C9orf72 Frontotemporal Dementia And/or Amyotrophic Lateral Sclerosis

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Summary

Clinical characteristics.

C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis (C9orf72-FTD/ALS) is characterized most often by frontotemporal dementia (FTD) and upper and lower motor neuron disease (MND); however, atypical presentations also occur. Age at onset is usually between 50 and 64 years (range: 20-91 years) irrespective of the presenting manifestations, which may be pure FTD, pure amyotrophic lateral sclerosis (ALS), or a combination of the two phenotypes. The clinical presentation is highly heterogeneous and may differ between and within families, causing an unpredictable pattern and age of onset of clinical manifestations. The presence of MND correlates with an earlier age of onset and a worse overall prognosis.

Diagnosis/testing.

The diagnosis of C9orf72-FTD/ALS is established in a proband with suggestive findings and a heterozygous abnormal G₄C₂ (GGGGCC) hexanucleotide repeat expansion in C9orf72 identified by molecular genetic testing.

Management.

Treatment of manifestations: Care is often provided by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor.

Surveillance: Routine follow up by multidisciplinary specialists to monitor neurologic findings, mobility and activities of daily living, psychiatric/behavioral manifestations, nutrition and safety of oral feeding, respiratory and bladder function, and needs of affected individuals and care providers for psychosocial support.

Genetic counseling.

C9orf72-FTD/ALS is inherited in an autosomal dominant manner. Almost all individuals diagnosed with C9orf72-FTD/ALS inherited a C9orf72 G₄C₂ repeat expansion from a heterozygous parent. In most families the heterozygous parent is affected; however, a heterozygous parent may not have clinical manifestations of the disorder due to age-dependent reduced penetrance. Each child of an individual with C9orf72-FTD/ALS has a 50% chance of inheriting the C9orf72 G₄C₂ repeat expansion. Once a C9orf72 G₄C₂ repeat expansion has been identified in an affected family member, prenatal and preimplantation genetic testing for the presence of the C9orf72 G₄C₂ repeat expansion are possible. (Note: The presence of a C9orf72 G₄C₂ repeat expansion cannot predict the disease course in any given individual.)

Diagnosis

In this GeneReview, C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis (C9orf72-FTD/ALS) refers to the spectrum of phenotypes caused by C9orf72 G₄C₂ pathogenic repeat expansions, also sometimes referred to as the C9orf72 FTD/ALS complex.

Suggestive Findings

C9orf72-FTD/ALS should be suspected in probands with the following clinical and neuroimaging findings and family history [Van Mossevelde et al 2018, Cammack et al 2019, Moore et al 2020].

Clinical Findings

Age at onset ranges from 20 to 91 years, with a mean of 58 ± 8-10 years [Van Mossevelde et al 2017a].

Neurologic findings (See also Table 1.)

Frontotemporal dementia (FTD), the most common clinical presentation, is characterized by progressive behavioral impairment, decline in executive function, and/or language impairment (see Table 1). Of the three FTD clinical syndromes, behavioral variant FTD (bvFTD) is more often present than the two language variants (collectively identified as primary progressive aphasia [PPA]: semantic variant PPA [svPPA] and non-fluent variant PPA [nfvPPA]).
Manifestations specific to C9orf72-FTD include prominent neuropsychiatric symptoms, such as hallucinations and delusions. Often, some parkinsonian features are present.
Motor neuron disease includes both the upper and lower motor neuron involvement that characterizes amyotrophic lateral sclerosis (ALS) as well as upper and/or lower motor neuron dysfunction that may or may not fulfill criteria for the full ALS phenotype.
Atypical presentations mimicking other neurodegenerative disorders

Table 1.

