In a previous post, I asserted that there are no single genes that are strongly associated with conventional mental illnesses (depression, schizophrenia, etc). However, there are individual genes linked to familial forms of neurodegeneration that do warrant a mention. In this post, we look at these genes in addition to single gene disorders that tend to cause neurological and mental illness co-morbidities.
What do I mean by single-gene conditions?
These are conditions caused by genetic variation to a single gene. For example, sickle cell anaemia is caused by a genetic change to the Haemoglobin B (HBB) gene. Inheritance patterns with single-gene conditions can be predictable, so we can reliably calculate the likelihood of future family members being affected by those conditions. There are a few different single-gene inheritance patterns. These are dependent on a couple of factors:
- Whether the disease state is dominant or recessive compared to the non-disease state. If dominant, only one copy of the changed gene is required for the disease to present. If recessive, two altered copies are required.
- Where in the genome the gene is located. Is it on a numbered chromosome (or autosome), X or Y chromosome, or part of the mitochondrial genome?
If you would like to know more about inheritance patterns, there is a free 30-minute online lesson on it here. Additionally, with these single-gene conditions, relatively quick genetic tests can be used for a couple of purposes:
- Diagnostic testing: To confirm a diagnosis in individuals who have started to show signs and symptoms of a condition.
- Predictive testing: To predict whether a condition will manifest in a currently asymptomatic individual later in life.
Single-gene Neurodegenerative Conditions
- Gene: Huntingtin (HTT)
- Inheritance pattern: Autosomal dominant (like that seen in the title image). If the condition is passed down from generation to generation (especially when paternally transmitted), the genetic change is likely to become more pronounced (a phenomenon referred to as ‘anticipation‘). This can make the condition manifest at an earlier age, and progress at a faster rate.
- Clinical features: Differing mental health symptoms in the early stages. These can include mood disorders, personality change, concrete thinking, psychotic symptoms, irritability, disinhibition, and suicidality. Progressive decline in motor function; characteristic involuntary movements of the face, limbs, and trunk. Significant weight loss. Progressive and global decline in cognitive function. The onset of symptoms is likely to occur around the age of 35, and death usually occurs 10-15 years after the onset of symptoms.
- Commentary: One of the first conditions to be mapped to a specific gene, Huntington’s Disease (HD) is also one of the most well-known genetic conditions. It is arguably the most likely single-gene condition to lead to adult mental health services involvement (due to the potential for psychotic symptoms and suicidal ideation to manifest before significant movement disorder and cognitive impairment is seen). The genetic variation that leads to the onset of HD tends to be isolated to one specific region of the gene, making the genetic test for HD very straightforward. However, intensive genetic counselling is required before the test is agreed to. This is because there is no cure for the condition, and a positive result can have serious implications for close family members (e.g. siblings and children). If psychotropic medication is considered necessary, olanzapine is often prescribed. This can have mood stabilising and antipsychotic effects, but the obesogenic effects of olanzapine can be viewed as an unorthodox strength when used for a condition that usually results in weight loss.
- Genes: LRRK2, PARK7, PINK1, PRKN, or SNCA
- Inheritance Pattern: Depends on the single gene that has been affected. Autosomal dominant for LRRK2 or SNCA; Autosomal recessive for PARK7, PINK1, or PRKN. However, 85% of cases involve none of these genes and are sporadic in nature.
- Clinical features: Early symptoms usually involve a distinctive movement disorder (e.g. fine tremor, bradykinesia, muscle rigidity) similar to extrapyramidal side effects of 1st generation antipsychotics. Progressive cognitive impairment. Possible onset of mood disorder and psychotic symptoms.
- Commentary: Genetic testing will not always be considered with Parkinson’s disease, due to most cases not having a single-gene cause. However, early onset of symptoms or a strong family history may prompt the option of genomic testing. The onset of psychotic symptoms can be made more likely if an individual is prescribed levodopa for movement disorder-related symptoms. In addition, levodopa may also lead to personality changes and impulsive/hedonic behaviours. If antipsychotics are considered necessary, a weak dopamine receptor antagonist (e.g. clozapine or quetiapine) is usually prescribed. This is to prevent an exacerbation of movement disorder symptoms.
