Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis
(ALS) are two brain diseases associated with neurodegeneration, the
abnormally rapid death of brain cells. The most common genetic cause of the brain diseases FTD and ALS is a mutation in
the C9orf72 gene.
Researchers from VIB and UAntwerp, headed by Prof.
Christine Van Broeckhoven, have demonstrated that if an affected parent
passes on this mutation, the children will be affected at a younger age
(than the parent). There are no indications that the disease progresses
‘In most families, the children were affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) at a younger age, but there were no indications that the disease was progressing more quickly.’
These results are published today in the international
scientific journal JAMA Neurology
Prof. Christine Van Broeckhoven (VIB-UAntwerp): "This research is
based on our team's previous results, which showed that the same C9orf72
mutation leads to both FTD and ALS. As this mutation occurs in a
substantial group of ALS and FTD patients, it is important to extract as
much knowledge about this mutation and the disease process as
Brain diseases associated with neurodegeneration
In FTD, the frontal lobes and
temporal lobes are affected first, causing changes in the patient's
behavior and personality, or problems with language. Loss of memory
functions occurs only later on in the disease. After Alzheimer's
disease, FTD is the most common form of dementia in young patients. A
fraction of the FTD patients show symptoms consistent with ALS, a
disease in which the nerve cells that control the muscles, in the brain
and spinal cord, are affected. This causes ALS patients to
progressively lose muscle mass, resulting in loss of strength in the
limbs and problems with speaking, swallowing, and breathing. ALS is more
common without FTD symptoms.
A common hereditary factor
Previous research by Prof. Van Broeckhoven's group demonstrated a
genetic link between FTD and ALS, namely a mutation in the same gene
Prof. Christine Van Broeckhoven (VIB-UAntwerp): "The C9orf72
mutation is the most frequent mutation in FTD and ALS. In the Belgian
population, 37% of patients with ALS and 25% of patients with FTD can be
explained by the presence of this C9orf72 mutation. The C9orf72
mutation is present in 88% of patients with FTD plus ALS."
dating from 2012 were published in The Lancet Neurology (Gijselinck et
al.). The mutation in C9orf72 consists of a repetition of a short DNA
sequence GGGGCC which can expand in patients up to several thousands of
repetitions. It is not yet known why some patients get FTD and others
The length of the C9orf72 repeat is determinative for the age of onset of the disease
The age at first presentation of disease symptoms ranges in
patients from 29 to 82 years, even in patients from the same family.
Until recently, there was no explanation for this high variability.
VIB-UAntwerp's researchers demonstrated in 2016 that the age of onset is
determined by the number of GGGGCC repeats: the more repetitions, the
earlier the age of onset. In C9orf72 families in which the affected
parent had a late age of onset and their affected children an earlier
age of onset, the researchers provided evidence that the GGGGCC repeat
in the C9orf72 gene expanded from a short sequence of repeats (less than
200 repeats) to a long one (more than a thousand) (Gijselinck et al.
Molecular Psychiatry 2016).
Dr. Sara Van Mossevelde (VIB-UAntwerp): "In a new clinical study in
36 C9orf72 families, we analyzed the age of onset of the patients in two
to four generations. We found that there was a significant difference in
the ages of onset between successive generations. In most families, the
children were affected by the disease at a younger age, but there were
no indications that the disease was progressing more quickly. We also
found that in families with both FTD and ALS patients, if the parent had
FTD the child was more likely to have FTD, and a similar principle
applied to ALS."