C9orf72-FTD/ALS: Frequency of Diagnoses Based on Clinical Findings Alone

Diagnosis	Frequency	Comments (Frequency)
FTD	34.8%	Behavioral variant FTD (31.4%) Nonfluent/agrammatic variant PPA (1.8%) Semantic variant PPA (0.9%) Other tauopathy: corticobasal degeneration, progressive supranuclear palsy, other PPA (0.7%)
ALS	19.3%
FTD-ALS	11.0%
Atypical presentations mimicking other kinds of neurodegenerative brain diseases	35.0%	Alzheimer disease, Parkinson disease, Huntington disease, & dementia w/Lewy bodies are common. Also incl vascular dementia & dementia not otherwise specified Atypical parkinsonian syndromes ¹

: Based on Moore et al [2020]
: ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; PPA = primary progressive aphasia
1.: Van Mossevelde et al [2018]

Neuroimaging

Brain MRI. The pattern of atrophy in C9orf72-FTD is remarkably symmetric and generalized. Cortical atrophy can be seen in the frontal and temporal regions, also the insular and cingulate regions, as well as more posterior cortical areas. Also notable is involvement of subcortical structures and the cerebellum [Cash et al 2018, Van Mossevelde et al 2018].

Brain FDG-PET. The pattern of predominant frontotemporal hypometabolism is mostly congruent with the atrophy patterns seen on brain MRI; however, FDG-PET abnormalities can usually be detected earlier than suggestive brain MRI findings [Greaves & Rohrer 2019].

CSF biomarkers. Nonspecific abnormalities in Alzheimer disease CSF biomarkers, such as (slightly) increased levels of total tau or decreased levels of amyloid beta 1-42, may or may not be present [Niemantsverdriet et al 2018].

Family History

Family history may be positive and consistent with autosomal dominant inheritance (e.g., males and females in multiple generations with ALS, FTD, and/or other manifestations within the C9orf72-FTD/ALS spectrum) or the family history may be negative; absence of a known family history does not preclude the diagnosis. C9orf72 G₄C₂ repeat expansions are to date the most frequent cause of ALS and FTD in individuals representing simplex cases (i.e., a single occurrence within a family) [Van Mossevelde et al 2018].

Note: Simplex cases 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 C9orf72-FTD/ALS is established in a proband with suggestive findings and a heterozygous abnormal G₄C₂ (GGGGCC) hexanucleotide repeat expansion in C9orf72 identified by molecular genetic testing [DeJesus-Hernandez et al 2011, Renton et al 2011, Gijselinck et al 2012] (see Table 2).

Note: Pathogenic G₄C₂ repeat expansions in C9orf72 cannot be detected by sequence-based multigene panels, exome sequencing, or genome sequencing.

Repeat sizes

Normal. Range from 2 to 24 G₄C₂ repeats
Uncertain significance. Range from 25 to 60 G₄C₂ repeats
- Repeats in this range are rare in the general population and typically do not segregate in families with C9orf72-FTD/ALS.
- The shortest G₄C₂ repeat identified in white blood cells and reported to cosegregate with the disorder in a family with C9orf72-FTD/ALS was 47 G₄C₂ repeats [Gijselinck et al 2016]. However, in different brain regions of the individual who was heterozygous for the short expansion, a pool of short and long expansion sizes (>1100 repeat units) was apparent, pointing to somatic mosaicism [Gijselinck et al 2016].
Pathogenic. Range from 61 to >4000 of G₄C₂ repeats
Pathogenic expansions >60 to hundreds or thousands of G₄C₂ repeats show age-dependent reduced penetrance [Murphy et al 2017].

Molecular genetic testing relies on targeted analysis to characterize the number of C9orf72 G₄C₂ repeats (see Table 8).

Table 2.

Molecular Genetic Testing Used in C9orf72-FTD/ALS

Gene ¹	Method ^2, 3	Proportion of Probands with a Pathogenic Variant Detectable by Method
C9orf72	Targeted analysis for G₄C₂ hexanucleotide expansions	100%

1.: See Table A. Genes and Databases for chromosome locus and protein name.
2.: See Table 8 for specific methods to characterize the number of GGGGCC (G₄C₂) repeats in C9orf72.
3.: Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene.

