Glossary

• DNA: The structure in the nucleus of every cell in the body is made of nucleic acids, which have the instructions to make ‘you’
• Nucleic acids: a type of molecule that is a part of DNA. There are four types found in DNA, ‘A’ ‘T’ ‘C’ and ‘G’, which in a specific order, make the instructions on how to make ‘you’
• Gene: Sections of the DNA that make proteins
• Proteins: The building blocks of all structures in the body, from the components in the cells to the fingernails
• Phenotype: The expression of genes that can be seen and recorded
• Penetrance: The number of individuals who carry a specific gene, who then also express the associated phenotype

Introduction

Dementia is a term used to describe the broad range of symptoms associated with damage to the brain, whether that be from a traumatic brain injury or a neurodegenerative disease, where the loss of function is gradual over time. Frontotemporal dementia, also known as frontal lobe dementia or Pick's disease, is a rare form of dementia that is defined by a loss of neurons around the frontal and temporal lobes of the brain, which are located on the front and both sides of the brain. Among the rarer dementias, this one is the most frequently found in individuals below the age of 65. Like other forms of dementia, there is no current cure or way to slow down the progression of symptoms, but there are palliative treatments that can make the symptoms more manageable. Frontotemporal dementia (FTD) can have a genetic basis in some people, meaning that the likelihood of developing the condition may be passed down in families. This means that offering Genomic counselling is vital in cases where a person is found to have a genetic cause of their FTD diagnosis. 

This article will outline the symptoms of FTD, how FTD can be diagnosed, the genetics of FTD and its heritability (how the condition is inherited from family), what a genomic counsellor is, and the role they play in the care of families with FTD.

What is FTD?

FTD is a neurodegenerative condition, which means it is a condition where the brain slowly loses function over time. A recent study identified that in Europe, cases of FTD are about 2.36 per 100,000 people. The name of the condition, frontotemporal dementia, comes from the fact that the degeneration occurs in the frontal and temporal lobes of the brain. 

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The degeneration of these lobes leads to some specific symptoms related to the function of these areas. The frontal lobe acts as a logic and emotional processing centre. When it is functional, it allows us to process our emotions, ruminate over decisions, and form memories, and it helps us make decisions based on emotional reasoning. The temporal lobe also acts in memory function but has some distinct functions, such as processing sensation, sight, touch, smell, and sound, and understanding language.

When these regions begin to degrade as FTD progresses, it commonly leads to these symptoms.

• Drastic personality changes, usually becoming more easily agitated, less emotionally sensitive, and less empathetic.
• Depressive symptoms include neglecting personal hygiene, overeating, and loss of motivation to do activities that formerly brought joy.
• Loss of ‘plastic’ thinking, such as being unable to imagine concepts, formulate plans, adapt to new plans or routines, and having poor organisational skills.
• Loss of memory and/ or an inability to form new memories.

The damage to the frontal and temporal regions of the brain that cause this damage is caused by the accumulation of proteins, which leads to damage to the brain tissue. In a recent paper, three main phenotypes (how the condition can appear) of FTD.

What are proteins?

In biology, proteins are the building blocks made by our DNA to make structures that the body needs. Every cell in our body has a full copy of our DNA, which was inherited from our parents at conception. Our DNA is the full instruction book of ‘how to make you’, and is written in a code we call nucleic acids, which are represented by the letters A, C, T and G. The order of these letters makes the instructions that our cells read. Genes are sections of DNA that make stuff that can be seen in the body; hence, genes are the sections comprising A, T,' 'A''T''C' and 'G' that tell the body to make stuff.

For example, if you have a gene for brown hair, you have a section of DNA that gives the instruction ‘make brown hair’. When that gene is ‘read’ and the cell gets the instruction to make what the gene dictates, the first thing that gets made is amino acids. Amino acids are a chain of molecules, and when this chain is folded into a specific 3D structure, this will make a protein. Sometimes, proteins are made of lots of the same chain folded together or different chains from different genes being fit together. These proteins then come together to make the brown hair that grows out of your body. which, when ‘read’, will make a chain

When the proteins are made and folded correctly, they make the specific structures to make stuff that the body needs. In FTD, the brain damage that occurs is caused by clumps of misfolded proteins, which cause brain damage, and as these clumps continue to grow, larger and larger areas of the brain continue to be damaged. These clumps of protein are known as convulsions.

What is the genetic basis for FTD? 

As proteins are made by your genes, which are a part of your DNA, if there is a ‘typo’ in a gene, this can cause a protein to be made incorrectly. As your DNA is inherited from your parents, if one or both of the parents carry the same ‘typo,’ this can be inherited by the offspring. These typos are known as genetic mutations, and the nature of the typo can vary from letters being deleted, repeated, or mistyped.

