Moving Toward Patient-Tailored Treatment in ALS and FTD: The Potential of Genomic Assessment as a Tool for Biological Discovery and Trial Recruitment

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two devastating and intertwined neurodegenerative diseases. Historically, ALS and FTD were considered distinct disorders given differences in presenting clinical symptoms, disease duration, and predicted risk of developing each disease. However, research over recent years has highlighted the considerable clinical, pathological, and genetic overlap of ALS and FTD, and these two syndromes are now thought to represent different manifestations of the same neuropathological disease spectrum. In this review, we discuss the need to shift our focus from studying ALS and FTD in isolation to identifying the biological mechanisms that drive these diseases—both common and distinct—to improve treatment discovery and therapeutic development success. We also emphasize the importance of genomic data to facilitate a “precision medicine” approach for treating ALS and FTD.

A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

“…FTD shares clinical, genetic and pathogenic features with ALS [37,52]. ALS is caused by degeneration of upper and lower motor neurons leading to progressive paralysis and death [3]. Unlike FTLD-FET, autosomal dominant mutations in FUS account for 5-10% ALS [15,44,82].…”

“…Loss of function or missense variants in the gene encoding FUS, one of the main components of the aggregates of FTLD-FET cases, typically cause amyotrophic lateral sclerosis (ALS) [ 44 , 82 , 91 ], a motor neuron disease that shares overlapping genetic and pathological features with FTD [ 3 ]. Such ALS mutations are inherited or occur de novo [ 60 ] and post-mortem analysis of patient tissues show nuclear depletion and cytoplasmic aggregation of FUS [ 35 , 78 ], similar to that of FTLD-FET [ 31 , 51 , 66 ].…”

The Complex Mechanisms by Which Neurons Die Following DNA Damage in Neurodegenerative Diseases

“…Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder that mainly affects the frontal and anterior temporal cortex, leading to impairment of executive functioning, behavioural changes, and a decline in language proficiency [ 343 ]. FTD is the second most common form of dementia in individuals younger than 65 years [ 343 ], and ALS and FTD are thought to form opposite ends of the same disease spectrum [ 344 ]. Several mechanisms are implicated in the pathophysiology of FTD, including ER stress [ 345 ], mitochondrial dysfunction [ 346 ], oxidative stress [ 347 ], disruption in intracellular trafficking [ 275 ], proteostasis disruption [ 320 ], excitotoxicity [ 348 ], DNA damage [ 347 ], and abnormal RNA homeostasis [ 320 ].…”

Investigating the Genetic Profile of the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS-FTD) Continuum in Patients of Diverse Race, Ethnicity and Ancestry

“…Individuals with ALS experience progressive paralysis that ultimately results in death within an average of three to five years after symptom onset [ 1 ]. ALS has long been recognized to form a neurodegenerative continuum with frontotemporal dementia (FTD), a progressive disorder affecting behavior and language, by a common underlying TDP43 neuropathology [ 2 ]. It has been reported that up to 50% of individuals with ALS develop cognitive impairment associated with FTD, and up to 30% of individuals with FTD develop symptoms of motor neuron disease [ 3 ].…”

“…It has been reported that up to 50% of individuals with ALS develop cognitive impairment associated with FTD, and up to 30% of individuals with FTD develop symptoms of motor neuron disease [ 3 ]. The recent discoveries of common genetic etiologies have led to a growing recognition that ALS and FTD represent opposite ends of one common phenotypic spectrum [ 2 , 4 ].…”