FTLD-ALS: Frontotemporal Lobar Degeneration with Motor Neuron Disease

FTLD-ALS: Frontotemporal Lobar Degeneration with Motor Neuron Disease

FTLD-ALS (also known as FTLD-MND) is a rare neurodegenerative condition that represents the clinical overlap between Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). This syndrome demonstrates the biological intersection of TDP-43 proteinopathies affecting both cortical and motor [neurons](/entities/neurons).

Overview

FTLD-ALS is characterized by the concurrent or sequential development of frontotemporal dementia symptoms (including behavioral changes, language impairment, and executive dysfunction) and motor neuron disease symptoms (progressive muscle weakness, atrophy, and spasticity)[@lomenhoerth2002]. The condition accounts for approximately 5-15% of all ALS cases and up to 30% of FTLD cases show some evidence of motor neuron involvement[@burrell2011].

Genetics

The strongest genetic association for FTLD-ALS is with the C9orf72 gene hexanucleotide repeat expansion, which is found in approximately 25-40% of FTLD-ALS cases[@dejesushernandez2011]. This same expansion is the most common genetic cause of both familial ALS and FTLD.

Other implicated genes include:

• TARDBP (TDP-43): Mutations cause rare cases of FTLD-ALS[@benajiba2009]
• FUS: Rare causes of combined FTLD-ALS[@kwong2008]
• GRN (Progranulin): Primarily associated with FTLD-TDP but can present with ALS features[@van2009]

Neuropathology

TDP-43 Pathology

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FTLD-ALS: Frontotemporal Lobar Degeneration with Motor Neuron Disease

FTLD-ALS (also known as FTLD-MND) is a rare neurodegenerative condition that represents the clinical overlap between Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS). This syndrome demonstrates the biological intersection of TDP-43 proteinopathies affecting both cortical and motor [neurons](/entities/neurons).

Overview

FTLD-ALS is characterized by the concurrent or sequential development of frontotemporal dementia symptoms (including behavioral changes, language impairment, and executive dysfunction) and motor neuron disease symptoms (progressive muscle weakness, atrophy, and spasticity)[@lomenhoerth2002]. The condition accounts for approximately 5-15% of all ALS cases and up to 30% of FTLD cases show some evidence of motor neuron involvement[@burrell2011].

Genetics

The strongest genetic association for FTLD-ALS is with the C9orf72 gene hexanucleotide repeat expansion, which is found in approximately 25-40% of FTLD-ALS cases[@dejesushernandez2011]. This same expansion is the most common genetic cause of both familial ALS and FTLD.

Other implicated genes include:

• TARDBP (TDP-43): Mutations cause rare cases of FTLD-ALS[@benajiba2009]
• FUS: Rare causes of combined FTLD-ALS[@kwong2008]
• GRN (Progranulin): Primarily associated with FTLD-TDP but can present with ALS features[@van2009]

Neuropathology

TDP-43 Pathology

The hallmark of FTLD-ALS is TDP-43 proteinopathy. Pathological TDP-43 aggregates are found in:

• Motor neurons of the spinal cord and brainstem
• Cortical neurons (especially layer II)
• Hippocampal formation
• Basal ganglia and thalamus[@mackenzie2010]

Brain Regions Affected

| Region | Pathological Changes |
|--------|---------------------|
| Motor [Cortex](/brain-regions/cortex) | TDP-43 inclusions, neuronal loss |
| Spinal Cord | Anterior horn cell loss, gliosis |
| Frontal/Temporal Cortex | TDP-43 inclusions, microvacuolation |
| [Hippocampus](/brain-regions/hippocampus) | TDP-43 in dentate gyrus and CA1 |

Clinical Features

Frontotemporal Dementia Symptoms

• Behavioral variant FTD: Disinhibition, apathy, loss of empathy, compulsivity
• Semantic variant PPA: Loss of word meaning, object knowledge
• Non-fluent/agrammatic variant: Speech production difficulties
• Executive dysfunction and impaired judgment[@rascovsky2011]

Motor Neuron Disease Symptoms

• Progressive muscle weakness (bulbar, cervical, lumbar regions)
• Muscle atrophy and fasciculations
• Spasticity and hyperreflexia
• Dysphagia and dysarthria
• Respiratory insufficiency (late stage)[@chio2012]

Clinical Course

The typical disease course involves:

Simultaneous onset: ~30% of cases present with both cognitive and motor symptoms

Sequential onset: ~70% develop cognitive/behavioral symptoms within 2-3 years of motor symptoms (or vice versa)

Disease progression: Median survival 2-4 years from symptom onset[@phukan2012]

Diagnosis

Clinical Diagnostic Criteria

NINDS-ADS criteria require:

Presence of ALS (El Escorial criteria)

Presence of FTLD (core diagnostic features)

Temporal relationship (either condition develops within 4 years of the other)[@strong2017]

Biomarkers

• Neuroimaging: Frontotemporal atrophy on MRI, sometimes upper motor neuron signs on DTI
• Neurophysiology: Evidence of upper and lower motor neuron involvement
• CSF biomarkers: Elevated NFL ([neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain) correlates with disease progression[@lu2015]
• Genetic testing: C9orf72 expansion testing is recommended

Management

Pharmacological Approaches

• Riluzole: May provide modest survival benefit
• Edaravone: FDA-approved for ALS, may slow functional decline
• Behavioral interventions: SSRIs for disinhibition, antipsychotics for severe behavioral symptoms[@pagano2016]

