What is a CLCN4 related condition?

CLCN4 related conditions (or CLCN4 for short) are caused by changes (or ‘glitches’) in the CLCN4 gene that stop the gene from working properly. 

The CLCN4 gene is located on the X chromosome and is needed to help regulate and control brain development and function.  More information about genes and chromosomes can be found here.

No two individuals with CLCN4 are the same.

No two individuals with CLCN4 are the same. Even family members with the same genetic change in their CLCN4 gene can experience a different range and severity of symptoms.

Females and males can both be affected by CLCN4. The impact on females often varies depending on whether they are the first person in the family to have the CLCN4 genetic change (de novo), or they inherited the genetic change from a parent (more details below).  All males with a glitch in the CLCN4 gene will develop some symptoms, but as highlighted below, the number and severity of  these symptoms range hugely between individuals. 

What are the main symptoms of CLCN4 and how should they be screened for and treated?

Glitches in the CLCN4 gene have been linked to a range of symptoms affecting the nervous (neurological) system, including learning and behavioural challenges, epilepsy, vision and movement (motor) function. Currently there are less than a hundred families identified around the world with CLCN4 changes, so we are still learning about this condition.   As we learn more about CLCN4, the following symptoms are more commonly seen.  It is really important to recognize that not every person with CLCN4 will get all these problems: they may only get one or a few, and to varying degrees of severity. 

1. Impact on learning and development 

To date all males with CLCN4 and all females with a de novo CLCN4 gene change have some degree of learning difficulty. This may range from normal ‘IQ’ score with specific learning difficulties, to individuals with borderline, mild, or moderate-severe intellectual disability.

Females who have an inherited change in the CLCN4 gene may have completely normal learning ability or may have mild learning difficulties. We are aware of at least one female with an inherited CLCN4 variant who has severe intellectual disability. We have more to learn about why there is such a wide variation in how CLCN4 affect girls and women.

It is therefore important that all individuals with CLCN4 see a developmental pediatrician or learning specialist (such as an educational and clinical psychologist and/ or  school counsellor) so that their learning strengths and challenges can be  properly assessed and appropriate early intervention or specialist schooling or educational support put in place.

Both girls and males and females often have speech and language development particularly affected (children often are slower to learn to speak) and speech support should be a particular focus of early intervention.

In the UK, children and young people with a learning disability should be assessed for special educational needs (SEN): more information can be found here.

In Australia, children and adults with a learning disability will qualify from support through the NDIS (National Disability Insurance Scheme) : more information on the NDIS can be found here. Your paediatrician and clinical geneticist can write a letter of support for your NDIS application.

In the US, children with CLCN4 should be eligible to access funded early intervention due to the known association of CLCN4 and developmental delay: more information can be here and programs pre and post school are summarized here.

The following supports may be recommended:

Prior to school entry:  speech pathology (to help with motor control of speech and feeding) and / or speech and language therapy (to help with communication), occupational therapy (to help with fine motor development and learning to do everyday things like dressing and eating and taking part in activities at and outside the home).  

Physiotherapy (to help with gross motor activities such as walking and climbing stairs).

During school: assessment by school counsellor and special educational needs teacher. The above listed therapies (speech, OT and physiotherapy) may also continue to be helpful.

After school: additional support for specialist education and training. The above listed therapies (speech, OT and physiotherapy) may also continue to be helpful.



2. Autism

About 4 out of 10 boys, and 2 out of 10 girls with CLCN4 have symptoms that would fall into the autism spectrum. More information can be found about autism spectrum here . It is important that any concerns regarding a possible autism spectrum diagnosis are carefully checked, so that children or adults with this additional diagnosis can get appropriate assessments and support.

3. Epilepsy

About half of all individuals with CLCN4 have a diagnosis of epilepsy over their lifespan. Most often epilepsy will start in early childhood, but occasionally it may start as late as teenage years. More information about what epilepsy is, how to cope and live with epilepsy, and information on treatments and therapies can be found here.

 It is recommended that any unusual movements, ‘blank spells’ or ‘funny turns’ be discussed with a doctor. Any concerns that an individual may be having epileptic seizures should be investigated, for example EEG (brain wave recording). It can also be helpful for a relative or carer to video any events that they think might be epileptic seizures on their smartphone or camera and to keep a record of that information to share with their doctors, for example using an event record or diary.

4. Other neurological (nervous system) impacts

Although some individuals with CLCN4 have completely typical motor (movement) development, many children will be slower to meet their early childhood milestones of sitting, standing and walking. Many children have lower body muscle tone as a baby or young child. Physiotherapy can be very helpful. A proportion of children when walking are noted to walk with a wide stance, be somewhat hesitant, and may have some unusual movements (hand flapping or tremor). It is therefore helpful for a neurologist (nervous system specialist) doctor to carefully assess these aspects and advise on appropriate therapies. 

5. Feeding difficulties, gastro-oesophageal reflux, constipation and/ or slower growth

A proportion of children with CLCN4 have ‘functional’ gastrointestinal symptoms such as gastroesophageal reflux, constipation or difficulties with feeding and gaining weight. In particular, slow gains in weight, height and head circumference have been linked to specific genetic changes within the CLCN4 gene, (such as the recurrent amino acid substitution from arginine to valine at position 555 of the protein p.Ala555Val recurrent genetic variant in females).

It is recommended that all children have regular weight, heights and head circumferences measured by their family doctor and/ or paediatrician. Symptoms of gastroesophageal reflux and constipation should be checked for and treated. If there are concerns regarding growth, a referral to an endocrinology (hormone) specialist doctor may be appropriate.


6. Hearing and vision

For all children with an increased chance of developmental delay, it is important that their hearing and vision be checked, and we recommend all individuals with CLCN4 get a formal vision (eye) and audiology (hearing) check.  A small proportion of children with CLCN4 may have specific eye problems such as strabismus (‘turn’ to the eye) or difficulties with vision due to long or short sightedness or problems with the optic nerve (optic nerve atrophy) or ‘cortical visual impairment’.  Any concerns with eye sight should be investigated by an optometrist and/or ophthalmologist (eye specialist doctor).

7. Mental health conditions

Mental health conditions are common in the general population, but research so far suggests that adolescents and adults with CLCN4 have an increased chance of impacts on their mental health and wellbeing, such as anxiety, depression and bipolar affective disorder. It is important that any concerns about an individual’s mental wellbeing are recognized so that appropriate treatments and supports can be put in place.  For individuals with limited language skills, changes in their emotional and mental wellbeing may show up as changes in their behaviour. For more information about It is important that an individual’s family doctor and/ or pediatrician regularly check in with patients and their carers about their emotional wellbeing. Some general information and mental health checklists can be found here, and specifically for individuals with learning difficulties here. (Australia).  This website has links and practical parent factsheets on helping recognize and support mental wellbeing and behaviour for children with learning difficulties due to genetic conditions. 

Overall, it is recommended that individuals with CLCN4 have at least an annual health check with their family doctor and/ or paediatrician so that their physical and emotional wellbeing can be checked. 

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