Now there is a twist. A study has found the existence of anticipation in diseases caused by different errors - not a DNA repeat - in fatal neurodegenerative disorder Familial Amyloid Polyneuropathy (FAP).
Familial Amyloid Polyneuropathy is a progressive and fatal neurodegenerative (where neurons die) disorder still without a cure or a clear mechanism. Like in many age-related neurodegenerative disorders including Alzheimer’s and Parkinson’s, the disease is linked to deposits of a mutated protein on neurons, which later die compromising whatever functions they normally control. In the case of FAP, the mutated protein is a liver protein called Transthyretin (TTR) and the neurons affected belong mostly to the autonomic nervous system, which controls many of our non-conscious visceral functions.
As a consequence, the symptoms that start by a tingling followed by loss of sensation in the lower limbs that spreads to the rest of the body, as the nerve destruction continues eventually reach the autonomic functions crucial to our survival. This leads to breathing and heart issues that result in death in as little as 10 years.
The latest discovery has two implications: first it opens the door to the possibility that many more diseases could show anticipation, including Alzheimer’s and cancer, like has been suggested but dismissed as experimental error. Second, though FAP is a fatal incurable disease, that it becomes worse from generation to generation might seem like bad news, but it has a very positive side: really knowing the mechanism of how the disease becomes worse means science might be able to stop it, and predicting the age of disease onset provides a transmission pattern that can help patients’ management.
The new study found an effect of gender on FAP onset with men having the disease earlier than women, suggesting a role for sex hormones in the disease and further unveiling this pattern.
There is no effective treatment for FAP, though liver transplants are sometimes done. In 2011, a new drug called Tafamidis (which binds the mutated protein, stopping its aggregation) was made available that can delay the disease’s progression. If initiated early enough, it can be very efficient arresting the nerve damage, though it cannot cure FAP.
Another puzzling aspect is that though the disease is rare, when it occurs it can show an incredibly high incidence devastating entire communities. A good example is Póvoa de Varzim and Vila do Conde, two of the most affected areas of Portugal (where FAP was first described) where 1 in every 1000 individuals has the disease, and 1 in every 538 are carriers of the mutated gene.
All this meant that the possibility that FAP had anticipation, if true, could represent a potentially important tool to understand the disease and, at the minimum, help patients’ management.
With this aim in mind the teams leaded by Alda Sousa decided to look into the largest database of FAP patients in the world, property of the Hospital de Santo António in Porto, Portugal. 2440 FAP patients from 572 families collected and studied over 70 years, since the disease was first described in the 60s in Portugal. From these, Lemos and colleagues used 926 pairs of parents and children, from 284 different families coming from all over Portugal. And what they discovered was a remarkable pattern of disease transmission.
FAP normally appears in adulthood but when the researchers discovered depended much from when the patients’ parents had the disease. For example while most parents with late onset disease (after 50 years of age) had early onset children (around 40 years of age), no early onset parent had late-onset children. Furthermore, the risk of having a very early onset (before 30 years of age) was high for the children of parents with an early onset (around 40 years of age), but null for those with parents developing PAF in their 70s. Finally, the older the parents were when the disease appeared, less probable was that their descendants had early or very early disease. The results were analysed statistically to assure that the differences were real, and the conclusion was that existed a clear pattern of children developing the disease earlier than their parents proving that FAP showed anticipation.
Interestingly Lemos and colleagues also saw that women tended to have later disease than men, whether among parents or children, revealing an effect of gender on FAP onset. This was confirmed by the observation that sons from affected mothers had the larger anticipations (difference between parent-child age of disease onset), while father-daughter pairs showed almost none.
Until now anticipation had only been proved in diseases caused by abnormal repeats of a piece of DNA, which are highly unstable and, as they pass between generations, tend to multiply even more causing an increase in disease severity. FAP, however, results from a point mutation (which if the TTR gene is seen like a beads necklace, it is a change in a single bead) and yet also shows anticipation. This proves anticipation as a real biological phenomenon, opening the possibility that it might exist in many other disorders.
As Lemos adds “Our results can have some important implications for other diseases caused by point mutations as well, since these mechanisms of anticipation (independent of repeat expansions) are still mysterious.” A potential implication will in the study of neurodegenerative disorders linked to age, which not only show a similar disease mechanism to FAP (deposits of abnormal proteins killing neurons) but have already been suggested to have anticipation.
For those carrying the TTR mutation, to prove the existence of anticipation and a gender effect reveals a pattern of disease transmission that will allow better counselling, and, most importantly, earlier detection and treatment, a crucial factor for Tafamidis ‘effectiveness. Also as Lemos adds “now that we gained more insight into parent-of-origin effects, a strategy to identify genetic modifiers should focus on families, rather than individuals, aiming to unravel the mechanisms of anticipation”
Although what causes anticipation in PAF is still a mystery, there are suspicions that it could result from several interacting factors in different families, including effects from other genes, epigenetic mechanisms (inherited mechanism that do not involve DNA change, for example an environmental influence) and/or hormonal effects. This last possibility has gained support with the present study showing that the age of disease onset seems to be different for women and men.
So what’s next? “Our current strategies are to search for genetic modifiers, within or closely linked to the TTR gene and to study candidate-genes, associated with TTR pathways that may also be influencing age of onset “ - says Lemos - “We are also looking for epigenetic mechanisms that may explain the observed variability in the different generations.”
After all, if we researchers understand why neural death starts earlier, they might be able to stop it.
Citation: Overcoming artefact: anticipation in 284 Portuguese kindreds with familial amyloid polyneuropathy (FAP) ATTRV30M, Journal of Neurology, Neurosurgery and Psychiatry 2014 Mar;85(3):326-30, doi: 10.1136/jnnp-2013-305383.