Are there any alternative names?
CLN3 disease, Juvenile may also be referred to as Juvenile CLN3 disease. It has previously been called Spielmeyer-Sjogren-Vogt disease and Juvenile Neuronal Ceroid Lipofuscinosis (JNCL); though was more commonly known as Juvenile Batten Disease.
What specifically causes CLN3 disease?
CLN3 disease is caused by mutations on the CLN3 gene, found on chromosome 16. The gene was discovered in 1995. While there are more than 112 different mutations associated with CLN3 disease, most patients have the same mutation (called the ~1kb deletion) which is present in 75% of all juvenile CLN3 disease.
The CLN3 gene codes for a transmembrane protein which is found in tissues throughout the body but currently the function of this protein remains elusive. Its role in lysosomes is the most well studied. CLN3 protein sits in the lysosomal membrane and is associated with many cellular functions such as maintaining the relative acidity (pH) of the lysosome which is important for the function of key enzymes involved in breaking down and recycling cellular components. Research into the primary function of the CLN3 protein is ongoing but gene mutations prevent the normal working of the protein resulting in the build-up of material that stops the cell from working properly. Light sensing cells (rods and cones) in the eye and neurons (nerve cells) are particularly vulnerable to the damage caused and, over time, this leads to the symptoms associated with CLN3 disease with loss of eyesight usually being the first symptom.
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 CLN3 disease?
CLN3 disease is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the CLN3 gene. Therefore, both biological parents of a child with this diagnosis will be carriers of the disease but physically unaffected by it.
A child born to parents who both carry the autosomal recessive mutation in the CLN3 gene has a 25% (1 in 4) chance of inheriting the abnormal malfunctioning genes from both parents and developing CLN3 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 the disease. 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, we refer to there being a 2 in 3 chance of a child being a carrier, once it is established that they are unaffected by the disease. 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 or young people will probably have been seen by a paediatrician and paediatric ophthalmologist due to a progressive loss of vision. A number of investigations will often have been undertaken to look for the cause of the presenting visual impairment.
The diagnosis of CLN3 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.
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?
Approximately 4 children are diagnosed with CLN3 disease each year in the UK. We estimate there are currently 35-50 affected children in the UK. Children have been diagnosed with this condition in many countries and from a variety of ethnic backgrounds.
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.
Children with CLN3 disease appear to be healthy and develop normally for the first few years of life. The first sign of the disease usually presents as a loss of vision between 4 and 7 years of age, which may first be noticed in a nursery or school environment. Each child's level of vision will change rapidly over a 6 - 12-month period initially, however it is likely that some awareness of colour along with variations between light and dark will be retained until later. By the end of their attendance at primary school, children tend to begin showing some difficulties with concentration, short-term memory, and learning. Many are still able to attend a mainstream school, though may require additional learning support in the classroom. Changes in behavioural patterns can become apparent at various stages of the disease and may prove particularly challenging to those around the child or young person. Professional and specialist support in addressing and managing this symptom is often required, though may not immediately be connected to the disease by those around the family.
The next stage of the disease begins with the onset of epileptic seizures (average age of onset is at 10 years old). Often, motor seizures are the first to present with violent jerking of the limbs and loss of consciousness. Seizures may be controlled by medicines for several months or years, yet will always recur, eventually becoming difficult to control completely. The pattern of seizures may change over time and other seizure types may evolve, such as vacant spells and episodes of partial awareness that may occur alongside episodes of "fiddling" behaviour and muddled speech.
During the teenage years, children and young people slowly become more unsteady on their feet. At around the same period their speech becomes repetitive then gradually more difficult to understand. Not uncommonly, children and young people demonstrate anxiety and may demonstrate a tendency to worry about a wide range of things. Some may even hear voices and sense or see things that are unreal. Teenagers are likely to become less able and increasingly dependent, yet the course of the disease is extremely variable even for those affected within the same family. Individual teenagers and young adults may present as much more able on some days as opposed to others. This can be particularly evident in terms of mobility, communication and feeding skills. The disease progresses with periods of stability that may last months or years. These tend to alternate with phases of deterioration lasting several months, which may sometimes be triggered by an intercurrent illness.
Children and young people affected by Batten Disease will develop childhood dementia, resulting in increasing learning difficulties, difficulties with short term memory, unusual behaviours, poor concentration, difficulties in sleeping, mood swings, hallucinations, confusion and anxiety. Although short term memory skills decline, long term memory remains largely intact and remains a strength.
Sadly, most children and young people who have CLN3 disease die between the ages of 15 and 35 years.
Are there any treatments?
Currently there is no cure for CLN3 disease and therefore specialist symptom management and therapy are essential to assist in maintaining a good quality of life for children and their families. Holistic support for parents, siblings and wider family members is extremely important throughout their journey.
Epileptic seizures start on average at age 10. The most common type are tonic-clonic seizures, where limbs can jerk, and loss of consciousness occur. Other types of seizure include partial seizures where only one part of the body is affected by abnormal movement and altered consciousness may not be obvious. A consultant neurologist's guidance is essential for managing seizures. The monitoring of effectiveness of medication on seizure control and checking for side-effects needs to be done as a collaboration between families of affected children or young people and their neurologist often working with other professionals such as GPs and specialist nurses.
Drug treatment of seizures depends on their severity and frequency. Anti-epileptic medications are often the first treatments introduced.
The anti-epileptic drugs carbamazepine and gabapentin have been found to be of no use in CLN3 disease.