- Genes: Amyloid Precursor Protein (APP), Presenilin 1 & 2 (PSEN1 & PSEN2)
- Inheritance Pattern: Any pathogenic alterations to genes above lead to an autosomal dominant inheritance pattern. However, 95% of cases involve none of these genes and are sporadic in nature.
- Clinical features: Progressive decline in cognition. Memory is significantly affected, with anterograde amnesia as an early symptom. Possible mood disorder, agitation and psychotic symptoms as the condition progresses. Histopathology will show the unnatural accumulation of amyloid plaques between neurons and neurofibrillary tangles within neurons.
- Commentary: In most cases, symptom onset is past 65. However, early-onset symptoms are likely to be due to genetic variation. This means that, as with Parkinson’s disease, unless there is an early presentation (younger than 55), or there is a strong family history, genomic testing is unlikely to be offered. In addition to APP and PSEN1&2 genes, the ε4 variant of the APOE gene is associated with an increased risk of developing Alzheimer’s Disease. Two copies of the ε4 variant will increase the likelihood of dementia by 10-fold. It is thought that up to 30% of all cases of Alzheimer’s are due to this variant (Royal College of Psychiatrists, 2023). However, because the ε4 variant doesn’t necessarily lead to the onset of dementia, it isn’t tested for within the NHS. Individuals with Down’s Syndrome are highly likely to show symptoms of Alzheimer’s disease past the age of 50. The APP gene is found on Chromosome 21, so individuals with Down’s Syndrome will have three copies of the APP gene instead of two. This leads to a greater production of Amyloid Protein, which contributes to a pathogenic buildup of amyloid plaque.
Frontotemporal Dementia (FTD):
- Genes: Many different ones. However 95% of all inherited cases involve GRN, MAPT & C9orf72
- Inheritance Pattern: Around 30% of cases are hereditary, and these follow an autosomal dominant inheritance pattern. The other cases are sporadic.
- Clinical Features: This is more of a family of neurodegenerative conditions with common molecular features. Signs and symptoms can vary dramatically between individuals – even between affected family members. Likely to be described as one of the following:
- Behavioral Variant Frontotemporal Dementia (bvFTD; previously referred to as Pick’s Disease): Changes in personality and behaviour, and impaired judgment.
- Primary Progressive Aphasia (PPA): Expressive and receptive aspects of communication become increasingly impaired. There may also be behavioural changes.
- Movement disorder variants: Two of these variants have similar motor symptoms to Parkinson’s Disease (progressive supranuclear palsy; frontotemporal dementia with parkinsonism). Other variants cause different types of motor dysfunction.
- Commentary: Although FTD is considerably rarer than Alzheimer’s Disease, there are as many cases of early-onset familial FTD as there are early-onset familial Alzheimer’s Disease. Different variants of FTD are associated with different levels of heritability: A strong family history is seen in nearly 50% of individuals with bvFTD, but only 12% of individuals with PPA. Regardless of the clinical presentation however, the Royal College of Psychiatrists (2023, Pg 8) recommends that genetic testing should be considered for all individuals suspected of having FTD.
Other Neurodegenerative Conditions Of Note
CADASIL and CARASIL are autosomal dominant and recessive versions of a rare type of multi-infarct dementia. In other words, small but numerous ischaemic strokes occur (regardless of lifestyle in affected individuals) over a number of years, leading to steady decrease in cognitive function.
Single-Gene Neurological Conditions that Affect Mental Health
As we saw with the post on Chromosomal changes, Copy Number Variants and Mental Health, there are a number of conditions that lead co-morbid learning disabilities and complications with mental health. Although there are numerous genes where single-gene pathogenic alterations may lead to learning disability and behavioural disturbance, there are two genes that need particular mention, as they are the most likely to lead to mental health nurse intervention.
Tuberous Sclerosis Complex (TSC):
- Genes: Tuberous Sclerosis Complex 1 & 2 (TSC1 & TSC2).
- Inheritance Pattern: Autosomal dominant. Occurs as a spontaneous genetic change in 70% of cases.
