ALS and Frontotemporal Degeneration

The discovery in 2011 that the C9orf72 gene mutation can cause both FTD and amyotrophic lateral sclerosis (ALS) has transformed a long held belief that ALS is ‘purely’ a movement disorder and that FTD is ‘purely’ a cognitive or behavioral form of dementia.

It is now recognized that the C9orf72 gene is the most common gene causing hereditary FTD, ALS and ALS with FTD. We now know that several other genes can also cause both diseases. FTD or frontotemporal degeneration is a progressive brain disease with changes in behavior, personality, and language dysfunction due to loss of nerve cells in the frontal and temporal lobes. ALS is a neurodegenerative disease with loss of upper (located in the brain) and lower (located in the spinal cord) motor neurons that leads to paralysis, dysphagia, dysarthria and eventually respiratory failure.

Describing the clinical syndrome where both FTD and ALS occur in the same person has been an area of active research and our knowledge of the underlying genetics, pathology and clinical features is still unfolding. At present, the most comprehensive description found in the research literature refers to this complex as ALS-Frontotemporal spectrum disorder.

The current understanding of ALS with language deficits is still incomplete. Both the non-fluent agrammatic and semantic variants of primary progressive aphasia have been reported in association with ALS.

Know the Signs… Know the Symptoms

Symptoms of frontotemporal degeneration (commonly: bvFTD symptoms) are often noticed first, with motor symptoms identified later. In addition to changes in behavior, personality and language skills that characterize FTD, people with ALS and FTD also have difficulty walking, standing, using their hands, speaking, swallowing, or breathing. The spinal cord and nerves outside the central nervous system (brain and spinal cord) that communicate with muscles are affected, as well as the frontal and temporal lobes. Motor symptoms may include:

Muscle weakness

A progressive inability to move the arms, legs, face, tongue or neck. It often begins on one side of the body, and ultimately leads to paralysis. Examples include:

  • Weakness in legs can lead to tripping and falls
  • Difficulty grasping a pen or cup
  • Difficulty lifting arms above the head
  • Clumsiness when carrying out fine motor movements with hands or fingers (e.g. those needed to type, button a shirt, write, etc.)
  • Difficulty breathing.

Muscle atrophy

The loss of muscle tissue.


Fasciculations

Brief, spontaneous, uncontrolled twitching of the muscles.


Spasticity

Prolonged, uncontrollable contraction of a muscle, leading to tightness and stiffness.


Dysarthria

Slow, slurred speech, due to an inability to move the mouth and facial muscles.


Dysphagia

The inability to swallow. Symptoms include drooling and choking on food or saliva. This can lead to malnutrition.

Diagnosis

The most recent work on diagnosing ALS (Strong, 2017) recognizes a wide spectrum of ALS presentations. The spectrum includes ALS with only motor symptoms, as well as ALS with behavioral or cognitive deficits not sufficient to meet dementia diagnosis criteria. And there are persons with ALS with behaviorial or language symptoms sufficient to be defined as ALS with frontotemporal degeneration. If you are concerned that you or a loved one may be experiencing one of these conditions, or about any of the signs and symptoms listed above, it is important to consult a doctor.

Treatment, Management and What to Expect

There is no cure for ALS or FTD. Riluzole, the first drug approved for use in the treatment of ALS, has been shown to slow the progression of ALS for some patients and increase survival. Rasagiline developed for Parkinson’s disease, is a monoamine oxidase inhibitor but demonstrates neuroprotective action.  It has been used to treat ALS and, in a recent randomized controlled study, appears to increase survival. Other medications may help relieve the symptoms of muscle cramping and spasticity. At present, there are no approved medicines for FTD. Symptomatic treatment has been attempted with medications developed for other disorders, but have had limited success in frontotemporal degeneration disorders.

Patients with this diagnosis usually experience a rapid decline in both physical and cognitive abilities. The course of ALS with frontotemporal degeneration may run as quickly as 2 to 3 years, as opposed to the 5-to-10-year course more commonly seen for other forms of FTD.

Physical therapy, including stretching exercises and low-impact exercise can help relieve muscle symptoms. Devices such as ramps, braces, walkers, and wheelchairs can help patients conserve energy and remain mobile. Speech therapy can help a patient develop strategies to speak more clearly. Over time, alternate means of communication, such as speech synthesizers, may be of use.

The ALS features of the disorder eventually render patients unable to stand, walk, get in or out of bed on their own, or use their hands and arms. Difficulty swallowing and chewing impair the patient’s ability to eat normally and increase the risk of choking. Patients eventually lose the ability to breathe on their own and will require support on a ventilator for survival.

It is important for caregivers and families to think about long-term management issues and identify a team of experts who can help with difficult medical, financial and emotional challenges. It is imperative to have a physician who is knowledgeable about both ALS and FTD and approaches to treatment. Other medical specialists who may be helpful include: speech therapists, occupational and physical therapists, neuropsychologists, nurses (especially home-care nursing) and genetic counselors.

Genetics

As many as half of people diagnosed with ALS exhibit behavioral changes or a decline in language skills similar to those observed in behavioral variant FTD or primary progressive aphasia. Conversely, up to 30% of people diagnosed with FTD develop motor symptoms consistent with ALS.

This overlap is what led experts to propose that FTD and ALS belong to a common disease spectrum, especially in light of the recent discovery that mutation of the C9orf72 gene is the most common genetic cause of both disorders. The C9orf72 gene mutation produces an expansion of an area of the gene consisting of six nucleotides, called a hexanucleotide repeat of GGGGCC. Carriers of this gene expansion can have hundreds to thousands of repeats of the hexanucleotide compared to 30 or less in someone without C9orf72-related ALS or FTD. A small number of rare genes have been shown to have a role in inherited ALS with frontotemporal degeneration. These are VCP, SQSTMI, UBQLN2 and CHMP2B.

Pathology

In most cases, ALS with frontotemporal degeneration is associated with abnormal accumulation of the protein TDP-43. Accumulations of the fused in sarcoma (FUS) protein are found in a minority of individuals.

 


References

Strong, M.J., Abrahams, S., Goldstein, L.H. et al. Amyotrophic lateral sclerosis – frontotemporal spectrum disorder (ALS-FTSD): Revised diagnostic criteria. Amyotrophic Lateral Sclerosis Frontotemporal Degeneration. May 2017.

Ng, A.S.L., Rademakers, R. and Miller, B.L. Frontotemporal dementia: a bridge between dementia and neuromuscular disease. Ann NY Acad Sci. March 2015.

Ji, A-L., Zhang, W-W., Huang, W-J. Genetics insight into the amyotrophic lateral sclerosis/frontotemporal dementia spectrum. J. Med. Genet. March 2017.

Saxon, J.A., Thompson, J.C., Jones, M. et al. Examining the language and behavioral profile in FTD and ALS-FTD. J. Neurol. Neurosurg. Psychiatry. June 2017.