Genetic mutations can also happen by chance, without any previous occurrence in the family. These are known as sporadic cases.

FTD can either be sporadic or inherited, meaning either someone randomly acquired the mutation that causes the inclusions, or the mutation was passed down the family.

How is FTD diagnosed?

The only way FTD can be truly diagnosed is through autopsy, where the brain can be examined to see if the protein clusters are present at the frontal and temporal lobes. Before this, doctors will examine behavioural patterns and do investigative tests to rule out other potential causes such as infection, stroke, or injury, until all other possibilities are ruled out. It is known as a differential diagnosis.

If there is a known family history of FTD, then a genetic test can be ordered to find out if the gene has been inherited. However, only 40% of people with FTD have a known family history of FTD or other neurodegenerative conditions such as Alzheimer’s or Motor Neurone Disease. Of the 40%, only about 10% of that group will have a known FTD-causing gene identified. One of the main genetic panel tests, wherein multiple mutations are tested for from one sample, 28 genes for investigated.

If a test from a patient returns positive for a known FDS-causing gene, then the patient and their family can be offered genomic counselling.

What is a genomic counsellor? 

Genetic counsellors are highly specialised healthcare professionals who play a big part in delivering care for patients with genetic conditions and their families. Genomic counselling is not the same as counselling you would get from a psychologist. Their responsibilities can include diagnosing genetic conditions, investigating the cause and inheritance of a diagnosed condition, and empowering the family to make the right choice for them by educating them on the condition and all possible options in an empathetic manner.

How do genomic counsellors support FTD care?

Diagnosis

• When a suspected genetic cause to a condition is suspected or confirmed, the genomic counsellor will work alongside clinical geneticists to order the most appropriate tests to confirm a suspected genetic condition

Education, empowerment, and support

• The genomic counsellor will support the family in delivering news of the diagnosis and outlining all possible options for the extended family to also be tested
• The genomic counsellor should empower the family to make the best decisions possible for themselves, whether they choose to obtain a test or not. The counsellor's responsibility is to make all possible options clear so anyone can make a fully informed decision
• They will also educate the family about how having a genetic mutation can lead to the condition's presentation. Although a mutation can be associated with a condition developing, different mutations can have different penetrance, where a mutation only has a certain percentage of being expressed and causing disease

Investigation and heritability.

• The genomic counsellor can conduct an investigation by obtaining genetic tests for extended family or conducting interviews to find out about family history to draw a pedigree. A pedigree is a family tree with the line of inheritance included to show how the mutation is passed down
  • The inheritance could be found to be autosomal dominant, where only one copy of a mutated gene needs to be present to cause a condition.
  • Autosomal recessive, where a copy of a mutated gene needs to be inherited from both parents for a condition to present
  • Sex-linked traits are conditions that may be passed along the X or Y chromosome, so a condition may only be present depending on the sex of the offspring
  • Gonadal mosaicism, when in a parent, their body cells, also known as somatic cells, do not have a mutation, but some of their sex cells (sperm or egg), also known as gametes, do carry a mutation. This is an incredibly rare inheritance pattern, and it is equally rare that someone can inherit a condition from this

Family planning

•  Genomic counsellors can give options for future family planning. For example, they may conduct a genetic test during future pregnancies from samples of amniotic fluid
• There are also options for preimplantation genetic testing, wherein an egg is fertilised in the lab via IVF, and the fertilised egg can be tested to see if the developing foetus would carry the FTD-causing gene

Emotional well-being support

• Although genomic counsellors are not the same as psychological counsellors, they still employ counselling techniques to support the family during these discussions
• They will also look out for signs that someone may need more support, and can signpost patients to support groups. In the case of people and families affected by FTD, The Brain Charity, FTD Talk, Rare Dementia Support, and Alzheimer's Research UK are just some of the support groups available in the UK
• Genomic counsellors should be aware of the societal stigmas people with FTD and their families may face, and provide support in educating them about these issues and providing support

Summary

Frontotemporal dementia (FTD) is a progressive neurodegenerative condition. Much genetic research has been undertaken; however, only about 40% of cases include a clear family history, and only 10% of that group will have a clear disease-causing gene identified.

FTD has no cure, but symptom management can be undertaken to improve the patient's quality of life.

Genetic counselling is vital in delivering care plans for families who find a clear genetic cause. They will support finding how the condition is inherited, ordering appropriate tests, supporting future decisions in family planning, and finding peer and professional mental health and well-being support.