- Clinical Features: Widely variable signs and symptoms, based on the growth of multiple benign tumours over the body. These can occur over the skin, heart, kidney and brain. Benign growths in the brain result in a wide variety of neurological symptoms, referred to as TAND (TSC-Associated Neuropsychiatric Disorders). Symptoms of TAND include intractable seizures, learning disabilities, learning differences (e.g. ADHD and Autistic Spectrum Condition (ASC)) and mental illness. For more detail on the mental health considerations, see the TAND checklist here. TSC can be life-threatening due to the potential for treatment-resistant seizure activity, cardiac failure, or renal failure.
- Commentary: Around 50% of individuals with TSC will have global intellectual abilities within normal range. However, there are likely to be specific aspects of intellectual disability that will vary from individual to individual (depending on the location of the benign growths within the brain).
- Gene: FMR1
- Inheritance Pattern: Described as X-linked dominant, although women are likely to show milder symptoms. As with Huntington’s Disease, an increase in genetic change (or anticipation) may lead to more severe symptoms in offspring. With FMR1 however, anticipation is only seen when the genetic change is maternally transmitted.
- Clinical Features: Fragile X is the most common single-gene cause of learning disabilities and ASC. Delayed speech and language development; Particular difficulties with numeracy, visuospatial skills and visual motor abilities. Symptoms of ADHD likely, as well as ASC. Social anxiety with aversion to eye contact are very likely. Self-injury (e.g. hand-biting) likely to occur with frustrating or anxiety-provoking situations. Obsessive-compulsive features are likely. Distinctive facial features (long face; protruding ears; prominent jaw). Macroorchidism (large testicles) in males. Physical health complications include joint hypermobility, aortic dilatation and/or mitral valve prolapse. One in five/six will be diagnosed with epilepsy.
- Commentary: Individuals with a ‘premutation’ (a genetic change that does not bring about the full syndrome) are described as ‘carriers’. Carriers may show some neuropsychiatric features. 50% of individuals experience depression and anxiety, insomnia, chronic fatigue, chronic pain, or fibromyalgia. Carriers are also at risk of developing an age-related form of neurodegeneration called fragile X-associated tremor/ataxia syndrome (FXTAS).
Why This Matters as a Mental Health Nurse
With familial neurodegenerative conditions, it’s important to identify these as soon as possible through diagnostic genetic/genomic testing. Although psychiatrists would order the test, mental health nurses could advocate for the test to be ordered. Service users may be eligible if they show symptoms of FTD, develop symptoms at a young age (usually before 50), or have a first degree relative (father, mother, brother, or sister) with the same neurodegenerative condition. Conventional clinical management options are likely to be tailored to the diagnosis, and there are clinical trials that could potentially lead to a more permanent halt in the progression of the condition. Relatives of family members may want to know of the chances that they may develop the condition themselves, and may pursue a predictive genetic test. There may even be the possibility of individuals seeking pre-implantation genetic testing (a form of IVF where embryos can be selectively chosen to not have the familial pathogenic genetic change).
Likewise, children with learning disabilities/ developmental delay with co-existing dysmorphic features or familial clustering may be eligible for a referral to genomic services. Genetic testing and counselling options could then be offered to the immediate family.
Picture References
- Autosomal Dominant Pedigree Chart (2022) Adapted by Ben Murphy from Jerome Walker (Creative Commons).
- Fragile X (2014) Peter Saxon (Creative Commons)
- Mustaqim K, Mohd Ghazi A, Harun Nor Rashid S (2013). “Managing Different Spectrums of Tuberous Sclerosis Facial Angiofibroma: A Report of Two Cases”. Cureus 15 (2). DOI:10.7759/cureus.35200
Information Source References
- Genomics Education Programme: Genomics Glossary
- Genomics Education Programme: Genomics 101: Dominant, Recessive and Beyond
- National Institute for Health and Care Excellence (NICE): British National Formulary (BNF)
- National Institutes of Health: Frontotemporal Disorders
- National Institutes of Health: MedlinePlus Genetics
- The Royal College of Psychiatrists: The role of genetic testing in mental health settings
- The Society for the Study of Behavioural Phenotypes (SSBP): Syndrome Information Sheets.
- TSC International: TAND Checklist
- YouTube: Impact of HD Chorea: Examples of Movement
- YouTube: 7 Motor Symptoms of Parkinsons Disease
