Are there any alternative names?
CLN10 disease, congenital may also be referred to as congenital neuronal ceroid lipofuscinosis, Cathepsin D deficiency, Cathepsin D deficient neuronal ceroid lipofuscinosis, Neuronal ceroid lipofuscinosis 10 or Neuronal ceroid lipofuscinosis due to cathepsin D deficiency.
What specifically causes CLN10 disease?
CLN10 disease is caused by mutations in the CLN10 gene, which is found on chromosome 11. The gene was identified in 2006 and there are at least 20 different mutations that are known to cause this type of Batten disease.
The CLN10 gene, also called CTSD, produces an enzyme called cathepsin D. This is a lysosomal protein that works by breaking down other proteins. Mutations that cause CLN10 disease mean this enzyme does not work and, consequently, proteins and fats are not broken down properly. The lysosomes cannot 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 CLN10 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 CLN10 disease?
CLN10 disease is inherited as an autosomal recessive disorder, which means that both chromosomes carry mutations in the CLN10 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 CLN10 gene has a 25% (1 in 4) chance of inheriting the abnormal malfunctioning genes from both parents and developing CLN10 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?
Some babies are born with microcephaly (an undersized head and brain). In the newborn period the babies have refractory seizures (doesn't respond to drugs) and apnoea's (breathing problems).
Babies will probably have been seen by a paediatrician and paediatric neurologist, because of these symptoms. A number of investigations will have been done to look for the cause of the seizures.
The diagnosis of CLN10 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, and by enzyme (cathepsin D) tests on blood samples. Genetic testing is recommended to identify the exact mutations or mistakes in the CLN10 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?
This is one of the least common forms of Batten disease. There are currently no cases in the UK.
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 affected by congenital CLN10 will have symptoms before or shortly after birth. These include microcephaly, problems controlling their movements, muscle stiffness, respiratory issues and seizures. These symptoms are due to the lack of Cathepsin D. These babies do not survive for long.
In some cases, people with CLN10 disease develop symptoms later in life such as during infancy, childhood or adulthood. In these individuals some cathepsin D is made but it does not work as well as it should. This may lead to a more gradual onset of symptoms including ataxia, loss of speech and vision and cognitive problems. The lifespan of later onset CLN10 individuals is shortened but varies depending on when their symptoms first started.
Are there any treatments?
Currently there is no cure for CLN10 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.
What research is being done?
Research into possible methods for treating the disease is ongoing with various theoretical approaches being considered and investigated.
Are there any clinical trials looking into CLN10 disease?
There are currently two observational studies that are investigating the natural history of CLN10 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 CLN10 disease is usually diagnosed in an infant means that some families will possibly have older unaffected siblings who 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 CLN10 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 CLN10 disease, families should be offered support from various professionals attached to their local health, social, educational services and the BDFA Family 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 considered.
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 CLN10 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?
Due to the severity of congenital CLN10 disease families will need support with coming to terms with the outcome. It is likely that an affected infant will spend the majority of their life in medical care so there is a need for help with caring for other children in the family.
Will there be an impact on the child's education?
Sadly, due to the presence of congenital CLN10 disease at birth and its rapid progression, the infant will not be attending an educational establishment. Support will be required for any siblings who are of an age to attend school, and parents will need guidance in managing this process.
In what other ways can families be supported?
The realities of caring for a child who has variant late-infantile CLN10 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.