Are there any alternative names?
CLN14 disease, juvenile, was once thought to be an NCL as symptoms resemble those for NCL. It is no longer considered to be an NCL and is more properly also to be referred to as Progressive Myoclonus Epilepsy 3 (PME3).
What specifically causes CLN14 disease?
CLN14 disease is caused by mutations in the KCTD7 gene, which is found on chromosome7. The gene was identified as the cause of infantile progressive myoclonic epilepsy (PME) in 2007 and subsequently suggested to be CLN14 disease in 2013. There is only one known mutation causing CLN14 disease, the others cause PME or an opsoclonus-myoclonus ataxia-like syndrome, neither of which affect vision or cause NCL disease-like storage.
KCTD7 codes for protein called Potassium Channel Tetramerization Domain-containing protein 7 (KCTD7). The current function of the protein is unknown, but it interacts with other proteins involved in protein breakdown and evidence suggests it interacts with CLN5, another NCL gene. Mutations in KCTD7 prevent lysosomes from working 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 this 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 CLN14 disease?
PME3 is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the KCTD7 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 KCTD7 gene has a 25% (1 in 4) chance of inheriting the abnormal malfunctioning genes from both parents and developing CLN14 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, 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 learning difficulties and mood changes. A number of investigations may have been undertaken to look for the cause of these.
The diagnosis of PME3 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 KCTD7 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?
Most mutations in KCTD7 are associated with PME, opsoclonus-myoclonus ataxia-like syndrome.
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.
Infantile onset of PME3 symptoms include progressive myoclonic epilepsy, cognitive impairment, vision loss, motor regression and NCL-like storage material seen in pathology.
Are there any treatments?
Currently there is no cure for PME3 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.
Individuals with this disease responded to levodopa along with the development of levodopa-induced dyskinesias (abnormal, involuntary movements).
Epilepsy can be difficult to treat and therefore obtaining complete control of seizures is not always possible. Anticonvulsant medications will be necessary from the early stages of the disease process.
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. Along with spasticity (unusually tight or stiff muscles), these symptoms can be managed with different medications.
Various professionals including doctors, nurses, physiotherapists, occupational therapists and speech and language therapists should be involved in the care of children with PME3 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, skin and mouth care is essential and infants will 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 current consideration of several possible therapeutic strategies being investigated.
Gene therapy is an experimental treatment where the aim is to introduce a healthy copy of a defective (abnormal) gene into the patient cells. Small molecule therapies are also being investigated using compounds, or drugs, which may mimic the function of the enzyme.
Are there any clinical trials looking into CLN14 disease?
There are currently two observational studies that are investigating the natural history of NCL 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 PME3 is usually diagnosed in a child 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 PME3. 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 PME3, 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 PME3 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 a child with CLN14 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?
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.
The Children and Families Act (September 2014) introduced major reforms in provision for children and young people with Special Educational Needs (SEN). Many SEN services have Early Years and Childcare teams who can help identify and provide advice regarding the provision needed to support infants with complex needs. Local sensory services and organisations such as SENSE should be able to lend additional support.
In what other ways can families be supported?
The realities of caring for a child who has PME3 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.