Clinical Characteristics

Clinical Description

C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis (C9orf72-FTD/ALS) is characterized most often by frontotemporal dementia (FTD) and upper and lower motor neuron disease (MND); however, atypical presentations also occur. Mean age at onset is usually 50-64 years (range: 20-91 years) irrespective of the presenting manifestations, which may be pure FTD, pure ALS, or a combination of the two phenotypes. The clinical presentation is highly heterogeneous and may differ between and within families, causing an unpredictable pattern and age of onset of clinical manifestations (see Table 3). The presence of MND correlates with an earlier age of onset and a worse overall prognosis [Van Mossevelde et al 2018, Moore et al 2020].

Like the age of onset, life expectancy is highly variable and mainly associated with the clinical manifestations.

Table 3.

C9orf72-FTD/ALS: Frequency of Disease Features

Feature		Frequency			Comment
Feature		Nearly all	Common ¹	Infrequent	Comment
Cognitive deterioration
Executive dysfunction		●			Problems w/planning, problem solving, organizing
Memory impairment			●		Amnesia, mostly recent memory
Language impairment			●		Deficits in speech production or comprehension
Apraxia			●		Impaired execution of learned motor tasks
Dyscalculia			●		Diminished mathematical reasoning
Behavioral & psychological manifestations of dementia
Disinhibition			●		Impulsivity, socially unacceptable behavior, risk taking
Apathy			●		Indifference, lack of interest
Delusions/hallucinations			●		Often bizarre delusions, mostly visual hallucinations
Psychosis			●		Psychosis, often as initial symptom
Anxiety			●		Generalized stress & apprehension
Repetitive, compulsive behavior			●		Often complex, ritualistic behaviors mimicking OCD
Preference for sweet food				●	↑ craving for sweet foods
Motor symptoms
Upper MND			●		Weakness, spasticity, altered muscle tone
Lower MND			●		Weakness, fasciculations, atrophy
Bulbar involvement	Dysarthria			●	Motor language deficit
Bulbar involvement	Dysphagia			●	Problems swallowing food &/or liquids
Parkinsonism			●		Extrapyramidal findings such as resting tremor, rigidity, akinesia

: MND = motor neuron disease; OCD = obsessive compulsive disorder
1.: Features are ranked as common if present in >33%, if frequency was mentioned.

Initial manifestations may be pure FTD or ALS; additional manifestations in the C9orf72-FTD/ALS spectrum may appear during the disease course [Van Mossevelde et al 2018, Moore 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 PPA (nfvPPA). Most individuals with C9orf72-FTD and C9orf72-FTD/ALS present with bvFTD.

Cognitive deficits associated with FTD are mostly early loss of executive functions, memory impairment, and language problems (mostly dynamic aphasia). Other findings, such as parietal lobe involvement (dyscalculia, apraxia), are common as the disease progresses.

C9orf72-bvFTD includes most of the typical bvFTD behavioral changes: early disinhibition, early apathy or inertia, early loss of empathy, as well as repetitive and ritualistic behaviors. Although sweet food preference occurs, it is less common. Other prominent neuropsychiatric symptoms include early delusions and hallucinations, psychosis, and anxiety.

C9orf72-PPA presents with early and prominent language deficits – speech apraxia and frequent grammatical errors in the more common nfvPPA or decreased understanding of language in svPPA.

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 C9orf72-ALS and C9orf72-FTD/ALS. Spinal onset (involving limb muscles) is more frequent than bulbar onset (including involvement of swallowing and speech) in C9orf72-ALS (54% vs 39%). Some early cognitive impairment may be present even in individuals who had been diagnosed with pure ALS [Cammack et al 2019]. See Amyotrophic Lateral Sclerosis Overview for a definition of this phenotype.

Atypical Presentations

Atypical presentations of the C9orf72-FTD/ALS spectrum mimicking other neurodegenerative brain diseases – including Alzheimer disease, Parkinson disease, Huntington disease (see linked GeneReview chapters for definitions of these phenotypes), and dementia with Lewy bodies – are common. In addition to MND, motor manifestations may also include extrapyramidal signs, most commonly as a symmetric akinetic-rigid syndrome. Clinical diagnoses of atypical parkinsonian syndromes are also relatively common.