Emotional, behavioural and psychological difficulties are common in all stages of CLN3 disease with the potential for psychotic episodes to appear in the later phases of the disease. These include restlessness, anxiety, panic attacks, aggressive behaviour, hallucinations, delusions and depression. Familiar supportive environments that are peaceful and structured can make a significant difference in managing these challenges along with a focus on promoting self-esteem and flexibly adapting activities to each individual's abilities (acknowledging that these can sometimes vary rapidly depending on fatigue, underlying illness etc).
Sometimes medication is of use in dealing with behavioural problems, hallucinations and agitation.
Sleep disturbance can be a problem in CLN3 disease. This is best managed by attention to sleep routine and making every effort to help with strategies that help a child or young person relax. If medication is needed, then options include melatonin or one of the drugs from the benzodiazepine family.
Deteriorating motor skills e.g. problems with balance and walking can be first addressed through promoting various activities such as walking, swimming, cycling and riding. Regular physiotherapy and other similar input should be utilised as the disease progresses with a focus on maintaining mobility for as long as possible and, although there can be great variation in each individual, there will ultimately be a need for mobility aids and other specialist equipment for which Occupational Therapy input is invaluable.
At some stage a child or young person with CLN3 disease is likely to develop difficulties with chewing and swallowing. It can become a challenge to maintain adequate nutrition and hydration which can lead to weight loss and problems giving medication. Symptoms of reflux can occur and may lead to distress and pain so causing behavioural disturbance. There may be difficulty with swallowing saliva leading to excessive dribbling. Difficulties in swallowing can sometimes cause choking and put a person at increased risk of chest problems.
Professionals including dieticians, speech and language therapists, physiotherapists, doctors, and nurses should be involved to help with these problems. Medications such as antacids and omeprazole or lanzoprazole to suppress excess stomach acid can be of use. Attention to correct consistency of food and correct positioning whilst being fed are important. Correct head support whilst sitting may help with dribbling.
Ultimately it may well be that insertion of a gastrostomy (feeding tube into the stomach) is the best way to make sure a child or young person can get enough food and drink and can be given their medication safely.
Various professionals including doctors, nurses, physiotherapists, occupational therapists, dieticians, ophthalmologists and speech and language therapists should be involved in the care of children and young people with CLN3 disease at various stages of the disease. They will work collaboratively and in conjunction with the family to provide a holistic approach to care.
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 investigating potential drugs which may alleviate some of the symptoms of the disease or slow its progression.
Gene therapy for CLN3 disease is being investigated, which aims to introduce a copy of the defective gene into the cells so that they can then produce a correct functioning protein within the brain and the eye. Researchers are looking into another type of gene therapy known as Anti-Sense Oligonucleotides (ASOs) that could correct the information used to make the protein rather than permanently adding a corrective gene.
Are there any clinical trials looking into CLN3 disease?
Miglustat is a drug approved to treat other diseases that affect the lysosome, including Gaucher disease type I and Niemann Pick disease type C. It works by reducing the build-up of substances that damage cells. As a result of this, a clinical trial to examine safety, pharmacokinetic and efficacy in Batten disease has taken place (NCT05174039), and details can be found on: https://clinicaltrials.gov/ct2/home. Hopefully this will go into further testing in 2025.
In addition to the above trial, there is an active trial using gene therapy (NCT03770572), and a safety trial due to start at the end of 2023 using a drug PLX-200 (NCT04637282).
There are currently two observational studies that are investigating the natural history of CLN3 disease. NCT01873924 is a study based in Rochester, USA and NCT04613089 is a study in Hamburg, Germany. While these are not investigating treatments, they are important studies 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 CLN3 disease is usually diagnosed in a child or young person means that some families will have younger siblings who may be affected but have not displayed any symptoms.
Older unaffected siblings may be carriers of the abnormal gene and may want to think about their family choices when they are older, such as the risk of their children having CLN3 disease. When only one parent is a carrier of the abnormal gene, and the other is non-affected, there is no chance a child will be affected, and a 50% (1 in 2) chance that any child will be an unaffected carrier like their parent.
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 CLN3 disease, families should be offered support from various professionals attached to their local health, social, educational services and the BDFA Support and Advocacy Team. Ideally a "Team Around the Child" will be formed, with one of the professionals appointed as a Keyworker for the family.
The child'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.
A child 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 child can vary, an individualised plan of care and support is essential.
How can families manage the financial challenges?
Caring for a child with CLN3 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 initially likely to be focused on addressing challenges associated with living with a visual impairment, though will ultimately include specialist seating, 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 or young person's needs.
It is likely that changes will be needed in the home environment to enable the family to appropriately care for a child or young person with CLN3 disease. These may initially include particular adaptations to promote independence for living with a visual impairment e.g. specialist lighting, tactile labelling, introducing contrasting colours for objects and areas, as well as installing suitable floor surfaces. In the latter stages of the disease, it may be necessary to install ramps, widen doorways or invest in a purpose-built wet room with a specialist bath or shower, whilst 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?
Education will continue to be important for the child or young person and family and there will be many aspects that require consideration and significant assistance from those around them. Specialist Visual Impairment services exist to support both children and young people and the education professionals working with them and these will play an important role in facilitating the appropriate quality of access to education for those affected by CLN3 disease. Communication is often another aspect that may need to be focused on should individuals begin to have difficulties with their speech.
Education, Health and Care Plans have now replaced statements. All children and young people with an NCL diagnosis will require an Education, Health and Care Plan. These plans are personalised plans that should meet the education, health and care needs of the child or young person. 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 a child who has variant late-infantile CLN3 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.