common [Gitcho et al 2008, Kabashi et al 2008, Kühnlein et al 2008, Corrado et al 2009], no individuals with pure UMN involvement (i.e. primary lateral sclerosis) have been reported.

More than half of non-Asian individuals with a TARDBP pathogenic variant have first symptoms in the upper extremities, a rate that is double that found in other forms of the disease. However, bulbar onset appears to predominate in Asian individuals [Corcia et al 2012] and intra- and interfamilial variability in the site of onset is observed even with the same pathogenic variant (see Genotype-Phenotype Correlations).

As with other forms of ALS, individuals with TARDBP-related ALS die of respiratory failure when phrenic and thoracic motor neurons become severely involved. However, the median disease survival in non-Asian individuals with a TARDBP pathogenic variant is 62 months, which is significantly longer than the survival of individuals without a known TARDBP pathogenic variant, either with simplex ALS (35 months) or familial ALS (31 months). Interestingly, Asian individuals with a TARDBP pathogenic variant appear to have even slower rates of progression of disease, with median disease duration of 108 months [Corcia et al 2012]. Disease duration is also influenced by which pathogenic variant is present, and although the median survival is favorable, progression to death within a year is not uncommon (see Genotype-Phenotype Correlations).

Although these trends are visible in aggregated cohorts of affected individuals, the range of age at onset, pattern of symptoms at onset, and disease duration are quite broad and substantially overlap with all other causes of ALS. As a result, phenotypic features do little to inform whether genetic testing should be pursued.

Genotype-Phenotype Correlations

Correlations between specific pathogenic variants and clinical phenotype are available for only the most commonly reported pathogenic variants in TARDBP. For the vast majority of pathogenic variants, the numbers are too few to draw reliable conclusions. However:

  • As predicted by early reports, the p.Gly298Ser pathogenic variant demonstrates an earlier age of onset (mean 50.7 years) and the most rapid rate of progression of disease (mean 27 months) [Van Deerlin et al 2008, Corcia et al 2012].
  • The p.Ala315Thr pathogenic variant was initially reported in two families with a slowly progressive limb-only LMN-predominant phenotype [Gitcho et al 2008, Kabashi et al 2008]. Large groups of individuals with this pathogenic variant now confirm a much later age at onset (mean 66 years) and much longer survival (mean 110 months) [Corcia et al 2012].
  • Other more common pathogenic variants including p.Ala382Thr, p.Met337Val, and p.Gly348Cys are intermediate in their average ages at onset and survival times [Corcia et al 2012].
  • Within families, no genotype-phenotype correlations have been made with regard to site of onset, with both limb onset and bulbar onset being observed in the same family.
  • Disparate sites of onset were seen in unrelated persons with the same pathogenic variant, including the following: p.Gly287Ser [Corrado et al 2009, Kabashi et al 2008], p.Gly294Val [Corrado et al 2009, Del Bo et al 2009], and p.Ala382Thr [Kabashi et al 2008].

Penetrance

Like pathogenic variants in other ALS-related genes (e.g., SOD1), penetrance is clearly incomplete. This is evident from the number of individuals with apparently simplex ALS who have a TARDBP pathogenic variant, which may have been inherited from an ostensibly asymptomatic (or undiagnosed) parent. However, accurate estimates are difficult to achieve for the following reasons:

  • Few unaffected individuals in families with TARDBP-related ALS have been genotyped or longitudinally followed for the emergence of symptoms.
  • The parents and relatives of apparently simplex ALS cases with TARDBP pathogenic variants have not been reported in detail.

Prevalence

The prevalence of TARDBP pathogenic variants in:

  • All individuals with ALS (FALS and SALS) is 1.6% (49/3108 persons);
  • FALS is 3.4% (21/618 probands), but ranges from 0% to 12% across studies [Gitcho et al 2008, Gijselinck et al 2009];
  • SALS is 1.1% but ranges from 0% to 5% across studies [Guerreiro et al 2008, Kabashi et al 2008].

Pathogenic variants in TARDBP have been reported worldwide:

  • North America [Gitcho et al 2008, Kabashi et al 2008]
  • Europe [Kühnlein et al 2008, Sreedharan et al 2008, Corrado et al 2009, Daoud et al 2009, Del Bo et al 2009]
  • Japan [Yokoseki et al 2008]
  • China [Van Deerlin et al 2008]

A higher prevalence in Italian, French, and Taiwanese populations has been reported [Kabashi et al 2008, Corrado et al 2009, Daoud et al 2009, Del Bo et al 2009]. The p.Ala382Thr pathogenic variant is very common in Sardinia due to a founder effect. It accounts for 80% of familial ALS and 9% of simplex cases [Orrù et al 2012].

Differential Diagnosis

For a detailed discussion of these disorders and the differential diagnosis of ALS, see Amyotrophic Lateral Sclerosis Overview.

TARDBP-associated ALS must be differentiated from conditions that have overlapping features of ALS. Detailed clinical evaluation (as outlined above) is usually sufficient to exclude 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 neuropathy
  • Cervical spondylosis
  • Adult-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

The number of other genes associated with FALS (see Note) has been rapidly increasing and is tracked at the ALSoD site. Some examples:

  • ALS1. SOD1 (encoding the protein superoxide dismutase)
  • ALS4. SETX (encoding the protein probable helicase senataxin)
  • ALS6. FUS/TLS (encoding the protein )
  • ALS8. VAPB (encoding the protein vesicle-associated membrane protein-associated protein B/C)
  • ALS9. ANG (encoding the protein angiogenin)
  • DCTN1 (encoding the protein dynactin subunit 1)

Note: Pathogenic variants 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).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs 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 involvement
  • Pulmonary function testing to detect and stage respiratory involvement
  • Speech 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 communication
  • Physical and occupational therapy evaluation to determine what adaptive devices are needed to maximize function
  • Nutritional evaluation
  • Screening for depression and need for psychosocial support
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

The management of TARDBP-related ALS is identical to that of ALS resulting from other causes, and is outlined in the American Academy of Neurology practice parameter on this topic [Miller et al 2009a, Miller et al 2009b].

  • 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].

Note: See Author Notes, Miller Laboratory for a link to investigative reports on accurate assessments of the risks and benefits of specific proposed therapies.

Prevention of Secondary Complications

Adequate 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].

Surveillance

Monitoring 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.

Agents/Circumstances to Avoid

Long-term use of minocycline, which was studied in a randomized-controlled trial in individuals with ALS, was associated with worse outcomes [Gordon et al 2007].

Excessive exercise to the point of inducing fatigue in already weakened muscles is cautioned against by many practitioners based on experience.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

While no current clinical trials are specifically designed to target TARDBP-related ALS, many ongoing trials address the broader category of ALS.

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for access to information on clinical studies for a wide range of diseases and conditions.