A C9orf72 pathogenic G₄C₂ repeat expansion is seen in fewer than 1% of individuals with clinically diagnosed Alzheimer disease (AD). In most of these individuals, the underlying pathology is frontotemporal lobar degeneration (FTLD) [Murray et al 2011, Dobson-Stone et al 2012, Majounie et al 2012a, Cacace et al 2013, Harms et al 2013, Kohli et al 2013]. Similar observations were made in individuals with clinical Parkinson disease (PD) [Lesage et al 2013, Theuns et al 2014, Wilke et al 2016].

The association of C9orf72 G₄C₂ pathogenic repeat expansions with AD, PD, and atypical parkinsonian syndromes may be due to relatively common AD or PD co-pathology occurring in an individual with primary C9orf72-related disease. Moreover, most of the studies reporting on this association defined cohorts of affected individuals solely on clinical diagnoses, leaving the possibility of misclassification of an individual with C9orf72-FTD [Lesage et al 2013, Theuns et al 2014, Wilke et al 2016].

A C9orf72 G₄C₂ repeat expansion was observed in 6.5% of individuals with a diagnosis of depressive pseudodementia [Bieniek et al 2014] and in 2% of Huntington disease phenocopies lacking an HTT CAG trinucleotide repeat expansion [Beck et al 2013, Hensman Moss et al 2014].

Rarely, C9orf72-related corticobasal syndrome, progressive supranuclear palsy, and olivopontocerebellar degeneration have also been reported [Snowden et al 2012, Lesage et al 2013, Lindquist et al 2013, Schottlaender et al 2015, Wilke et al 2016, Bourinaris & Houlden 2018, Cali et al 2019].

Life Expectancy

Life expectancy for individuals with C9orf72-FTD/ALS is highly variable and mainly associated with an individual's clinical features. Overall disease duration averages 6.4 years (range 0-36), which is significantly lower than in individuals with GRN frontotemporal dementia and MAPT frontotemporal dementia [Moore et al 2020].

For C9orf72-ALS, G₄C₂ repeat expansions are associated with an average disease duration of 2.9 ± 2.8 years [Cammack et al 2019, Moore et al 2020].
For C9orf72-FTD, disease duration averages between 7.5 and 14 years, depending on the cohort. As expected, survival in FTD is markedly compromised (on average 1.8 years) when ALS manifestations become apparent [Van Mossevelde et al 2018, Moore et al 2020].

Genotype-Phenotype Correlations

Heterozygous expanded G₄C₂ repeats. Clinical findings cannot predict the presence or size of a C9orf72 G₄C₂ repeat expansion, nor can the presence of a G₄C₂ repeat expansion predict the disease course in any given individual.

Biallelic expanded G₄C₂ repeats. To date, one individual homozygous for an expanded C9orf72 G₄C₂ repeat has been reported. This individual (whose parents were consanguineous) was homozygous for >800 G₄C₂ repeats and presented with early-onset bvFTD at age 43 years followed by rapid deterioration that was nonetheless within the range of the usual disease spectrum [Fratta et al 2013].

Another individual, compound heterozygous for two expanded alleles (one with ±50 G₄C₂ repeats and one with >2000 G₄C₂ repeats), had onset age of 58 years of bvFTD associated with parkinsonism [Cooper-Knock et al 2013].

Penetrance

Heterozygosity for a pathogenic C9orf72 G₄C₂ repeat expansion is associated with age-dependent reduced penetrance, with the youngest individuals developing disease in their twenties and a small number of heterozygotes remaining asymptomatic in their nineties. Age-dependent penetrance is estimated as follows [Benussi et al 2015, Murphy et al 2017]:

~0% at age 35 years
50% at age 58 years
Near 100% at age 80 years

Anticipation

A decreasing age of onset in consecutive generations of family members heterozygous for a C9orf72 G₄C₂ repeat expansion has been reported by some investigators [Van Mossevelde et al 2017b, Moore et al 2020] but not others [DeJesus-Hernandez et al 2011, Renton et al 2011, Barbier et al 2017]. Explanations for this discrepancy could include the following: (1) an apparent earlier age of onset due to observational or recall bias in families experienced with the disorder that prompted earlier medical attention and diagnosis; and (2) technical difficulties as well as age-related and tissue-related issues in correctly sizing the G₄C₂ repeat (see Molecular Genetics).

