Are there any alternative names?
CLN11 disease may also be referred to as GRN-related Neuronal Ceroid Lipofuscinosis.
What specifically causes CLN11 disease?
CLN11 disease is caused by mutations in the GRN gene, which is found on chromosome 17. The gene was discovered in 1991 and there are at least 9 mutations that are associated with CLN11 disease. Mutations in the CLN11 gene are responsible for two quite different clinical diagnoses depending on whether the second copy is normal or also mutated.
GRN normally encodes a protein called progranulin which is active in many different tissues of the body, where it helps control growth and survival of cells, particularly nerve cells. It is thought to be involved in proper lysosomal function and when absent, the cells are unable to dispose of or recycle material correctly and there is build-up of material inside cells that stops them working properly. Neurons (nerve cells) are particularly vulnerable to the damage caused and, over time, this leads to symptoms associated with CLN11 disease.
How are NCLs inherited?
Most forms of NCL are bi-allelic disorders where the inheritance "autosomal recessive". This is one of several ways that a trait, disorder, or disease can be passed down through families. An autosomal recessive disorder means that both copies of the gene are abnormal (one inherited from each parent) with neither working properly. The parent (or a sibling) carrying only one abnormal gene is healthy because the second copy of the gene is still working. The disease does not depend on the sex of an individual.
What are the chances of inheriting CLN11 disease?
CLN11 disease is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the CLN11 gene. Therefore, both biological parents of a child with this diagnosis will be carriers of one defective CLN11 gene. This unfortunately means they could be affected by Frontotemporal Dementia (FTD) as some cases of FTD have been found to be caused by mutations on one copy of the CLN11 gene.
A child born to parents who both carry the autosomal recessive mutation in the CLN11 gene has a 25% (1 in 4) chance of inheriting the abnormal malfunctioning genes from both parents and developing CLN11 disease. They will have a 50% (1 in 2) chance of inheriting one abnormal gene, which would make them a carrier who is unaffected by CLN11 disease but might mean they develop FTD when an adult (like their parent).
There is a 25% (1 in 4) chance of the child being born with two normal genes and therefore being non-affected (not a carrier).
When it is known that both parents are carriers of the abnormal gene, and a child is already known to be unaffected, we refer to there being a 2 in 3 chance of a child being a carrier. With any pregnancy, the probability of a child inheriting one or both genes from their parents is the same each time, irrespective of any sibling's status.
How is it diagnosed?
Children will probably have been seen by a paediatrician and paediatric neurologist, because of symptoms such as seizures. A number of investigations will have been done to look for the cause of the seizures.
The diagnosis of CLN11 disease is usually made by genetic tests, looking at lots of genes at the same time, all of which are known to cause the same type of symptoms as Batten disease. A blood or saliva sample will be taken to extract DNA from the cells for the test. Genetic testing is recommended to identify the exact mutations or mistakes in the CLN5 gene.
In the past, before the NCL genes were identified, blood or skin cells were looked at using an electron microscope to see the abnormal storage bodies in the cells. These can have characteristic patterns, depending on the type of NCL.
How common is it?
CLN11 disease is extremely rare with only 11 cases reported in the scientific literature.
What are the symptoms and how does the disease progress?
Usually, the affected individual appears to be healthy and develop normally until symptoms start. There are various differences in terms of the age of onset and the progression of each genetic variant. Each variant will have a usual age range where symptoms start to appear although individuals may be described as atypical onset if they become symptomatic outside of the normal age range.
Symptoms begin in childhood, adolescence or early adulthood and is characterized by rapidly progressive loss of vision due to retinal dystrophy (retinitis pigmentosa), seizures (often involving a loss of consciousness, muscle stiffness (rigidity), and generalized convulsions (tonic-clonic seizures), problems with balance and coordination (cerebellar ataxia) and cognitive decline. Affected individuals may also develop cataracts and a rapid, involuntary movement of the eyes (nystagmus).
Other symptoms can include muscle twitches (myoclonus), walking problems and falling, impaired speech (dysarthria), short-term memory loss, impaired executive functioning, irritability and impulsiveness, and visual hallucinations.
Are there any treatments?
Currently there is no cure for CLN11 disease and therefore specialist symptom management and therapy are essential to assist in maintaining a good quality of life for affected individuals and their families. Holistic support for parents, siblings and wider family members is extremely important throughout their journey.
Epilepsy can be difficult to treat and therefore attaining complete control of seizures is not always possible. Anti-epileptic drugs will be necessary from the early stages of the disease process, however the response to these from variant late-infantile CLN11 patients is often poor after some initial benefit. Myoclonic (involuntary muscle spasms) seizures can be worsened with the use of medications such as lamotrigine.
Various professionals including doctors, nurses, physiotherapists, occupational therapists and speech and language therapists are all likely to be involved in the care of the individual with CLN11 disease. They will work collaboratively and in conjunction with the family to provide a holistic approach to care.