Supportive Care

• Multidisciplinary ALS clinic involvement
• Speech therapy and augmentative communication devices
• Nutritional support and gastrostomy
• Non-invasive ventilation
• Physical and occupational therapy[@shoesmith2020]

Relationship to Other Conditions

FTLD-ALS exists on a spectrum with:

• ALS without cognitive impairment: Isolated motor neuron disease
• FTLD without MND: Frontotemporal dementia without motor features
• Dementia with Lewy Bodies: When Lewy bodies are present alongside TDP-43
• ALS-FTD: Often used interchangeably with FTLD-ALS

Research Directions

Clinical Trials

Current trials targeting FTLD-ALS include:

• C9orf72-targeted antisense oligonucleotides
• TDP-43 aggregation inhibitors
• Neuroinflammation modulators (e.g., anti-MIF antibodies)[@petri2023]

Biomarker Development

Emerging biomarkers under investigation:

• Plasma and CSF TDP-43 species
• Neurofilament light chain (NFL) for disease progression
• C9orf72 repeat expansion carriers for prevention trials

Cross-Links

Related Diseases

• [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Lobar Degeneration (FTLD)](/diseases/frontotemporal-lobar-degeneration)
• [Behavioral Variant FTD](/diseases/behavioral-variant-ftd)
• [Semantic Variant PPA](/diseases/semantic-dementia)

Related Genes

• [C9orf72](/entities/c9orf72)
• [TARDBP](/genes/tardbp)
• [FUS](/entities/fus-protein)
• [GRN](/genes/grn)

Related Mechanisms

• [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
• [RNA Metabolism Defects](/mechanisms/rna-metabolism-defects)
• [C9orf72 Hexanucleotide Repeat Expansion](/c9orf72-hexanucleotide-repeat-expansion)
• [Motor Neuron Degeneration](/mechanisms/motor-neuron-degeneration)

See Also

• [Amyotrophic Lateral Sclerosis (ALS)](/diseases/amyotrophic-lateral-sclerosis)
• [Frontotemporal Lobar Degeneration (FTLD)](/diseases/frontotemporal-lobar-degeneration)
• [Behavioral Variant FTD](/diseases/behavioral-variant-ftd)
• [Semantic Variant PPA](/diseases/semantic-dementia)
• [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
• [RNA Metabolism Defects](/mechanisms/rna-metabolism-defects)
• [C9orf72 Hexanucleotide Repeat Expansion](/c9orf72-hexanucleotide-repeat-expansion)
• [Motor Neuron Degeneration](/mechanisms/motor-neuron-degeneration)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[Neary, D., et al. (2005), Frontotemporal disorders (2005)](https://pubmed.ncbi.nlm.nih.gov/16234678/)

[Lomen-Hoerth, C., et al. (2002), Are amyotrophic lateral sclerosis and frontotemporal dementia distinct diseases? (2002)](https://pubmed.ncbi.nlm.nih.gov/12446710/)

[Burrell, J.R., et al. (2011), The overlap of amyotrophic lateral sclerosis and frontotemporal dementia (2011)](https://pubmed.ncbi.nlm.nih.gov/22006847/)

[DeJesus-Hernandez, M., et al. (2011), Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS (2011)](https://pubmed.ncbi.nlm.nih.gov/21944778/)

[Benajiba, L., et al. (2009), TARDBP mutations in motoneuron disease with frontotemporal lobar degeneration (2009)](https://pubmed.ncbi.nlm.nih.gov/19349579/)

[Kwong, L.K., et al. (2008), FUS pathology in basophilic inclusion body disease (2008)](https://pubmed.ncbi.nlm.nih.gov/18598245/)

[Van Swieten, J.C., et al. (2009), Phenotypic variation in progranulin mutation carriers (2009)](https://pubmed.ncbi.nlm.nih.gov/19520914/)

[Mackenzie, I.R., et al. (2010), Classification and clinicopathological correlates of TDP-43 proteinopathy diseases (2010)](https://pubmed.ncbi.nlm.nih.gov/20400474/)

[Rascovsky, K., et al. (2011), Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia (2011)](https://pubmed.ncbi.nlm.nih.gov/21784357/)

[Chio, A., et al. (2012), Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature (2012)](https://pubmed.ncbi.nlm.nih.gov/22516619/)

[Phukan, J., et al. (2012), The syndrome of cognitive impairment and amyotrophic lateral sclerosis: a continuum (2012)](https://pubmed.ncbi.nlm.nih.gov/23060488/)

[Strong, M.J., et al. (2017), Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria (2017)](https://pubmed.ncbi.nlm.nih.gov/28340349/)

[Lu, C.H., et al. (2015), Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis (2015)](https://pubmed.ncbi.nlm.nih.gov/25904057/)

[Pagano, M., et al. (2016), Riluzole for amyotrophic lateral sclerosis (ALS) (2016)](https://pubmed.ncbi.nlm.nih.gov/27063123/)

[Shoesmith, C.L., et al. (2020), Practice parameter update: The care of the patient with amyotrophic lateral sclerosis (2020)](https://pubmed.ncbi.nlm.nih.gov/32761034/)

[Petri, S., et al. (2023), C9orf72-associated ALS/FTD: From pathogenesis to therapeutic approaches (2023)](https://doi.org/10.1007/s13311-023-01299-0)