Thus, to date, G₄C₂ repeat size as measured in leukocyte DNA does not provide prognostic information, such as predicted presence or absence of clinical manifestations of C9orf72-FTD/ALS in an individual, or – if manifestations do develop – the age of onset or severity [Van Mossevelde et al 2017a].

Prevalence

Detailed epidemiologic studies of the prevalence of the C9orf72 G₄C₂ repeat expansion have not been performed. Based on the estimated prevalence of FTD and ALS in the general population and the frequency of a C9orf72 G₄C₂ pathogenic repeat expansion in cohorts of individuals with FTD and ALS, the following rough estimates of C9orf72-FTD/ALS spectrum have been calculated.

With the prevalence of FTD estimated at 1-461:100,000 [Hogan et al 2016] and with an average frequency of 4%-29% of C9orf72 G₄C₂ repeat expansions in FTD cohorts [Van Mossevelde et al 2018], a rough estimate of C9orf72-FTD is 0.04-134:100,000.
The prevalence of ALS is estimated at 5-12:100,000. Among individuals with ALS, about 10% have a family history consistent with autosomal dominant inheritance and about 90% have no family history of the disorder [Oskarsson et al 2018, Masrori & Van Damme 2020]. A pathogenic C9orf72 G4C2 repeat expansion is observed on average in 30%-50% of individuals with familial ALS and 4%-10% of individuals with no family history of ALS [Majounie et al 2012b, Oskarsson et al 2018, Masrori & Van Damme 2020].

It is important to note that the frequency of C9orf72 G₄C₂ repeat expansions greatly depends on ethnicity and geographic region.

The highest repeat expansion frequencies are observed in individuals of northern European heritage.
Markedly elevated expansion frequencies were reported in Scandinavian countries [Majounie et al 2012b, Lindquist et al 2013, van der Zee et al 2013, Smith et al 2013].
By contrast, in Asian populations, expansion frequency is much lower [Majounie et al 2012b, Tsai et al 2012, Konno et al 2013, Zou et al 2013].
Few studies have investigated the effect of repeat expansions in cohorts of African heritage [Nel et al 2019].

Differential Diagnosis

The frequency of C9orf72 G₄C₂ repeat expansions significantly exceeds that of pathogenic variants in any other gene causing frontotemporal dementia (FTD) or amyotrophic lateral sclerosis (ALS).

Family history. The frequency of pathogenic C9orf72 G₄C₂ repeat expansions is about twice as high in individuals with a family history of FTD and/or ALS compared to those without a family history of these disorders. A C9orf72 G₄C₂ repeat expansion is found in:

25% of familial FTD;
30%-50% of familial ALS (Of note, only 10% of individuals with ALS have a positive family history and simplex cases [i.e., a single occurrence in a family] outnumber familial cases among individuals with C9orf72-ALS.);
Up to 88% of individuals with manifestations of both FTD and ALS and a positive family history of these disorders [Cruts et al 2013, Masrori & Van Damme 2020].

Differential diagnosis for C9orf72-FTD

Other types of dementia, especially with behavioral changes. Differential diagnosis includes "frontal variant" Alzheimer disease (see Alzheimer Disease Overview), diffuse Lewy body disease, Huntington disease, other forms of FTD (see GRN Frontotemporal Dementia), prion disease, corticobasal degeneration, and progressive supranuclear palsy.
Some individuals with C9orf72-FTD/ALS have a choreiform movement disorder which (especially when combined with behavioral abnormalities) may be confused with Huntington disease (see Clinical Description, Atypical Presentations) [Hensman Moss et al 2014].
Psychiatric disorders. Especially in C9orf72-bvFTD with prominent behavioral manifestations, often in young individuals, a psychiatric diagnosis such as depression, obsessive compulsive disorder, bipolar disorder, and schizophrenia may be considered. Diagnostic workup and longitudinal clinical follow up are likely to distinguish between psychiatric disorders and FTD; however, they may exist concomitantly.
Age of onset of C9orf72-FTD (mean 58.2 years) was later than in MAPT-FTD (mean 49.5 years) and earlier than in GRN-FTD (mean 61.3 years) [Moore et al 2020]. Most studies report a similar onset age in individuals with C9orf72-FTD and those with FTD of unknown cause [Van Mossevelde et al 2018].