Support and treatment will be needed for a range of issues including progressive difficulties with chewing and swallowing, oral secretions, motor disorder and sleep disturbance. Some individuals may even require drug treatment for behavioural issues though this must be carefully balanced with seizure control. Attention to mobility, posture, skin and mouth care is essential and many will eventually require additional nutritional support that may include consideration of a gastrostomy.
What research is being done?
Research into possible methods for treating the disease is ongoing with various theoretical approaches being considered and investigated. Researchers in the UK and worldwide are looking at potential drugs which may alleviate some of the symptoms of the disease or slow its progression.
Are there any clinical trials looking into CLN11 disease?
There is currently an observational study, NCT04613089 in Hamburg, Germany, investigating the natural history of CLN11 disease. While not investigating treatments, observational studies are important for future trials as they provide valuable information on how Batten disease progresses over time. If you are considering participating in a clinical trial, please contact us at the BDFA. The information for these clinical trials can be found on: https://clinicaltrials.gov/ct2/home.
What are the genetic considerations?
The age that CLN11 disease is usually diagnosed means that some families will have younger siblings who may be affected but have not displayed any symptoms. Older unaffected siblings may have a mutated copy and be at increased risk for developing frontotemporal dementia later in life. This may affect their family choices when they are older.
If parents who already have an affected child are considering having additional children, they can access specialist advice and support from their local clinical genetics service following a referral from their GP. Prenatal testing may be possible in the early stages of any future pregnancy.
Is support available to families?
As soon as possible following a diagnosis of CLN11 disease, families should be offered support from various professionals attached to their local health, social, educational services and the BDFA Support and Advocacy Team.
The individual's needs should be discussed with the parents and assessed by the team. The team will work together to ensure that the child and family receive the on-going care and support they need and that their choices are taken into account.
The individual's and family's needs will inevitably change as the disease progresses. As such, it is often helpful if a clear process for regular planned reviews is identified and that a system is established for enabling additional reviews as and when they are deemed necessary. As the rate or pattern of the progression of the disease for each individual can vary, an individualised plan of care and support is essential.
How can families manage the financial challenges?
Caring for an individual with CLN11 disease will bring additional financial challenges. It is vital that families are well informed about the full level of economic assistance available and the support that they are entitled to. They may well need help and guidance in accessing benefits and other sources of assistance. The professionals and services supporting the family should provide advice and guidance. The BDFA can also support families with these issues in various ways, the Small Grants Scheme being one example.
What are the practical implications for the family?
As the disease progresses, specialist equipment and aids will become necessary, and this is another area where the family will need help. Items are likely to include specialist seating, buggies/wheelchairs, bathing and toileting aids, hoisting equipment and a specialist bed/mattress. Professionals will play a key role in ensuring that these and other items are provided in a timely manner following proper assessment of the individual child's needs.
It is likely that changes will be needed in the home environment to enable the family to appropriately care for an individual with CLN11 disease. These may include installing ramps, widening doorways and providing suitable floor surfaces. A purpose-built wet room with a specialist bath or shower is commonly needed and there are various other aspects that will require consideration.
There are grants and funds available to ensure that the work involved is affordable. An occupational therapist will consult on all aspects of any adaptations and assist the family in undertaking this process.
Will there be an impact on the child's education?
Whether education or work will be affected is dependent on the age of symptom onset but will continue to be important for the individual and family and there will be many aspects that require consideration and significant assistance from those around them.
The Children and Families Act 2014 came into force in September 2014. The introduction of the 0-25 Education, Health and Care Plan should help children, young people and families affected by NCL. Education, Health and Care (EHC) Plans will gradually replace Statements of Special Educational Needs.
Children who do not yet have a Statement will have a statutory Education, Health and Care Needs assessment. An EHC Plan will be drawn up that is personalised to meet the education, health and care needs of the child.
It remains probable that many parents will continue to need guidance, understanding and support when trying to navigate the process of statutory assessment and the drawing up of the EHC Plan.
In what other ways can families be supported?
The realities of caring for an individual who has CLN11 disease can place enormous strain on a family, both physical and emotional. It will impact upon all members in numerous ways and so being made aware that support is available to groups and individuals to help with the challenges that will be faced is important. This support extends to wider family members and step-relatives.
There are several options to consider should families wish to explore ways of maximising the limited time available to share with their children. Contacting a charitable wish granting organisation may lead to them being able to create some valuable and significant memories.
It may also be appropriate for a referral to be made to a local children's hospice service, as this can offer an additional experienced and skilled source of holistic support.
Contributors- BDFA Head of Scientific Affairs, Professor Paul Gissen, Clinical Professor of Paediatric Metabolic Medicine, Professor Sara Mole, Professor of Molecular Cell Biology, Genetics & Genomic Medicine.
Some of the information contained in this leaflet is based upon chapters in "The Neuronal Ceroid Lipofuscinoses (Batten Disease) 2nd Edition" by Mole, Williams & Goebel (Eds), Oxford University Press 2011, and is used with permission.