Are there any alternative names?
CLN4 disease, adult may also be referred to as adult neuronal ceroid lipofuscinosis, ceroid lipofuscinosis, neuronal, 4B, autosomal dominant; CLN4B; Kufs disease type A and Parry disease.
What specifically causes CLN4 disease?
CLN4 disease is caused by a mutation in the DNAJC5 gene, which is found on chromosome 20. The gene was identified as a causal agent of this form in 2011 and there are only 4 mutations known to cause CLN4 disease.
DNAJC5 is responsible for making a protein called cysteine string protein alpha (CSPa) that is found in the brain where it works in recycling proteins involved in nerve impulse transmission. Proteins which should be recycled are not which results in a shortage of these important molecules and affects normal communication between nerve cells. There is also 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 CLN4 disease.
How are NCLs inherited?
CLN4 disease is an autosomal dominant inherited disorder which means only one chromosome carries a mutation in the gene and that causes disease even though the other gene is fine. Most likely one of the parents is also affected. The disease does not depend on the sex of an individual.
What are the chances of inheriting CLN4 disease?
CLN4 disease is inherited as an autosomal dominant disorder, which means that only one chromosome carries mutations in the CLN4 gene. Therefore, one of the biological parents of a child with this diagnosis will be both a carrier of the disease and physically affected by it.
A child born to parents where one carries the autosomal dominant mutation in the CLN4 gene has a 50% (1 in 2) chance of inheriting the abnormal malfunctioning gene from that affected parent and developing CLN4 disease. There is a 50% (1 in 2) chance of the child being born with two normal genes and therefore being non-affected (not 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?
CLN4 disease is extremely rare and difficult to diagnose. It first appears later than most of the NCL diseases: sometimes in adolescence but often not till the patient is aged around 30 or even older. It usually presents as myoclonus epilepsy but over time, the disease advances and the symptoms get worse.
The diagnosis of CLN4 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 CLN1 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?
CLN4 disease is very rare. We estimate there are currently less than 2 affected adults in the UK. People have been diagnosed with this condition in other 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.
Adolescents and adults appear to be healthy and develop normally until 15-30 years of age. The most common presenting symptom is progressive myoclonus epilepsy although sometimes cognitive decline (dementia), behavioural problems or motor changes may develop before seizures. They have frequent uncontrollable muscle jerks (myoclonus epilepsy), infrequent tonic-clonic seizures, coordination and balance issues (ataxia) and photosensitivity. Vision remains unaffected but dementia is inevitable. Disease progress is generally slow but variable in the symptom inset and progression even between family members.
Sadly, most people who have CLN4 disease die during about 15 years after symptom onset.
Are there any treatments?
Currently there is no cure for CLN4 disease and therefore specialist symptom management and therapy are essential to assist in maintaining a good quality of life for the 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 obtaining complete control of seizures is not always possible.
Myoclonic jerks (involuntary muscle spasms) are common, though should not be confused with epileptic seizures. They can interfere with rest and sleep as well as being distressing for children and their families.
Spasticity, characterised by unusually tight or stiff muscles, can be managed with baclofen.
Various professionals including doctors, nurses, physiotherapists, occupational therapists and speech and language therapists should be involved in the care of people with CLN4 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, constipation, hydration, respiratory function, oral secretions, motor disorder and sleep disturbance. Attention to posture, seating, skin and mouth care is essential and adults will require additional nutritional support that will 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 researching potential drugs which may alleviate some of the symptoms of the disease or slow its progression.
Are there any clinical trials looking into CLN4 disease?
There are currently two observational studies that are investigating the natural history of CLN4 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 CLN4 disease is usually diagnosed means that some families will have younger siblings and/or children of their own who may be affected but have not displayed any symptoms. If one parent is affected, and the other is non-affected, there is a 50% (1 in 2) chance that any child will be affected by the disease.
If parents 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 CLN4 disease, families should be offered support from various professionals attached to their local health, social, and the BDFA Support and Advocacy Team.
The individual's needs should be discussed with the family and assessed by the team. The team will work together to ensure that the affected individual and family receive the on-going care and support they need and that their choices are taken into account.
The 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 adolescent or adult with CLN4 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, 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 CLN4 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?
The impact on education will be determined by the age of symptom onset as affected individuals are usually of an age to be in full time employment. Education and or employment will continue to be important and there will be many aspects that require consideration and significant assistance from those around them.
There will be a requirement for assistance from social services as the disease progresses. It remains probable that many families will need guidance, understanding and support when trying to navigate this process.
In what other ways can families be supported?
The realities of caring for an individual who has adult CLN4 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 family member. 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.