Differential diagnosis for C9orf72-ALS

Isolated upper motor signs. Differential diagnosis includes compressive (cervical) myelopathy, hereditary spastic paraplegia, adrenomyeloneuropathy (see X-Linked Adrenoleukodystrophy), and cerebrotendinous xanthomatosis in individuals with isolated manifestations of upper motor involvement.
Lower motor signs. Plexopathy, chronic inflammatory polyradiculoneuropathy, as well as multifocal motor, toxic, infectious, or metabolic neuropathies or myopathies including inclusion body myositis (see Inclusion Body Myopathy with Paget Disease of Bone and/or FTD) and polymyositis can mimic lower motor signs [Masrori & Van Damme 2020].
Other forms of upper and lower motor neuron disorders. See ALS Overview, Differential Diagnosis.
A rare ALS/FTD variant of prion disease [Vicente-Pascual et al 2018]

Management

Consensus clinical management recommendations for C9orf72 frontotemporal dementia and/or amyotrophic lateral sclerosis (C9orf72-FTD/ALS) have not been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with C9orf72-FTD/ALS, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with C9orf72-FTD/ALS

System/Concern	Evaluation	Comment
Neurologic	Complete neurologic exam	Assess: UMN involvement: spasticity, Babinski signs, hyperreflexia; LMN involvement: weakness, amyotrophy, fasciculations; EMG.
Cognitive function	Neuropsychological exam	Evaluate extent & profile of cognitive disturbance.
Musculoskeletal/ ADL	Orthopedics / physical medicine & rehab / PT eval	To incl assessment of: Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores Need for adaptive devices Footwear needs PT needs Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs)
	OT	Assess: Fine motor function, e.g., hands, feet, face, fingers, & toes; Home adaptations for ADL & safety.
	Eval of driving safety	In case of cognitive impairment & impaired judgment, evaluate driving safety.
Psychiatric illness	History of psychiatric illness ¹	Attention to possible alcohol or drug abuse Referral for psychiatric eval as needed
Dysarthria	For those w/dysarthria: speech/language eval	Referral for speech therapy as needed
Dysphagia	For those w/frequent choking or severe dysphagia, assess: Nutritional status; Aspiration risk.	Consider involving a gastroenterology/nutrition/feeding team, incl formal swallowing eval.
Respiratory function	By pulmonologist	Assess respiratory function & need for respiratory support.
Genetic counseling	By genetics professionals ²	To inform patients & their families re nature, MOI, & implications of C9orf72-FTD/ALS spectrum to facilitate medical & personal decision making
Family support/ resources	Assess: Use of community or online resources such as Parent to Parent; Need for social work involvement for parental support; Need for home nursing referral.	Early discussion of advanced care planning The patient's perspective & burden must be considered in clinical decision making. The presence of cognitive impairment may raise ethical concerns.

: ADL = activities of daily living; EMG = electromyography; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron
1.: Devenney et al [2014], Piguet et al [2017], Oskarsson et al [2018], Masrori & Van Damme [2020]
2.: Medical geneticist, certified genetic counselor, or certified advanced genetic nurse

Treatment of Manifestations

Many individuals benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor.

For ALS-related treatment options, see also Amyotrophic Lateral Sclerosis Overview.

Table 5.

Treatment of Manifestations in Individuals with C9orf72-FTD/ALS

Manifestation/Concern	Treatment	Considerations/Other
UMN & LMN involvement / ADL	Physical medicine & rehab / PT/OT Riluzol Edaravone	Ankle-foot braces, walkers, wheelchairs, hospital beds, toileting equipment, lifts to improve functionality Note: Edaravone is not approved worldwide.
Spasticity	Baclofen, tizanidine, cannabinoids, & muscle stretching
Muscle cramps	Magnesium supplements, quinine sulfate, gabapentin, or carbamazepine
Parkinsonism	PT, levodopa trial	Because of psychiatric levodopa side effects, use only when functional impairment is significant.
Cognitive function	Cognitive rehab
Psychiatric/ behavioral manifestations	Environmental, behavioral, & physical interventions	To minimize occurrence & consequences of undesired behaviors
	Counseling	For those w/affective disorders or to support affected person &/or caretakers.
	SSRIs	For those w/affective disorders or disinhibition & challenging behaviors, the 1st-line approach is pharmacologic therapy.
	Venlafaxine	Used when apathy is prominent
	Atypical antipsychotics	For severe manifestations (agitation, aggressiveness, psychosis) refractory to SSRIs Often a temporizing measure until affected person becomes more apathetic Note: Risk of iatrogenic extrapyramidal syndrome
Pseudobulbar affect	Dextromethorphan/quinidine
Dysarthria	Speech/language therapy	Use of augmentative communication devices
Dysphagia	Continuous eval & therapy	Safe swallowing techniques, diet modifications, gastrostomy tube
Sialorrhea	Anticholinergic medications, salivary gland botulinum toxin injections, or radiotherapy	Note: Anticholinergic medication can affect cognition.
Respiratory function	Assisted ventilation	Noninvasive at first, proceeding to tracheostomy if necessary
Bladder dysfunction	Anticholinergics & intravesical botulinum toxin	Note: Anticholinergic medication can affect cognition.
Family/caregiver support/resources	Psychosocial support & education via caregiver & patient support groups	To ↓ stress & burden on caregivers

: Based on Andersen et al [2012], Siuda et al [2014], Piguet et al [2017], Oskarsson et al [2018], and Masrori & Van Damme [2020]
: ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor; UMN = upper motor neuron

Surveillance

Table 6.

Recommended Surveillance for Individuals with C9orf72-FTD/ALS

System/Concern	Evaluation	Frequency
System/Concern	Evaluation	ALS	FTD
Neurologic	Neurologic exam for new manifestations &/or response to medications	Every 2-3 mos	Undefined; depends on disease progression & presenting symptoms
Mobility/ADL	Physical medicine & rehab / PT/OT
Cognitive function	Rapid screening tools, incl tests of verbal fluency
Psychiatric/behavioral manifestations	Medical history, neurologic exam
Pseudobulbar affect	Medical history		Not applicable
Dysarthria	Eval by speech therapist	Every 3-6 mos	Undefined; depends on disease progression & presenting symptoms
Dysphagia	Medical history	Every 2-3 mos	Not applicable
Sialorrhea	Medical history
Respiratory function	Medical history, clinical exam, additional testing (e.g., forced vital capacity, vital capacity)
Bladder function	Medical history
Family/caregiver support/resources	Medical history, assess need for additional support.		Undefined; depends on disease progression & presenting symptoms

: Based on Andersen et al [2012], Piguet et al [2017]
: ADL = activities of daily living; OT = occupational therapy; PT = physical therapy

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Although results in a preclinical setting only are available to date, antisense oligonucleotide therapy may be promising as a disease-modifying therapy in C9orf72 repeat expansion heterozygotes. A Phase I clinical trial testing such an agent was commenced in 2018 (NCT03626012).

Other potential RNA therapies include the use of duplex and single-stranded small interfering RNAs to silence C9orf72 transcripts, as well as adeno-associated virus-delivered artificial microRNAs targeting C9orf72 [Panza et al 2020].

Promising results have been achieved in a Phase II/III clinical trial with the selective tyrosine kinase inhibitor masitinib, as an add-on therapy to riluzole in persons with ALS [Mora et al 2020]. An additional Phase III clinical trial to verify and further specify these effects is being set up (NCT03127267).

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.